Pneumonia and Bronchiolitis

Werther Brunow De Carvalho

Marcelo Cunio Machado Fonseca

Cintia Johnston

David G. Nichols

KEY POINTS

Pneumonia

The pathogenesis of pneumonia is dependent on host defense and microorganism virulence.

Bacterial pneumonia is not common in previously healthy children; it usually occurs after a viral infection or in the presence of an underlying chronic disease.

Diagnosis is clinical and based on history, physical examination, and epidemiologic data.

Admission criteria of children with community-acquired pneumonia (CAP) are not fully defined and accurate; many patients are hospitalized without adequate justification.

Pneumonia associated with mechanical ventilation is the second highest cause of nosocomial infections.

Important components of pneumonia therapy include nutrition; fluid-, electrolyte-, and acid-base balance; temperature control; heated and humidified O₂; and secretion management (chest physiotherapy, suctioning).

Antimicrobial therapy is guided by epidemiologic and clinical data, the patient’s age, the infective microorganism, and antimicrobial resistance.

Acute Bronchiolitis

Acute bronchiolitis (AB) is the most frequent and severe respiratory system syndrome involving children <2 years of age. It has an epidemic pattern and increased prevalence during the fall and winter. In winter, AB is one of the most frequent causes of infant hospitalization.

Respiratory syncytial virus (RSV subtypes A and B) is the most frequently involved agent, although other viral pathogens may be clinically indistinguishable.

Comorbidities associated with increased severity of AB include

a. Prematurity

b. Chronic lung disease

c. Immunodeficiency

d. Hemodynamically significant heart disease

Apnea may be a presenting sign of AB and warrants admission to a pediatric intensive care unit (PICU) because of the risk of recurrence.

Clinical or diagnostic signs of impending respiratory failure despite adequate O₂ therapy are indications for admission to the PICU.

Treatment of AB is supportive, as neither bronchodilators nor antibiotics have proven effective.

Adequate hydration and oxygenation remain the backbone of AB treatment, and respiratory support is indicated in patients with refractory and recurring episodes of apnea, progressive hypoxia, refractory hypercapnia, or increasing respiratory distress secondary to severe AB.

Careful hand-washing and other infection control measures are necessary to prevent the spread of RSV.

The monoclonal antibody palivizumab provides passive immunization against RSV in select populations of highrisk children.

PNEUMONIA

Introduction

Pneumonia is an inflammatory condition of the lung parenchyma, which distinguishes it from inflammatory conditions of the airways such as bronchiolitis, bronchitis or tracheitis. The etiology may be associated with infection, aspiration, hypersensitivity to inhaled materials (hydrocarbon and lipoid pneumonia), or drug- or radiation-induced pneumonitis. Pneumonia usually presents with clinical signs of alveolar compromise and radiographic opacification without lung volume loss. The term bronchopneumonia refers to characteristic clinical findings with multiple opacities on radiologic examination, generally poorly defined, without clear segmental limits, and associated with a more serious clinical presentation.

Classification

There are several approaches to the classification of pneumonia.

The World Health Organization (WHO) (1) classifies pneumonia into three stages based on clinical criteria:

Stage I, fever (≥38°C) and tachypnea (>50 bpm for ages 2-11 months, and >40 bpm for ages 1-5 years)
Stage II includes chest retractions
Stage III includes difficulty with breastfeeding or drinking and/or central cyanosis

Additional classification based on age and the underlying infectious agent is common in pediatrics, which reflects the distinct clinical findings associated with various age groups and organisms. The radiographic classification is based on anatomic location (lobar, lobular, alveolar, or interstitial).
The infection control classification distinguishes between community-acquired and nosocomial pneumonia, which are associated with different causative agents and hence different therapeutic decisions. Classification based on underlying chronic disease occurs in special populations because these children experience recurrent pneumonias with distinctive features. Examples include acute chest syndrome in sickle cell disease, gram-negative pneumonia in cystic fibrosis, or aspiration pneumonia in tracheoesophageal fistula or cleft palate patients.

