Pediatric Bacterial Infections

Pediatric Bacterial Infections Reference Bacterial Infections

Pediatric Bacterial Infections

Welcome to the comprehensive Pediatric Bacterial Infections Reference guide, designed for medical students, residents, fellows, and healthcare professionals working with children who have bacterial infectious diseases. This resource provides detailed information on the diagnosis, management, and treatment of common pediatric bacterial infections.

This reference tool serves as a quick access point for clinical presentations, diagnostic approaches, management protocols, and antibiotic recommendations for the wide array of bacterial infections seen in pediatric practice. From neonatal sepsis to community-acquired pneumonia, this guide covers essential topics for the care of children with bacterial infections.

Select a category below and click on specific topics to view comprehensive information, including age-specific presentations, diagnostic workup, treatment regimens, and special considerations for pediatric patients. This resource is regularly updated to reflect the latest evidence-based practices and guidelines.

Gram-Positive Cocci

Gram-Negative Cocci

Gram-Positive Bacilli

Gram-Negative Bacilli

Atypical Bacteria

Mycobacteria

Spirochetes

Anaerobic Bacteria

Zoonotic Infections

Clinical Syndromes

Antimicrobial Therapy

Prevention

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Staphylococcus Infections in Pediatrics

Overview & Definition

Staphylococcus species are gram-positive, catalase-positive cocci that appear in grape-like clusters. In pediatric populations, Staphylococcus aureus is the most clinically significant species, though coagulase-negative staphylococci (CoNS) like S. epidermidis are important pathogens in specific settings such as neonatal units and in children with indwelling devices.

Staphylococcal infections represent a significant burden of disease in pediatric populations, ranging from mild skin and soft tissue infections to life-threatening invasive diseases. The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has further complicated the management of these infections.

Epidemiology

Prevalence and Distribution:

  • Colonization: 30-50% of healthy children are intermittently colonized with S. aureus in the nares, axillae, perineum, or pharynx
  • MRSA colonization: Community rates vary by region (2-10% in most U.S. communities)
  • Infection rates: S. aureus is responsible for:
    • ~80% of skin and soft tissue infections in children
    • ~20% of pediatric osteomyelitis cases
    • ~10% of bacteremia episodes in children outside the neonatal period

Risk Factors for Infection:

  • Age-related: Higher risk in neonates, infants, and adolescents
  • Skin barrier disruption: Eczema, dermatitis, burns, wounds
  • Immunocompromise: Primary or secondary immunodeficiencies
  • Chronic medical conditions: Cystic fibrosis, diabetes, chronic kidney disease
  • Indwelling devices: Central lines, shunts, prosthetic materials
  • Recent antibiotic exposure: Alters normal flora
  • Hospitalization: Exposure to healthcare-associated strains
  • Close contact settings: Daycares, schools, athletic facilities, crowded households

Staphylococcal Resistance Patterns:

Type Definition Epidemiology
MSSA Methicillin-susceptible S. aureus 50-70% of pediatric S. aureus isolates in most regions
CA-MRSA Community-acquired MRSA
• Usually susceptible to non-β-lactam antibiotics
• Often carries PVL toxin genes 		• 30-50% of community S. aureus isolates in many U.S. regions
• USA300 is predominant clone in North America
• Higher rates in certain populations (athletes, daycare attendees)
HA-MRSA Healthcare-associated MRSA
• Often resistant to multiple antibiotic classes
• Less likely to carry PVL toxin 		• Varies by institution (10-50% in most pediatric centers)
• Risk factors: prior hospitalization, surgery, dialysis, long-term care
CoNS Coagulase-negative staphylococci
• Primarily S. epidermidis
• Usually methicillin-resistant 		• Leading cause of healthcare-associated bloodstream infections in NICU
• Common contaminant in blood cultures
• Important pathogen in device-associated infections

Pathophysiology

Virulence Factors:

  • Surface proteins:
    • Protein A: Binds Fc portion of IgG, preventing opsonization
    • Clumping factor: Binds fibrinogen, promotes adhesion
    • Fibronectin-binding proteins: Facilitate invasion of epithelial cells
  • Toxins:
    • Panton-Valentine leukocidin (PVL): Forms pores in leukocytes, associated with necrotizing pneumonia and severe skin infections, common in CA-MRSA
    • Alpha-toxin: Cytolytic to many cell types, especially platelets and monocytes
    • Toxic shock syndrome toxin-1 (TSST-1): Superantigen that causes toxic shock syndrome
    • Enterotoxins A-E: Cause food poisoning, act as superantigens
    • Exfoliative toxins A & B: Cause staphylococcal scalded skin syndrome
  • Enzymes:
    • Coagulase: Converts fibrinogen to fibrin, forms protective clot
    • Catalase: Neutralizes hydrogen peroxide, protecting against oxidative killing
    • Hyaluronidase: Breaks down connective tissue, facilitates spread
    • Beta-lactamases: Inactivate penicillins
  • Biofilm formation: Particularly important in CoNS infections and device-related infections

Mechanisms of Antibiotic Resistance:

  • Methicillin resistance: Mediated by mecA gene encoding PBP2a, an altered penicillin-binding protein with low affinity for β-lactams
  • SCCmec: Staphylococcal cassette chromosome carrying mecA gene; different types associated with HA-MRSA vs. CA-MRSA
  • Additional resistance mechanisms:
    • Beta-lactamases (penicillin resistance)
    • Enzymatic modification (aminoglycoside resistance)
    • Target site mutations (fluoroquinolone resistance)
    • Ribosomal protection proteins (tetracycline resistance)
    • Efflux pumps (macrolide, tetracycline resistance)

Clinical Manifestations

Staphylococcal infections in children present with a wide spectrum of clinical manifestations:

Skin and Soft Tissue Infections:

  • Impetigo: Superficial skin infection with honey-colored crusting, often on face
  • Folliculitis: Infection of hair follicles with small pustules
  • Furuncles/boils: Painful, deep-seated abscesses arising from hair follicles
  • Carbuncles: Coalescence of multiple furuncles with interconnecting sinus tracts
  • Cellulitis: Spreading infection of dermis and subcutaneous tissue with erythema, warmth, tenderness
  • Abscesses: Localized collections of pus, often requiring drainage
  • Wound infections: Surgical site infections or infected traumatic wounds

Toxin-Mediated Diseases:

  • Staphylococcal scalded skin syndrome (SSSS):
    • Caused by exfoliative toxins A and B
    • Most common in children <5 years old, especially infants
    • Presents with fever, diffuse erythema, and large flaccid bullae
    • Nikolsky sign positive (skin slips with gentle pressure)
    • Progresses to widespread desquamation, resembling a scald
  • Toxic shock syndrome:
    • Caused by TSST-1 or enterotoxins acting as superantigens
    • Characterized by rapid onset fever, diffuse macular rash, hypotension, and multiorgan involvement
    • Historically associated with tampon use in adolescents, but now more commonly seen with skin/soft tissue infections
  • Food poisoning:
    • Caused by heat-stable enterotoxins
    • Short incubation period (2-6 hours)
    • Presents with acute onset vomiting, abdominal cramps, diarrhea
    • Usually self-limited within 24-48 hours

Invasive Infections:

  • Bacteremia/sepsis:
    • Primary bacteremia or secondary to focal infection
    • Risk factors: indwelling devices, immunocompromise, prematurity
    • Presents with fever, tachycardia, hypotension, altered mental status
  • Pneumonia:
    • Primary infection or hematogenous seeding
    • CA-MRSA pneumonia often necrotizing with rapid progression
    • Presents with fever, cough, respiratory distress
    • May develop empyema, pneumatoceles, lung abscesses
  • Osteoarticular infections:
    • Osteomyelitis: Most commonly affects long bone metaphyses
    • Septic arthritis: Typically monoarticular, often hip or knee
    • Presents with fever, bone/joint pain, limited movement
    • May have subperiosteal or soft tissue abscesses
  • Pyomyositis: Deep muscle infection with abscess formation
  • Endocarditis: Infection of heart valves, more common in children with congenital heart disease or indwelling cardiac devices
  • Central nervous system infections:
    • Brain abscess, subdural empyema, meningitis
    • Often secondary to hematogenous spread

Device-Associated Infections:

  • Central line-associated bloodstream infections (CLABSI): More commonly caused by CoNS in neonates and immunocompromised children
  • Ventriculoperitoneal shunt infections: Presents with fever, headache, vomiting, altered mental status
  • Prosthetic joint infections: Presents with pain, decreased range of motion, signs of inflammation

Neonatal Staphylococcal Infections:

  • Late-onset sepsis: S. aureus and CoNS are leading causes, typically after 72 hours of life
  • Omphalitis: Infection of umbilical stump with surrounding erythema and purulent drainage
  • Pustulosis: Multiple small pustules, often in diaper area or skin folds
  • Mastitis: Breast tissue infection in neonates, presents with localized erythema, swelling, tenderness

Diagnostic Evaluation

Clinical Assessment:

  • Thorough history and physical examination
  • Special attention to:
    • Risk factors (recent skin trauma, household contacts with skin infections)
    • Previous MRSA infection or colonization
    • Systemic symptoms suggesting invasive disease
    • Presence of indwelling devices

Microbiologic Diagnosis:

  • Cultures:
    • Purulent lesions: Drainage and culture prior to antibiotics when possible
    • Blood cultures: For suspected invasive disease
    • Joint fluid: For suspected septic arthritis
    • Bone: For suspected osteomyelitis when possible
    • Respiratory specimens: For pneumonia (consider lower respiratory samples in intubated patients)
    • CSF: For suspected CNS infection
  • Gram stain: Shows gram-positive cocci in clusters
  • Laboratory identification:
    • Catalase-positive (distinguishes from streptococci)
    • Coagulase test (positive for S. aureus, negative for CoNS)
    • Automated systems (VITEK, MALDI-TOF) for species identification
  • Antimicrobial susceptibility testing:
    • Disk diffusion or automated methods
    • Cefoxitin or oxacillin screening for methicillin resistance
    • D-zone test for inducible clindamycin resistance
  • Molecular methods:
    • PCR for mecA gene (MRSA detection)
    • Molecular typing (PFGE, spa typing) for outbreak investigations
    • PCR for toxin genes (PVL, TSST-1) in select cases

Laboratory Studies:

  • Complete blood count (CBC): Leukocytosis common (though may be normal in localized infection)
  • Inflammatory markers:
    • C-reactive protein (CRP): Elevated in most infections, useful for monitoring response
    • Erythrocyte sedimentation rate (ESR): Elevated, particularly in osteoarticular infections
    • Procalcitonin: May help differentiate bacterial from viral infections
  • Coagulation studies: For suspected toxic shock syndrome or severe sepsis
  • Liver and kidney function tests: In systemic disease or before starting certain antibiotics

Imaging Studies:

  • Ultrasound:
    • Useful for soft tissue infections to identify and characterize abscesses
    • Can detect joint effusions, guide arthrocentesis
  • Radiographs:
    • Chest X-ray for suspected pneumonia
    • Bone films for suspected osteomyelitis (though often normal early in disease)
  • Magnetic resonance imaging (MRI):
    • Gold standard for osteomyelitis (early detection, extent of involvement)
    • Evaluates deep soft tissue infections, pyomyositis
    • Identifies complications (abscesses, sinus tracts)
  • Computed tomography (CT):
    • Useful for pneumonia complications (empyema, pneumatoceles)
    • Evaluates CNS infections or deep-seated collections
  • Echocardiography: For suspected endocarditis or persistent bacteremia

Management

General Principles:

  • Source control is essential (drainage of abscesses, removal of infected devices when possible)
  • Empiric therapy should consider local MRSA prevalence
  • De-escalate therapy based on culture results and clinical response
  • Duration of therapy depends on infection site and severity

Skin and Soft Tissue Infections:

Infection Type Management Approach
Simple abscess <2cm • Incision and drainage (I&D) alone
• No antibiotics typically needed if adequate drainage achieved
• Follow-up in 48-72 hours to assess response
Abscess with risk factors
(>2cm, systemic symptoms, rapid progression, immunocompromise, extremes of age, difficult-to-drain location)		 • I&D plus antibiotics
• Empiric MRSA coverage
• 5-7 days of therapy
Cellulitis without abscess • Antibiotics covering S. aureus and streptococci
• Consider MRSA coverage based on risk factors and local prevalence
• 5-7 days of therapy
Impetigo/Folliculitis • Topical mupirocin for limited disease
• Oral antibiotics for extensive disease (5 days)
SSSS • Hospitalization for extensive disease
• IV anti-staphylococcal β-lactam (MSSA typically causes)
• Fluid management, pain control, skin care
• 7-10 days of therapy

Invasive Infections:

Infection Type Management Approach
Bacteremia • IV antibiotics with MRSA coverage initially
• Source identification and control
• Repeat blood cultures to document clearance
• Echocardiography if persistent or risk factors for endocarditis
• 14 days for uncomplicated bacteremia, longer for complicated
Pneumonia • IV antibiotics with MRSA coverage
• Drainage of empyema if present
• Respiratory support as needed
• 14-21 days of therapy, longer for complicated disease
Osteomyelitis • IV antibiotics initially
• Surgical debridement if abscess present
• Transition to oral therapy once clinically improved
• Total 3-4 weeks for uncomplicated acute disease
• 4-6 weeks for complex or chronic disease
Septic arthritis • Joint drainage (surgical or repeated aspiration)
• IV antibiotics initially
• Transition to oral therapy once improved
• 2-3 weeks total therapy
Toxic shock syndrome • ICU care for hemodynamic support
• Source control (remove tampon, drain abscess)
• IV antibiotics (including protein synthesis inhibitor)
• IVIG may be considered in severe cases
• 10-14 days of therapy
Endocarditis • IV antibiotics for 4-6 weeks
• Consider surgical intervention for complications
• Echocardiography for diagnosis and monitoring

Antimicrobial Options:

For MSSA infections:

  • First-line IV: Nafcillin, oxacillin, cefazolin
  • First-line oral: Cephalexin, dicloxacillin
  • Alternatives: Clindamycin, TMP-SMX (with limitations)

For MRSA infections:

  • First-line IV: Vancomycin, clindamycin (if susceptible)
  • Alternative IV: Linezolid, daptomycin (not for pneumonia)
  • First-line oral: Clindamycin (if susceptible), TMP-SMX
  • Alternative oral: Linezolid, doxycycline (>8 years)

For CoNS infections:

  • First-line: Vancomycin (most isolates methicillin-resistant)
  • Alternatives: Linezolid, daptomycin

Prevention

Decolonization Strategies:

  • Indications:
    • Recurrent S. aureus infections
    • Household transmission
    • Preoperative for select high-risk surgeries
  • Methods:
    • Intranasal mupirocin twice daily for 5-7 days
    • Chlorhexidine body wash daily for 5-7 days
    • Dilute bleach baths (1/4-1/2 cup per full tub) twice weekly
  • Effectiveness: Temporary decolonization in 80-90%, but recolonization common

Infection Control Measures:

  • Hospital settings:
    • Hand hygiene before and after patient contact
    • Contact precautions for patients with MRSA infections
    • Cohort nursing in outbreak situations
    • Environmental cleaning of high-touch surfaces
    • Active surveillance in high-risk units
  • Community settings:
    • Hand hygiene education
    • Covering wounds with clean, dry bandages
    • Not sharing personal items (towels, razors, clothing)
    • Cleaning athletic equipment between users
    • Laundering clothing and linens in hot water

Household Management:

  • Consider screening household members if recurrent infections
  • Simultaneous decolonization of all household members in cases of recurrent infection
  • Environmental cleaning of high-touch surfaces and frequently handled objects
  • Separate personal care items and towels
  • Regular laundering of bed linens
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Pneumococcal Infections in Pediatrics

Overview & Definition

Streptococcus pneumoniae (pneumococcus) is a gram-positive, alpha-hemolytic, encapsulated diplococcus that represents one of the most significant bacterial pathogens in pediatrics. Despite vaccination advances, pneumococcal disease remains a leading cause of morbidity and mortality in children worldwide, particularly in resource-limited settings.

Pneumococci are characterized by their polysaccharide capsule, which is the primary virulence factor and basis for serotyping. Over 95 serotypes have been identified, with approximately 20-30 serotypes responsible for the majority of invasive disease in children. The organism typically colonizes the nasopharynx asymptomatically before potentially causing localized or invasive disease.

Epidemiology

Prevalence and Distribution:

  • Colonization: 20-60% of healthy children are colonized with S. pneumoniae in the nasopharynx
  • Age distribution: Highest incidence of invasive disease in children <2 years, especially 6-24 months
  • Global burden:
    • Approximately 300,000-500,000 deaths annually in children under 5 worldwide
    • Dramatic reduction in incidence in countries with established pneumococcal vaccination programs

Risk Factors for Invasive Disease:

Risk Factor Category Specific Factors
Host Factors • Age <2 years or >65 years
• Absence of pneumococcal vaccination
• Anatomic or functional asplenia (including sickle cell disease)
• Primary immunodeficiencies (especially complement, antibody defects)
• Secondary immunodeficiencies (HIV, malignancy, nephrotic syndrome)
• Cochlear implants
• CSF leaks
Environmental Factors • Daycare attendance
• Overcrowded living conditions
• Exposure to tobacco smoke
• Winter/early spring seasonality
• Recent viral respiratory infection
Underlying Medical Conditions • Chronic lung disease (including asthma)
• Congenital heart disease
• Diabetes mellitus
• Chronic kidney disease
• Neuromuscular disorders affecting respiratory function

Impact of Pneumococcal Conjugate Vaccines:

  • PCV7 introduction (2000): 80-90% reduction in invasive pneumococcal disease (IPD) caused by vaccine serotypes
  • PCV13 introduction (2010): Further reduction in remaining common serotypes (including 19A)
  • Serotype replacement: Increasing prevalence of non-vaccine serotypes after vaccine implementation
  • Herd immunity: Decreased rates of disease in unvaccinated populations

Antimicrobial Resistance:

  • Penicillin resistance: Variable by region (10-40% with reduced susceptibility)
  • Macrolide resistance: Increasing worldwide (20-50% in many regions)
  • Multidrug resistance: 15-30% of isolates in many countries
  • Risk factors for resistant strains: Recent antibiotic use, daycare attendance, areas with high antibiotic consumption

Pathophysiology

Colonization and Transmission:

  • Transmitted via respiratory droplets and direct contact
  • Colonizes nasopharynx before potentially spreading to adjacent structures or entering bloodstream
  • Colonization duration typically 4-6 weeks in children
  • Multiple serotypes can colonize simultaneously

Virulence Factors:

  • Polysaccharide capsule:
    • Primary virulence factor
    • Inhibits phagocytosis and complement activation
    • Basis for serotype classification
  • Cell wall components:
    • Peptidoglycan and teichoic acids stimulate inflammation
    • Trigger cytokine release and neutrophil activation
  • Surface proteins:
    • Pneumococcal surface proteins (PspA, PspC): Interfere with complement deposition
    • Pneumococcal surface adhesin A (PsaA): Mediates adhesion
    • Choline-binding proteins: Aid in colonization
  • Enzymes:
    • Pneumolysin: Pore-forming cytotoxin that damages epithelial cells and activates complement
    • Hyaluronidase: Degrades connective tissue, facilitating spread
    • Neuraminidase: Cleaves sialic acid, exposing receptors for bacterial adherence
    • IgA1 protease: Cleaves secretory IgA, compromising mucosal immunity

Pathogenesis of Major Clinical Syndromes:

  • Otitis media: Ascension through Eustachian tube, often following viral URI
  • Sinusitis: Impaired sinus drainage and mucociliary clearance
  • Pneumonia: Direct inhalation or aspiration of colonizing organisms
  • Bacteremia: Invasion through respiratory epithelium into bloodstream
  • Meningitis: Blood-brain barrier penetration or direct extension from sinusitis/otitis

Host Defense Mechanisms:

  • Physical barriers: Mucociliary clearance, cough reflex
  • Innate immunity: Complement, neutrophils, macrophages
  • Adaptive immunity: Serotype-specific anticapsular antibodies (primarily IgG2) critical for opsonization and clearance
  • Splenic function: Essential for filtering encapsulated bacteria from bloodstream

Clinical Manifestations

Pneumococcal infections present across a spectrum from mild localized disease to life-threatening invasive infections:

Non-Invasive Infections:

  • Acute Otitis Media (AOM):
    • Most common pneumococcal infection in children
    • S. pneumoniae accounts for 30-40% of bacterial AOM
    • Presents with otalgia, fever, irritability, decreased hearing
    • Tympanic membrane erythema, bulging, decreased mobility
    • Often follows viral upper respiratory infection
  • Sinusitis:
    • S. pneumoniae is the most common bacterial cause (30-40%)
    • Acute: Presents with purulent nasal discharge, facial pain/pressure, cough for >10 days
    • May follow viral upper respiratory infection
  • Pharyngitis/Tonsillitis:
    • Uncommon cause of pharyngitis in children (2-5% of cases)
    • Can present with sore throat, fever, cervical lymphadenopathy
  • Conjunctivitis:
    • Purulent conjunctival discharge
    • Conjunctival injection
    • Less common since PCV introduction

Invasive Pneumococcal Disease (IPD):

  • Pneumonia:
    • Most common invasive pneumococcal disease
    • Classic presentation: Abrupt onset fever, tachypnea, cough, chest pain
    • Physical findings: Decreased breath sounds, crackles, dullness to percussion
    • Complications: Parapneumonic effusion, empyema, necrotizing pneumonia, lung abscess
    • Radiographic findings: Lobar consolidation classically, though pattern can vary
  • Bacteremia:
    • Occult bacteremia: Fever without localizing source, most common in children 6-24 months (rare since PCV)
    • Secondary bacteremia: Complication of pneumonia (15-25%), meningitis, or other focal infection
    • Presents with high fever, tachycardia, irritability or lethargy
    • Can progress to septic shock with hypotension and end-organ dysfunction
  • Meningitis:
    • Most serious manifestation of pneumococcal disease
    • Higher mortality and neurologic sequelae than other bacterial causes
    • Age-dependent presentation:
      • Infants: Fever, poor feeding, irritability, lethargy, bulging fontanelle
      • Older children: Fever, headache, vomiting, photophobia, altered mental status, neck stiffness
    • Complications: Subdural effusion, cerebral edema, sensorineural hearing loss, developmental delay
  • Other Invasive Syndromes:
    • Septic arthritis: Typically monoarticular, presents with joint pain, swelling, limited range of motion
    • Osteomyelitis: Less common than S. aureus osteomyelitis, presents with bone pain, fever, localized tenderness
    • Peritonitis: Rare, seen primarily in children with nephrotic syndrome or ascites
    • Endocarditis: Rare complication in children with underlying heart disease
    • Hemolytic uremic syndrome: Rare complication of pneumococcal infection (primarily serotype 19A)

Special Populations:

Population Clinical Considerations
Neonates • Uncommon but potentially severe
• Usually early-onset (<7 days) sepsis
• Nonspecific presentation: temperature instability, poor feeding, respiratory distress
• Consider maternal colonization/infection as source
Asplenic children • Functional asplenia (sickle cell disease) or anatomic asplenia
• High risk for fulminant, overwhelming pneumococcal sepsis
• Rapid progression from mild symptoms to shock (hours)
• High mortality despite appropriate therapy
Immunocompromised • Higher risk of invasive disease
• May have atypical presentations
• Increased risk of recurrent infections
• Higher risk of antibiotic-resistant strains
Children with cochlear implants • Increased risk of pneumococcal meningitis
• Often via direct route from middle ear
• Requires aggressive management of otitis media

Diagnostic Evaluation

Clinical Assessment:

  • Thorough history and physical examination
  • Assessment of risk factors for pneumococcal disease
  • Vaccination status
  • Evaluation for signs of invasive disease

Microbiologic Diagnosis:

  • Gram stain: Gram-positive diplococci (lancet-shaped)
  • Culture methods:
    • Blood: Gold standard for invasive disease
    • CSF: For suspected meningitis
    • Pleural fluid: For complicated pneumonia
    • Middle ear fluid: For treatment-failure AOM (tympanocentesis)
    • Joint fluid: For suspected septic arthritis
  • Identification characteristics:
    • Alpha-hemolytic on blood agar
    • Optochin sensitive
    • Bile soluble
  • Antimicrobial susceptibility testing:
    • Minimum inhibitory concentration (MIC) determination
    • Interpretation based on site of infection (meningeal vs. non-meningeal breakpoints)
  • Serotyping: For epidemiologic purposes and outbreak investigations

Molecular and Antigen Detection Methods:

  • PCR: Increased sensitivity over culture, especially after antibiotic administration
  • Pneumococcal urinary antigen test: Not recommended in children due to high colonization rates
  • CSF antigen tests: May be helpful in partially treated meningitis

Laboratory Studies:

  • Complete blood count: Often shows leukocytosis with neutrophil predominance
  • Inflammatory markers:
    • C-reactive protein (CRP): Typically elevated in bacterial infections
    • Erythrocyte sedimentation rate (ESR): Elevated but less specific
    • Procalcitonin: May help differentiate bacterial from viral infections
  • Specific studies based on suspected site:
    • CSF analysis: Typically shows elevated protein, low glucose, neutrophilic pleocytosis
    • Pleural fluid analysis: Exudative with low pH, low glucose, high LDH

Imaging Studies:

  • Chest radiography: For suspected pneumonia (classically lobar consolidation)
  • Ultrasound:
    • Pleural effusions: Characterization and to guide drainage
    • Sinuses: For complicated sinusitis
  • CT scan:
    • Sinuses: For suspected complications (orbital or intracranial extension)
    • Chest: For complicated pneumonia, suspected necrotizing pneumonia
    • Brain: For suspected intracranial complications of meningitis
  • MRI: For better characterization of CNS complications

Management

General Principles:

  • Empiric therapy should consider local resistance patterns
  • Adjust therapy based on culture results and clinical response
  • Consider source control for collections (empyema, abscesses)
  • Duration of therapy depends on infection site and severity

Antimicrobial Therapy:

Infection Type Empiric Treatment Duration
Acute Otitis Media • First-line: Amoxicillin 80-90 mg/kg/day divided BID
• Second-line: Amoxicillin-clavulanate, cefdinir, cefuroxime
• Penicillin allergy: Cefdinir, cefuroxime, or clindamycin 		5-7 days for children ≥2 years with mild disease
10 days for severe disease or age <2 years
Sinusitis • First-line: Amoxicillin 80-90 mg/kg/day divided BID
• Second-line: Amoxicillin-clavulanate, cefdinir, cefuroxime
• Severe/complicated: Ampicillin-sulbactam or ceftriaxone (IV) 		10-14 days
Community-acquired pneumonia • Outpatient (mild): Amoxicillin 90 mg/kg/day divided BID
• Inpatient (moderate): Ampicillin IV or ceftriaxone IV
• Severe/complicated: Ceftriaxone or cefotaxime +/- vancomycin 		5-7 days for uncomplicated
10-14 days for complicated
21+ days for necrotizing pneumonia
Bacteremia without focus • Initial: Ceftriaxone or cefotaxime IV
• With risk for resistance: Add vancomycin 		10 days
Meningitis • Initial: Vancomycin PLUS ceftriaxone or cefotaxime IV
• De-escalate based on susceptibilities:
- For penicillin-susceptible: Penicillin G or ampicillin
- For ceftriaxone-susceptible: Ceftriaxone or cefotaxime monotherapy 		10-14 days
Septic arthritis • Initial: Ceftriaxone or cefotaxime IV
• With risk for resistance: Add vancomycin 		2-3 weeks total (IV → oral)

Adjunctive Therapies:

  • Corticosteroids:
    • Recommended in pneumococcal meningitis (dexamethasone 0.15 mg/kg IV q6h for 2-4 days)
    • Must be given before or with first dose of antibiotics
    • Not routinely recommended for pneumonia
  • Supportive care:
    • Fluid management and electrolyte correction
    • Respiratory support as needed
    • Blood pressure support for septic shock
    • Antipyretics for fever and analgesia for pain
  • Management of complications:
    • Drainage of significant pleural effusions or empyema
    • Monitoring for increased intracranial pressure in meningitis
    • Joint drainage for septic arthritis

Infection Prevention:

  • Chemoprophylaxis: Not routinely recommended for pneumococcal disease contacts
  • Special populations:
    • Daily penicillin prophylaxis for children with sickle cell disease until at least age 5
    • Antibiotic prophylaxis for asplenic children for fever/illness while awaiting medical evaluation

Prevention

Pneumococcal Vaccines:

Vaccine Type Formulation Recommendations
Pneumococcal conjugate vaccine (PCV) • PCV13: Contains 13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F)
• PCV15: Contains 15 serotypes (PCV13 + 22F, 33F)
• PCV20: Contains 20 serotypes (PCV15 + 8, 10A, 11A, 12F, 15B) 		• Routine: All infants receive 4 doses at 2, 4, 6, and 12-15 months
• Catch-up: Series begins before 2 years
• High-risk: PCV series plus PPSV23 for specific conditions
• Effectiveness: 80-97% against vaccine-type invasive disease
Pneumococcal polysaccharide vaccine (PPSV23) Contains 23 purified capsular polysaccharide antigens (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, 33F) • Not routinely given to healthy children
• High-risk: For children ≥2 years with:
  • Chronic heart or lung disease
  • Diabetes mellitus
  • CSF leaks or cochlear implants
  • Functional or anatomic asplenia
  • Immunocompromising conditions
• Given ≥8 weeks after last PCV dose
• Revaccination in 5 years for highest risk groups
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Enterococcal Infections in Pediatrics

Overview & Definition

Enterococci are gram-positive, catalase-negative cocci that typically appear in pairs or short chains. The two most clinically relevant species are Enterococcus faecalis (accounting for approximately 80-90% of clinical isolates) and Enterococcus faecium (10-15%). These facultative anaerobes are part of the normal gastrointestinal flora but can cause significant opportunistic infections, particularly in hospitalized and immunocompromised children.

Enterococci are characterized by their intrinsic resistance to numerous antibiotics and their ability to acquire additional resistance mechanisms, making them challenging pathogens in pediatric healthcare settings. The emergence of vancomycin-resistant enterococci (VRE) has further complicated the management of these infections.

Epidemiology

Prevalence and Distribution:

  • Colonization: Part of normal intestinal flora in 90-95% of healthy children
  • Hospital-acquired infections: Account for 5-15% of nosocomial infections in pediatric settings
  • VRE prevalence: Varies by institution (5-40% of enterococcal isolates)

Risk Factors for Infection:

  • Hospitalization: Prolonged hospital stays, particularly in ICU settings
  • Antibiotic exposure: Especially broad-spectrum antibiotics, vancomycin, third-generation cephalosporins
  • Indwelling devices: Central venous catheters, urinary catheters, endotracheal tubes
  • Immunocompromise: Malignancy, transplantation, congenital immunodeficiencies
  • Comorbidities: Renal failure, liver disease, congenital heart disease
  • Age: Neonates and infants have higher risk (immature immune system)
  • Gastrointestinal pathology: IBD, short bowel syndrome, abdominal surgery
  • Proximity to VRE-colonized patients: Shared hospital rooms or equipment

Enterococcal Resistance Patterns:

Resistance Type Mechanism Clinical Significance
Intrinsic Resistance • Low-level aminoglycoside resistance
• Cephalosporins
• Clindamycin
• Trimethoprim-sulfamethoxazole
• Low-level penicillin resistance 		• Limits empiric treatment options
• Requires combination therapy for serious infections
Acquired Resistance • High-level aminoglycoside resistance (HLAR)
• Beta-lactamase production
• PBP5 alterations (ampicillin resistance)
• VanA, VanB genes (vancomycin resistance) 		• E. faecium more likely to have multiple resistance
• HLAR negates synergy with cell wall agents
• VRE limits treatment to newer agents
VRE Phenotypes • VanA: High-level resistance to vancomycin and teicoplanin
• VanB: Variable resistance to vancomycin, susceptible to teicoplanin
• VanC: Low-level vancomycin resistance (E. gallinarum, E. casseliflavus) 		• VanA most common in pediatric clinical isolates
• VanA and VanB are transferable via plasmids
• VanC has limited clinical significance

Pathophysiology

Virulence Factors:

  • Adhesins:
    • Enterococcal surface protein (Esp): Promotes biofilm formation and colonization
    • Aggregation substance (AS): Facilitates adhesion to renal tubular cells and bacterial aggregation
    • Collagen-binding protein (Ace): Binds to extracellular matrix proteins
  • Toxins and enzymes:
    • Cytolysin: Beta-hemolytic toxin that damages host cells
    • Gelatinase: Hydrolyzes collagen, gelatin, and other peptides
    • Hyaluronidase: Degrades hyaluronic acid in connective tissue
  • Biofilm formation: Critical for device-associated infections and endocarditis
  • Antibiotic resistance: Both intrinsic and acquired resistance mechanisms

Pathogenesis of Common Infections:

  • Urinary tract infections: Ascending infection facilitated by adhesins
  • Bacteremia: Often translocation from GI tract or from infected indwelling catheters
  • Endocarditis: Adhesion to damaged valves followed by biofilm formation
  • Intra-abdominal infections: Translocation across intestinal mucosa, often polymicrobial
  • Device-associated infections: Biofilm formation on foreign material surfaces

Clinical Manifestations

Enterococcal infections in the pediatric population present with various clinical manifestations:

Urinary Tract Infections:

  • Most common enterococcal infection in children
  • Often associated with structural abnormalities or catheterization
  • Symptoms similar to other UTIs: fever, dysuria, frequency, urgency
  • May be asymptomatic, especially in neonates

Bacteremia and Sepsis:

  • More common in hospitalized, immunocompromised children
  • Often catheter-associated or secondary to GI source
  • May present with fever, chills, tachycardia
  • Often indolent compared to other gram-positive bacteremias
  • Risk of metastatic infections (endocarditis, meningitis)

Endocarditis:

  • Third most common cause of pediatric endocarditis
  • Risk factors: congenital heart disease, prosthetic valves
  • Presents with persistent bacteremia, fever, new murmur
  • Subacute presentation common
  • Risk of embolic complications

Neonatal Infections:

  • Late-onset sepsis in NICU patients
  • May present with temperature instability, feeding intolerance, lethargy
  • Risk of meningitis and other focal infections
  • Often associated with prematurity and prolonged hospitalization

Intra-abdominal Infections:

  • Often part of polymicrobial infections
  • Post-surgical complications, peritonitis
  • May present with fever, abdominal pain, ileus

Central Nervous System Infections:

  • Rare, typically in neonates or neurosurgical patients
  • Often associated with CSF shunts or other devices
  • May have indolent presentation with subtle neurological changes

Device-Associated Infections:

  • Central line-associated bloodstream infections
  • Ventriculoperitoneal shunt infections
  • Prosthetic joint infections
  • May present with fever and local signs of infection

Wound Infections:

  • Surgical site infections
  • Burn wound infections
  • Typically presents with erythema, purulence, delayed healing
  • Often polymicrobial

Diagnostic Evaluation

Microbiologic Diagnosis:

  • Culture:
    • Blood cultures (two sets recommended for suspected endocarditis)
    • Urine culture for suspected UTI
    • CSF culture for suspected meningitis
    • Wound cultures for soft tissue infections
    • Catheter tip cultures for suspected line infections
  • Gram stain: Gram-positive cocci in pairs or short chains
  • Laboratory identification:
    • Catalase-negative (distinguishes from staphylococci)
    • Growth in 6.5% NaCl
    • PYR test positive
    • Bile esculin hydrolysis positive
    • Automated systems (VITEK, MALDI-TOF) for species identification
  • Antimicrobial susceptibility testing:
    • Ampicillin susceptibility
    • Vancomycin susceptibility
    • High-level aminoglycoside resistance testing
    • E-test for MIC determination
  • Molecular methods:
    • PCR for vanA, vanB genes
    • Whole genome sequencing for outbreak investigations

Additional Diagnostic Workup:

Suspected Condition Recommended Studies
Bacteremia • Blood cultures (two sets)
• CBC with differential
• CRP, procalcitonin
• Source evaluation (urine, imaging)
• Echocardiography if persistent bacteremia (>72 hours)
Endocarditis • Blood cultures (three sets)
• Echocardiography (TEE preferred if available)
• CBC, CRP, ESR
• Urinalysis (for embolic phenomena)
• Imaging for embolic complications as indicated
UTI • Urinalysis and urine culture
• Renal ultrasound if recurrent or complicated
• VCUG if indicated by history and findings
Intra-abdominal infection • Abdominal ultrasound or CT scan
• Blood cultures
• Culture of abscess material if accessible
CNS infection • CSF analysis and culture
• Brain imaging (CT or MRI)
• Blood cultures
Device-associated infection • Blood cultures (peripheral and through device)
• Differential time to positivity (DTTP)
• Device removal and culture when possible
• Imaging of device site

Management

General Principles:

  • Source control is critical (catheter removal, drainage of abscesses)
  • Combination therapy recommended for serious infections
  • Consider infectious disease consultation for VRE infections
  • Antibiotic selection based on susceptibility results, site of infection, and severity

Antimicrobial Therapy:

Infection Type Vancomycin-Susceptible Enterococci Vancomycin-Resistant Enterococci
Uncomplicated UTI • Ampicillin or amoxicillin
• Nitrofurantoin (if susceptible)
• Duration: 7-10 days 		• Linezolid
• Nitrofurantoin (if susceptible)
• Fosfomycin (if susceptible)
• Duration: 7-10 days
Bacteremia • Ampicillin IV (if susceptible)
• Consider addition of gentamicin if no HLAR
• Vancomycin if ampicillin-resistant
• Duration: 10-14 days 		• Linezolid IV
• Daptomycin IV
• Consider ID consultation
• Duration: 10-14 days
Endocarditis • Ampicillin IV plus gentamicin IV (if no HLAR)
• Ampicillin IV plus ceftriaxone IV (if HLAR)
• Vancomycin IV (if ampicillin-resistant)
• Duration: 4-6 weeks 		• Linezolid IV
• Daptomycin IV (high-dose)
• Consider ID consultation
• Consider surgery for valve replacement
• Duration: 6-8 weeks
Meningitis • Ampicillin IV plus gentamicin IV
• Vancomycin IV (if ampicillin-resistant)
• Duration: 14-21 days 		• Linezolid IV
• Consider ID consultation
• Duration: 14-21 days
Intra-abdominal (part of polymicrobial infection) • Ampicillin IV plus metronidazole IV
• Include gram-negative coverage
• Duration: 7-14 days depending on source control 		• Linezolid IV plus metronidazole IV
• Include gram-negative coverage
• Duration: 7-14 days depending on source control
Device-associated infection • Device removal when possible
• Ampicillin IV (if susceptible)
• Consider addition of gentamicin if no HLAR
• Vancomycin if ampicillin-resistant
• Duration: 7-14 days after device removal 		• Device removal when possible
• Linezolid IV or daptomycin IV
• Duration: 7-14 days after device removal

Antimicrobial Options:

For Vancomycin-Susceptible Enterococci:

  • First-line: Ampicillin or amoxicillin (if susceptible)
  • Alternative: Vancomycin (for ampicillin-resistant strains)
  • Synergy: Gentamicin (if no high-level resistance)
  • Alternative synergy: Ceftriaxone (for E. faecalis with HLAR)

For Vancomycin-Resistant Enterococci:

  • First-line: Linezolid
  • Alternatives: Daptomycin (not for pneumonia), tigecycline (limited data in children)
  • Newer agents with pediatric data: Tedizolid, dalbavancin (limited experience)

Dosing in Pediatric Patients:

  • Ampicillin: 100-200 mg/kg/day IV divided q6h (max 12g/day)
  • Vancomycin: 60 mg/kg/day IV divided q6-8h (with therapeutic drug monitoring)
  • Linezolid: 30 mg/kg/day IV/PO divided q8h for children <12 years; 20 mg/kg/day IV/PO divided q12h for ≥12 years (max 1200 mg/day)
  • Daptomycin: 6-10 mg/kg IV once daily (higher doses for endocarditis)
  • Gentamicin (for synergy): 3 mg/kg/day IV divided q8h

Prevention

Infection Control Measures:

  • Hand hygiene: Most critical intervention to prevent transmission
  • Contact precautions: For patients with VRE infection or colonization
  • Environmental cleaning: Focus on high-touch surfaces
  • Antimicrobial stewardship: Limit unnecessary vancomycin and broad-spectrum antibiotic use
  • Active surveillance: Consider in high-risk units during outbreaks
  • Cohorting: Group VRE-positive patients with dedicated nursing staff
  • Education: Staff, patient, and family education on prevention measures

Device-Related Prevention:

  • Use indwelling devices only when necessary
  • Remove catheters and lines as soon as they are no longer needed
  • Adhere to central line insertion and maintenance bundles
  • Aseptic technique for all catheter manipulations

Decolonization:

  • Generally not recommended for VRE
  • No proven regimens for sustained decolonization
  • Focus on preventing transmission rather than decolonization

Special Considerations in Pediatrics

  • Neonates:
    • Higher risk due to immature immune systems and frequent interventions
    • Dosing must be adjusted based on gestational and postnatal age
    • Monitor closely for side effects of antimicrobials
  • Immunocompromised children:
    • Lower threshold for empiric coverage in febrile neutropenia
    • Higher risk of invasive disease from colonization
    • May require longer treatment courses
  • Linezolid considerations:
    • Monitor for bone marrow suppression with prolonged use
    • Risk of peripheral neuropathy, optic neuritis with extended therapy
    • Monitor CBC weekly for courses >2 weeks
  • Surgical prophylaxis:
    • Consider enterococcal coverage for high-risk GI or GU procedures
    • Not routinely needed for most pediatric surgical procedures
×

Streptococcal Infections in Pediatrics

Overview & Definition

Streptococci are gram-positive cocci that typically arrange in pairs or chains. They are catalase-negative, which differentiates them from staphylococci. In pediatric populations, streptococcal infections represent a significant disease burden, ranging from common throat infections to severe invasive diseases with potential long-term sequelae.

Classification of streptococci is based on hemolysis patterns on blood agar (alpha, beta, or gamma hemolysis) and Lancefield grouping (A through V, based on cell wall carbohydrates). In pediatric practice, the most clinically significant streptococci include:

  • Group A Streptococcus (GAS, Streptococcus pyogenes): Cause of pharyngitis, impetigo, invasive disease, and post-infectious sequelae
  • Group B Streptococcus (GBS, Streptococcus agalactiae): Leading cause of neonatal sepsis and meningitis
  • Streptococcus pneumoniae: Major cause of pneumonia, otitis media, sinusitis, and invasive disease
  • Viridans group streptococci: Part of normal oral flora; cause of dental infections and endocarditis

Epidemiology

Group A Streptococcus (GAS):

  • Prevalence:
    • Pharyngitis: 15-30% of sore throats in children 5-15 years old
    • Asymptomatic carriage: 5-15% of school-age children
    • Impetigo: Common in tropical climates and conditions of poor hygiene
    • Invasive disease: 3-5 cases per 100,000 children annually
  • Transmission: Person-to-person via respiratory droplets or direct contact with lesions
  • Seasonality: Pharyngitis peaks in late fall through early spring; impetigo more common in summer
  • Risk factors: School/daycare attendance, crowded living conditions, age 5-15 years for pharyngitis

Group B Streptococcus (GBS):

  • Maternal colonization: 15-30% of pregnant women (rectovaginal colonization)
  • Neonatal disease:
    • Early-onset: 0.3-0.5 per 1,000 live births (with intrapartum prophylaxis)
    • Late-onset: 0.3-0.4 per 1,000 live births
  • Risk factors for early-onset disease: Prematurity, prolonged rupture of membranes, intrapartum fever, previous infant with GBS disease, GBS bacteriuria during pregnancy

Antibiotic Resistance Patterns:

Organism Key Resistance Patterns Clinical Implications
Group A Streptococcus • Universally susceptible to penicillin
• Macrolide resistance: 5-15% (varies by region)
• Clindamycin resistance: 2-10% 		• Penicillin remains drug of choice
• Testing for inducible clindamycin resistance important in invasive disease
• Macrolide resistance may affect pharyngitis treatment in penicillin-allergic patients
Group B Streptococcus • Universally susceptible to penicillin
• Increasing resistance to erythromycin (30-40%)
• Clindamycin resistance: 15-25% 		• Alternative prophylaxis needed for penicillin-allergic mothers
• Vancomycin for serious penicillin allergies
Viridans group • Variable penicillin resistance
• Higher MICs to β-lactams
• Increasing multidrug resistance 		• Susceptibility testing important for endocarditis
• Higher doses of β-lactams often required

Pathophysiology

Group A Streptococcus Virulence Factors:

  • M protein: Major virulence factor; antiphagocytic, over 220 types identified
  • Capsule: Hyaluronic acid capsule inhibits phagocytosis
  • Exotoxins:
    • Pyrogenic exotoxins (SpeA, SpeB, SpeC): Act as superantigens in scarlet fever and toxic shock syndrome
    • Streptolysin O: Oxygen-labile hemolysin; antibodies (ASO) used in diagnosis
    • Streptolysin S: Oxygen-stable hemolysin; responsible for β-hemolysis on blood agar
    • DNases: Including DNase B (antibodies used diagnostically)
  • Invasins: Streptokinase, hyaluronidase, and other enzymes that facilitate tissue spread

Group B Streptococcus Virulence Factors:

  • Polysaccharide capsule: 10 serotypes (Ia, Ib, II-IX), with types Ia, Ib, II, III, and V causing most disease
  • Surface proteins: Alpha and beta C proteins, pili aid in adherence and invasion
  • Beta-hemolysin/cytolysin: Contributes to tissue injury and inflammation
  • Hyaluronidase and proteases: Facilitate tissue invasion

Post-Infectious Immune Mechanisms:

  • Acute rheumatic fever: Molecular mimicry between GAS M protein and human cardiac myosin, leading to autoimmune damage to heart valves
  • Post-streptococcal glomerulonephritis: Immune complex deposition in glomeruli following specific "nephritogenic" GAS strains
  • PANDAS/PANS: Proposed autoimmune mechanism following GAS infection affecting basal ganglia

Clinical Manifestations

Group A Streptococcal Infections:

1. Suppurative (Direct) Infections:

  • Pharyngitis/Tonsillitis:
    • Acute onset sore throat, fever, pharyngeal erythema, tonsillar exudate
    • Tender anterior cervical lymphadenopathy
    • Absence of cough, rhinorrhea, conjunctivitis (suggestive of viral etiology)
    • Most common in children 5-15 years old
  • Scarlet fever:
    • Pharyngitis with diffuse, erythematous, sandpaper-like rash
    • Begins on trunk and spreads to extremities (sparing palms/soles)
    • Circumoral pallor, strawberry tongue, Pastia's lines in skin folds
    • Desquamation during convalescence
  • Impetigo:
    • Superficial skin infection with honey-colored crusts
    • Most common on face and extremities
    • May coexist with S. aureus
  • Pyoderma: Deeper skin infection following trauma/insect bites
  • Erysipelas: Well-demarcated, raised, erythematous skin infection, often on face
  • Cellulitis: Acute spreading infection of dermis and subcutaneous tissues
  • Perianal dermatitis: Perianal erythema with pain on defecation
  • Vaginitis: Prepubertal girls; vaginal erythema, discomfort, discharge

2. Invasive GAS Disease:

  • Bacteremia: Can be with or without focus
  • Pneumonia: Often with empyema, rapid progression
  • Necrotizing fasciitis:
    • Rapidly progressive deep soft tissue infection
    • Severe pain out of proportion to exam findings initially
    • Progression to skin discoloration, bullae, crepitus
    • Systemic toxicity with high mortality
  • Streptococcal toxic shock syndrome (STSS):
    • Hypotension, multiorgan involvement
    • Fever, rash, hyperemia of mucous membranes
    • Desquamation during convalescence
    • Associated with specific M types and exotoxin production
  • Osteomyelitis and septic arthritis: Less common than S. aureus but important pathogen

3. Non-suppurative (Post-infectious) Sequelae:

  • Acute rheumatic fever (ARF):
    • Occurs 2-3 weeks after pharyngitis
    • Major manifestations (Jones criteria): Carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules
    • Minor manifestations: Fever, arthralgia, elevated acute phase reactants, prolonged PR interval
  • Post-streptococcal glomerulonephritis (PSGN):
    • Occurs 1-2 weeks after pharyngitis, 3-6 weeks after skin infection
    • Hematuria, proteinuria, edema, hypertension
    • Low C3 complement
  • PANDAS/PANS: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; abrupt onset OCD, tics, other neuropsychiatric symptoms (controversial)

Group B Streptococcal Infections:

1. Early-onset Disease (0-6 days):

  • Presents within hours of birth up to day 6 of life
  • Often fulminant illness with respiratory distress, pneumonia, septic shock
  • Meningitis in approximately 5-10% of cases
  • Acquired through vertical transmission

2. Late-onset Disease (7-90 days):

  • Presents between 7 days and 3 months of life
  • Bacteremia without focus, meningitis (30-40%), or focal infections
  • More indolent presentation than early-onset
  • Acquired vertically or horizontally

3. Beyond Early Infancy:

  • Rare except in immunocompromised children or those with anatomic abnormalities
  • Can cause osteoarticular infections, skin/soft tissue infections

4. Maternal Infections:

  • Chorioamnionitis, endometritis, urinary tract infection
  • Wound infections following cesarean delivery

Diagnostic Evaluation

Group A Streptococcus:

  • Pharyngitis:
    • Rapid antigen detection tests (RADT): 85-95% specificity, 70-90% sensitivity
    • Throat culture: Gold standard, 90-95% sensitivity
    • Testing strategy: RADT with culture backup for negative RADT in children (not needed in adults)
    • Clinical prediction rules: Centor/McIsaac criteria help guide testing decisions
  • Skin and soft tissue infections:
    • Culture of purulent material or tissue
    • Blood cultures for invasive disease or systemic symptoms
  • Serologic testing:
    • Antistreptolysin O (ASO): Rises 1 week after infection, peaks at 3-5 weeks
    • Anti-DNase B: Rises slower, better for skin infections
    • Used primarily for diagnosis of post-streptococcal sequelae, not acute infection

Group B Streptococcus:

  • Maternal screening: Rectovaginal culture at 36-37 weeks gestation
  • Neonatal infection:
    • Blood culture (gold standard)
    • CSF culture for suspected meningitis
    • Surface cultures not useful (represent colonization)
    • Gram stain of normally sterile fluids
  • Laboratory identification:
    • Beta-hemolytic on blood agar
    • CAMP test positive
    • Group B antigen identification
    • PCR-based methods for rapid identification

Post-streptococcal Sequelae:

  • Acute rheumatic fever:
    • Evidence of preceding GAS infection (positive culture, RADT, or elevated streptococcal antibodies)
    • Jones criteria (major and minor manifestations)
    • Echocardiography for carditis
  • Post-streptococcal glomerulonephritis:
    • Urinalysis (hematuria, proteinuria)
    • Serum complement levels (low C3, normal C4)
    • BUN, creatinine to assess renal function
    • Evidence of preceding GAS infection

Additional Laboratory Studies:

  • Complete blood count: Leukocytosis common in bacterial infections
  • Inflammatory markers: ESR, CRP elevated in invasive disease
  • Blood cultures: For suspected invasive disease
  • Imaging studies: Based on suspected focus of infection (chest radiography, ultrasound, MRI)
  • Surgical exploration: For suspected necrotizing fasciitis

Management

Group A Streptococcal Infections:

Infection Treatment Duration
Pharyngitis First line:
• Penicillin V PO
• Amoxicillin PO (better taste, once daily dosing possible)
• Benzathine penicillin G IM (single dose)

Penicillin allergy:
• Non-anaphylactic: Cephalexin
• Anaphylactic: Clindamycin, azithromycin, or clarithromycin 		• Oral: 10 days
• IM: Single dose
Impetigo • Limited: Topical mupirocin
• Multiple lesions: Oral antibiotics as for pharyngitis 		• Topical: 5-7 days
• Oral: 7 days
Cellulitis/Erysipelas • Mild: Oral antibiotics (amoxicillin, cephalexin)
• Moderate/severe: IV penicillin or cefazolin
• Consider MRSA coverage depending on epidemiology 		• 5-7 days for uncomplicated
• 10-14 days for severe
Necrotizing fasciitis • Surgical debridement (critical)
• Penicillin plus clindamycin IV
• IVIG may be considered 		• 2-3 weeks after source control
Toxic shock syndrome • Penicillin plus clindamycin IV
• Source control
• IVIG may be beneficial
• Supportive care in ICU 		• 10-14 days
Bacteremia • Penicillin G or ampicillin IV • 10-14 days

Group B Streptococcal Infections:

Condition Management
Maternal prophylaxis Indications:
• Positive GBS screening culture at 36-37 weeks
• Previous infant with invasive GBS disease
• GBS bacteriuria during current pregnancy
• Unknown GBS status plus: delivery <37 weeks, ROM ≥18 hours, or intrapartum fever

Regimens:
• First line: Penicillin G IV
• Alternative: Ampicillin IV
• Penicillin allergy, non-anaphylactic: Cefazolin IV
• Penicillin allergy, anaphylactic: Clindamycin or vancomycin IV
Neonatal sepsis/meningitis • Ampicillin plus gentamicin empirically
• Once confirmed, penicillin G or ampicillin
• Duration: 10 days for bacteremia without focus, 14-21 days for meningitis
• Supportive care as needed
Empiric therapy for febrile infant • <28 days: Ampicillin + gentamicin ± cefotaxime
• 29-90 days: Varies by institution and risk stratification

Post-streptococcal Sequelae:

  • Acute rheumatic fever:
    • Penicillin to eradicate any remaining GAS
    • Anti-inflammatory therapy (aspirin or other NSAIDs) for arthritis
    • Corticosteroids for moderate to severe carditis
    • Secondary prophylaxis (see Prevention)
  • Post-streptococcal glomerulonephritis:
    • Supportive care (fluid/sodium restriction if edema/hypertension)
    • Antihypertensive therapy if needed
    • Penicillin to eradicate GAS (does not alter course of nephritis)

Prevention

Group A Streptococcus:

  • Primary prevention:
    • Prompt diagnosis and treatment of GAS pharyngitis
    • Improved hygiene and living conditions
    • No vaccine currently available
  • Secondary prevention of ARF:
    Condition Duration
    ARF without carditis 5 years or until age 21 (whichever longer)
    ARF with carditis, no residual valvular disease 10 years or until age 21 (whichever longer)
    ARF with carditis and residual valvular disease 10 years or until age 40 (whichever longer); sometimes lifelong

    Regimens:

    • Benzathine penicillin G IM every 3-4 weeks (preferred)
    • Penicillin V PO twice daily
    • Sulfadiazine or macrolide if penicillin allergic
  • For recurrent GAS infections:
    • Consider tonsillectomy for very frequent infections (>7/year or >5/year for 2 consecutive years)
    • Investigate household carriers in cases of "ping-pong" spread

Group B Streptococcus:

  • Universal screening: All pregnant women at 36-37 weeks gestation
  • Intrapartum antibiotic prophylaxis: Per guidelines (see Management section)
  • GBS vaccines: Under development but not currently available
  • Risk-based approach: For women with unknown GBS status at delivery

Infection Control Measures:

  • Standard precautions for all patients
  • Droplet precautions for patients with pharyngitis (first 24 hours of antibiotics)
  • Contact precautions for patients with major skin infections
  • Return to school/daycare: 24 hours after initiating antibiotics for pharyngitis
×

Neisseria meningitidis in Pediatrics

Overview & Definition

Neisseria meningitidis (meningococcus) is a gram-negative, aerobic diplococcus that frequently colonizes the human nasopharynx. While colonization is common, invasive meningococcal disease is relatively rare but potentially devastating, with rapid progression and high mortality if untreated. In pediatric populations, N. meningitidis is a leading cause of bacterial meningitis and septicemia, especially after the introduction of Haemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines.