When a child presents with recurrent pneumonia, the possibility of an underlying disease (e.g., acquired or congenital lung anatomical abnormalities, immunodeficiency, prematurity, lung sequestration, tracheoesophageal fistula, foreign body, cystic fibrosis, heart failure, cleft palate, bronchiectasis, ciliary dyskinesia, neutropenia, or increased pulmonary blood flow) should be considered. Other predisposing factors are lower socioeconomic status, parental smoking, and prolonged critical illness.

Epidemiology

Pneumonia is one of the most frequent infections in children and one of the main causes of hospitalization. More than 95% of the episodes of pneumonia in the world occur in developing countries. UNICEF maintains current statistics on pneumonia in the developing world (http://data.unicef.org) and provides links to a WHO integrated management plan for resourcelimited environments.

It is estimated that 150 million cases of pneumonia occur annually in children who are <5 years old (2). Although the introduction of the pneumococcal vaccine has reduced hospitalization rates in developed countries, ˜50% of young children (<5 years old) with community-acquired pneumonia (CAP) still require hospitalization. The wealth of the society and the availability of medical resources impact the mortality rate, and pneumonia is the leading cause of mortality in developing countries.

Pathogenesis

Pneumonia typically occurs either by colonization of the upper airway followed by invasion of the lower respiratory tract or, less commonly, through hematogenous spread to pulmonary parenchyma (e.g., Streptococcus pneumoniae and Staphylococcus aureus). Lower respiratory tract invasion usually begins with population of the nasopharynx by a serotype, against which the patient lacks immunity. The child may experience cough, coryza, or pharyngitis. Subsequently, the virulent organism is either inhaled or aspirated into the trachea and distal airway. Once microorganisms inoculate the respiratory tract, a normal inflammatory response (including antibodies, complement, phagocytes, and cytokines) begins and causes injury to the functioning pulmonary tissue (3). The mobilization of immunoglobulins (IgG and IgM) and complement facilitates opsonization of microorganisms. Macrophages and polymorphonuclear leukocytes then phagocytize the antibody-coated microorganisms. The inflammatory response associated with this normal immune response leads to increased airway reactivity, transudation of plasma into the air spaces, and excess mucus production. The bronchiolar and alveolar epithelia may become necrotic in severe cases. The accumulation of fluid and cellular debris in the alveoli may lead to decreased ventilation relative to perfusion in the affected lung segments, which in turn leads to hypoxia.

Protection against respiratory pathogens includes the airway defense barriers, mainly the mucous membrane and the mucociliary layer, which are responsible for the clearance of foreign material or microorganisms. The bacteria that cause pneumonia may have specific virulence factors that increase their survival and reproduction and result in more extensive lesions.

Frequent histopathologic findings in viral pneumonia are congestion, inflammation, bronchial epithelium necrosis, and hemorrhage. Viral pneumonia also affects the lung through direct invasion, causing mucosal inflammation and respiratory cilial injury, allowing the possibility of secondary bacterial infection. Globally, viruses are responsible for ˜30%-67% of CAPs and are more frequently identified in children <1 year compared to those >2 years old (77% vs. 59%) (4).

Neonatal Pneumonia

It is estimated that 800,000 deaths occur worldwide due to respiratory infections during the neonatal period. Neonatal pneumonia may be either early-onset or late-onset depending on the route and mechanism of acquiring the pathogen. Early-onset neonatal pneumonia (<3 days of life) is classified as follows:

Congenital: acquired by transplacental (hematogenous) transmission
Intrauterine: caused by maternal chorioamnionitis and fetal aspiration of infected amniotic fluid
Intrapartum: due to aspiration of organisms colonizing the maternal genital tract

Clinical Presentation of Neonatal Pneumonia

The newborn with bacterial pneumonia usually presents with tachypnea, grunting, nasal flaring, and chest wall retractions. Other nonspecific signs, including poor feeding, vomiting, irritability, lethargy, and apnea, are also seen with bacteremia and meningitis, which makes the diagnosis of pneumonia difficult without a chest radiography. In preterm newborns, lower respiratory tract infection may present as apnea without fever or tachycardia. Infants with Chlamydia trachomatis pneumonia usually present between 3 weeks and 3 months of age with staccato cough, tachypnea, and rales.