Meningococcal disease presents primarily as meningitis, bacteremia/septicemia, or both. Less common manifestations include pneumonia, septic arthritis, pericarditis, and chronic meningococcemia. The classic presentation of petechial or purpuric rash with fever and meningeal signs should raise immediate concern for meningococcal disease in any child.

Epidemiology

Prevalence and Distribution:

  • Annual incidence in the United States: 0.1-1.0 cases per 100,000 population
  • Higher incidence in the "meningitis belt" of sub-Saharan Africa (10-1000 cases/100,000 during epidemics)
  • Serogroups B, C, W, and Y cause most disease in the U.S.
  • Serogroup A predominates in Africa; serogroup B in Europe
  • Peak incidence occurs in children <5 years old, with a second peak in adolescents (16-21 years)

Risk Factors for Invasive Disease:

Category Risk Factors
Host factors • Age: Infants, young children, adolescents
• Complement deficiencies (C5-C9, properdin, factor D)
• Asplenia (functional or anatomic)
• HIV infection
• Certain genetic polymorphisms
Environmental factors • Household crowding
• Active or passive smoking
• Dormitory living
• Military barracks
• Recent viral respiratory infections
• Winter/early spring season
Exposure factors • Close contact with an infected person
• New carrier state (risk highest in first week after acquisition)
• Travel to endemic/epidemic regions

Transmission:

  • Person-to-person via respiratory droplets or secretions
  • Asymptomatic carriage in nasopharynx (5-10% of general population; up to 25% in adolescents)
  • Incubation period: 1-10 days (usually 3-4 days)
  • Period of communicability: Until meningococci are no longer present in discharges from nose and mouth (usually within 24 hours of starting effective antibiotics)

Pathophysiology

Virulence Factors:

  • Capsule: Polysaccharide capsule (defines serogroups A, B, C, W, X, Y) provides resistance to phagocytosis and complement-mediated lysis
  • Pili: Facilitate attachment to mucosal epithelial cells
  • Outer membrane proteins:
    • PorA and PorB: Form pores in host cell membranes
    • Opa and Opc: Mediate adhesion and invasion
  • IgA1 protease: Cleaves human IgA1, compromising mucosal immunity
  • Iron acquisition systems: Transferrin-binding proteins and lactoferrin-binding proteins
  • Endotoxin (lipooligosaccharide, LOS): Major contributor to inflammatory cascade and shock

Pathogenic Sequence:

  1. Colonization: Attachment to nasopharyngeal epithelium via pili and outer membrane proteins
  2. Invasion: Penetration of mucosal barriers into bloodstream
  3. Survival in bloodstream: Resistance to complement-mediated killing and phagocytosis via capsule
  4. Endothelial damage: Adherence to endothelium, causing vascular damage
  5. Inflammatory response: Release of endotoxin triggers cytokine cascade (TNF-α, IL-1, IL-6, IL-8)
  6. Clinical manifestations: Meningitis, septicemia, or both, depending on bacterial load and host response

Clinical Manifestations

Meningococcal disease in children can present with a spectrum of clinical manifestations:

Prodromal Phase:

  • Nonspecific symptoms: fever, headache, myalgia, malaise
  • Often mistaken for viral illness in early stages
  • Upper respiratory symptoms may precede invasive disease

Meningococcal Meningitis:

  • Classical symptoms:
    • Fever (usually high-grade)
    • Headache (severe, progressively worsening)
    • Neck stiffness (may be subtle or absent in infants)
    • Photophobia
    • Nausea/vomiting
    • Altered mental status (irritability to coma)
  • Age-specific presentations:
    • Neonates/young infants: Fever or hypothermia, poor feeding, lethargy, irritability, bulging fontanelle, seizures; classic meningeal signs often absent
    • Older children: More likely to exhibit classic meningeal signs (nuchal rigidity, Kernig's and Brudzinski's signs)
  • Rash: Present in approximately 50-80% of meningitis cases

Meningococcal Septicemia (Meningococcemia):

  • Characteristic features:
    • Rapid onset high fever
    • Petechial or purpuric rash (initially pink, blanching macules that rapidly evolve to non-blanching petechiae or purpura)
    • Signs of circulatory compromise (tachycardia, prolonged capillary refill, hypotension)
    • Cold extremities, pallor
    • Rapid progression to shock
  • Fulminant meningococcemia (Waterhouse-Friderichsen syndrome):
    • Overwhelming sepsis with DIC, adrenal hemorrhage, and multi-organ failure
    • Extensive purpura fulminans (large ecchymotic areas with sharply defined borders)
    • Shock refractory to interventions
    • Rapid progression to death (can occur within hours of symptom onset)

Combined Meningitis and Septicemia:

  • Approximately 40% of cases present with both meningitis and septicemia
  • Features of both syndromes may be present

Less Common Presentations:

Manifestation Characteristics
Pneumonia • More common with serogroups Y and W
• May present with typical pneumonia symptoms
• Often occurs without meningitis or classic rash
Septic arthritis • Usually monoarticular
• Joint pain, swelling, limited range of motion
• Can occur with or without meningitis
Pericarditis • Chest pain, friction rub, ECG changes
• May develop several days after onset of meningococcal disease
Chronic meningococcemia • Recurrent fever, rash, arthralgia
• Intermittent bacteremia without meningitis
• Can persist for weeks if untreated
Conjunctivitis • Primary meningococcal conjunctivitis can lead to invasive disease
• Consider in purulent conjunctivitis with gram-negative diplococci

Complications of Meningococcal Disease:

  • Acute complications:
    • Cerebral edema
    • Subdural effusions
    • Hydrocephalus
    • Cerebral infarction or hemorrhage
    • Seizures
    • DIC with bleeding complications
    • Multi-organ failure
    • Peripheral gangrene (may require amputation)
  • Long-term sequelae:
    • Hearing loss (8-10% of meningitis survivors)
    • Neurological deficits (seizures, motor deficits, visual impairment)
    • Cognitive impairment
    • Developmental delays
    • Psychological effects (post-traumatic stress, anxiety)
    • Skin scarring from necrotic lesions
    • Limb amputations

Diagnostic Evaluation

Clinical Assessment:

  • Thorough history and physical examination
  • Special attention to rash characteristics (petechial, purpuric)
  • Assessment of mental status and meningeal signs
  • Evaluation for shock (vital signs, perfusion, capillary refill)

Laboratory Studies:

Test Findings in Meningococcal Disease
Blood cultures • Positive in 50-75% of untreated cases
• Should be obtained before antibiotics when possible
• Essential for identification and susceptibility testing
CSF analysis
(if no contraindications to lumbar puncture)		 • Elevated WBC count (typically 1,000-5,000/mm³ with neutrophil predominance)
• Elevated protein (usually >100 mg/dL)
• Decreased glucose (often <40 mg/dL or CSF:serum ratio <0.4)
• Gram stain: gram-negative diplococci in 60-80% of untreated cases
• Culture: positive in 70-85% if obtained before antibiotics
Complete blood count • Leukocytosis (>15,000/mm³) or leukopenia (<5,000/mm³, poor prognostic sign)
• Thrombocytopenia (common in septicemia, associated with DIC)
Coagulation studies • Prolonged PT/PTT
• Decreased fibrinogen
• Elevated D-dimer
• Evidence of DIC in severe disease
Metabolic panel • Electrolyte abnormalities
• Elevated BUN/creatinine (renal dysfunction)
• Acidosis (metabolic, lactic)
• Hypo/hyperglycemia
Inflammatory markers • Elevated C-reactive protein
• Elevated procalcitonin (highly sensitive for meningococcal disease)

Microbiologic Diagnosis:

  • Culture-based methods:
    • Blood culture
    • CSF culture
    • Culture of petechial skin lesions (needle aspiration or biopsy)
    • Culture of joint fluid (in septic arthritis)
  • Molecular methods:
    • PCR of blood or CSF (increases yield by 30% over culture alone)
    • Particularly valuable after antibiotic administration
    • Can detect specific serogroups
  • Antigen detection:
    • Latex agglutination tests for CSF (low sensitivity, not recommended as sole test)

Imaging Studies:

  • Head CT:
    • Not routinely indicated before lumbar puncture unless focal neurologic deficits, papilledema, altered consciousness, or immunocompromise
    • May show complications: cerebral edema, hydrocephalus, infarcts, hemorrhage
  • MRI:
    • More sensitive for parenchymal abnormalities
    • Better for evaluating complications or residual damage
  • Chest X-ray:
    • For suspected meningococcal pneumonia
    • To evaluate for ARDS in severe sepsis

Management

Initial Stabilization:

  • Airway management (consider early intubation in severe sepsis or altered consciousness)
  • Breathing support (oxygen, ventilation as needed)
  • Circulatory support:
    • Aggressive fluid resuscitation (20 mL/kg boluses, repeated as needed)
    • Inotropic support for shock unresponsive to fluids
    • Central venous access for medication administration and monitoring
  • Continuous monitoring of vital signs and neurological status

Antimicrobial Therapy:

Phase Recommendation
Empiric therapy
(before confirmation)		 First-line:
• Infant/child: Ceftriaxone (100 mg/kg/day, q12-24h, max 4g/day) OR
• Cefotaxime (200-300 mg/kg/day, q6-8h, max 12g/day)

Alternatives (PCN allergy or ceftriaxone unavailable):
• Meropenem (120 mg/kg/day, q8h, max 6g/day) OR
• Chloramphenicol (75-100 mg/kg/day, q6h, max 4g/day)
Definitive therapy
(after confirmation)		 • Continue ceftriaxone or cefotaxime
• If susceptible: Penicillin G (300,000 units/kg/day, q4-6h, max 24 million units/day)
• Duration: 5-7 days for meningitis, 5-7 days for uncomplicated meningococcemia

Adjunctive Therapies for Severe Disease:

  • Corticosteroids:
    • Not routinely recommended in meningococcal meningitis
    • Consider if suspect concurrent pneumococcal meningitis (dexamethasone 0.15 mg/kg Q6h for 2-4 days, given before or with first dose of antibiotics)
  • Management of shock:
    • Goal-directed resuscitation
    • Vasopressors/inotropes (norepinephrine, epinephrine, dopamine)
    • Hydrocortisone for catecholamine-resistant shock (1-2 mg/kg/dose Q6h)
  • Management of raised intracranial pressure:
    • Head elevation, maintain normal PaCOâ‚‚
    • Osmotherapy (mannitol, hypertonic saline)
    • Sedation, neuromuscular blockade if needed
    • CSF drainage in selected cases
  • Management of DIC:
    • Fresh frozen plasma, cryoprecipitate, platelet transfusions for active bleeding or invasive procedures
    • No role for heparin in DIC associated with meningococcal disease
  • Monitoring and supportive care:
    • Frequent neurological assessment
    • Fluid and electrolyte management
    • Glycemic control
    • Prevention of complications (DVT prophylaxis, stress ulcer prophylaxis)

Infection Control Measures:

  • Respiratory isolation for 24 hours after initiation of effective antibiotic therapy
  • Standard precautions for handling body fluids

Prevention

Chemoprophylaxis:

Aspect Recommendation
Indications • Close contacts (household members, daycare contacts, direct exposure to secretions)
• Anyone who has had intimate contact with the case (kissing, shared utensils/toothbrushes)
• Healthcare workers with direct exposure to respiratory secretions
• Must be administered as soon as possible (ideally within 24 hours, effectiveness decreases after 14 days)
Regimens Preferred:
• Rifampin:
- Children <1 month: 5 mg/kg PO Q12h for 2 days
- Children ≥1 month: 10 mg/kg (max 600 mg) PO Q12h for 2 days
- Adults: 600 mg PO Q12h for 2 days

Alternatives:
• Ceftriaxone:
- Children <15 years: 125 mg IM single dose
- Children ≥15 years and adults: 250 mg IM single dose

• Ciprofloxacin:
- Adults: 500 mg PO single dose
- Children ≥1 year (if no alternative): 20 mg/kg (max 500 mg) PO single dose
- Not routinely recommended for persons <18 years of age
Index case • Patients treated with penicillin or ampicillin should receive chemoprophylaxis before discharge
• Not needed if treated with ceftriaxone or cefotaxime

Immunization:

Vaccine Type Characteristics and Recommendations
Meningococcal conjugate vaccines (MenACWY) • Contains: Serogroups A, C, W, Y
• Products: Menactra®, Menveo®, MenQuadfi®
• Routine recommendation:
- First dose at age 11-12 years
- Booster dose at age 16 years
• High-risk children (complement deficiency, asplenia, HIV):
- Initial series starting at age 2 months (depends on product)
- Boosters every 3-5 years if risk persists
Meningococcal B vaccines (MenB) • Contains: Serogroup B antigens
• Products: Bexsero®, Trumenba®
• Routine recommendation: Not routinely recommended; may be given based on shared clinical decision-making for adolescents 16-23 years (preferred age 16-18 years)
• High-risk individuals: Recommended for persons ≥10 years with complement deficiency, asplenia, or during outbreaks
Outbreak control • Mass vaccination may be recommended during outbreaks
• Vaccine selection based on serogroup causing the outbreak
• Coordinated by public health authorities

Long-term Follow-up:

  • Audiologic evaluation for all survivors of meningitis
  • Neurodevelopmental assessment for children with complicated disease
  • Psychological support for survivors and families
  • Consider referral to specialized services for management of sequelae
×

Neisseria gonorrhoeae Infections in Pediatrics

Overview & Definition

Neisseria gonorrhoeae is a gram-negative diplococcus that causes the sexually transmitted infection gonorrhea. In pediatric populations, gonococcal infections raise significant clinical and social concerns, as they may indicate sexual abuse in prepubertal children. Diagnosis requires a high index of suspicion, proper specimen collection, and appropriate laboratory techniques.

N. gonorrhoeae is an obligate human pathogen that primarily infects columnar and transitional epithelium of the genitourinary tract, rectum, pharynx, and conjunctiva. The organism is non-motile, non-spore forming, and oxidase-positive. It has fastidious growth requirements, requiring enriched media and increased COâ‚‚ for cultivation.

Epidemiology

Prevalence and Distribution:

  • In the United States, reported gonorrhea rates in adolescents (15-19 years) are 2-4 times higher than in adults
  • Neonatal gonococcal infections occur in approximately 0.3-1% of births to infected mothers without prophylaxis
  • In prepubertal children beyond the neonatal period, gonococcal infection is rare and most commonly associated with sexual abuse

Transmission Patterns in Pediatrics:

Age Group Mode of Transmission Public Health Implications
Neonates • Vertical transmission during passage through infected birth canal
• Ascending infection with premature rupture of membranes (rare) 		• Preventable with appropriate maternal screening and treatment
• Universal ocular prophylaxis for newborns
Infants and young children • Sexual abuse (most common)
• Very rarely: autoinoculation, fomite transmission (controversial) 		• Mandated reporting to child protective services
• Requires investigation for other STIs and signs of abuse
Adolescents • Sexual contact (consensual or non-consensual)
• High-risk behaviors (multiple partners, inconsistent condom use) 		• Screening recommended for sexually active females
• Partner notification and treatment
• Assessment for other STIs including HIV

Risk Factors:

  • Neonates: Maternal infection, lack of prenatal care, absence of ocular prophylaxis
  • Prepubertal children: Sexual abuse, household contact with infected individuals
  • Adolescents: Early sexual debut, multiple partners, prior STIs, inconsistent condom use, substance use

Antimicrobial Resistance:

  • Rising rates of multidrug-resistant N. gonorrhoeae globally
  • Widespread resistance to penicillins, tetracyclines, and fluoroquinolones
  • Emerging resistance to azithromycin
  • Decreased susceptibility to cephalosporins is concerning
  • Pediatric isolates generally mirror resistance patterns seen in adult populations in the same region

Pathophysiology

Virulence Factors:

  • Pili: Facilitate initial attachment to epithelial cells and resist phagocytosis
  • Opacity (Opa) proteins: Mediate tight adherence to epithelial cells and neutrophils
  • Porin (PorB): Forms channels in host cell membranes, interferes with neutrophil function
  • IgA1 protease: Cleaves secretory IgA, compromising mucosal immunity
  • Lipooligosaccharide (LOS): Endotoxin that stimulates inflammatory response
  • Transferrin and lactoferrin receptors: Acquire iron in host environments

Host-Pathogen Interactions:

  • Initial attachment via pili to CD46 receptors on host cells
  • Invasion of epithelial cells via Opa proteins binding to CEACAM receptors
  • Transcytosis through epithelial layer to subepithelial tissue
  • Neutrophil recruitment resulting in purulent discharge
  • Antigenic variation of surface structures (particularly pili) to evade immune response
  • In pediatric hosts, anatomical and immunological factors influence infection patterns:
    • Thin vaginal epithelium (prepubertal) is less susceptible to gonococcal attachment
    • Alkaline pH of prepubertal vagina is less favorable for gonococcal growth
    • Immature immune responses in neonates increase susceptibility to dissemination

Mechanisms of Antibiotic Resistance:

  • β-lactam resistance: Chromosomal mutations in penA (PBP2), mtrR, penB, ponA genes
  • Fluoroquinolone resistance: Mutations in gyrA and parC genes
  • Tetracycline resistance: Ribosomal protection via tetM plasmid
  • Macrolide resistance: Mutations in 23S rRNA and/or efflux pumps
  • Extended-spectrum cephalosporin resistance: Mosaic penA alleles and additional mutations

Clinical Manifestations

Clinical presentations of N. gonorrhoeae infections in children vary by age group and site of infection:

Neonatal Infections:

  • Ophthalmia neonatorum:
    • Onset typically 2-5 days after birth
    • Presents with conjunctival hyperemia, chemosis, and copious purulent discharge
    • Can progress to corneal ulceration and perforation if untreated
    • Bilateral in approximately 50% of cases
  • Disseminated gonococcal infection (DGI):
    • Bacteremia with sepsis, meningitis, or arthritis
    • May present with temperature instability, poor feeding, irritability
    • Joint involvement typically presents as limited movement and swelling
  • Scalp abscess: Can occur at site of fetal monitoring electrode placement
  • Rhinitis: Bloody or purulent nasal discharge
  • Anorectal infection: Usually asymptomatic but may cause purulent discharge

Prepubertal Children:

  • Vulvovaginitis:
    • Primary manifestation in prepubertal girls
    • Presents with vaginal discharge, dysuria, genital pain, or pruritus
    • May be asymptomatic in up to 50% of cases
    • Examination reveals vaginal erythema and purulent discharge
  • Urethritis:
    • More common in boys
    • Presents with urethral discharge, dysuria, or penile pain
    • May be asymptomatic
  • Pharyngeal infection:
    • Usually asymptomatic
    • Occasionally presents with sore throat or pharyngeal erythema
  • Anorectal infection:
    • May be asymptomatic or present with rectal pain, pruritus, tenesmus, or discharge
  • Conjunctivitis: Acute onset of conjunctival injection and purulent discharge

Adolescents:

Site of Infection Clinical Presentation Asymptomatic Rate
Cervicitis (females) • Mucopurulent cervical discharge
• Cervical friability
• Abnormal vaginal bleeding
• Lower abdominal pain
• Dysuria 		50-80%
Urethritis (males) • Purulent urethral discharge
• Dysuria
• Urethral itching or burning 		10-15%
Pharyngeal • Usually asymptomatic
• Mild pharyngitis
• Tonsillitis 		>90%
Rectal • Rectal pain
• Discharge
• Bleeding
• Tenesmus 		50-85%

Complications:

  • Pelvic inflammatory disease (PID):
    • Significant concern in adolescent females
    • Presents with lower abdominal pain, cervical motion tenderness, adnexal tenderness
    • Can lead to tubo-ovarian abscess, perihepatitis (Fitz-Hugh-Curtis syndrome)
    • Long-term sequelae include infertility, ectopic pregnancy, chronic pelvic pain
  • Epididymitis/orchitis: Testicular pain, swelling, tenderness in adolescent males
  • Disseminated gonococcal infection (DGI):
    • Occurs in 0.5-3% of untreated infections
    • Presents as bacteremia with fever, skin lesions (pustular or hemorrhagic), tenosynovitis, septic arthritis
    • More common in adolescent females during menses or pregnancy
  • Perihepatitis: Right upper quadrant pain, elevated liver enzymes
  • Increased HIV transmission risk: 3-5 fold increase in HIV acquisition

Diagnostic Evaluation

Laboratory Diagnosis:

Proper specimen collection and testing methodology are crucial for accurate diagnosis, particularly in pediatric patients where implications of positive results are significant.

Diagnostic Method Description Considerations in Pediatrics
Nucleic acid amplification tests (NAATs) • Highly sensitive (>95%) and specific (>99%)
• PCR, transcription-mediated amplification, strand displacement
• Can be performed on various specimen types 		• FDA-cleared for genital specimens in adults and adolescents
• Not FDA-cleared for extragenital sites or children
• Recommended for prepubertal children with confirmation by culture
• Consider legal implications in suspected abuse cases
Culture • Modified Thayer-Martin or chocolate agar with antibiotics
• Requires viable organisms and special handling
• Less sensitive (50-70%) but highly specific 		• Gold standard for prepubertal children
• Allows for antimicrobial susceptibility testing
• Preferred for legal evidence in abuse cases
• Delayed transport reduces yield significantly
Gram stain • Direct microscopic visualization of gram-negative diplococci within PMNs
• Rapid preliminary diagnosis 		• High sensitivity for symptomatic males (urethral)
• Poor sensitivity for females and extragenital sites
• Not recommended for pharyngeal/rectal specimens
• Limited utility in prepubertal children
Point-of-care tests • Immunochromatographic assays
• Results available in 30-60 minutes 		• Limited sensitivity (70-90%)
• Not widely used in pediatric settings
• Not recommended for legal cases

Specimen Collection by Age Group:

  • Neonates:
    • Conjunctival swabs for ophthalmia neonatorum
    • Blood cultures if sepsis suspected
    • CSF culture if meningitis suspected
    • Joint fluid if arthritis present
  • Prepubertal children:
    • Girls: Vaginal vestibule swab (not cervical); avoid hymenal trauma
    • Boys: Urethral meatus swab (introital)
    • Throat and rectal swabs as indicated by history
    • Preserve chain of custody if abuse suspected
  • Adolescents:
    • Females: Endocervical, vaginal, or urine specimens
    • Males: First-void urine or urethral swab
    • Extragenital testing (pharyngeal, rectal) based on sexual practices

Additional Evaluation:

  • Testing for co-infections (chlamydia, syphilis, HIV, hepatitis B, trichomoniasis)
  • Pregnancy testing for adolescent females
  • Complete blood count and inflammatory markers if systemic infection suspected
  • Joint aspiration for suspected septic arthritis
  • Blood cultures for suspected disseminated infection

Social and Forensic Evaluation:

  • Mandatory reporting to child protective services for suspected abuse in prepubertal children
  • Involvement of child abuse team and specialized sexual assault nurse examiners when available
  • Proper documentation and preservation of evidence
  • Assessment of safety and risk factors
  • Age-appropriate interview techniques

Management

General Principles:

  • Empiric treatment should be initiated while awaiting culture/NAAT results in symptomatic patients
  • Treatment regimens must account for increasing antimicrobial resistance
  • Partner notification and treatment is essential in adolescents
  • Follow-up testing is recommended to ensure cure in pediatric patients
  • Consideration of legal and ethical aspects in cases of suspected abuse

Antimicrobial Therapy by Age Group and Clinical Presentation:

Clinical Scenario Recommended Treatment Alternative Regimen
Neonatal ophthalmia • Ceftriaxone 25-50 mg/kg IV/IM (max 125 mg) single dose
• Plus saline eye irrigation 		• Cefotaxime 100 mg/kg IV/IM single dose
Neonatal disseminated infection or meningitis • Ceftriaxone 25-50 mg/kg/day IV/IM QD for 7-14 days (without meningitis)
• Ceftriaxone 80-100 mg/kg/day IV QD for 10-14 days (with meningitis)
• Maximum 1-2 g daily 		• Cefotaxime 50 mg/kg IV Q8h for 7-14 days
Uncomplicated infection in children <45 kg • Ceftriaxone 50 mg/kg IM single dose (max 250 mg) • Cefixime 8 mg/kg PO single dose (max 400 mg)
Uncomplicated infection in children >45 kg and adolescents • Ceftriaxone 500 mg IM single dose • Cefixime 800 mg PO single dose
• Gentamicin 240 mg IM plus azithromycin 2 g PO, both as single doses
Pelvic inflammatory disease • Ceftriaxone 500 mg IM single dose, plus
• Doxycycline 100 mg PO BID for 14 days (if >8 years old), plus
• Metronidazole 500 mg PO BID for 14 days 		• For hospitalization: Cefotetan or cefoxitin plus doxycycline
Disseminated gonococcal infection in children/adolescents • Ceftriaxone 1 g IV/IM daily for 7 days (14 days if meningitis/endocarditis) • Cefotaxime 1 g IV Q8h or
• Ceftizoxime 1 g IV Q8h

Co-infection Treatment:

  • Due to high rates of co-infection with Chlamydia trachomatis:
    • Neonates: Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided QID for 14 days
    • Children <45 kg: Azithromycin 20 mg/kg (max 1 g) orally in a single dose
    • Children >45 kg and adolescents: Azithromycin 1 g orally in a single dose or doxycycline 100 mg orally BID for 7 days (if >8 years)

Additional Management Considerations:

  • Neonatal ophthalmia: Saline irrigation of eyes, topical antibiotics not required with systemic therapy
  • Hospitalization indications: Neonates, young children, severe disease, inability to tolerate oral medications, concerns about compliance, suspected septic arthritis
  • Partner management for adolescents: Treatment of all sexual partners from past 60 days
  • Test of cure: Recommended for all pediatric patients 1-2 weeks after treatment completion
  • Expedited partner therapy: Consider for adolescent patients when partner follow-up is unlikely
  • Repeat screening: Recommended 3 months after treatment for sexually active adolescents

Social and Legal Management:

  • Mandatory reporting of suspected sexual abuse in prepubertal children
  • Confidential services for adolescents per local regulations
  • Sexual risk reduction counseling for adolescents
  • Assessment and management of other social determinants of health
  • Psychological support and counseling referrals

Prevention

Neonatal Prevention:

  • Universal prenatal screening for pregnant women at first prenatal visit
  • Repeat screening in third trimester for high-risk women
  • Treatment of infected pregnant women before delivery
  • Ocular prophylaxis for all newborns regardless of delivery method:
    • Erythromycin (0.5%) ophthalmic ointment applied to each eye once
    • Alternative: Tetracycline (1%) ophthalmic ointment
    • Not effective for prevention of nasopharyngeal colonization

Prevention in Adolescents:

  • Screening recommendations:
    • Annual screening for sexually active females <25 years
    • Screening of males in high-prevalence settings
    • Screening at anatomic sites of exposure (genital, pharyngeal, rectal)
  • Risk reduction counseling:
    • Consistent and correct condom use
    • Limiting number of sexual partners
    • Regular STI screening
    • Mutual monogamy with uninfected partner
  • Sexual health education:
    • Age-appropriate comprehensive education
    • Information about STI transmission and prevention
    • Communication skills for negotiating safer sex

Public Health Approaches:

  • Expedited partner therapy where legally permitted
  • Contact tracing and partner notification
  • School-based health centers with STI services
  • Community-based screening programs
  • Increased access to confidential STI testing for adolescents

Vaccine Development:

  • No licensed vaccine currently available
  • Several vaccine candidates in development targeting:
    • Outer membrane proteins
    • Pilus proteins
    • Transferrin-binding proteins
    • Lipooligosaccharide
    • Novel antigens identified through reverse vaccinology
  • Challenges include antigenic variation and lack of correlates of protection
×

Moraxella Infections in Pediatrics

Overview & Definition

Moraxella species are aerobic, oxidase-positive, gram-negative diplococci that can appear as short coccobacilli. Moraxella catarrhalis (formerly known as Branhamella catarrhalis) is the species most clinically relevant in pediatric patients, being the third most common bacterial cause of acute otitis media and a significant cause of sinusitis and lower respiratory tract infections in children.

While typically considered a respiratory tract commensal, M. catarrhalis has emerged as an important respiratory pathogen in children, particularly those with underlying conditions like asthma, cystic fibrosis, or immunodeficiencies. Unlike some more virulent pathogens, Moraxella infections tend to cause localized disease rather than invasive infections in immunocompetent children.

Epidemiology

Prevalence and Distribution:

  • Colonization rates:
    • Nasopharyngeal carriage in healthy children: 30-75%
    • Peak colonization: 2-3 years of age
    • Decreases with age to 1-5% in healthy adults
  • Disease burden:
    • Responsible for 15-20% of acute otitis media episodes in children
    • Causes 10-15% of acute bacterial sinusitis in pediatric patients
    • Accounts for 10% of acute exacerbations in children with chronic lung disease
  • Seasonality: Higher prevalence during fall and winter months

Risk Factors for Infection:

Risk Factor Category Specific Factors
Age-related • Children <5 years of age (peak 1-3 years)
• Premature infants
Environmental • Daycare attendance
• Exposure to tobacco smoke
• Winter season
• Crowded living conditions
Medical conditions • Asthma/reactive airway disease
• Cystic fibrosis
• Ciliary dyskinesia
• COPD (in adolescents)
• Immunodeficiencies (particularly humoral)
Anatomical • Eustachian tube dysfunction
• Adenoid hypertrophy
• Craniofacial abnormalities
Prior exposures • Recent viral respiratory infection
• Recent antibiotic use (selective pressure)
• Prior otitis media episodes

Antimicrobial Resistance:

  • Nearly all strains (>95%) produce β-lactamases (BRO-1 and BRO-2 types)
  • Universally resistant to penicillin, ampicillin, and amoxicillin
  • Generally susceptible to amoxicillin-clavulanate, cephalosporins, macrolides, and fluoroquinolones
  • Resistance rates to trimethoprim-sulfamethoxazole: 15-30% (varies by region)
  • Resistance to tetracyclines remains relatively low (5-10%)

Pathophysiology

Virulence Factors:

  • Adhesins:
    • UspA1 and UspA2: Bind to epithelial cells and extracellular matrix proteins
    • MID/Hag protein: Facilitates attachment to respiratory epithelium
    • Pili: Enhance adherence to mucosal surfaces
  • Defensive factors:
    • Outer membrane proteins: Provide resistance to complement-mediated killing
    • IgA proteases: Cleave secretory IgA, compromising mucosal immunity
    • β-lactamases: BRO-1 and BRO-2 enzymes that inactivate penicillins
    • Biofilm formation: Enhances survival on mucosal surfaces and protects from antibiotics
  • Other factors:
    • Lipooligosaccharide (LOS): Endotoxin that triggers inflammatory response
    • Iron acquisition systems: Allow survival in iron-limited environments

Pathogenesis Mechanism:

  1. Colonization: Adherence to nasopharyngeal mucosa via adhesins
  2. Viral co-infection: Often precedes clinical disease by damaging respiratory epithelium
  3. Migration: Spreads to middle ear, sinuses, or lower respiratory tract
  4. Inflammation: LOS triggers cytokine release and neutrophil recruitment
  5. Immune evasion: IgA proteases and resistance to complement help evade host defenses
  6. Persistence: Biofilm formation contributes to chronic or recurrent infections

Clinical Manifestations

Moraxella catarrhalis causes a spectrum of upper and lower respiratory tract infections in children:

Upper Respiratory Tract Infections:

Clinical Entity Presentation Distinguishing Features
Acute Otitis Media • Ear pain
• Irritability in infants
• Fever
• Hearing loss
• Bulging, erythematous tympanic membrane 		• Often less severe than pneumococcal AOM
• More common in children 6-24 months
• May have concurrent conjunctivitis ("conjunctivitis-otitis syndrome")
• High spontaneous resolution rate
Sinusitis • Nasal discharge/congestion
• Facial pain/pressure
• Cough
• Halitosis
• Post-nasal drip 		• Persistent symptoms >10 days
• May follow viral URI
• Less often causes severe complications compared to S. pneumoniae
Rhinitis • Mucopurulent nasal discharge
• Nasal congestion
• Sneezing 		• Often difficult to distinguish from viral rhinitis
• More common in daycare attendees
Pharyngitis/Tonsillitis • Sore throat
• Tonsillar erythema/exudates
• Cervical lymphadenopathy 		• Uncommon as sole pathogen
• Usually mixed infection or colonization
• Less severe than streptococcal pharyngitis
Conjunctivitis • Purulent eye discharge
• Conjunctival erythema
• Eyelid swelling 		• May occur concurrently with otitis media
• More common in infants and young children

Lower Respiratory Tract Infections:

  • Bronchitis:
    • Productive cough with purulent sputum
    • Chest discomfort
    • Low-grade fever
    • More common in children with underlying pulmonary conditions
  • Pneumonia:
    • Less common than other pathogens (accounts for 1-5% of pediatric community-acquired pneumonia)
    • Presentation similar to other bacterial pneumonias: fever, cough, tachypnea, decreased breath sounds
    • Typically less severe than pneumococcal pneumonia
    • Radiographic findings often show patchy infiltrates; lobar consolidation uncommon
  • Bronchiolitis:
    • Rare as primary pathogen; usually secondary infection following viral bronchiolitis
    • Wheezing, tachypnea, crackles, prolonged expiratory phase
  • Exacerbations of chronic lung disease:
    • Important pathogen in acute exacerbations of asthma, cystic fibrosis, and chronic bronchitis
    • Increased cough, sputum production, and respiratory symptoms

Uncommon Manifestations:

  • Bacteremia: Rare in immunocompetent children; more common in immunocompromised hosts or neonates
  • Meningitis: Extremely rare; reported in neonates or severely immunodeficient patients
  • Endocarditis: Case reports in children with structural heart disease
  • Septic arthritis: Rare; occasional case reports in pediatric literature

Age-Specific Presentations:

  • Neonates: Rare cause of sepsis or pneumonia; may be acquired during passage through colonized birth canal
  • Infants (1-12 months): Primarily causes otitis media and conjunctivitis
  • Toddlers (1-3 years): Peak incidence of otitis media and sinusitis
  • School-age children: Sinusitis and lower respiratory infections more common
  • Adolescents: Primarily sinusitis and bronchitis; important in those with chronic respiratory conditions

Diagnostic Evaluation

Clinical Diagnosis:

  • Diagnosis often presumptive based on clinical presentation
  • Microbiological confirmation usually not pursued for uncomplicated otitis media or sinusitis
  • Should be considered in the differential diagnosis for respiratory infections, especially in children with risk factors

Specimen Collection:

  • Middle ear fluid: Tympanocentesis (rarely performed except in research or treatment failures)
  • Sinus aspirates: Not routinely obtained; reserved for complicated or refractory cases
  • Sputum: Difficult to obtain quality specimens in young children; induced sputum may be needed
  • Bronchoalveolar lavage: For lower respiratory infections in immunocompromised hosts or severe pneumonia
  • Blood cultures: Low yield except in immunocompromised patients

Laboratory Identification:

  • Gram stain: Gram-negative diplococci or short coccobacilli
  • Culture characteristics:
    • Growth on blood and chocolate agar (requires hemin but not NAD)
    • No growth on MacConkey agar (differentiates from Neisseria)
    • Gray-white, opaque colonies that can be pushed intact across agar ("hockey puck" test)
  • Biochemical tests:
    • Oxidase-positive
    • Catalase-positive
    • DNase-positive
    • Nitrate reduction-negative (distinguishes from Neisseria)
    • Butyrate esterase-positive (rapid test)
  • Molecular methods:
    • PCR for detection in research settings or persistent/recurrent cases
    • Multiplex PCR panels for respiratory pathogens
    • MALDI-TOF mass spectrometry for rapid identification

Antimicrobial Susceptibility Testing:

  • β-lactamase testing essential due to high production rates
  • Disk diffusion or broth microdilution methods
  • Automated systems (VITEK, Phoenix) commonly used

Imaging Studies:

  • Otitis media: Not routinely indicated
  • Sinusitis:
    • Not recommended for uncomplicated cases
    • CT scan for suspected complications or chronic/recurrent sinusitis
  • Pneumonia:
    • Chest X-ray may show patchy infiltrates
    • Often indistinguishable from other bacterial pneumonias

Management

General Principles:

  • Consider local resistance patterns when selecting empiric therapy
  • Due to nearly universal β-lactamase production, avoid penicillin and ampicillin
  • Reserve antibiotics for bacterial infections; many cases resolve spontaneously
  • Supportive care important for symptom management

Antimicrobial Therapy:

Infection First-Line Therapy Alternative Therapy Duration
Acute Otitis Media Amoxicillin-clavulanate
(90 mg/kg/day of amoxicillin component) 		• Cefdinir, cefuroxime, cefpodoxime
• Azithromycin (if β-lactam allergic) 		5-7 days (>2 years)
10 days (<2 years)
Sinusitis Amoxicillin-clavulanate
(90 mg/kg/day of amoxicillin component) 		• Cefdinir, cefuroxime, cefpodoxime
• Levofloxacin (if β-lactam allergic)* 		10-14 days
Pneumonia • Outpatient: Amoxicillin-clavulanate
• Inpatient: Ampicillin-sulbactam or ceftriaxone 		• Azithromycin (if atypical suspected)
• Levofloxacin (if β-lactam allergic)* 		7-10 days
Bronchitis/Exacerbation Amoxicillin-clavulanate • Azithromycin
• Doxycycline (>8 years) 		5-7 days
Conjunctivitis Polymyxin-trimethoprim or fluoroquinolone ophthalmic drops Erythromycin or azithromycin ophthalmic ointment 5-7 days

*Note: Fluoroquinolones generally avoided in children unless benefits outweigh risks.

Supportive Care:

  • Otitis media: Analgesics for pain (acetaminophen, ibuprofen)
  • Sinusitis: Saline nasal irrigation, nasal decongestants (short-term)
  • Lower respiratory infections: Hydration, antipyretics, oxygen if needed

Management of Treatment Failures:

  • Obtain appropriate cultures when possible
  • Consider broader-spectrum antibiotics
  • Evaluate for complications or underlying conditions
  • Consider prolonged therapy in chronic infections

Special Considerations:

  • Cystic fibrosis: May require longer courses and higher doses
  • Immunodeficiency: Consider broader initial coverage and microbiological confirmation
  • Penicillin allergy: Macrolides or (in severe infections) fluoroquinolones

Prevention

Infection Control Measures:

  • Hand hygiene - critical for preventing spread in daycare and household settings
  • Respiratory etiquette (covering coughs and sneezes)
  • Proper disposal of nasal secretions
  • Avoiding sharing of personal items
  • Standard precautions in healthcare settings

Risk Reduction Strategies:

  • Reduction of environmental tobacco smoke exposure
  • Breastfeeding to enhance mucosal immunity
  • Pneumococcal vaccination may indirectly reduce Moraxella infections by preventing preceding viral respiratory infections
  • Influenza vaccination to prevent viral co-infections that predispose to bacterial superinfection

Future Directions:

  • Protein D-containing pneumococcal vaccines show cross-protection against Moraxella
  • Specific Moraxella vaccines targeting UspA and other antigens under investigation
  • Novel prevention strategies targeting biofilm formation and quorum sensing

Prognosis

  • Generally excellent with appropriate therapy
  • Spontaneous resolution occurs in many uncomplicated infections
  • Complications rare in immunocompetent children
  • Recurrence common due to repeat colonization
  • Children with underlying conditions (CF, immunodeficiency) may have persistent or recurrent infections
×

Listeria Infections in Pediatrics

Overview & Definition

Listeria monocytogenes is a gram-positive, facultatively anaerobic, non-spore-forming bacillus that causes listeriosis, an infection with significant morbidity and mortality in vulnerable pediatric populations. Distinctive features include its ability to grow at refrigeration temperatures (4°C) and its intracellular lifecycle, allowing it to evade host immune defenses.

Listeriosis primarily affects specific high-risk pediatric populations, including neonates, immunocompromised children, and those with underlying medical conditions. The organism is ubiquitous in the environment and can be found in soil, water, vegetation, and animal feces. Food contamination is the most common source of human infection.

Epidemiology

Incidence and Distribution:

  • Annual incidence: 0.1-0.7 cases per 100,000 children in most developed countries
  • Neonatal listeriosis: 2-13 cases per 100,000 live births
  • Seasonal variation: Higher incidence during summer months
  • Most pediatric cases occur in neonates (>50%)

Risk Factors:

Population Risk Factors
Pregnant women
(affecting fetus/neonate)		 • Maternal consumption of contaminated foods
• Inadequate food handling practices
• Maternal occupation with animal exposure
Neonates • Prematurity
• Low birth weight
• Maternal infection
• Nosocomial transmission (rare)
Children • Primary or acquired immunodeficiency
• Malignancy, especially hematologic
• Solid organ or stem cell transplantation
• Immunosuppressive therapy
• HIV infection
• Hemoglobinopathies
• Iron overload conditions

Transmission:

  • Vertical transmission:
    • Transplacental: Maternal bacteremia leading to placental colonization and fetal infection
    • Ascending: From colonized vaginal tract, especially with prolonged rupture of membranes
    • During delivery: Exposure to contaminated birth canal
  • Foodborne transmission:
    • Consumption of contaminated food products:
    • Unpasteurized dairy products (soft cheeses, raw milk)
    • Ready-to-eat deli meats and hot dogs
    • Smoked seafood
    • Raw vegetables (particularly if inadequately washed)
  • Nosocomial transmission: Rare but documented in neonatal units

Pathophysiology

Virulence Factors:

  • Internalins (InlA, InlB): Surface proteins that mediate bacterial entry into host cells
  • Listeriolysin O (LLO): Pore-forming toxin that allows escape from phagosomes
  • ActA protein: Facilitates intracellular movement and cell-to-cell spread
  • Phospholipases (PlcA, PlcB): Aid in vacuolar escape and cell-to-cell spread
  • Bile salt hydrolase: Enhances survival in intestinal environment

Pathogenesis:

  1. Intestinal invasion: Organism crosses intestinal epithelium via M cells or directly invades enterocytes
  2. Intracellular survival: Escapes phagosome via listeriolysin O and replicates in cytoplasm
  3. Cell-to-cell spread: Moves through cells via actin-based motility without exposure to extracellular environment
  4. Systemic dissemination: Reaches bloodstream through lymphatics or direct invasion
  5. Organ tropism: Preferentially invades placenta and CNS due to specific interactions with host receptors

Host Defense Mechanisms:

  • Innate immunity: Recognition via TLR2, NOD-like receptors; neutrophils essential for early control
  • Cell-mediated immunity: CD8+ T cells critical for clearance of intracellular bacteria
  • Interferon-gamma: Key cytokine in activating macrophages for Listeria killing
  • Pregnancy-related immunosuppression: Contributes to increased maternal susceptibility
  • Neonatal immune system immaturity: Impaired neutrophil function and T-cell responses

Clinical Manifestations

Listeria infections in the pediatric population present primarily in two distinct age groups - neonates and immunocompromised children - with different clinical syndromes:

Neonatal Listeriosis:

Form Timing Clinical Features
Early-onset 0-7 days
(typically within 24-48 hours)		 • Presents as severe sepsis syndrome
• Often mimics group B streptococcal sepsis
• Respiratory distress, pneumonia
• Hepatosplenomegaly
• Disseminated granulomatosis (granulomatosis infantiseptica)
• Characteristic rash with small granulomas or papules
• Associated with premature birth
• High mortality (20-30%)
Late-onset 7-28 days
(average 14 days)		 • Predominant presentation is meningitis
• Fever, irritability, poor feeding
• Seizures in up to 25% of cases
• Bulging fontanelle
• Can present with isolated bacteremia
• Often occurs in term infants
• Lower mortality (10-15%) but significant neurologic sequelae

Maternal Infection:

  • Fever, flu-like illness, often mild and nonspecific
  • Gastrointestinal symptoms (diarrhea, abdominal pain)
  • May be asymptomatic despite significant fetal impact
  • Pregnancy complications: Chorioamnionitis, preterm labor, spontaneous abortion, stillbirth

Listeriosis in Immunocompromised Children:

  • CNS infections:
    • Meningitis: Fever, headache, altered mental status, meningeal signs, cranial nerve palsies
    • Encephalitis: Altered consciousness, seizures, focal neurologic deficits
    • Brain abscess: More common in solid organ transplant recipients
    • Rhombencephalitis: Distinctive brainstem involvement with ataxia, cranial nerve deficits
  • Bacteremia without focal infection: Fever, malaise, occasionally rash
  • Focal infections:
    • Endocarditis: Rare but reported in children with congenital heart disease
    • Peritonitis: Particularly in children with nephrotic syndrome or peritoneal dialysis
    • Septic arthritis: Monoarticular joint infection, particularly in immunosuppressed hosts
    • Osteomyelitis: Rare presentation

Febrile Gastroenteritis:

  • Self-limited gastroenteritis following ingestion of heavily contaminated food
  • Fever, watery diarrhea, abdominal pain, headache, myalgias
  • Incubation period: 24-48 hours
  • Duration: Usually 1-3 days
  • May occur in outbreaks
  • Generally affects immunocompetent hosts, including otherwise healthy children

Diagnostic Evaluation

Clinical Suspicion:

  • Consider listeriosis in:
    • Neonates with sepsis, especially if maternal fever/illness during peripartum period
    • Early-onset neonatal sepsis with prominent respiratory distress
    • Infants with meningitis and CSF profile showing monocytosis
    • Immunocompromised children with meningitis not responding to empiric therapy
    • Brainstem encephalitis in any age group

Laboratory Studies:

  • Blood cultures: Gold standard for diagnosis; should be obtained in all suspected cases
  • CSF analysis:
    • Typically shows moderate pleocytosis (100-10,000 cells/μL)
    • Often with predominance of monocytes/lymphocytes (unlike other bacterial meningitis)
    • Elevated protein (100-500 mg/dL)
    • Decreased glucose (<50% of serum glucose in ~30% of cases)
    • Gram stain: Positive in only 30-40% of cases, shows small gram-positive rods or coccobacilli
    • Culture: Most sensitive method for CSF
  • Other specimens for culture:
    • Placenta and amniotic fluid in suspected vertical transmission
    • Gastric aspirate, meconium, or ear swabs from neonates
    • Stool cultures if febrile gastroenteritis is suspected
  • Laboratory identification:
    • Catalase-positive, esculin-positive
    • Characteristic "tumbling motility" at room temperature
    • CAMP test reaction (reverse Christie-Atkins-Munch-Peterson test)
    • Beta-hemolysis on blood agar
  • Molecular diagnostic methods:
    • PCR of CSF or blood may provide rapid diagnosis
    • Particularly useful when cultures are negative due to prior antibiotic exposure
    • MALDI-TOF for rapid bacterial identification from positive cultures

Imaging Studies:

  • Cranial ultrasound: In neonates to detect ventriculitis, hydrocephalus, or abscesses
  • CT or MRI of brain:
    • For suspected complications of meningitis
    • Particularly important in cases with focal neurologic findings
    • May show basilar enhancement in rhombencephalitis
    • Abscesses tend to be multiple and small
  • Chest radiograph: In neonates with respiratory symptoms (may show pattern similar to Group B strep pneumonia)
  • Echocardiography: In prolonged bacteremia or if endocarditis suspected

Differential Diagnosis:

  • Neonatal sepsis/meningitis: Group B Streptococcus, E. coli, other gram-negative bacilli
  • Meningitis in children: S. pneumoniae, N. meningitidis, H. influenzae type b, enteroviruses
  • Rhombencephalitis: Herpes simplex virus, enterovirus, tuberculosis
  • Febrile gastroenteritis: Salmonella, Campylobacter, viral gastroenteritis

Management

Antimicrobial Therapy:

Setting Recommended Regimen Alternative Regimen
First-line therapy
(all invasive infections)		 Ampicillin + Gentamicin
• Ampicillin: 200-300 mg/kg/day IV divided q6h
• Gentamicin: 5-7.5 mg/kg/day IV divided q8h 		Trimethoprim-sulfamethoxazole
• 10-20 mg/kg/day (TMP component) IV divided q6-8h
Penicillin allergy Trimethoprim-sulfamethoxazole
• As above 		Meropenem
• 120 mg/kg/day IV divided q8h (max 6g/day)
CNS infection Ampicillin + Gentamicin
• Ampicillin: 300-400 mg/kg/day IV divided q4-6h
• Gentamicin: as above 		Meropenem
• As above

Duration of Therapy:

  • Bacteremia without focus: 2 weeks minimum
  • Meningitis: 3 weeks minimum
  • Brain abscess/encephalitis: 4-8 weeks (guided by clinical and radiological improvement)
  • Endocarditis: 4-6 weeks
  • Febrile gastroenteritis: Treatment not typically required in immunocompetent hosts

Antimicrobial Considerations:

  • Synergistic activity: Combination of cell-wall active agent (ampicillin) with aminoglycoside (gentamicin) shows synergy against L. monocytogenes
  • Cephalosporins: Not effective against Listeria (intrinsic resistance)
  • Vancomycin: Less effective than ampicillin in clinical studies
  • Carbapenems: Active but less clinical experience in pediatrics
  • Linezolid: In vitro activity; limited clinical data

Supportive Care:

  • Neonatal intensive care: For early-onset disease with respiratory distress or hemodynamic instability
  • Neurological monitoring: For CNS infections, with close attention to signs of increased intracranial pressure
  • Seizure management: Anticonvulsants as needed for seizures
  • Fluid and electrolyte management: Particularly important in neonates and young infants
  • Respiratory support: As needed for pneumonia or ARDS

Complications Management:

  • Hydrocephalus: May require neurosurgical consultation for CSF diversion
  • Brain abscess: Rarely requires surgical drainage unless large or causing mass effect
  • Persistent bacteremia: Consider echocardiography to rule out endocarditis
  • Developmental follow-up: Essential for survivors of neonatal meningitis

Prevention

Food Safety for High-Risk Groups:

  • Dietary recommendations for pregnant women and immunocompromised children:
    • Avoid unpasteurized dairy products (soft cheeses, raw milk)
    • Heat ready-to-eat deli meats and hot dogs until steaming hot (>165°F) before consumption
    • Avoid refrigerated smoked seafood
    • Wash raw vegetables thoroughly
    • Follow safe food handling practices (proper refrigeration, avoiding cross-contamination)

Infection Control:

  • Hospital settings:
    • Standard precautions adequate for most cases
    • No need for isolation unless patient has uncontained secretions
    • Proper hand hygiene crucial
    • Potential clustering of cases should prompt investigation for common source

Antenatal Screening:

  • Not routinely recommended due to transient nature of carriage
  • Consider testing in pregnant women with fever of unknown origin or flu-like illness

Prophylaxis:

  • No established role for antimicrobial prophylaxis in exposed individuals
  • Pregnant women with laboratory-confirmed exposure in a foodborne outbreak should be monitored closely for symptoms

Outcomes and Prognosis

Mortality Rates:

  • Early-onset neonatal disease: 20-30%
  • Late-onset neonatal meningitis: 10-15%
  • Listeriosis in immunocompromised children: 10-20%
  • Febrile gastroenteritis: <1%

Long-term Sequelae:

  • Neonatal survivors:
    • Neurological sequelae in 30-50% of meningitis survivors
    • Hydrocephalus
    • Developmental delay
    • Hearing loss
    • Visual impairment
    • Seizure disorders
  • Immunocompromised children:
    • Sequelae primarily dependent on site of infection
    • CNS infections may result in persistent neurological deficits

Follow-up Recommendations:

  • Neurodevelopmental assessment for infants with CNS involvement
  • Hearing screening at discharge and follow-up
  • Regular developmental monitoring
  • Neuroimaging follow-up for those with complications
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Corynebacterium diphtheriae Infections in Pediatrics

Overview & Definition

Corynebacterium diphtheriae is a non-spore-forming, non-motile, pleomorphic gram-positive bacillus that causes diphtheria, a potentially life-threatening vaccine-preventable disease. The organism is characterized by its distinctive club-shaped appearance and metachromatic granules visible on microscopy. C. diphtheriae produces a potent exotoxin that causes the systemic manifestations of diphtheria through inhibition of protein synthesis in host cells.