Early-Onset Neonatal Pneumonia

Group B streptococcus (GBS) is the most common cause of early-onset pneumonia in developed countries. Vaginal colonization in the mother, prematurity, and premature or prolonged (>18 hours) rupture of membranes are major risk factors for early-onset GBS pneumonia. GBS pneumonia usually occurs as part of GBS sepsis. Diffuse alveolar infiltrates mimic hyaline membrane disease. Severely affected infants may develop persistent pulmonary hypertension of the newborn. Maternal screening for GBS colonization and the use of intrapartum antibiotic prophylaxis have decreased the incidence and severity of GBS pneumonia, although racial and ethnic disparities persist, with greater incidence and severity among black newborns.

Although microbiologic studies from newborns with pneumonia in developing countries are more limited, gram-negative enteric organisms (especially Klebsiella spp.) as well as Staphylococcus aureus and Streptococcus pneumoniae appear to be responsible for most early-onset neonatal pneumonia. These organisms may produce significant lung damage, including abscess, empyema, and pneumatocele.

Among viral etiologies of neonatal pneumonia, herpes simplex virus (HSV) is most common and carries a high mortality rate. Approximately half of newborns with disseminated
HSV infection will exhibit pneumonia as part of the disease. Because the presentation of disseminated HSV with pneumonia is often indistinguishable from early-onset neonatal sepsis, acyclovir should be included in empiric therapy until HSV can be excluded.

Empiric treatment of early-onset neonatal pneumonia takes the earlier microbiologic patterns into account. Parenteral antibiotics are necessary and should cover microorganisms known to colonize or infect the mother. Ampicillin, gentamicin, and acyclovir are a useful antibiotic combination until cultures and polymerase chain reaction (PCR) studies are available to tailor therapy.

Early-onset pneumonia may also be noninfectious in origin as when fetal asphyxia and gasping respirations result in meconium aspiration syndrome (MAS) (5). MAS is usually readily distinguished from infectious early-onset pneumonia based on clinical and radiographic criteria:

Meconium staining of the amniotic fluid, newborn skin, and airway secretions
Respiratory distress immediately at birth
History of fetal distress (Apgar score < 8)
Small for gestational age or postmaturity
Linear (“streaky”) infiltrates and hyperinflation on chest radiograph

Late-Onset Neonatal Pneumonia

Late-onset neonatal pneumonia is defined as pneumonia occurring 48-72 hours after birth but within the first month of life and usually reflects a postpartum nosocomial infection. The newborn acquires the infectious agent from fomites, contaminated devices, or caregivers who are carriers. The microorganisms gain access to the lung via either the respiratory tract or the circulation. Prolonged mechanical ventilation represents the most important risk factor for late-onset pneumonia and often leads to ventilator-associated pneumonia (VAP) with Pseudomonas aeruginosa as a common pathogen. Staphylococcus spp. (S. aureus, S. pyogenes, or S. epidermidis) are also common agents especially in newborns with vascular access devices or other invasive devices. Late-onset GBS usually presents with bacteremia or meningitis rather than pneumonia. Respiratory syncytial virus (RSV) is the most common cause of late-onset neonatal pneumonia of viral origin (see later).

Community-Acquired Pneumonia

The British Thoracic Society (BTS) defines communityacquired pneumonia (CAP) as the presence of signs and symptoms in previously healthy children with an infection that has been acquired outside the hospital. The Infectious Diseases Society of America and the BTS have published clinical practice guidelines recently in an attempt to streamline the management of pediatric CAP (6,7,8). Most CAP in children >6 months of age can be managed on an outpatient basis. This section focuses on severe CAP requiring hospitalization and pediatric intensive care unit (PICU) admission.

Microbiology Based on Age Group and Symptoms

Among infants <2 months old, the bacterial etiologies are more frequent, including Streptococcus pneumoniae, group B streptococci, gram-negative bacilli (from maternal genital tract or hospital flora), Staphylococcus aureus, and C. trachomatis. Even though the introduction of routine vaccination against Haemophilus influenzae type B (Hib) and pneumococcal disease in developed countries has significantly lowered infection rates among children <2 years old, infants <6 months old will not have completed the primary vaccination series against these agents. Young infants with “typical” bacterial pneumonia are usually highly febrile (>39°C) and tachypneic, and appear toxic. C. trachomatis (or less commonly Mycoplasma hominis, or Ureaplasma urealyticum) may cause a syndrome of “afebrile pneumonia of infancy” among infants 2 weeks to 4 months old.