Diphtheria primarily affects the upper respiratory tract, particularly the pharynx, larynx, and tonsils, resulting in the formation of a characteristic pseudomembrane. While respiratory diphtheria is the most common and severe form, the organism can also cause cutaneous infections and, rarely, infections in other sites such as the eye, ear, or genitals.

Epidemiology

Global Distribution:

  • Historically widespread, now rare in countries with high vaccination coverage
  • Remains endemic in parts of Asia, Eastern Europe, the Middle East, Africa, and South America
  • Sporadic outbreaks occur in underimmunized populations
  • Most cases in developed countries involve unvaccinated individuals or imported cases

Incidence & Demographics:

Parameter Details
Age predilection • Highest incidence in unimmunized children aged 1-5 years
• Can affect any age if immunity is absent or waned
Seasonality • Peak incidence during autumn and winter in temperate climates
• Less seasonal variation in tropical regions
Risk factors • Incomplete or absent immunization
• Waning immunity in adolescents/adults
• Crowded living conditions
• Travel to endemic regions
• Immunocompromised status
Reservoirs • Humans are the only known reservoir
• Asymptomatic carriers can harbor the organism in nasopharynx or skin

Transmission:

  • Respiratory diphtheria: Primarily spread by respiratory droplets or direct contact with respiratory secretions
  • Cutaneous diphtheria: Direct contact with infected skin lesions
  • Incubation period: Usually 2-5 days (range: 1-10 days)
  • Period of communicability: Untreated patients remain infectious for 2-4 weeks; treatment with antibiotics typically ends communicability within 48 hours

Biotypes: Four biotypes of C. diphtheriae exist (gravis, mitis, intermedius, and belfanti), distinguished by biochemical properties. While historically gravis was associated with more severe disease, toxin production rather than biotype is now recognized as the primary virulence determinant.

Pathophysiology

Virulence Factors:

  • Diphtheria toxin: The primary virulence factor
    • 69 kDa protein encoded by the tox gene
    • Expression regulated by iron concentration (low iron promotes toxin production)
    • Acquired through lysogenic conversion by a bacteriophage (corynephage β)
    • AB toxin structure with:
      • Fragment A: Enzymatic domain that ADP-ribosylates elongation factor-2 (EF-2), inhibiting protein synthesis
      • Fragment B: Receptor-binding and translocation domain
  • Other virulence factors:
    • Cord factor (trehalose dimycolate): Contributes to inhibition of phagocytosis
    • Pili and fimbriae: Mediate adherence to respiratory mucosa
    • Neuraminidase: Facilitates attachment and may enhance colonization

Sequence of Pathogenic Events:

  1. Initial colonization: Organism attaches to respiratory epithelium (or skin in cutaneous form)
  2. Local multiplication: Bacteria proliferate and produce exotoxin
  3. Local tissue damage: Toxin causes necrosis of epithelial cells
  4. Inflammatory response: Fibrinous exudate forms over damaged tissue
  5. Pseudomembrane formation: Characteristic gray-white adherent membrane composed of fibrin, leukocytes, dead epithelial cells, and bacteria
  6. Systemic toxin effects: Toxin enters circulation and affects distant tissues, particularly:
    • Myocardium: Myocarditis, conduction abnormalities
    • Peripheral nerves: Demyelination leading to neuropathy
    • Kidneys: Tubular necrosis, proteinuria

Host Immune Response:

  • Neutralizing antibodies against the toxin provide protective immunity
  • Cell-mediated immunity plays a role in bacterial clearance
  • Prior infection or vaccination induces antitoxin antibodies that prevent systemic toxin effects
  • Recovery from disease does not necessarily confer immunity to reinfection

Clinical Manifestations

Respiratory Diphtheria:

The classic form involves the tonsils, pharynx, and/or larynx with progression through distinct phases:

Stage Clinical Features
Prodromal phase
(1-2 days)		 • Low-grade fever
• Malaise
• Sore throat
• Anorexia
Early local disease
(2-3 days)		 • Increasing throat pain
• Development of tonsillar and pharyngeal erythema
• Initial patches of white-gray exudate
• Cervical lymphadenopathy
Established disease • Classic pseudomembrane: adherent gray-white membrane that bleeds when removal is attempted
• "Bull neck" appearance (marked cervical lymphadenopathy with edema)
• Foul-smelling breath
• Fever typically not high (38-38.5°C)
• Tachycardia out of proportion to fever
Advanced disease • Respiratory distress/stridor if laryngeal involvement
• Signs of systemic toxicity
• Manifestations of toxin-mediated complications

Anatomic Classification of Respiratory Diphtheria:

  • Anterior nasal diphtheria:
    • Usually milder, often unilateral
    • Presents with serosanguineous discharge, minimal systemic symptoms
    • May cause septal erosion with prolonged infection
  • Tonsillar-pharyngeal diphtheria:
    • Most common presentation
    • Pseudomembrane on tonsils, extending to soft palate, uvula, pharynx
    • Moderate systemic toxicity
  • Laryngeal diphtheria:
    • May be primary or extension from pharyngeal disease
    • Presents with hoarseness, barking cough, stridor
    • Can rapidly progress to airway obstruction
    • Higher mortality risk, particularly in young children
  • Combined/extensive diphtheria:
    • Involvement of multiple sites
    • Associated with highest morbidity and mortality
    • Severe systemic toxicity common

Complications of Respiratory Diphtheria:

  • Airway obstruction: Due to pseudomembrane extension, can be rapidly fatal
  • Myocarditis:
    • Occurs in 10-25% of patients
    • Typically presents in week 1-2 of illness
    • Manifests as cardiac conduction abnormalities, heart failure
    • ECG may show AV block, ST-T wave changes
    • Can be fatal or lead to chronic cardiomyopathy
  • Neurologic complications:
    • Occurs in approximately 5-10% of patients
    • Biphasic pattern:
      • Early: Palatal and pharyngeal paralysis (2-3 weeks after onset)
      • Late: Peripheral neuropathy, typically symmetrical ascending pattern (5-8 weeks)
    • Usually reversible but recovery may take months
  • Renal involvement: Proteinuria, acute tubular necrosis
  • Death: 5-10% mortality even with appropriate treatment; higher in very young children and delayed treatment

Cutaneous Diphtheria:

  • More common in tropical regions and resource-limited settings
  • Usually presents as non-healing ulcers with gray membrane
  • Often coinfected with Staphylococcus aureus or Streptococcus pyogenes
  • Less likely to cause systemic toxicity than respiratory form, but can serve as reservoir for transmission

Other Sites of Infection:

  • Ocular diphtheria: Membranous conjunctivitis
  • Otic diphtheria: Chronic otitis media with membrane formation
  • Genital diphtheria: Rare; ulcerative lesions with pseudomembrane
  • Umbilical diphtheria: Primarily in neonates in endemic regions

Diagnostic Evaluation

Clinical Diagnosis:

  • Diphtheria should be suspected in any child with:
    • Adherent pharyngeal pseudomembrane
    • Sore throat with bull neck appearance
    • Compatible illness in unimmunized or partially immunized child
    • Compatible illness after travel to endemic area
  • Clinical diagnosis is critical as laboratory confirmation takes time
  • Treatment should not be delayed while awaiting test results

Laboratory Confirmation:

  • Specimen collection:
    • Swab from beneath edge of membrane or nasopharynx
    • Two swabs recommended: one for culture, one for toxigenicity testing
    • Special care not to dislodge membrane during collection (risk of bleeding and respiratory distress)
  • Culture:
    • Selective media: Tellurite-containing media (Löffler's, Tinsdale, or cystine-tellurite blood agar)
    • Characteristic black colonies due to tellurite reduction
    • Incubation for 24-48 hours
  • Identification:
    • Gram stain: Chinese-letter or palisading arrangement
    • Metachromatic granules on Albert's or Neisser's stain
    • Biochemical tests for differentiation from other coryneforms
  • Toxigenicity testing:
    • Modified Elek test: Immunoprecipitation assay to detect toxin production
    • PCR for tox gene: Faster but detects gene presence, not expression
    • MALDI-TOF: For rapid species identification

Additional Investigations:

Test Purpose
Complete blood count • Usually shows moderate leukocytosis (12,000-15,000/mm³)
• Lymphocytosis may be present
Electrocardiogram • Baseline and serial monitoring for myocarditis
• Look for: PR prolongation, ST-T wave changes, arrhythmias
Cardiac enzymes • Troponin I or T to evaluate for myocarditis
Renal function tests • BUN, creatinine to assess renal involvement
Liver function tests • May show mild transaminitis in severe disease
Throat culture for other pathogens • Rule out co-infection or alternative diagnosis
Chest X-ray • If pulmonary involvement suspected
• To evaluate cardiac silhouette if myocarditis present
Endoscopy • Rarely needed but may help visualize extent of pseudomembrane
• Must be performed with extreme caution due to risk of membrane dislodgment

Differential Diagnosis:

  • Infectious etiologies:
    • Streptococcal pharyngitis
    • Infectious mononucleosis (EBV)
    • Adenoviral pharyngitis
    • Herpetic gingivostomatitis
    • Vincent's angina (acute necrotizing ulcerative gingivitis)
    • Candidiasis (thrush)
    • Bacterial tracheitis
  • Non-infectious etiologies:
    • Chemical burns
    • Foreign body aspiration (for laryngeal symptoms)

Management

General Principles:

  • Suspected diphtheria is a medical emergency requiring immediate intervention
  • Notify public health authorities immediately upon suspicion (reportable disease)
  • Isolate patient using droplet precautions
  • Institute treatment before laboratory confirmation

Specific Therapy:

1. Antitoxin Administration:

  • Diphtheria antitoxin (DAT) is the mainstay of treatment
  • Equine-derived hyperimmune globulin that neutralizes circulating toxin
  • Does not neutralize toxin already bound to tissues
  • Dosage based on clinical severity and duration of illness:
Clinical Presentation Recommended Antitoxin Dose
Anterior nasal or cutaneous diphtheria (localized) 10,000-20,000 units
Pharyngeal or laryngeal disease <48 hours duration 20,000-40,000 units
Extensive disease or duration >48 hours 40,000-60,000 units
Severe disease with neck edema or systemic toxicity 80,000-100,000 units
  • Important considerations for DAT:
    • Test for hypersensitivity before administration (scratch test, conjunctival test, intradermal test)
    • Have epinephrine and resuscitation equipment available
    • Desensitization protocol for patients with positive sensitivity test
    • Administered IV for severe cases (slower infusion) or IM for mild cases
    • Single dose is usually sufficient; rarely repeated if clinical deterioration
  • Availability: DAT is not commercially available in many countries; may require special release from central repositories or health departments

2. Antimicrobial Therapy:

  • Antibiotics eliminate the organism, prevent toxin production, and reduce communicability
  • Do not substitute for antitoxin but used concurrently
  • First-line options:
    • Penicillin G: 100,000-150,000 units/kg/day IV divided q6h (max 24 million units/day) for 14 days, OR
    • Erythromycin: 40-50 mg/kg/day IV or PO divided q6h (max 2 g/day) for 14 days
  • Alternative options:
    • Azithromycin: 10 mg/kg on day 1 (max 500 mg), then 5 mg/kg/day (max 250 mg) for total of 5 days
    • Clarithromycin: 15 mg/kg/day divided q12h (max 1 g/day) for 14 days
    • Clindamycin: 20-40 mg/kg/day IV or PO divided q6-8h (max 1.8 g/day) for 14 days
  • Can switch from IV to oral therapy once clinically improved
  • Obtain cultures 24 hours after completing therapy to confirm eradication

3. Supportive Care:

  • Airway management:
    • Close monitoring for obstruction
    • Avoid manipulation of pseudomembrane (risk of dislodgment)
    • Early consultation with airway specialists
    • Intubation or tracheostomy may be necessary for laryngeal involvement
  • Cardiac monitoring:
    • Continuous cardiac monitoring for at least 2 weeks
    • Serial ECGs to detect early conduction abnormalities
    • Bed rest during acute illness to minimize cardiac demands
  • Fluid and nutritional support:
    • IV fluids if unable to maintain oral intake
    • Nasogastric feeding if prolonged dysphagia
    • Speech therapy evaluation for swallowing if palatal paralysis develops
  • Management of complications:
    • Cardiac: Standard heart failure management if myocarditis develops
    • Neurological: Supportive care, physical therapy for neuropathies
    • Respiratory: Mechanical ventilation if needed

Management of Contacts:

  • Close contacts: All household members and other close contacts should receive:
    • Throat culture regardless of immunization status
    • Antimicrobial prophylaxis: Single dose of benzathine penicillin G (600,000 units for children <6 years; 1.2 million units for older children) OR 7-10 days of oral erythromycin
    • Update of diphtheria toxoid-containing vaccine if immunization incomplete
    • Close observation for 7 days for signs of infection
  • Healthcare workers: Similar approach as close contacts if exposure not protected by appropriate infection control
  • Carriers: Treat with same antibiotic regimen as symptomatic cases

Prevention

Active Immunization:

  • Diphtheria toxoid vaccine is highly effective (>95% protection)
  • Always combined with tetanus toxoid and typically with pertussis (DTaP, Tdap, DT, Td)
  • Childhood immunization schedule:
    • Primary series: DTaP at 2, 4, 6 months
    • Booster doses: DTaP at 15-18 months and 4-6 years
    • Adolescent booster: Tdap at 11-12 years
    • Adult boosters: Td every 10 years (substitute one dose with Tdap)
  • Special circumstances:
    • Catch-up schedules for incompletely immunized children
    • Post-exposure vaccination if immunization status incomplete
    • Consider early booster if traveling to high-risk areas

Infection Control Measures:

  • Isolation: Droplet precautions until cultures negative on two consecutive samples after completing antibiotics
  • Contact tracing: Identify all close contacts for prophylaxis and surveillance
  • Monitoring: Active surveillance in outbreak situations
  • Education: Public health education in endemic areas

Prognosis:

  • Mortality rate 5-10% even with treatment; higher (>20%) in young children and delayed treatment
  • Cardiac complications associated with poorer outcomes
  • Neurological complications usually resolve completely but may take months
  • Early antitoxin administration significantly improves outcomes
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Escherichia coli Infections in Pediatrics

Overview & Definition

Escherichia coli (E. coli) is a gram-negative, facultatively anaerobic, rod-shaped bacterium that belongs to the family Enterobacteriaceae. While many strains are harmless commensals in the human intestinal tract, pathogenic variants cause significant disease in pediatric populations across multiple organ systems.

E. coli infections represent a substantial burden of disease in children, ranging from common urinary tract infections to life-threatening conditions like neonatal meningitis and hemolytic uremic syndrome (HUS). The bacterium is classified into pathotypes based on virulence factors, clinical syndromes, and epidemiology.

Major E. coli Pathotypes:

  • Extraintestinal pathogenic E. coli (ExPEC): Causes infections outside the GI tract
  • Diarrheagenic E. coli: Various pathotypes causing distinct intestinal syndromes

Epidemiology

Prevalence and Distribution:

  • E. coli is the most common cause of urinary tract infections in children (80-90% of community-acquired UTIs)
  • Leading cause of gram-negative bacteremia in neonates and infants
  • Second most common cause of neonatal meningitis (after Group B Streptococcus)
  • Primary cause of diarrhea in children in resource-limited settings
  • STEC (particularly O157:H7) causes approximately 73,000 illnesses annually in the US with highest incidence in children <5 years old

Risk Factors:

Clinical Syndrome Key Risk Factors
UTI • Female gender (except in first year of life when males predominate)
• Uncircumcised male infants
• Vesicoureteral reflux
• Urinary tract anomalies
• Constipation
• Dysfunctional voiding
• Prior antibiotic exposure
Neonatal sepsis/meningitis • Prematurity
• Low birth weight
• Prolonged rupture of membranes
• Maternal peripartum infection
• Maternal colonization with virulent strains
Diarrheagenic infections • Age <5 years
• Childcare attendance
• Exposure to farm animals (STEC)
• Consumption of undercooked meat, unpasteurized dairy, contaminated produce
• International travel
• Immunocompromised state
Intra-abdominal infections • Appendicitis
• Bowel perforation
• Necrotizing enterocolitis (in neonates)
• Prior abdominal surgery

Antimicrobial Resistance Patterns:

  • ESBL-producing E. coli: Increasing worldwide, with rates of 5-30% in pediatric isolates depending on region
  • Fluoroquinolone resistance: Increasing globally, though still less common in pediatric than adult isolates
  • Carbapenem-resistant Enterobacteriaceae (CRE): Emerging concern in pediatric settings, particularly in healthcare-associated infections
  • Risk factors for resistant infections: Prior antibiotic exposure, hospitalization, indwelling devices, international travel to high-prevalence regions

Pathophysiology

Virulence Factors:

Factor Type Examples Function
Adhesins • Type 1 fimbriae
• P fimbriae
• Dr adhesins
• Intimin 		• Mediate attachment to host cells
• P fimbriae bind to uroepithelial cells (UTI)
• Intimin facilitates intestinal colonization (EPEC, EHEC)
Toxins • Shiga toxins (Stx1, Stx2)
• Heat-labile (LT) and heat-stable (ST) enterotoxins
• Hemolysin
• Cytotoxic necrotizing factor 1 (CNF1) 		• Stx: Inhibits protein synthesis, damages endothelium (HUS)
• LT/ST: Cause secretory diarrhea (ETEC)
• Hemolysin: Forms pores in host cell membranes
• CNF1: Modifies host cell cytoskeleton (UTI)
Iron acquisition systems • Siderophores (enterobactin, aerobactin)
• Heme receptors 		• Scavenge iron from host environment
• Essential for bacterial growth and survival
Capsules • K1 capsule
• Other K antigens 		• Evade phagocytosis and complement-mediated killing
• K1 critical for meningeal invasion
Invasion factors • Invasins
• Type III secretion system 		• Facilitate entry into host cells (EIEC)
• Inject effector proteins into host cells (EPEC)
Immune evasion • Lipopolysaccharide (LPS)
• O-antigen variation 		• Evade host immune recognition
• Trigger inflammatory responses

Pathogenic Mechanisms of Major E. coli Pathotypes:

  • UPEC (Uropathogenic E. coli):
    • Ascends urethra to bladder and potentially kidneys
    • Adheres to uroepithelium via fimbriae
    • Forms biofilms and intracellular bacterial communities
    • Produces toxins causing tissue damage
  • STEC/EHEC (Shiga toxin-producing/Enterohemorrhagic E. coli):
    • Adheres to intestinal epithelium via intimin
    • Forms attaching and effacing lesions
    • Produces Shiga toxins that enter circulation
    • Toxins damage endothelial cells in kidneys, causing HUS
  • EPEC (Enteropathogenic E. coli):
    • Forms characteristic attaching and effacing lesions
    • Disrupts intestinal brush border
    • Alters host cell signaling pathways
  • ETEC (Enterotoxigenic E. coli):
    • Colonizes small intestine via colonization factors
    • Produces LT and/or ST enterotoxins
    • Toxins increase cAMP/cGMP, causing chloride secretion and watery diarrhea
  • EIEC (Enteroinvasive E. coli):
    • Invades colonic epithelial cells
    • Spreads cell-to-cell
    • Causes inflammatory colitis (similar to Shigella)
  • EAEC (Enteroaggregative E. coli):
    • Forms characteristic "stacked brick" adherence pattern
    • Produces biofilms and enterotoxins
    • Causes persistent diarrhea
  • NMEC (Neonatal meningitis E. coli):
    • K1 capsule evades immune response
    • Crosses gut epithelium into bloodstream
    • Traverses blood-brain barrier
    • Replicates in CSF causing meningeal inflammation

Clinical Manifestations

Urinary Tract Infections:

  • Cystitis: Dysuria, frequency, urgency, suprapubic pain, enuresis in toilet-trained children
  • Pyelonephritis: Fever (often high), flank pain, vomiting, general toxicity
  • In infants: Often presents with nonspecific symptoms - fever, irritability, poor feeding, vomiting, failure to thrive
  • Neonates: May present with jaundice, lethargy, hypothermia, or sepsis-like picture

Neonatal Sepsis and Meningitis:

  • Early-onset sepsis: Presents within 72 hours of life with respiratory distress, temperature instability, poor perfusion
  • Late-onset sepsis/meningitis: Often after 72 hours, with lethargy, poor feeding, irritability, seizures, bulging fontanelle
  • Complications: Ventriculitis, brain abscess, hydrocephalus, developmental delays

Intestinal Infections:

Pathotype Clinical Presentation Epidemiology
STEC/EHEC • Watery diarrhea progressing to bloody diarrhea
• Severe abdominal pain
• Minimal or no fever
• HUS in 5-10% (usually 5-7 days after diarrhea onset) 		• Most common in children <5 years
• Often from contaminated food (ground beef, produce)
• O157:H7 is most common serotype in North America
EPEC • Watery diarrhea, often protracted
• Vomiting
• Low-grade fever
• Dehydration 		• Primarily affects infants <2 years
• Common in developing countries
• Outbreaks in childcare settings
ETEC • Watery diarrhea without blood
• Abdominal cramps
• Nausea, vomiting
• Usually self-limited (3-5 days) 		• Leading cause of travelers' diarrhea
• Common in developing countries
• All age groups affected
EIEC • Dysentery-like illness
• Bloody mucoid stools
• Fever
• Tenesmus 		• Less common than other pathotypes
• All age groups affected
• Endemic in resource-limited settings
EAEC • Persistent watery diarrhea (>14 days)
• Malnutrition
• Growth impairment with chronic infection 		• Affects children in developing countries
• Associated with persistent diarrhea
• Emerging pathogen in developed nations

Hemolytic Uremic Syndrome (HUS):

  • Classic triad: Microangiopathic hemolytic anemia, thrombocytopenia, acute kidney injury
  • Additional manifestations: Pallor, petechiae, oliguria/anuria, hypertension
  • Extrarenal involvement: Neurological (10-25%), pancreatic, cardiac, hepatic
  • Long-term sequelae: Chronic kidney disease, hypertension, neurological deficits

Intra-abdominal Infections:

  • Peritonitis: Fever, abdominal pain, distension, guarding, decreased bowel sounds
  • Intra-abdominal abscess: Persistent fever, localized pain, mass effect
  • Necrotizing enterocolitis (NEC) in neonates: Abdominal distension, bloody stools, pneumatosis intestinalis

Diagnostic Evaluation

Clinical Assessment:

  • Detailed history (including exposures, travel, antibiotic use)
  • Physical examination with attention to:
    • Vital signs (fever, tachycardia, hypotension)
    • Abdominal findings (tenderness, distension, guarding)
    • Signs of dehydration
    • Neurological status
    • Skin findings (petechiae, purpura in HUS)

Laboratory Studies:

  • Urinary tract infections:
    • Urinalysis: Leukocyte esterase, nitrites, pyuria (>5 WBC/HPF)
    • Urine culture: Gold standard (≥50,000 CFU/mL of a uropathogen)
    • Blood culture: In febrile infants <3 months and children with suspected urosepsis
    • CBC, CRP, ESR: Elevated in pyelonephritis
  • Neonatal sepsis/meningitis:
    • Blood culture: Essential before antibiotics when possible
    • CSF analysis: Cell count, protein, glucose, Gram stain, culture
    • CBC with differential: May show leukocytosis or leukopenia
    • CRP, procalcitonin: Elevated in bacterial infection
  • Diarrheal illness:
    • Stool microscopy: Leukocytes (in inflammatory diarrhea)
    • Stool culture: For isolation and identification
    • STEC-specific testing: Sorbitol-MacConkey agar, immunoassays for Shiga toxins, PCR
    • Multiplex PCR panels: Detecting multiple pathogens simultaneously
    • Hemogram, electrolytes, BUN/creatinine: Assess severity and complications
  • HUS evaluation:
    • CBC with smear: Hemolytic anemia with schistocytes, thrombocytopenia
    • Renal function: Elevated BUN/creatinine
    • LDH: Markedly elevated
    • Haptoglobin: Decreased/absent
    • Coagulation studies: Normal (unlike DIC)
    • Stool studies: May no longer be positive for STEC when HUS develops

Microbiologic Diagnosis:

  • Culture methods:
    • Standard media: MacConkey, blood agar
    • Selective/differential media: Sorbitol-MacConkey for O157:H7
    • Biochemical identification
  • Non-culture methods:
    • Immunoassays for Shiga toxins
    • Molecular detection (PCR for virulence genes)
    • Serotyping for specific O:H antigens
  • Antimicrobial susceptibility testing:
    • Disk diffusion or broth microdilution
    • ESBL screening and confirmation tests
    • Carbapenemase detection

Imaging Studies:

  • UTI:
    • Renal ultrasound: First-line imaging for febrile UTI
    • Voiding cystourethrogram (VCUG): For recurrent UTI or abnormal ultrasound
    • DMSA scan: Gold standard for pyelonephritis and renal scarring
  • Neonatal meningitis:
    • Cranial ultrasound: Bedside screening for complications
    • MRI: Preferred for detailed evaluation
    • CT: If MRI unavailable or in emergencies
  • Intra-abdominal infections:
    • Abdominal ultrasound: First-line, especially in stable patients
    • CT scan: Superior for abscess detection and characterization
    • MRI: Alternative when CT contraindicated

Management

General Principles:

  • Treatment approach depends on pathotype, infection site, severity, and resistance patterns
  • Empiric therapy should consider local resistance epidemiology
  • De-escalate therapy based on culture results when available
  • Supportive care often as important as antimicrobial therapy

Antimicrobial Therapy for Specific Infections:

Infection First-Line Therapy Alternative Therapy Duration
Uncomplicated UTI
(Lower tract)		 • TMP-SMX
• Nitrofurantoin 		• Cephalexin
• Amoxicillin-clavulanate 		5-7 days
Pyelonephritis • IV: Ceftriaxone, gentamicin
• Oral: Cefixime, ciprofloxacin (>18y) 		• IV: Ampicillin + gentamicin
• Oral: TMP-SMX (if susceptible) 		7-14 days
Neonatal sepsis/meningitis • Ampicillin + gentamicin or
• Ampicillin + cefotaxime 		• Meropenem
• Cefepime 		• Sepsis: 10-14 days
• Meningitis: 21 days or longer
Diarrheal illness • ETEC/EAEC/EPEC: Azithromycin, ciprofloxacin (>18y)
• EIEC: Azithromycin, ciprofloxacin (>18y)
• STEC: Avoid antibiotics (increased HUS risk) 		• TMP-SMX
• Rifaximin (travelers' diarrhea >12y) 		• 3-5 days if treated
Intra-abdominal infection • Ceftriaxone + metronidazole
• Piperacillin-tazobactam 		• Ciprofloxacin + metronidazole
• Meropenem 		• 5-7 days after source control
• 10-14 days if inadequate source control
ESBL-producing E. coli • Carbapenems (meropenem, ertapenem) • Piperacillin-tazobactam (select UTIs)
• Aminoglycosides
• Fosfomycin (lower UTI only) 		• Infection-specific

Supportive Care:

  • UTI:
    • Adequate hydration
    • Antipyretics for fever
    • Pain management
  • Diarrheal illness:
    • Oral rehydration therapy (first-line)
    • IV fluids if severe dehydration or inability to tolerate oral intake
    • Zinc supplementation (in developing countries)
    • Avoid antimotility agents in bloody diarrhea
  • HUS management:
    • Supportive care is the mainstay of treatment
    • Careful fluid and electrolyte management
    • Renal replacement therapy (30-60% of cases)
    • Blood product transfusions for severe anemia
    • Antihypertensive therapy as needed
    • Avoid platelet transfusions unless active bleeding or requiring procedures
    • Neurological monitoring and management of complications
  • Neonatal meningitis:
    • Neurosurgical consultation for hydrocephalus or abscess
    • Anticonvulsants for seizures
    • Serial neuroimaging
    • Early developmental follow-up

Surgical Interventions:

  • Source control for intra-abdominal infections
  • Drainage of abscesses
  • Management of intestinal perforation
  • Urological interventions for obstructive uropathy

Prevention

General Preventive Measures:

  • Hand hygiene: Proper handwashing, especially after toileting and before food preparation
  • Food safety:
    • Thorough cooking of meat (especially ground beef) to 160°F
    • Avoiding cross-contamination of foods
    • Washing fruits and vegetables
    • Safe handling and storage of foods
    • Consumption of pasteurized milk and juices
  • Water safety: Clean drinking water, avoiding swallowing recreational water
  • Proper sanitation and sewage disposal

UTI Prevention:

  • Adequate hydration
  • Regular and complete bladder emptying
  • Proper perineal hygiene (wiping front to back)
  • Avoiding bladder irritants
  • Antibiotic prophylaxis for select patients with recurrent UTIs or vesicoureteral reflux
  • Management of constipation
  • Treatment of dysfunctional voiding

Prevention of Resistant Infections:

  • Antimicrobial stewardship
  • Infection control measures in healthcare settings
  • Screening and isolation for high-risk patients
  • Limiting unnecessary antibiotic exposures

Vaccination:

  • No licensed vaccines currently available for pathogenic E. coli in children
  • Several vaccines under development:
    • ETEC vaccines (in clinical trials)
    • STEC vaccines targeting O157:H7
    • ExPEC vaccines for prevention of UTI and neonatal disease

Special Considerations and Controversies

Antibiotic Use in STEC/EHEC Infections:

  • Controversial - antibiotics may increase Shiga toxin release
  • Generally avoided in suspected or confirmed STEC infections, particularly O157:H7
  • Some newer studies suggest certain antibiotics (azithromycin) may be less problematic
  • Research ongoing regarding timing and specific agents

UTI Management Controversies:

  • Duration of therapy: Shortened courses (3-5 days) may be sufficient for uncomplicated lower UTI
  • Oral vs. parenteral therapy: Increasing evidence for effectiveness of oral therapy in mild-moderate pyelonephritis
  • Imaging after first febrile UTI: Guidelines differ regarding routine imaging
  • Antibiotic prophylaxis: Conflicting evidence for effectiveness in preventing recurrent UTI

Emerging Therapies:

  • Monoclonal antibodies:
    • Anti-Shiga toxin antibodies for STEC infections
    • May prevent or mitigate HUS development
  • Bacteriophage therapy:
    • Alternative for multi-drug resistant infections
    • Research ongoing, particularly for ExPEC infections
  • Probiotics and microbiome modulation:
    • Potential role in preventing colonization and infection
    • Evidence still limited in pediatric populations
  • Novel antimicrobials and approaches:
    • FimH antagonists for UTI prevention
    • Siderophore-antibiotic conjugates
    • Anti-virulence strategies targeting adhesins and toxins

Key Points for Practice

  • E. coli causes a diverse spectrum of infections in children, with pathotype-specific clinical syndromes
  • UTIs are the most common E. coli infections in pediatrics, while STEC remains the leading cause of HUS
  • Increasing antimicrobial resistance is a major concern, particularly ESBL-producing strains
  • Do not use antibiotics in suspected STEC infections due to potential increased risk of HUS
  • Supportive care is critical in the management of diarrheal disease and HUS
  • Prevention strategies focus on hand hygiene, food safety, and appropriate use of antimicrobials
  • Consider local resistance patterns when selecting empiric antimicrobial therapy
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Mycoplasma Pneumoniae Infections in Pediatrics

Overview & Definition

Mycoplasma pneumoniae is a unique bacterial pathogen that lacks a cell wall, making it naturally resistant to beta-lactam antibiotics. It is a major cause of community-acquired pneumonia in children and adolescents, often referred to as "atypical pneumonia" or "walking pneumonia." Beyond respiratory illness, M. pneumoniae can cause a range of extrapulmonary manifestations, particularly in the pediatric population.

As the smallest free-living organism capable of self-replication, M. pneumoniae occupies an important niche in pediatric infectious diseases, being responsible for approximately 10-40% of community-acquired pneumonia cases in school-aged children and adolescents.

Epidemiology

Prevalence and Distribution:

  • Age distribution: Most common in school-aged children (5-15 years) and adolescents; less common but can be more severe in children under 5 years
  • Seasonal patterns: Endemic year-round with peaks in late summer and early fall in temperate climates
  • Epidemic cycles: Major outbreaks typically occur every 3-7 years
  • Global distribution: Worldwide occurrence with varying prevalence (10-40% of pediatric community-acquired pneumonia)

Transmission:

  • Person-to-person via respiratory droplets during close contact
  • Prolonged incubation period (2-3 weeks) facilitates transmission
  • Prolonged shedding (up to 8-14 weeks even after treatment)
  • Highest transmission in settings with close contact (schools, households, military barracks)

Risk Factors:

  • School attendance (primary and secondary school settings)
  • Crowded living conditions
  • Household exposure to infected individuals
  • Underlying asthma (associated with more severe disease)
  • Immunocompromised status (at risk for more severe or disseminated disease)
Age Group Prevalence Among CAP Cases Clinical Presentation
Infants (<2 years) ~5-10% Often milder, may present with bronchiolitis-like illness
Preschool (2-5 years) ~10-20% Variable presentation, may have wheezing
School-age (5-15 years) ~30-40% Classic atypical pneumonia, extrapulmonary manifestations more common
Adolescents (>15 years) ~20-30% Similar to adults, may have more severe symptoms

Pathophysiology

Organism Characteristics:

  • Lacks rigid cell wall (pleomorphic shape)
  • Size: 0.2-0.8 μm (smaller than most bacteria, larger than viruses)
  • Requires close association with host cells due to limited biosynthetic capabilities
  • Fastidious organism requiring specialized media for growth

Mechanisms of Infection:

  1. Attachment: Specialized attachment organelle with adhesins (P1 adhesin) facilitates binding to respiratory epithelium
  2. Cytadherence: Primarily to ciliated respiratory epithelial cells
  3. Local damage:
    • Hydrogen peroxide production (major virulence factor)
    • Ciliostasis leading to impaired mucociliary clearance
    • Direct cytotoxicity to respiratory epithelium
  4. Inflammatory response:
    • Peribronchiolar and interstitial mononuclear infiltrates
    • Neutrophil recruitment
    • Cytokine production (IL-8, TNF-α)

Immune Response and Immunopathology:

  • Both humoral and cell-mediated immunity involved in response
  • Production of IgM, IgG, and secretory IgA antibodies
  • Cross-reactive antibodies may contribute to extrapulmonary manifestations through molecular mimicry
  • Cold agglutinins (IgM antibodies that agglutinate RBCs at 4°C) produced in ~50% of infections

Extrapulmonary Disease Mechanisms:

  • Direct invasion: Rare systemic spread due to organism's limited capabilities
  • Immune-mediated: Most extrapulmonary manifestations result from:
    • Molecular mimicry (M. pneumoniae antigens share epitopes with human tissues)
    • Immune complex formation
    • Cell-mediated immune responses against cross-reactive antigens

Clinical Manifestations

Respiratory Manifestations:

  • Classic "atypical" pneumonia:
    • Gradual onset over several days
    • Non-productive or minimally productive cough that becomes persistent and may last weeks
    • Low-grade fever (often lower than bacterial pneumonia)
    • General malaise, headache, sore throat
    • Physical exam often reveals minimal findings relative to symptoms ("walking pneumonia")
    • Bilateral diffuse findings more common than lobar consolidation
  • Other respiratory presentations:
    • Bronchitis/bronchiolitis (especially in younger children)
    • Pharyngitis (can be the primary manifestation without pneumonia)
    • Croup (less common)
    • Wheezing/asthma exacerbation (important trigger)
  • Complications:
    • Pleural effusion (usually small)
    • Pneumatoceles or lung abscess (rare)
    • Bronchiolitis obliterans (rare sequela)
    • ARDS (in severe cases)

Extrapulmonary Manifestations:

System Manifestations Notes
Dermatologic • Erythema multiforme
• Stevens-Johnson syndrome
• Urticaria
• Maculopapular rashes 		Most common extrapulmonary manifestations; occur in 10-25% of children with M. pneumoniae infection
Neurologic • Encephalitis
• Aseptic meningitis
• Transverse myelitis
• Guillain-Barré syndrome
• Acute disseminated encephalomyelitis (ADEM)
• Cerebellitis
• Opsoclonus-myoclonus syndrome 		Can occur with minimal or absent respiratory symptoms; leading infectious cause of encephalitis in school-age children in some series
Hematologic • Cold agglutinin-mediated hemolytic anemia
• Thrombocytopenia
• Coagulopathy 		Cold agglutinins present in ~50% of infections but clinically significant hemolysis in only 3-10%
Cardiac • Myocarditis
• Pericarditis
• Conduction abnormalities 		Relatively uncommon but important to consider with new-onset arrhythmias or cardiac symptoms
Musculoskeletal • Arthralgia
• Arthritis (reactive, usually oligoarticular)
• Myalgia 		Usually self-limited; large joints most commonly affected
Gastrointestinal • Hepatitis
• Pancreatitis
• GI symptoms (nausea, vomiting, diarrhea) 		Mild elevations in hepatic enzymes common; significant hepatitis rare
Renal • Glomerulonephritis
• Tubulointerstitial nephritis
• IgA nephropathy 		Rare but documented in case series
Ocular • Conjunctivitis
• Uveitis
• Optic neuritis 		Conjunctivitis may be part of initial presentation

Age-Specific Considerations:

  • Infants and young children:
    • More likely to present with upper respiratory symptoms or bronchiolitis-like illness
    • May have more non-specific presentations, including fever without source
    • Wheezing more common than in older children
  • School-age children:
    • Classic atypical pneumonia presentation most common
    • Highest rate of extrapulmonary manifestations
    • School outbreaks common
  • Adolescents:
    • Similar to adults with prominent headache, malaise
    • May have more prolonged cough
    • Extrapulmonary manifestations still common

Diagnostic Evaluation

Clinical Diagnosis:

  • History of gradual onset of persistent cough with minimal sputum
  • School-age child or adolescent with community-acquired pneumonia
  • Exposure to similar illness in family or school contacts
  • Lack of response to beta-lactam antibiotics
  • Presence of extrapulmonary manifestations

Laboratory Studies:

  • Complete blood count (CBC):
    • Often normal white blood cell count (normal or mildly elevated)
    • Unlike typical bacterial pneumonia which often shows leukocytosis
  • Inflammatory markers:
    • C-reactive protein (CRP) and ESR may be mildly elevated
    • Generally lower than with typical bacterial pneumonia
  • Cold agglutinins:
    • Present in approximately 50% of infections
    • Low sensitivity and specificity (also found in other infections)
    • Rarely used as a primary diagnostic test today

Microbiologic Diagnosis:

Test Characteristics Utility in Pediatrics
PCR (respiratory samples) • High sensitivity (80-90%)
• High specificity (>90%)
• Rapid results (hours)
• Can detect non-viable organisms 		• Current gold standard
• Preferred test in children (minimally invasive if NP swab used)
• Often included in multipathogen PCR panels
Serology • IgM appears within 1 week, peaks at 3-4 weeks
• IgG rises later, peaks at 4-6 weeks
• Four-fold rise in titer considered diagnostic 		• Limited utility for initial diagnosis due to timing
• Requires paired sera (acute and convalescent)
• More useful for epidemiologic studies than clinical care
Rapid antigen detection • Variable sensitivity (50-80%)
• Good specificity (>90%) 		• Less sensitive than PCR
• May be useful in resource-limited settings
Culture • Requires specialized media
• Slow growth (2-6 weeks)
• Labor-intensive 		• Rarely performed in clinical settings
• Limited to research and reference laboratories
• Not practical for routine diagnosis

Imaging Studies:

  • Chest radiography:
    • Reticular or reticulonodular infiltrates in a peribronchial distribution
    • Bilateral lower lobe involvement more common than lobar consolidation
    • Hilar lymphadenopathy may be present
    • Findings often more extensive than physical examination would suggest
    • Pleural effusions typically small if present
  • Chest CT: Rarely indicated but may show ground-glass opacities, bronchial wall thickening, and centrilobular nodules

Additional Testing for Extrapulmonary Manifestations:

  • Neurologic: CSF analysis, MRI, EEG based on presentation
  • Cardiac: ECG, echocardiogram, cardiac enzymes if suspected
  • Hematologic: Direct Coombs test, cold agglutinin titers if hemolysis suspected
  • Dermatologic: Skin biopsy rarely needed (clinical diagnosis)

Management

General Approach:

  • Mild disease: Often self-limited, supportive care may be sufficient
  • Decision to treat: Based on severity, age, comorbidities, and diagnostic certainty
  • Hospitalization criteria:
    • Respiratory distress or hypoxemia
    • Inability to tolerate oral intake
    • Significant extrapulmonary manifestations
    • High-risk comorbidities (immunocompromise, chronic lung disease)
    • Young age with moderate-severe disease

Antimicrobial Therapy:

Antibiotic Class Specific Agents and Dosing Comments
Macrolides
(First-line)		 Azithromycin:
• Children: 10 mg/kg on day 1 (max 500 mg), then 5 mg/kg (max 250 mg) once daily for 4 days
• Adolescents: 500 mg on day 1, then 250 mg once daily for 4 days

Clarithromycin:
• 15 mg/kg/day divided BID (max 1g/day) for 7-14 days 		• First-line therapy in most guidelines
• Good tissue penetration
• Convenient dosing (especially azithromycin)
• Anti-inflammatory properties may be beneficial
• Resistance increasing in some regions (10-30%)
Tetracyclines
(Alternative)		 Doxycycline:
• Children >8 years: 4 mg/kg/day divided BID (max 200 mg/day) for 7-14 days 		• Effective alternative to macrolides
• Low resistance rates
• Limited to children >8 years of age (dental staining concerns in younger children)
• Consider in regions with high macrolide resistance
Fluoroquinolones
(Limited use)		 Levofloxacin:
• 6 months-5 years: 10 mg/kg BID
• >5 years: 10 mg/kg once daily (max 750 mg/day) 		• Generally reserved for severe cases or treatment failures
• Limited approval in pediatrics
• Concerns about cartilage toxicity (though risk is low)
• Use only when benefits outweigh risks

Duration of Therapy:

  • Azithromycin: 5-day course (3-day course may be sufficient for mild cases)
  • Other antibiotics: 7-14 days depending on severity and clinical response
  • Longer courses may be needed for:
    • Severe pneumonia
    • Extrapulmonary manifestations
    • Underlying comorbidities
    • Slow clinical response

Management of Extrapulmonary Manifestations:

  • Neurologic:
    • Antimicrobial therapy (longer courses often used)
    • Consideration of corticosteroids or IVIG for immune-mediated disease
    • Anticonvulsants if seizures present
    • Neurologic consultation
  • Dermatologic:
    • Supportive care for mild-moderate rashes
    • Dermatology consultation for severe cases (Stevens-Johnson syndrome)
    • Consideration of corticosteroids for severe manifestations
  • Hematologic:
    • Management of hemolysis if significant (rarely requires transfusion)
    • Avoidance of cold exposure if cold agglutinins present
  • Cardiac:
    • Cardiology consultation
    • NSAIDs for pericarditis
    • Standard management of myocarditis with cardiac support
  • Musculoskeletal:
    • NSAIDs for arthralgia/arthritis
    • Usually self-limited

Supportive Care:

  • Antipyretics for fever and comfort
  • Adequate hydration
  • Cough management (honey for children >1 year, consider antitussives for older children if sleep-disrupting)
  • Oxygen therapy if hypoxemic
  • Bronchodilators if wheezing present

Complications and Prognosis

Complications:

  • Respiratory:
    • Pleural effusion/empyema (uncommon)
    • Pneumatocele formation (rare)
    • Lung abscess (rare)
    • ARDS (rare but serious)
    • Bronchiolitis obliterans (rare long-term sequela)
    • Prolonged cough (weeks to months)
  • Extrapulmonary: As detailed in clinical manifestations section

Prognosis:

  • Generally excellent in immunocompetent children
  • Complete recovery expected in most cases
  • Cough may persist for 3-8 weeks even after appropriate therapy
  • Most extrapulmonary manifestations resolve without sequelae
  • Neurologic manifestations may occasionally result in long-term deficits
  • Mortality extremely rare in otherwise healthy children
  • Recurrent infections possible (no long-lasting immunity)

Prevention

Infection Control Measures:

  • Droplet precautions: For hospitalized patients
  • School/daycare attendance:
    • Children should stay home until fever-free and symptoms improving
    • Note that cough may persist for weeks despite non-infectiousness
  • Hand hygiene: Regular handwashing to reduce transmission
  • Respiratory hygiene: Cover coughs/sneezes
  • Household measures: Avoid sharing drinks, utensils, towels during illness

Prophylaxis:

  • Not routinely recommended for contacts
  • May be considered in specific situations:
    • Institutional outbreaks (immunocompromised settings)
    • Household contacts with high-risk conditions
  • If used, same agents as treatment (typically azithromycin)

Vaccine Development:

  • No licensed vaccine currently available
  • Several candidates in development/early trials
  • Challenges include providing long-lasting immunity and safety profile
×

Mycobacterium tuberculosis Infections in Pediatrics

Overview & Definition

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, an aerobic, non-motile, non-spore-forming, acid-fast bacillus. In pediatric populations, TB presents unique challenges in diagnosis and management due to differences in pathophysiology, clinical presentation, and treatment considerations compared to adults.

Pediatric TB has historically been neglected in global TB control efforts despite accounting for approximately 10-15% of the total TB disease burden. Children are particularly vulnerable to progression from infection to disease, with the highest risk in infants and young children under 5 years of age and adolescents.

Epidemiology

Global Burden:

  • Approximately 1.2 million children develop TB disease annually worldwide
  • Over 200,000 children die from TB each year, with approximately 80% of deaths occurring in children under 5 years of age
  • At least 55% of childhood TB cases are not reported or diagnosed
  • Highest incidence in Africa and Southeast Asia

Risk Factors for TB Infection:

  • Contact-related: Close or household contact with infectious TB case (most important risk factor)
  • Environmental: Overcrowded living conditions, poor ventilation
  • Geographic: Residence in or travel from high-prevalence areas
  • Social determinants: Poverty, limited access to healthcare

Risk Factors for Progression to TB Disease:

Risk Factor Relative Risk
Age • <1 year: 50-60% risk
• 1-2 years: 30-40% risk
• 2-5 years: 20-30% risk
• 5-10 years: 5-10% risk
• Adolescents: 10-20% risk
Immunosuppression • HIV infection: 20-30× higher risk
• Malnutrition: 2-3× higher risk
• Immunosuppressive therapy: 4-8× higher risk
Timing of exposure • Recent infection (within 2 years): 5× higher risk
Co-morbidities • Diabetes: 2-4× higher risk
• Chronic respiratory disease: 2-3× higher risk

Pathophysiology

The pathogenesis of TB in children follows a continuum from exposure to infection and potentially to disease:

Infection Stages:

  1. Exposure: Contact with an infectious case without evidence of infection
  2. TB infection (TBI): Evidence of immunologic response to TB antigens without clinical or radiographic manifestations (formerly called latent TB infection)
  3. TB disease: Clinical, radiological, or microbiological evidence of active disease

Primary Infection Process:

  • Inhalation of aerosolized bacilli into alveoli
  • Phagocytosis by alveolar macrophages
  • Initial multiplication within macrophages
  • Formation of primary (Ghon) focus in lungs
  • Lymphatic spread to regional lymph nodes forming primary complex (Ghon complex)
  • Hematogenous dissemination during initial infection period

Immune Response:

  • Development of cell-mediated immunity (CMI) 2-8 weeks after infection
  • CMI limits bacillary multiplication but may not eradicate all organisms
  • Granuloma formation: Organized structure of macrophages, T-cells, B-cells, and fibroblasts that contains infection
  • Dynamic balance between host immunity and bacillary replication

Differences in Pediatric TB Pathophysiology:

  • Children more likely to develop primary progressive disease after recent infection
  • Less likely to form cavities due to reduced immunopathologic response
  • Higher risk of extrapulmonary and disseminated disease
  • Lower bacillary burden (paucibacillary disease) making microbiologic confirmation challenging
  • More rapid progression from infection to disease, especially in younger children

Clinical Manifestations

The spectrum of TB disease in children ranges from asymptomatic infection to severe disseminated disease:

Pulmonary TB:

  • Intrathoracic lymphadenopathy: Most common manifestation in children <5 years
  • Clinical features:
    • Persistent, non-remitting cough >2 weeks
    • Fever (often low-grade) persisting >2 weeks
    • Weight loss or failure to thrive
    • Reduced playfulness/activity
    • Night sweats
  • Physical findings:
    • Often normal despite extensive radiographic disease
    • Localized wheeze or decreased breath sounds if airway compression
    • Rales in areas of parenchymal involvement
  • Complicated forms:
    • Airway compression (wheezing, stridor, respiratory distress)
    • Pleural effusion (chest pain, dullness to percussion)
    • Cavitary disease (more common in adolescents)

Extrapulmonary TB:

Extrapulmonary TB Form Common Presentations
TB meningitis
(5-10% of pediatric TB)		 • Subacute onset with prodromal stage (1-2 weeks)
• Irritability, behavioral changes, headache
• Vomiting, lethargy progressing to altered consciousness
• Cranial nerve palsies (especially III, VI, VII)
• Focal neurologic deficits, seizures
• Meningeal signs may be absent in early stages
• Hydrocephalus and raised intracranial pressure
Lymph node TB
(Peripheral lymphadenitis)
(10-30% of pediatric TB)		 • Painless, progressive swelling of lymph nodes
• Cervical region most commonly affected (scrofula)
• Initially firm, discrete nodes that may become fluctuant
• Can develop overlying skin changes and fistula formation
• Systemic symptoms often mild or absent
Osteoarticular TB
(10-20% of extrapulmonary TB)		 • Spinal TB (Pott's disease): Back pain, gibbus deformity, neurological deficits
• Large weight-bearing joints (hip, knee): Monoarticular pain, swelling, limited range of motion
• Insidious onset with gradual progression
• Constitutional symptoms may be minimal
Abdominal TB • Abdominal pain, distension
• Ascites, masses (mesenteric lymphadenopathy)
• Intestinal obstruction
• Weight loss, fever
• Can mimic inflammatory bowel disease
Pleural TB • More common in children >5 years and adolescents
• Chest pain, dyspnea
• Fever, weight loss
• Dullness to percussion, decreased breath sounds
Disseminated TB
(Miliary TB)		 • Acute or subacute progressive illness
• High fever, marked weight loss
• Hepatosplenomegaly
• Respiratory distress
• Multi-organ involvement
• Miliary pattern on chest radiograph
• High mortality if untreated

TB in Special Populations:

  • Neonates:
    • Acquired congenitally or postnatally
    • Non-specific presentation resembling bacterial sepsis
    • Hepatosplenomegaly, respiratory distress, poor feeding
    • High mortality without prompt treatment
  • HIV-infected children:
    • Increased risk of dissemination
    • Atypical presentations common
    • Rapid progression
    • Poorer treatment outcomes
    • Immune reconstitution inflammatory syndrome (IRIS) risk
  • Adolescents:
    • More "adult-type" disease pattern
    • Higher prevalence of cavitary disease
    • Increased risk of transmission

Diagnostic Evaluation

Diagnosing TB in children is challenging due to paucibacillary disease and non-specific symptoms:

Diagnostic Approach:

  • Careful history (especially TB contacts)
  • Thorough clinical examination
  • Tuberculin skin test (TST) or interferon-gamma release assay (IGRA)
  • Chest radiography
  • Microbiological confirmation when possible
  • Appropriate sampling based on disease site

Immunodiagnostic Tests:

Test Advantages Limitations
Tuberculin Skin Test (TST) • Inexpensive
• No laboratory required
• Extensive experience in children 		• Requires return visit for reading (48-72h)
• False positives with BCG vaccination
• False negatives in immunosuppression, malnutrition, recent TB infection, overwhelming TB
• Reader variability
Interferon-Gamma Release Assays (IGRAs)
(QFT-Plus, T-SPOT.TB)		 • Not affected by BCG vaccination
• Single visit
• More specific than TST 		• Expensive
• Requires laboratory facilities
• Blood processing time constraints
• Indeterminate results in young children
• Limited data in children <2 years

Microbiological Diagnosis:

  • Specimen collection:
    • Gastric aspirates (young children unable to expectorate)
    • Induced sputum
    • Nasopharyngeal aspiration
    • Bronchoalveolar lavage
    • Fine needle aspiration of lymph nodes
    • CSF for TB meningitis
    • Other tissue/fluid specimens based on disease site
  • Diagnostic methods:
    • Microscopy: Acid-fast bacilli (AFB) smear - low sensitivity in children (10-15%)
    • Culture: Gold standard but slow (2-8 weeks), sensitivity 30-40% in pediatric TB
    • Nucleic acid amplification tests:
      • Xpert MTB/RIF and Xpert Ultra: Rapid (2 hours), detects M. tuberculosis and rifampin resistance
      • Improved sensitivity over smear microscopy (60-70% for pulmonary TB in children)
      • WHO-recommended as initial diagnostic test for all children with suspected TB
    • Line probe assays: Detect resistance to first- and second-line drugs
    • Whole genome sequencing: Comprehensive resistance detection, epidemiological investigations

Imaging Studies:

  • Chest radiography:
    • Essential for pulmonary TB diagnosis
    • Common findings: Hilar/mediastinal lymphadenopathy, parenchymal opacities, miliary pattern, pleural effusion
    • Frontal and lateral views recommended
  • Computed tomography (CT):
    • Higher sensitivity for detecting lymphadenopathy and early parenchymal changes
    • Useful for complicated cases
    • Not routinely indicated
  • Other imaging: Based on site of disease
    • Brain MRI for TB meningitis
    • Spine MRI for Pott's disease
    • Abdominal ultrasound or CT for abdominal TB
    • Joint/bone imaging for osteoarticular TB

Diagnostic Algorithm Approach:

When bacteriological confirmation is not possible, diagnosis often relies on:

  1. Careful history of TB contact or symptoms
  2. Clinical examination consistent with TB
  3. Positive immunodiagnostic test (TST or IGRA)
  4. Radiographic findings suggestive of TB
  5. Exclusion of alternative diagnoses
  6. Positive response to anti-TB therapy