Pertussis (“whooping cough”) is making resurgence worldwide, but especially in developed countries, where introduction of universal vaccination against Bordetella pertussis was once thought to have nearly eradicated the disease (9). Young infants are at greatest risk for complications of the disease. The presentation is characteristic with prolonged staccato cough, followed by an inspiratory “whoop.” Many infants will vomit after the coughing spasm. Infants with pertussis pneumonia are critically ill with extreme leukocytosis (WBC > 50,000-60,000 cells/µL), pulmonary hypertension, hypoxia, apnea (15%-30% incidence), and seizures (1% incidence). A high index of suspicion is needed to diagnose pertussis early when an upper respiratory tract infection does not resolve after a week, but instead progresses with worsening cough. The diagnosis should be made based on clinical grounds but confirmed with culture and PCR. The American Academy of Pediatrics Committee on Infectious Disease (“Redbook”) recommends azithromycin for treatment of young infants with pertussis. The US Food and Drug Administration (FDA) has not approved azithromycin for infants <6 months old. The risk of infantile hypertrophic pyloric stenosis should be considered with the use of erythromycin in infants <1 month of age. The risk of cardiac electrical abnormalities should be considered with azithromycin use in infants with prolonged QT syndrome, those on antiarrhythmic therapy, and those with abnormal potassium or magnesium levels. Strict use of droplet precautions (e.g., caregiver mask) avoids nosocomial spread of pertussis.

Among infants 6-12 months old, viruses are the main pneumonia-causative pathogens (10). RSV and influenza are most common, but parainfluenza, adenovirus, rhinovirus, coronavirus, measles, rubella, varicella, cytomegalovirus, or herpes may also cause pneumonia. A viral etiology (as opposed to a bacterial one) is more likely if the infant with tachypnea has a temperature <38.5°C, WBC < 20,000, and no evidence of lobar infiltrates on chest radiograph.

Among children 1-5 years, viruses remain the predominant cause of pneumonia. To date, S. pneumonia remains the most common cause of bacterial pneumonia in this age group, although further reductions in prevalence of pneumococcal disease are expected following the conversion from a 7-valent pneumococcal vaccine to a 13-valent vaccine in 2009. The incidence of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has increased in many regions of the world, but especially in the United States (US). MRSA is more commonly associated with necrotizing pneumonia and empyema than other organisms. The knowledge of local and regional antibiotic resistance patterns is critically important for the treating intensivist. Clinical deterioration in a young child with influenza or varicella may arise because of secondary infection with Staphylococcus aureus or Staphylococcus pyogenes, respectively.

Less common pathogens include helminths (Ascaris lumbricoides, Strongyloides stercoralis, Toxocara kennels), human metapneumovirus (hMPV), B. pertussis, Mycobacterium tuberculosis, Listeria monocytogenes, Legionella pneumophila, Hantavirus, Coxiella burnetii, protozoa (e.g., Toxoplasma gondii), fungi (including Pneumocystis jiroveci), and physical and chemical agents.

Among children >3-5 years of age, Streptococcus pneumoniae, Chlamydophila pneumoniae, and Mycoplasma pneumoniae are the most common bacterial causes of pneumonia. The relative incidence of Mycoplasma pneumonia increases with age, and it accounts for approximately half of all pneumonias among college students. Viral pneumonia is verified
based on laboratory investigations in ˜8% of older children with pneumonia. Diagnostic studies will be negative in 50%-60% of older children with clinical pneumonia (11).

Specific Pneumonia Treatment

The Pediatric Infectious Diseases Society and the Infectious Diseases Society of America have developed evidence-based recommendations for CAP antibiotic therapy that are based on the child’s immunization status (Table 48.1).

For the treatment of infections caused by C. trachomatis and M. pneumoniae, a macrolide is the drug of choice. Data suggest the use of azithromycin for 5 days for the treatment of C. pneumoniae pneumonia (12).