Management

Treatment Principles:

  • Early initiation of effective therapy
  • Appropriate drug combinations and dosages
  • Adequate duration of treatment
  • Adherence support
  • Monitoring for adverse events and response
  • Consideration of drug-resistant TB where prevalent

Treatment of TB Infection:

Regimen Dosing Duration Comments
Isoniazid (INH) 10 mg/kg (max 300 mg) daily 6-9 months • Traditional regimen
• Supplement with pyridoxine in adolescents, malnourished
• Not recommended if source case has INH resistance
Rifampin (RIF) 15 mg/kg (max 600 mg) daily 4 months • For INH-resistant source cases
• Multiple drug interactions
INH + Rifapentine • INH: 25-30 mg/kg (max 900 mg)
• Rifapentine: 300-900 mg (weight-based) 		12 weekly doses • Directly observed therapy recommended
• Approved for ≥2 years of age
• Better completion rates
INH + RIF • INH: 10 mg/kg (max 300 mg) daily
• RIF: 15 mg/kg (max 600 mg) daily 		3 months • Shorter duration
• Good efficacy
• Higher risk of hepatotoxicity

Treatment of Drug-Susceptible TB Disease:

  • First-line drugs:
    Drug Daily Dosage (mg/kg) Maximum Daily Dose Common Side Effects
    Isoniazid (INH) 10-15 300 mg Hepatotoxicity, peripheral neuropathy
    Rifampin (RIF) 15-20 600 mg Orange body fluids, drug interactions, hepatotoxicity
    Pyrazinamide (PZA) 30-40 2000 mg Hepatotoxicity, hyperuricemia, arthralgia
    Ethambutol (EMB) 15-25 1600 mg Optic neuritis (rare in children at correct dosing)
  • Treatment regimens:
    • Pulmonary and most extrapulmonary TB:
      • 2-month intensive phase: INH, RIF, PZA, +/- EMB*
      • 4-month continuation phase: INH, RIF
      • *EMB may be omitted in non-severe disease with low risk of drug resistance
    • TB meningitis and osteoarticular TB:
      • 2-month intensive phase: INH, RIF, PZA, +/- EMB
      • 10-month continuation phase: INH, RIF
      • Consider adding a fluoroquinolone for TB meningitis

Management of Drug-Resistant TB:

  • Always based on drug susceptibility results (when available) or information about the source case
  • Consultation with pediatric TB expert recommended
  • Multidrug-resistant TB (MDR-TB) regimens:
    • Newer shorter regimens (9-12 months) with bedaquiline, linezolid, fluoroquinolone, and other effective drugs
    • Most drugs now have pediatric formulations or dosing guidelines

Adjunctive Therapies:

  • Corticosteroids: Recommended for TB meningitis and pericarditis; consider for severe airway compression
  • Vitamin D: May be beneficial, especially in deficient children
  • Nutritional support: Essential for malnourished children
  • Surgery: May be needed for drainage of abscesses, relief of obstructions, or removal of infected tissue

Monitoring During Treatment:

  • Clinical monitoring:
    • Monthly weight measurements (adjust doses as needed)
    • Assessment of symptom resolution
    • Evaluation of treatment adherence
    • Monitoring for adverse effects
  • Laboratory monitoring:
    • Baseline liver function tests (LFTs), particularly for adolescents
    • Regular LFTs if baseline abnormalities, symptoms of hepatotoxicity, or pre-existing liver disease
    • Follow-up sputum samples in adolescents with initially positive bacteriology
  • Radiological monitoring: Chest radiograph at completion of therapy for pulmonary TB (sooner if poor clinical response)

Prevention

BCG Vaccination:

  • Protects against severe forms of TB in young children (70-80% protection against TB meningitis and miliary TB)
  • Limited protection against pulmonary TB (0-50%)
  • WHO recommends in countries with high TB burden
  • Contraindicated in HIV-infected children with symptoms
  • Usually given at birth or in early infancy

Contact Investigation:

  • Systematic screening of household and close contacts of infectious TB cases
  • Highest priority for children <5 years and immunocompromised contacts
  • Includes symptom screening, TST/IGRA, and chest radiograph
  • TB infection treatment for eligible contacts without TB disease

TB Infection Treatment:

  • Also called TB preventive therapy (TPT) or preventive treatment
  • Reduces risk of progression to TB disease by 60-90%
  • Priority populations:
    • All children <5 years who are household contacts of TB cases
    • HIV-infected children of any age
    • Children receiving immunosuppressive therapy

Infection Control:

  • Most children with TB are not highly infectious
  • Adolescents with adult-type cavitary disease may transmit TB
  • Standard precautions:
    • Isolation of confirmed/suspected infectious cases
    • Use of masks or other barriers for procedures that induce coughing
    • Good ventilation in healthcare settings
×

Treponema Pallidum Infections in Pediatrics

Overview & Definition

Treponema pallidum is a spiral-shaped, highly motile spirochete bacterium responsible for causing syphilis. While congenital syphilis is a major concern in pediatrics, acquired syphilis can also affect children and adolescents. This section focuses specifically on acquired (non-congenital) T. pallidum infections in the pediatric population.

Acquired syphilis in children and adolescents is classified into stages similar to adults:

  • Primary syphilis: Characterized by a painless chancre at the site of inoculation
  • Secondary syphilis: Systemic dissemination with mucocutaneous manifestations
  • Latent syphilis: Asymptomatic infection with positive serology
  • Tertiary syphilis: Late manifestations affecting multiple organ systems (rare in pediatrics)

Epidemiology

Prevalence and Distribution:

  • Rising incidence in pediatric populations, particularly among adolescents
  • Rates highest in adolescents 15-19 years of age
  • Geographic disparities with higher rates in resource-limited settings
  • In children <10 years old, acquired syphilis is rare and raises concern for sexual abuse

Transmission:

  • Sexual contact: Primary mode in adolescents
  • Sexual abuse: Must be considered in prepubertal children
  • Rare non-sexual transmission: Very close household contact with infectious lesions (extremely uncommon)

Risk Factors:

Category Risk Factors
Behavioral • Early sexual debut
• Multiple sexual partners
• Inconsistent condom use
• Exchange of sex for money or substances
• Substance use
Social • Limited access to healthcare
• Homelessness or unstable housing
• History of incarceration
• Commercial sexual exploitation
Comorbid • Other sexually transmitted infections
• HIV infection
• Mental health disorders
For prepubertal children • Sexual abuse
• Household contact with person with active infectious syphilis (extremely rare)

Pathophysiology

Organism Characteristics:

  • Gram-negative spirochete (cannot be visualized with standard Gram stain)
  • 10-15 μm in length with tight, regular spirals
  • Highly motile with characteristic corkscrew movement
  • Unable to be cultured on artificial media
  • Genome sequenced but many virulence mechanisms remain poorly understood

Pathogenesis:

  1. Invasion: Penetration through mucous membranes or breaks in skin
  2. Local multiplication: At site of entry (3-90 days)
  3. Local immune response: Leading to primary chancre formation
  4. Hematogenous dissemination: To multiple organ systems
  5. Immune evasion: Through antigenic variation and limited surface proteins
  6. Persistent infection: Ability to remain dormant for long periods

Immune Response:

  • Both humoral and cell-mediated immune responses are activated
  • Antibody production begins 1-2 weeks after infection
  • Incomplete immunity develops (reinfection can occur)
  • Treponema can persist despite robust immune response
  • Children may mount different immune responses compared to adults

Clinical Manifestations

Clinical presentations in pediatric patients vary by stage of infection:

Primary Syphilis:

  • Chancre: Painless, indurated ulcer with raised borders
  • Location: Genitals, anus, rectum, pharynx, lips, or other site of inoculation
  • Characteristics:
    • Usually single lesion
    • Develops 3-90 days after exposure (average 21 days)
    • Highly infectious
    • Resolves spontaneously in 3-6 weeks without treatment
  • Associated findings: Regional lymphadenopathy
  • Note: Often undetected in children due to location and painless nature

Secondary Syphilis:

  • Timing: 4-10 weeks after primary infection
  • Cutaneous manifestations:
    • Maculopapular rash: Non-itchy, copper-colored, involving palms and soles
    • Condylomata lata: Moist, flat, wart-like lesions in warm, moist areas
    • Mucous patches: Painless ulcers in mouth, pharynx, or genital mucosa
  • Systemic symptoms:
    • Fever, malaise, headache, weight loss
    • Generalized lymphadenopathy
    • Hepatosplenomegaly
  • Other manifestations:
    • Anterior uveitis, iritis
    • Patchy alopecia ("moth-eaten" appearance)
    • Hepatitis, nephritis, gastritis (less common)
  • Duration: Resolves spontaneously in 2-6 weeks without treatment

Latent Syphilis:

  • Early latent: Infection <1 year duration
  • Late latent: Infection >1 year duration
  • Characteristics:
    • Absence of clinical signs and symptoms
    • Positive serologic tests
    • Potentially infectious in early latent phase (especially during first year)

Tertiary Syphilis:

  • Rare in pediatric patients with acquired infection
  • Usually develops 10-30 years after initial infection
  • Can involve any organ system but classically affects:
    • Cardiovascular system (aortitis, aortic insufficiency)
    • Central nervous system (tabes dorsalis, general paresis)
    • Skin and subcutaneous tissues (gummas)

Neurosyphilis:

  • Can occur at any stage of syphilis
  • More commonly asymptomatic in children
  • Symptomatic forms include:
    • Meningitis
    • Cranial nerve abnormalities
    • Altered mental status
    • Seizures
  • Higher risk in HIV-coinfected patients
Stage Key Clinical Features in Children/Adolescents Duration/Infectivity
Primary • Painless chancre at site of inoculation
• Regional lymphadenopathy 		• 3-6 weeks without treatment
• Highly infectious
Secondary • Widespread rash including palms/soles
• Condylomata lata
• Mucous patches
• Lymphadenopathy
• Systemic symptoms 		• 2-6 weeks without treatment
• Highly infectious
Early Latent • Asymptomatic
• Positive serology
• <1 year duration 		• Potentially infectious
• May relapse to secondary
Late Latent • Asymptomatic
• Positive serology
• >1 year duration 		• Non-infectious (sexually)
• May progress to tertiary

Diagnostic Evaluation

General Approach:

  • High index of suspicion needed, especially in high-risk adolescents
  • Diagnosis requires integration of clinical findings, history, and serologic testing
  • In prepubertal children with suspected acquired syphilis, sexual abuse evaluation is mandatory

Direct Detection Methods:

  • Darkfield microscopy:
    • Identification of spirochetes from lesion exudate
    • Highly specific but limited sensitivity
    • Requires specialized equipment and experienced microscopist
    • Not recommended for oral lesions (contamination with commensal treponemes)
  • Direct fluorescent antibody testing:
    • More specific than darkfield microscopy
    • Can be performed on oral lesions
    • Limited availability
  • PCR:
    • Increasing availability and utility
    • High sensitivity and specificity
    • Can be performed on various sample types

Serologic Testing:

Two types of serologic tests used in combination:

Test Type Examples Characteristics
Nontreponemal Tests • Rapid Plasma Reagin (RPR)
• Venereal Disease Research Laboratory (VDRL) 		• Detect antibodies to cardiolipin
• Good screening tests
• Can be quantified (titers)
• Used to monitor treatment response
• Can be falsely positive (autoimmune diseases, pregnancy, viral infections)
• Can be falsely negative (very early or late infection, prozone phenomenon)
Treponemal Tests • Fluorescent Treponemal Antibody Absorption (FTA-ABS)
• T. pallidum Particle Agglutination (TP-PA)
• Enzyme Immunoassays (EIA)
• Chemiluminescence Immunoassays (CIA)
• Immunochromatographic (point-of-care) tests 		• Detect specific antibodies against T. pallidum
• Confirmatory tests
• Usually remain positive for life after infection
• Cannot distinguish active from treated infection
• Not useful for monitoring treatment
• Less subject to false positives than nontreponemal tests

Traditional vs. Reverse Sequence Algorithm:

  • Traditional algorithm:
    • Initial nontreponemal test (RPR/VDRL)
    • If positive, confirm with treponemal test
  • Reverse sequence algorithm:
    • Initial treponemal test (EIA/CIA)
    • If positive, perform nontreponemal test
    • If nontreponemal test negative, perform second, different treponemal test

Neurosyphilis Evaluation:

  • Lumbar puncture for CSF analysis indicated in:
    • Neurologic, ophthalmic, or otic symptoms
    • Treatment failure
    • Late latent syphilis or unknown duration
    • HIV co-infection with CD4 <350 or serum RPR ≥1:32
  • CSF evaluation includes:
    • Cell count and protein
    • CSF-VDRL (specific but not sensitive)
    • CSF-FTA-ABS (sensitive but not specific)

Additional Evaluation:

  • HIV testing (high rate of co-infection)
  • Screening for other STIs
  • Pregnancy testing in adolescent females
  • Sexual abuse evaluation in prepubertal children
  • Partner notification and testing

Management

Antimicrobial Therapy:

Penicillin remains the treatment of choice for all stages of syphilis in children and adolescents. No documented resistance to penicillin has been reported to date.

Stage Recommended Treatment Alternative (Penicillin Allergy)
Primary, Secondary, or Early Latent Benzathine penicillin G
• Age ≥12 years: 2.4 million units IM × 1 dose
• Age <12 years: 50,000 units/kg IM (max 2.4 million units) × 1 dose 		Doxycycline (≥8 years):
• 100 mg PO BID × 14 days

OR

Penicillin desensitization (preferred)
Late Latent or Unknown Duration Benzathine penicillin G
• Age ≥12 years: 2.4 million units IM weekly × 3 doses
• Age <12 years: 50,000 units/kg IM (max 2.4 million units) weekly × 3 doses 		Doxycycline (≥8 years):
• 100 mg PO BID × 28 days

OR

Penicillin desensitization (preferred)
Neurosyphilis Aqueous crystalline penicillin G
• 200,000-300,000 units/kg/day IV (max 18-24 million units/day) divided q4h × 10-14 days 		Penicillin desensitization followed by standard treatment

Management Considerations:

  • Jarisch-Herxheimer reaction:
    • Acute febrile reaction occurring within 24 hours of treatment
    • More common in early syphilis
    • Symptoms: fever, headache, myalgia, tachycardia
    • Self-limited; treat symptomatically
    • Patients should be warned about possibility
  • Sexual abuse considerations:
    • Mandatory reporting for suspected abuse in children
    • Comprehensive medical and psychological evaluation
    • Involvement of child protective services
  • Partner management:
    • Notification, evaluation, and treatment of sexual partners
    • For primary, secondary, and early latent: partners within 90 days
    • For late latent: long-term partners should be evaluated

Follow-up and Monitoring:

  • Clinical evaluation:
    • Assess for resolution of symptoms
    • Evaluate for treatment complications
  • Serologic testing:
    • Quantitative nontreponemal tests at 3, 6, and 12 months
    • More frequent monitoring for HIV-infected patients
    • Expected 4-fold decline in titer within 6-12 months
  • Treatment failure: Defined as:
    • Persistent or recurrent symptoms
    • Sustained 4-fold increase in nontreponemal titer
    • Failure of titer to decrease 4-fold within 6-12 months
  • Retreatment considerations:
    • Reevaluate for HIV
    • Consider lumbar puncture
    • Assess for reinfection vs. treatment failure
    • Retreatment typically with 3 weekly doses of benzathine penicillin G

Prevention

Primary Prevention:

  • Education: Age-appropriate sexual health education
  • Safer sex practices: Consistent and correct condom use
  • Regular screening: For sexually active adolescents
  • Child abuse prevention: Education, screening, and intervention programs

Secondary Prevention:

  • Routine screening: In high-risk populations
  • Prompt diagnosis and treatment: To prevent progression and transmission
  • Partner notification and treatment: To prevent reinfection

Screening Recommendations:

  • All sexually active adolescents with:
    • HIV infection (annually)
    • Multiple or anonymous partners
    • Men who have sex with men (every 3-6 months)
    • History of incarceration
    • Exchange of sex for money or drugs
    • Residing in areas with high syphilis prevalence
  • All pregnant adolescents:
    • First prenatal visit
    • Third trimester and delivery in high-risk areas or populations
  • Children:
    • Those being evaluated for sexual abuse
    • Those with physical findings suggestive of syphilis

Research and Future Directions:

  • Vaccine development (multiple candidates under investigation)
  • Improved point-of-care diagnostic tests
  • Alternative treatments for penicillin-allergic patients
  • Enhanced strategies for prevention and partner notification

Suggested Reading

Textbooks:

  • Feigin and Cherry's Textbook of Pediatric Infectious Diseases
  • Red Book: Report of the Committee on Infectious Diseases (American Academy of Pediatrics)
  • Sexually Transmitted Diseases, 4th Edition (Holmes KK, et al.)
  • Nelson Textbook of Pediatrics

Journals:

  • Pediatric Infectious Disease Journal
  • Clinical Infectious Diseases
  • Sexually Transmitted Diseases
  • Journal of Pediatric and Adolescent Gynecology
  • MMWR: CDC Guidelines for Treatment of Sexually Transmitted Diseases
×

Actinomyces Infections in Pediatrics

Overview & Definition

Actinomyces species are gram-positive, filamentous, branching, non-spore-forming, slow-growing anaerobic or microaerophilic bacteria that are part of the normal flora of the oropharynx, gastrointestinal tract, and female genital tract. In pediatric populations, these organisms can become pathogenic when normal mucosal barriers are breached, leading to chronic, indolent, and often granulomatous infections characterized by abscess formation, fistula development, and tissue fibrosis.

The hallmark of actinomycosis is the presence of sulfur granules in infected tissues or drainage, which are visible yellow-white granules composed of filamentous bacterial colonies.

Epidemiology

Prevalence and Distribution:

  • Relatively uncommon in the pediatric population, with an estimated incidence of 1 in 300,000 children
  • Most common species: Actinomyces israelii (most frequent), A. naeslundii, A. odontolyticus, A. viscosus, and A. gerencseriae
  • No gender predilection in children (unlike adults where males predominate)
  • Can affect children of any age, but uncommon in neonates

Risk Factors:

  • Disruption of mucosal barriers:
    • Dental procedures or oral trauma
    • Surgery or foreign bodies
    • Aspiration
  • Poor oral hygiene
  • Dental caries
  • Immunocompromised status (less common factor in children than adults)
  • Use of intrauterine devices (relevant for adolescent females)

Pathophysiology

Actinomyces species are opportunistic pathogens that cause disease through the following mechanisms:

  • Mucosal barrier disruption: Traumatic or surgical disruption of mucous membranes allows these commensal organisms to invade deeper tissues
  • Biofilm formation: Actinomyces can form biofilms that contribute to chronic infection and resistance to host defenses
  • Synergistic infection: Often occurs as a polymicrobial infection with other oral or anaerobic organisms that potentiate pathogenicity
  • Granuloma formation: Characterized by central suppuration surrounded by granulation tissue and dense peripheral fibrosis
  • Direct tissue invasion: Rather than hematogenous spread, actinomycosis typically progresses through direct extension across tissue planes with little regard for anatomical barriers

The natural history of untreated infection involves:

  1. Initial acute inflammatory response
  2. Formation of granulation tissue
  3. Extensive fibrosis
  4. Development of sinus tracts that may discharge characteristic sulfur granules

Clinical Manifestations

Actinomycosis in children typically presents in several distinct clinical forms based on anatomical location:

Clinical Form Features Pediatric Considerations
Cervicofacial
(50-60% of pediatric cases)		 • Firm, non-tender or mildly tender mass in jaw or neck
• Slow progression with eventual formation of sinus tracts
• "Woody" induration of affected tissues
• Possible trismus if masseter involved
• May follow dental extraction or oral trauma 		• Most common form in children
• Often starts as dental infection
• May be misdiagnosed as dental abscess or infected lymphadenitis
• Lower incidence of sinus tract formation than in adults
Thoracic
(15-20% of pediatric cases)		 • Chronic, indolent pneumonia
• Pleural effusion or empyema
• Possible chest wall involvement with sinus tract formation
• Weight loss, fatigue, low-grade fever
• May mimic tuberculosis or malignancy 		• Often follows aspiration in children with neurological disorders
• More common in immunocompromised children
• May occur without obvious aspiration event
• Slower progression than typical bacterial pneumonia
Abdominal/Pelvic
(10-15% of pediatric cases)		 • Indolent abdominal mass or abscess
• Possible fistula formation (enteric or cutaneous)
• Nonspecific symptoms: abdominal pain, weight loss, fever
• May mimic inflammatory bowel disease or malignancy 		• Often associated with appendicitis or following abdominal surgery
• Pelvic disease rare in prepubertal children
• Can occur with foreign body ingestion
Musculoskeletal
(5-10% of pediatric cases)		 • Vertebral osteomyelitis
• Long bone osteomyelitis
• Chronic joint infection
• Soft tissue infection after trauma 		• Rare in children but can occur after trauma or orthopedic surgery
• Vertebral disease less common than in adults
• Often misdiagnosed initially as typical bacterial osteomyelitis
Central Nervous System
(<5% of pediatric cases)		 • Brain abscess
• Meningitis
• Subdural empyema
• Headache, focal neurological deficits, seizures 		• Extremely rare in children
• Often results from hematogenous spread or direct extension from cervicofacial disease
• Higher mortality than other forms
Disseminated
(<1% of pediatric cases)		 • Multiorgan involvement
• Systemic symptoms predominate
• Multiple abscesses in different anatomical locations 		• Exceedingly rare in immunocompetent children
• More likely in significantly immunocompromised patients
• Carries high morbidity and mortality

Unique Pediatric Presentations:

  • Lacrimal Canaliculitis: Infection of lacrimal apparatus, more common in children than adults with actinomycosis
  • Scalp Infection: Can occur following trauma or surgery involving the scalp
  • Tonsillar Actinomycosis: Chronic tonsillitis with actinomycotic colonies visible as white spots on tonsillar crypts

Diagnostic Evaluation

Clinical Assessment:

  • Thorough history focusing on potential inciting events or risk factors
  • Comprehensive physical examination with attention to sinuses, mouth, teeth, neck, chest, and abdomen
  • High index of suspicion required as presentation often mimics other conditions

Microbiologic Diagnosis:

  • Direct microscopy:
    • Gram stain: Gram-positive filamentous branching bacteria
    • Modified acid-fast stain: Partially acid-fast (differentiates from Nocardia)
    • Identification of sulfur granules: Macroscopic yellow grains (1-2mm) in pus or tissue
  • Culture:
    • Anaerobic culture on blood agar (growth takes 5-7 days minimum)
    • Special transport and handling required for optimal recovery
    • Warn laboratory about suspected actinomycosis
  • Molecular methods:
    • 16S rRNA gene sequencing for definitive species identification
    • PCR assays for direct detection from clinical specimens
  • Histopathology:
    • Chronic granulomatous inflammation
    • Sulfur granules (basophilic center with eosinophilic terminal clubs)
    • Surrounding neutrophils, macrophages, and fibrosis

Laboratory Studies:

  • Complete blood count: Often shows mild leukocytosis
  • Inflammatory markers: Elevated ESR and CRP in most cases
  • Blood cultures: Usually negative (hematogenous spread uncommon)

Imaging Studies:

Imaging Modality Findings Utility
Conventional Radiography • Nonspecific infiltrates or consolidation in thoracic disease
• Periosteal reaction or bone destruction in osteomyelitis
• Limited utility in soft tissue disease 		• Initial screening tool
• Limited sensitivity for early disease
• Better for bone involvement
Ultrasound • Hypoechoic mass with heterogeneous internal echoes
• Helpful for identifying fluid collections or abscesses
• Can guide diagnostic aspiration 		• Excellent for cervicofacial and superficial lesions
• Good for abdominal and soft tissue involvement
• Safe, radiation-free option for children
CT Scan • Dense, enhancing soft tissue mass
• Surrounding inflammation crossing fascial planes
• Possible adjacent bone erosion
• Characteristic finding: low-attenuation center with peripheral enhancement 		• Best for thoracic, abdominal, and CNS disease
• Helps define extent of disease
• Identifies complications (fistulae, bone involvement)
MRI • T1: Intermediate-low signal intensity
• T2: Heterogeneous high signal intensity
• Strong peripheral enhancement with contrast
• Superior soft tissue contrast 		• Preferred for CNS, spinal, and musculoskeletal involvement
• Best defines soft tissue extension
• No radiation exposure
PET-CT • Increased FDG uptake in affected areas
• Can help distinguish from malignancy in some cases 		• Limited role in routine diagnosis
• May help in assessing disease extent in difficult cases
• Useful for monitoring treatment response

Differential Diagnosis:

  • Cervicofacial: Dental abscess, tuberculosis, cat-scratch disease, nocardiosis, fungal infection, malignancy
  • Thoracic: Tuberculosis, fungal pneumonia, lung abscess, empyema, bronchiectasis, lung cancer
  • Abdominal: Crohn's disease, appendicitis, tuberculosis, malignancy, amebiasis
  • Musculoskeletal: Bacterial osteomyelitis, tuberculosis, fungal osteomyelitis, Ewing sarcoma

Management

General Principles:

  • Combined surgical and medical approach often required
  • Prolonged antibiotic therapy is the cornerstone of treatment
  • Frequent reassessment and monitoring for treatment response essential

Antimicrobial Therapy:

Treatment Phase Preferred Regimens Alternative Regimens Duration
Initial Parenteral Phase First choice:
• Penicillin G 200,000-400,000 units/kg/day IV divided q4-6h (max 24 million units/day) 		• Ampicillin 100-200 mg/kg/day IV divided q6h
• Ceftriaxone 50-100 mg/kg/day IV/IM daily or divided q12h
• Clindamycin 30-40 mg/kg/day IV divided q6-8h (if penicillin allergic) 		2-6 weeks, depending on:
  • Clinical severity
  • Site of infection
  • Response to therapy
Continuation Oral Phase First choice:
• Amoxicillin 40-50 mg/kg/day PO divided q8h (max 1.5g/day) 		• Penicillin V 25-50 mg/kg/day PO divided q6h
• Doxycycline 2-4 mg/kg/day PO divided q12h (for children >8 years)
• Clindamycin 20-30 mg/kg/day PO divided q6-8h 		• Mild disease: 2-3 months
• Moderate disease: 3-6 months
• Severe/CNS disease: 6-12 months

Notes on Antimicrobial Therapy:

  • Consider adding metronidazole or clindamycin initially for polymicrobial coverage
  • Actinomyces are typically susceptible to β-lactams, tetracyclines, clindamycin, and erythromycin
  • Resistance to metronidazole, aminoglycosides, and trimethoprim-sulfamethoxazole is common
  • Transition to oral therapy when clinically improved (usually after 2-6 weeks of parenteral therapy)
  • Duration of therapy should be individualized based on clinical response and site of infection

Surgical Management:

  • Indications:
    • Abscess drainage
    • Debridement of necrotic tissue
    • Removal of foreign bodies
    • Excision of persistent sinus tracts
    • Management of complications (empyema, fistulae)
    • Diagnostic tissue acquisition
  • Approach by Site:
    • Cervicofacial: Incision and drainage, extraction of involved teeth
    • Thoracic: Video-assisted thoracoscopic surgery, decortication for empyema
    • Abdominal: Drainage of abscesses, resection of severely affected bowel segments
    • Musculoskeletal: Debridement, sequestrectomy
  • Minimally invasive approaches with image guidance preferred when feasible

Monitoring and Follow-up:

  • Regular clinical assessment (every 2-4 weeks initially)
  • Serial inflammatory markers to assess treatment response
  • Follow-up imaging at 1-3 month intervals until resolution
  • Monitoring for medication adverse effects during prolonged therapy
  • Dental evaluation and treatment for cervicofacial disease

Prognosis and Complications

Prognosis:

  • Generally good with appropriate treatment
  • Mortality rare in uncomplicated cases treated appropriately
  • Complete recovery expected in 80-90% of pediatric cases
  • Relapse can occur if treatment duration inadequate (10-15% of cases)
  • Factors associated with poorer outcomes:
    • Delayed diagnosis
    • CNS involvement
    • Disseminated disease
    • Immunocompromised status
    • Inadequate surgical drainage

Complications:

  • General: Chronic sinus tract formation, scarring, disfigurement
  • Cervicofacial: Mandibular osteomyelitis, trismus, salivary gland destruction
  • Thoracic: Empyema, bronchopleural fistula, chest wall invasion, pericarditis
  • Abdominal: Fistula formation, strictures, obstruction, peritonitis
  • CNS: Increased intracranial pressure, neurologic sequelae, hydrocephalus

Prevention

No specific preventive measures exist for actinomycosis, but risk reduction strategies include:

  • Good oral hygiene and regular dental care
  • Prompt treatment of dental infections
  • Proper wound care after trauma or surgery
  • Aspiration precautions in children with neurological disorders
  • Antibiotic prophylaxis consideration for high-risk dental procedures in immunocompromised children

Special Considerations in Pediatrics

  • Diagnostic challenges:
    • Low clinical suspicion due to rarity in children
    • Often misdiagnosed as more common conditions
    • Difficulty obtaining adequate specimens in young children
  • Treatment considerations:
    • Compliance challenges with prolonged oral therapy
    • Need for age-appropriate antibiotic dosing
    • PICC line may be needed for extended IV therapy
    • Taste and palatability issues with oral suspensions
  • Psychosocial aspects:
    • Impact of chronic disease and prolonged treatment on development
    • School absences and social implications
    • Cosmetic concerns with cervicofacial disease
×

Brucella Infections in Pediatrics

Overview & Definition

Brucellosis is a zoonotic infection caused by gram-negative, aerobic coccobacilli of the genus Brucella. The most common species affecting humans are B. melitensis (most virulent), B. abortus, B. suis, and rarely B. canis. In pediatric populations, brucellosis can present as an acute febrile illness or manifest as a chronic, debilitating disease with multisystem involvement.

The disease is characterized by its ability to cause persistent infection due to the organism's capacity to survive within host macrophages. Pediatric brucellosis represents approximately 20-25% of all cases worldwide, with distinctive clinical patterns compared to adults.

Epidemiology

Global Distribution:

  • Endemic in Mediterranean basin, Middle East, Central Asia, India, Mexico, Central and South America
  • In the United States, most cases are imported or related to consumption of unpasteurized dairy products from endemic regions
  • Estimated 500,000 new cases worldwide annually, with significant underreporting

Pediatric Considerations:

  • Children account for 20-25% of cases in endemic regions
  • Higher incidence in rural areas where contact with livestock and consumption of unpasteurized dairy is common
  • Peak age distribution: school-aged children (5-14 years)
  • Male predominance in regions where boys are more involved in animal husbandry

Transmission Routes:

Route Mechanism Risk Factors in Children
Foodborne Consumption of unpasteurized dairy products (milk, cheese, butter, ice cream) • Family consumption of raw dairy
• Living in rural/farming communities
• Travel to endemic regions
Direct contact Contact with infected animals, placentas, or aborted fetuses through skin abrasions or mucous membranes • Participation in animal husbandry
• Living on farms
• Contact with pets (especially dogs, in case of B. canis)
Inhalation Aerosolized bacteria in animal enclosures, slaughterhouses, or laboratories • Living near animal pens/barns
• Visiting farms/petting zoos
Vertical Transplacental transmission, contamination during delivery, or via breast milk • Maternal infection during pregnancy
• Breastfeeding from infected mother

Pathophysiology

Microbiology:

  • Small (0.5-0.7 µm) gram-negative, non-motile, non-spore-forming, aerobic coccobacilli
  • Facultative intracellular pathogens with tropism for reticuloendothelial system
  • Slow-growing organisms requiring special media (Brucella agar, blood culture systems)
  • Four main species pathogenic to humans:
    • B. melitensis (most virulent, from sheep/goats)
    • B. abortus (cattle)
    • B. suis (swine)
    • B. canis (dogs)

Host-Pathogen Interaction:

  • Entry: Mucosal surfaces, broken skin, inhalation
  • Initial spread: Regional lymph nodes with macrophage uptake
  • Intracellular survival:
    • Inhibition of phagosome-lysosome fusion
    • Modification of phagosomal compartment
    • Resistance to oxidative killing
    • Reduced antigen presentation
  • Dissemination: Hematogenous spread to reticuloendothelial organs (liver, spleen, bone marrow, lymph nodes)
  • Granulomatous inflammation: Focal microabscesses and non-caseating granulomas
  • Chronicity factors: Ability to evade immune detection and survive within macrophages

Immunological Response:

  • Initial innate immune response (neutrophils, NK cells)
  • Cell-mediated immunity critical for control (Th1 predominant response)
  • Humoral immunity (antibodies) useful for diagnosis but less effective for clearance
  • Incomplete immunity after infection (reinfection possible)

Clinical Manifestations

Clinical presentations of brucellosis in children span a wide spectrum from asymptomatic infection to severe, disseminated disease. The incubation period typically ranges from 1-4 weeks but can be as long as several months.

General Classification of Disease:

Classification Criteria Frequency in Children
Acute Duration <8 weeks 60-70%
Subacute Duration 8-52 weeks 20-30%
Chronic Duration >52 weeks or persistent focal disease 5-10%
Relapse Recurrence after treatment completion 5-15%

Common Clinical Features in Children:

  • Constitutional symptoms:
    • Fever (>90%): typically undulant in adults but often persistent in children
    • Malaise, fatigue (70-90%)
    • Weight loss, anorexia (40-70%)
    • Night sweats (20-50%)
  • Musculoskeletal manifestations (20-60%):
    • Arthralgia or arthritis (knee, hip, ankle most common)
    • Myalgia
    • Osteomyelitis (vertebral rare in children compared to adults)
  • Lymphadenopathy (10-50%):
    • Generalized or regional (cervical, axillary, inguinal)
  • Hepatosplenomegaly (20-60%):
    • Hepatomegaly more common than splenomegaly
    • Usually mild to moderate enlargement

Focal Complications:

  • Osteoarticular (most common focal form in children):
    • Monoarthritis (typically large joints)
    • Sacroiliitis
    • Spondylitis (uncommon in children)
    • Osteomyelitis
  • Gastrointestinal/Hepatobiliary:
    • Mild hepatitis (elevated transaminases)
    • Abdominal pain
    • Rare: liver abscess, cholecystitis, pancreatitis
  • Neurological (3-5% in children):
    • Meningitis or meningoencephalitis
    • Brain abscess
    • Peripheral neuropathy
    • Guillain-Barré-like syndrome
  • Cardiovascular (rare in children):
    • Endocarditis (usually requiring surgery when it occurs)
    • Myocarditis, pericarditis
  • Genitourinary:
    • Epididymo-orchitis (in post-pubertal males)
    • Glomerulonephritis (rare)
  • Respiratory:
    • Bronchitis, pneumonia
    • Pleural effusion
    • Hilar lymphadenopathy
  • Dermatologic (5-10%):
    • Maculopapular rash
    • Erythema nodosum
    • Petechiae
  • Hematologic:
    • Anemia (normocytic, normochromic)
    • Leukopenia
    • Thrombocytopenia
    • Pancytopenia (particularly with bone marrow involvement)

Special Pediatric Considerations:

  • Neonatal brucellosis:
    • Acquired transplacentally, during delivery, or via breast milk
    • Presents with fever, jaundice, hepatosplenomegaly
    • May resemble neonatal sepsis
  • Differences from adult presentation:
    • Higher frequency of acute forms
    • Lower frequency of chronic disease and relapses
    • More common acute arthritis, less common sacroiliitis/spondylitis
    • Fever pattern often not "undulant" as classically described in adults

Diagnostic Evaluation

Clinical Approach:

  • High index of suspicion in endemic areas or with relevant exposure history
  • Consider brucellosis in children with:
    • Prolonged unexplained fever
    • Arthritis or arthralgia
    • Hepatosplenomegaly
    • History of animal contact or unpasteurized dairy consumption

Laboratory Diagnosis:

Diagnostic Method Description Comments
Blood Culture • Gold standard for definitive diagnosis
• Higher yield in acute phase (first 2 weeks)
• May require prolonged incubation (up to 4 weeks) 		• Sensitivity: 30-90% (varies with disease stage and prior antibiotics)
• Automated systems improve yield
• Laboratory should be alerted about suspicion of brucellosis
Bone Marrow Culture • Higher sensitivity than blood culture
• Less affected by prior antibiotic use 		• Sensitivity: 60-95%
• Invasive procedure, usually reserved for difficult cases
Other Specimen Cultures • CSF, synovial fluid, tissue, abscess material • Important in focal disease
Serology Standard Agglutination Test (SAT):
• Detects total antibodies
• Titer ≥1:160 in endemic areas, ≥1:80 in non-endemic areas considered positive

Rose Bengal test:
• Rapid screening test

Coombs anti-Brucella test:
• Detects non-agglutinating antibodies
• Useful in chronic cases

ELISA (IgM, IgG, IgA):
• Higher sensitivity and specificity
• Useful for disease staging and monitoring 		• IgM appears first, peaks at 3-4 weeks
• IgG rises later, persists longer
• Serology may be negative early in disease
• Cross-reactions with Yersinia, Francisella, Vibrio, Salmonella
Molecular Methods • PCR on blood, serum, or other specimens
• Real-time PCR for species identification 		• Rapid results
• High sensitivity and specificity
• Less affected by prior antibiotics
• Not standardized or widely available

Additional Laboratory Findings:

  • Complete blood count:
    • Normal white blood cell count (leukocytosis uncommon, leukopenia in 20-25%)
    • Anemia (25-40% of cases)
    • Thrombocytopenia (10-20%)
    • Pancytopenia (rare, usually with bone marrow involvement)
  • Inflammatory markers:
    • ESR and CRP: moderately elevated in most cases
    • Less pronounced elevation than many bacterial infections
  • Liver function tests:
    • Mild to moderate elevation of transaminases (40-60%)
    • Usually <2-3 times upper limit of normal

Imaging Studies:

  • Osteoarticular involvement:
    • Radiographs: Often normal in early disease
    • Ultrasound: For joint effusions
    • MRI: Most sensitive for early bone/joint involvement
    • Bone scan: For multifocal disease
  • Neurobrucellosis:
    • MRI: May show meningeal enhancement, white matter changes, abscesses, granulomas
    • CSF analysis: Lymphocytic pleocytosis, elevated protein, normal or low glucose

Management

Principles of Treatment:

  • Combination antimicrobial therapy essential due to intracellular nature of the pathogen
  • Prolonged treatment required to prevent relapse
  • Age-appropriate regimens necessary in pediatrics
  • Antimicrobial penetration into affected tissues is crucial

Antimicrobial Regimens in Children:

Age Group Recommended Regimen Duration
Children <8 years First Line:
Trimethoprim-sulfamethoxazole (TMP-SMX) 10mg/kg/day of TMP component (divided q12h)
PLUS
Rifampin 15-20 mg/kg/day (divided q12-24h, max 600-900 mg/day)

Alternative:
TMP-SMX + Gentamicin 5-7.5 mg/kg/day (divided q8h) for first 5-7 days 		6 weeks
Children ≥8 years First Line:
Doxycycline 2-4 mg/kg/day (divided q12h, max 200 mg/day)
PLUS
Rifampin 15-20 mg/kg/day (divided q12-24h, max 600-900 mg/day)

Alternative:
Doxycycline + Gentamicin 5-7.5 mg/kg/day (divided q8h) for first 5-7 days 		6 weeks
Neonates & Infants <3 months Rifampin 10-15 mg/kg/day (divided q12h)
PLUS
TMP-SMX (if >1 month old) OR Gentamicin 5 mg/kg/day (divided q8h) 		6 weeks
Severe/Complicated Disease
(any age)		 Triple therapy:
• Age-appropriate dual therapy PLUS
• Third agent: Gentamicin, fluoroquinolone (if >18 years), or ceftriaxone 		• Neurobrucellosis: 3-6 months
• Endocarditis: 6-12 months
• Spondylitis: 3-6 months
• Other complicated infections: individualized

Management of Specific Complications:

  • Neurobrucellosis:
    • Triple therapy with CNS-penetrating agents (doxycycline, TMP-SMX, rifampin, ceftriaxone)
    • Consider corticosteroids for severe inflammation or cranial nerve involvement
    • Extended therapy (3-6 months)
  • Osteoarticular disease:
    • Standard dual therapy often sufficient
    • Surgical drainage for abscesses or sequestra
    • Joint aspiration for septic arthritis
    • Extended therapy for vertebral osteomyelitis (3-6 months)
  • Endocarditis:
    • Triple therapy with doxycycline (if age-appropriate), rifampin, and aminoglycoside
    • Prolonged treatment (at least 6 months)
    • Surgical valve replacement often necessary
    • Cardiology consultation

Monitoring and Follow-up:

  • Clinical assessment at 2-4 weeks after starting therapy, then monthly until 6 months after completion
  • Monitor for treatment response, adverse effects, and signs of relapse
  • Consider repeat serology at end of treatment and 3-6 months later
  • Falling antibody titers suggest successful treatment
  • Re-evaluate with persistent or recurrent symptoms

Prognosis:

  • Generally favorable with appropriate therapy
  • Relapse rates: 5-15% (usually within 6 months of treatment completion)
  • Lower relapse rates in children than adults
  • Mortality rate <1% with adequate treatment (higher with endocarditis, neurobrucellosis)
  • Most focal complications resolve without sequelae
  • Chronic fatigue may persist in 10-30% of cases

Prevention

Individual Prevention Measures:

  • Food safety:
    • Avoid consumption of unpasteurized dairy products
    • Adequate cooking of meat from potentially infected animals
    • Education about risks in endemic areas
  • Occupational/recreational exposure:
    • Protective clothing when handling animals or animal products
    • Hand hygiene after animal contact
    • Caution during farm/zoo visits in endemic areas
  • Healthcare provider education:
    • Awareness of brucellosis in differential diagnosis
    • Early recognition in endemic areas or with relevant exposure history

Public Health Measures:

  • Animal disease control:
    • Vaccination of susceptible livestock
    • Test and slaughter programs
    • Quarantine of imported animals
  • Food safety regulations:
    • Mandatory pasteurization of dairy products
    • Inspection of dairy facilities
  • Surveillance:
    • Reportable disease in most countries
    • Case investigation and contact tracing

Post-Exposure Management:

  • Consider post-exposure prophylaxis for high-risk exposures (laboratory accidents)
  • Serological monitoring after significant exposure
  • Early treatment if symptoms develop

Human Vaccination:

  • No licensed human vaccine available in most countries
  • Live attenuated vaccines used in some countries (Russia, China) but not approved in US/Europe due to safety concerns
  • Research ongoing for safer, more effective vaccines
×

Empirical Antibiotic Therapy in Pediatrics

Overview & Principles

Empirical antibiotic therapy refers to the initiation of antimicrobial treatment based on clinical assessment before definitive identification of the causative pathogen. In pediatric practice, this approach is crucial for prompt management of potentially serious bacterial infections while awaiting culture results.

Key Principles:

  • Timing is critical: Timely administration of appropriate antibiotics reduces morbidity and mortality in serious bacterial infections
  • Balance broad vs. narrow coverage: Initial therapy should cover the most likely pathogens while minimizing unnecessary broad-spectrum exposure
  • Age-specific considerations: Likely pathogens and drug pharmacokinetics vary significantly with age (neonates vs. infants vs. older children)
  • Local epidemiology: Empiric choices should reflect local resistance patterns and prevalent organisms
  • De-escalation: Narrow therapy once culture results are available (typically within 48-72 hours)
  • Source control: Drainage of abscesses or removal of infected foreign bodies when indicated
  • Reassessment: Clinical response should be evaluated within 48-72 hours to guide continuation or modification of therapy

Factors Influencing Empiric Antibiotic Selection

Factor Clinical Considerations
Patient Age • Neonates (0-28 days): Higher risk of Group B Streptococcus, Listeria, E. coli
• Infants (1-3 months): Consider herpes simplex virus in addition to bacterial pathogens
• Older infants and children: S. pneumoniae, S. aureus, H. influenzae more common
Immune Status • Immunocompromised children require broader coverage for opportunistic pathogens
• Neutropenic patients: coverage for Pseudomonas and resistant gram-negative organisms
• Asplenia: enhanced coverage for encapsulated organisms
Infection Site • Each anatomic site has characteristic flora requiring specific antibiotic coverage
• Consider ability of antibiotics to penetrate specific tissues (CNS, bone, abscess)
Severity • More severe infections may warrant broader initial coverage
• Septic shock requires immediate broad-spectrum therapy
• Mild infections may allow more narrow-spectrum approach
Acquisition Setting • Community-acquired: Different pathogens than healthcare-associated
• Healthcare-associated: Higher risk of resistant organisms
• Daycare attendance: Increased risk of resistant S. pneumoniae
Prior Antibiotic Exposure • Recent antibiotic use increases risk of resistant organisms
• Consider different class if exposed to antibiotics in previous 3 months
Local Resistance Patterns • Antibiograms vary by region and institution
• Consider local MRSA prevalence, pneumococcal resistance, and gram-negative resistance patterns

Age-Specific Empiric Therapy Recommendations

Neonatal Infections (0-28 days):

Syndrome Common Pathogens Recommended Empiric Therapy
Early-onset sepsis
(0-72 hours)		 Group B Streptococcus, E. coli, Listeria, Enterococcus Ampicillin + Gentamicin
OR
Ampicillin + Cefotaxime
Late-onset sepsis
(>72 hours)		 Coagulase-negative staphylococci, S. aureus, Gram-negative bacilli, Candida spp. Vancomycin + Gentamicin
OR
Vancomycin + Cefotaxime
Meningitis Group B Streptococcus, E. coli, Listeria Ampicillin + Cefotaxime
Consider adding vancomycin if MRSA is suspected
Necrotizing enterocolitis Polymicrobial: Enterobacteriaceae, Anaerobes, Enterococcus Ampicillin + Gentamicin + Metronidazole
OR
Piperacillin-tazobactam

Infants and Children (>28 days):

Syndrome Common Pathogens Recommended Empiric Therapy
Meningitis S. pneumoniae, N. meningitidis
H. influenzae (unvaccinated)		 Ceftriaxone or Cefotaxime
+ Vancomycin (areas with high pneumococcal resistance)
Community-acquired pneumonia • Typical: S. pneumoniae, H. influenzae
• Atypical: M. pneumoniae, C. pneumoniae
• Severe: Above plus S. aureus 		• Outpatient: Amoxicillin (preferred) or Azithromycin
• Hospitalized: Ampicillin or Ceftriaxone
• Severe/ICU: Ceftriaxone + Vancomycin ± Azithromycin
Urinary tract infection E. coli, Klebsiella, Proteus, Enterococcus • Uncomplicated: Cephalexin or TMP-SMX
• Pyelonephritis: Ceftriaxone or Gentamicin
• Complex UTI: Ampicillin + Gentamicin or Piperacillin-tazobactam
Skin/soft tissue infections S. aureus (MSSA/MRSA), Group A Streptococcus • Mild-moderate: Cephalexin (MSSA) or Clindamycin/TMP-SMX (MRSA coverage)
• Severe: Vancomycin or Clindamycin IV
Osteomyelitis/septic arthritis S. aureus, Group A Streptococcus, Kingella kingae • No MRSA concern: Cefazolin or Nafcillin
• With MRSA concern: Vancomycin + Ceftriaxone
Intra-abdominal infections Enterobacteriaceae, Anaerobes, Enterococcus • Mild-moderate: Ampicillin-sulbactam or Piperacillin-tazobactam
• Severe: Piperacillin-tazobactam or Meropenem

Special Populations:

Population Considerations Empiric Therapy Modifications
Febrile neutropenia • High risk of rapid progression
• Pseudomonas coverage essential
• Consider local resistance patterns 		• Monotherapy: Cefepime, Piperacillin-tazobactam, or Meropenem
• Add vancomycin for hemodynamic instability, suspected catheter infection, or high MRSA prevalence
• Add antifungal if fever persists >4-7 days
Asplenia/Functional asplenia • Higher risk for encapsulated organisms
• Potential for fulminant sepsis 		• Febrile illness: Ceftriaxone + Vancomycin
• Lower threshold for early broad-spectrum coverage
Cystic fibrosis • Colonization with resistant organisms
• Pseudomonas, Burkholderia, MRSA common 		• Higher doses of β-lactams
• Based on previous culture data
• Often combination therapy (e.g., β-lactam + aminoglycoside)
Healthcare-associated infections • Multi-drug resistant organisms more common
• Consider previous microbiology 		• Broader spectrum coverage (e.g., Piperacillin-tazobactam, Meropenem)
• Consider MRSA coverage with Vancomycin

Antibiotic Dosing Considerations in Pediatrics

Pediatric dosing requires special attention to developmental pharmacokinetics and pharmacodynamics:

Age-Related Pharmacokinetic Differences:

  • Neonates and young infants:
    • Decreased renal clearance
    • Immature liver metabolism
    • Higher percentage of total body water
    • Lower plasma protein levels
  • Infants and young children:
    • Higher metabolic rates
    • Faster clearance (weight-adjusted) than adults
    • May require more frequent dosing

Dosing Approaches:

  • Weight-based dosing: Most common approach, mg/kg/dose
  • Body surface area (BSA): Used for some drugs, particularly chemotherapeutic agents
  • Age-tiered dosing: Different doses for different age groups
  • Therapeutic drug monitoring: Essential for drugs with narrow therapeutic index (vancomycin, aminoglycosides)

Specific Considerations:

  • Aminoglycosides: Extended interval dosing increasingly used (once daily)
  • β-lactams: Higher doses often needed for meningitis to ensure CNS penetration
  • Vancomycin: Higher trough levels (15-20 μg/mL) for CNS infections and serious MRSA infections
  • Renal adjustment: Required for drugs with significant renal elimination

Antibiotic Administration Routes

Route Advantages Limitations Indications
Intravenous (IV) • Rapid achievement of therapeutic levels
• Reliable bioavailability
• Option for drugs without oral formulations 		• Requires venous access
• Risk of line infections
• Higher cost
• Limited outpatient options 		• Severe infections
• Meningitis
• Sepsis/bacteremia
• Osteomyelitis (initial therapy)
• Inability to take oral medications
Oral (PO) • Convenience
• Lower cost
• Facilitates outpatient management
• Reduced line-associated complications 		• Variable absorption
• Compliance concerns
• Limited penetration to some sites
• Palatability issues in children 		• Mild-moderate infections
• Step-down therapy after IV antibiotics
• Prophylaxis
• Compliant patients/families
Intramuscular (IM) • Option when IV access difficult
• Better bioavailability than PO
• Single-dose option for some antibiotics 		• Pain with administration
• Limited volume can be given
• Variable absorption
• Poor acceptance by children 		• Limited use in pediatrics
• Single-dose ceftriaxone for UTI
• Penicillin G benzathine for streptococcal pharyngitis or syphilis
Topical • High local concentration
• Minimal systemic absorption
• Fewer systemic side effects 		• Limited to superficial infections
• Potential for contact dermatitis
• Limited spectrum of available agents 		• Impetigo
• Minor skin infections
• Conjunctivitis
• Otitis externa

Duration of Therapy

Recent evidence supports shorter courses of antibiotics for many common pediatric infections:

Infection Traditional Duration Evidence-Based Shorter Duration Comments
Acute otitis media 10 days 5-7 days • Shorter course for children ≥2 years without severe symptoms
• 10 days still recommended for children <2 years or severe disease
Streptococcal pharyngitis 10 days 10 days • Full 10-day course still recommended to prevent rheumatic fever
• Some evidence for 5-day course with certain antibiotics (e.g., azithromycin)
Community-acquired pneumonia 7-14 days 5-7 days • Duration based on clinical response
• Longer courses for complicated pneumonia or certain pathogens
Uncomplicated UTI 7-14 days 3-5 days • Short course for cystitis in older children
• 7-10 days still recommended for pyelonephritis or younger children
Skin/soft tissue infection 7-14 days 5-7 days • Duration based on infection severity and clinical response
• Adequate drainage is key for abscesses
Acute bacterial sinusitis 14-21 days 10-14 days • Duration based on symptom resolution
• Shorter courses for milder cases
Acute bacterial meningitis • H. influenzae: 7-10 days
• N. meningitidis: 7 days
• S. pneumoniae: 10-14 days 		Similar to traditional • Shorter courses being studied but not yet widely recommended
• Duration based on causative organism and clinical response
Osteomyelitis 4-6 weeks 3-4 weeks • Early transition to oral therapy after clinical improvement
• Duration guided by clinical and inflammatory marker response

Monitoring Response to Therapy

Clinical Parameters:

  • Temperature curve: Defervescence typically expected within 48-72 hours
  • Vital signs: Normalization of heart rate, respiratory rate, blood pressure
  • Clinical symptoms: Improvement in infection-specific symptoms
  • Oxygen requirements: For respiratory infections
  • Intake/output: Improvement in oral intake, urine output
  • Local findings: Reduction in erythema, swelling, tenderness in localized infections

Laboratory Parameters:

  • WBC count: Normalization of initial abnormalities
  • C-reactive protein (CRP): Should decrease within 48-72 hours of effective therapy
  • Procalcitonin: Rapid decrease with appropriate therapy
  • Microbiological response: Clearance of organisms from blood or other sites
  • Clinical laboratory parameters: Improvement in organ-specific tests (e.g., liver enzymes, renal function)

Therapeutic Drug Monitoring:

  • Vancomycin:
    • Trough levels before 4th dose
    • Target: 10-15 μg/mL for routine infections, 15-20 μg/mL for severe infections
  • Aminoglycosides:
    • Peak and trough levels for traditional dosing
    • Trough levels <1 μg/mL for gentamicin/tobramycin
    • Single level 8-12 hours post-dose for extended-interval dosing

Indications for Antibiotic Modification:

  • Failure to improve: Persistent fever, worsening clinical status
  • Culture results: Narrow based on sensitivities
  • Adverse effects: Rash, diarrhea, elevation in liver/renal function tests
  • Superinfection: New fever, new symptoms after initial improvement
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GPay: dipax75@oksbi