For patients with suspicion for S. pneumoniae pneumonia, therapy is driven by the local antimicrobial susceptibility pattern, and IV ampicillin or ceftriaxone (in cases with probability of penicillin resistance) is used. Vancomycin is rarely necessary for the treatment of suspected S. pneumoniae pneumonia (may depend on incidence of cephalosporin resistance in the community), but should be added if MRSA is prevalent in the community. When infection due to Hib is suspected (e.g., unimmunized child), ceftriaxone, cefotaxime, or ampicillinsulbactam should be used because of the presence of β-lactamase -mediated resistance to ampicillin in several Hib strains. The optimal duration of the antimicrobial therapy for complicated or uncomplicated pneumonia has not been established for the majority of pathogens. However, most pneumonia are treated for 10 days, although shorter courses may be indicated in mild disease in order to minimize microbial selection for resistance. Conversely, MRSA or pneumonia complicated by effusion or empyema is guided by clinical response and may extend to 2-4 weeks. Initial empiric therapy can be modified after the identification of the etiologic agent (Table 48.2).

TABLE 48.1 EMPIRIC THERAPY FOR PEDIATRIC COMMUNITY-ACQUIRED PNEUMONIA (CAP)

	EMPIRIC THERAPY
▪ SITE OF CARE	▪ PRESUMED BACTERIAL PNEUMONIA	▪ PRESUMED ATYPICAL PNEUMONIA	▪ PRESUMED INFLUENZA PNEUMONIA
Inpatient (all ages)
Fully immunized with conjugate vaccines for Haemophilus influenzae type b and Streptococcus pneumoniae; local penicillin resistance in invasive strains of pneumococcus is minimal	Ampicillin or penicillin G; alternatives: ceftriaxone or cefotaxime; addition of vancomycin or clindamycin for suspected CA-MRSA	Azithromycin (in addition to β-lactam, if diagnosis of atypical pneumonia is in doubt); alternatives: clarithromycin or erythromycin; doxycycline for children >7 years old; levofloxacin for children who have reached growth maturity, or who cannot tolerate macrolides	Oseltamivir or zanamivir (for children ≥7 years old; alternatives: peramivir, oseltamivir and zanamivir (all intravenous) are under clinical investigation in children; intravenous zanamivir available for compassionate use
Not fully immunized for H, influenzae type b and S. pneumoniae; local penicillin resistance in invasive strains of pneumococcus is significant	Ceftriaxone or cefotaxime; addition of vancomycin or clindamycin for suspected CA-MRSA; alternative: levofloxacin; addition of vancomycin or clindamycin for suspected CA-MRSA	Azithromycin (in addition to β-lactam, if diagnosis in doubt); alternatives: clarithromycin or erythromycin; doxycycline for children >7 years old; levofloxacin for children who have reached growth maturity or who cannot tolerate macrolides	As above
See Table 48.2 for dosages. CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus. Reproduced with permission from Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: Clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis 2011;53(7):e25-76.

Pneumonia in the Immunocompromised Host

In the immunocompromised child, pulmonary infection leads to increased morbidity and mortality from a wide spectrum of microorganisms, including opportunistic agents. The pathogenesis is similar to that of the healthy host, except that the impaired host defense allows ready spread of the organism from the upper respiratory tract. The clinical manifestations in an immunocompromised child are highly variable. Several chronic immune deficiency states are associated with characteristic pneumonia syndromes, which are discussed in detail in Chapter 50 (Chronic Respiratory Failure), Chapter 86 (Primary Immune Deficiency Disorders), Chapter 95 (Opportunistic Infections), Chapter 115 (Oncologic Emergencies), Chapter 117 (Stem Cell Transplantation), and Chapter 119 (Sickle Cell Disease). The radiologic pattern in immunocompromised children may indicate the probable pathogens:

Focal consolidation (Streptococcus pneumoniae, H. influenzae, Legionella sp., mycobacteria, and fungi)
Micronodular pattern (viruses, mycobacteria, Histoplasma, Candida sp., and Cryptococcus)
Nodular pattern (Aspergillus sp., other fungi, mucormycosis, Nocardia sp., and Epstein-Barr Virus (EBV)— lymphoproliferative disease)
Diffuse interstitial pattern (viruses, M. pneumoniae, Chlamydia, and P. jiroveci).

Children with immunodeficient conditions and presenting with tachypnea or hypoxia require immediate hospitalization, empiric antibiotics (pending the outcome of diagnostic tests), and close monitoring. Aggressive interventions (e.g., bronchopulmonary lavage or lung biopsy) may be needed to determine a definitive microbiologic diagnosis (13).

TABLE 48.2 ETIOLOGY-SPECIFIC THERAPY

▪ AGENT		▪ ANTIMICROBIALS
Chlamydia trachomatis		Azithromycin (10 mg/kg/day for 2 days, then 5 mg/kg/day), clarithromycin (15 mg/kg/day in 2 doses), oral erythromycin (40 mg/kg/day in 4 doses), or intravenous erythromycin lactobionate (20 mg/kg/day every 6 hours); for children >7 years old, doxycycline (2-4 mg/kg/day in 2 doses Levofloxacin 16-20 mg/kg/day every 12 hours for children 6 months to 5 years old and 8-10 mg/kg/day once daily for children 5-16 years old; maximum daily dose, 750 mg
Chlamydophila pneumoniae		Azithromycin (10 mg/kg/day for 2 days, then 5 mg/kg/day), clarithromycin (15 mg/kg/day in 2 doses), oral erythromycin (40 mg/kg/day in 4 doses), or intravenous erythromycin lactobionate (20 mg/kg/day every 6 hours); for children >7 years old, doxycycline (2-4 mg/kg/day in 2 doses Levofloxacin 16-20 mg/kg/day every 12 hours for children 6 months to 5 years old and 8-10 mg/kg/day once daily for children 5-16 years old; maximum daily dose, 750 mg
Mycoplasma pneumoniae		Azithromycin (10 mg/kg/day for 2 days, then 5 mg/kg/day), clarithromycin (15 mg/kg/day in 2 doses), oral erythromycin (40 mg/kg/day in 4 doses), or intravenous erythromycin lactobionate (20 mg/kg/day every 6 hours); for children >7 years old, doxycycline (2-4 mg/kg/day in 2 doses Levofloxacin 16-20 mg/kg/day every 12 hours for children 6 months to 5 years old and 8-10 mg/kg/day once daily for children 5-16 years old; maximum daily dose, 750 mg
Group B β-hemolytic streptococcus		Ampicillin (100-200 mg/kg/day) plus gentamicin (5 mg/kg/day) OR Plus amikacin (15 mg/kg/day)
Streptococcus pneumoniae
	Sensitive to penicillin	Crystalline penicillin (100,000-250,000 units/kg/day) or ampicillin (150-200 mg/kg/day)
	Intermediate sensitivity	Penicillin (200,000-250,000 units/kg/day)
	Resistant to penicillin	Cefotaxime (200 mg/kg/day) or ceftriaxone (100 mg/kg/day)
	Resistant to penicillin and cephalosporins	Vancomycin (40-60 mg/kg/day) or clindamycin (30-45 mg/kg/day) Levofloxacin 16-20 mg/kg/day every 12 hours for children 6 months to 5 years old and 8-10 mg/kg/day once daily for children 5-16 years old; maximum daily dose, 750 mg
With MICs for penicillin ≤2.0 µg/mL or resistant to penicillin, with MICs ≥4.0 µg/mL
Haemophilus influenzae
β-Lactamase negative		Ampicillin (100-200 mg/kg/day)
β-Lactamase positive		Cefotaxime (200 mg/kg/day), ceftriaxone (100 mg/kg/day), or levofloxacin (16-20 mg/kg/day every 12 hours for children 6 months to 5 years old and 8-10 mg/kg/day once daily for children 5-16 years old; maximum daily dose, 750 mg)
Staphylococcus aureus
Methicillin sensitive		Oxacillin (200 mg/kg/day)
Methicillin resistant		Vancomycin (40-60 mg/kg/day) or teicoplanin (10 mg/kg/day) plus clindamycin (30-35 mg/kg/day)
Simian retrovirus, influenza B, parainfluenza		Ribavirin (15-20 mg/kg/day) (orally or IV; IV not approved in US) for immunocompromised patients, premature babies, those with chronic pulmonary diseases, congenital heart disease, or pulmonary hypertension, or critically ill patients
Influenza A and B		Oseltamivir 3 mg/kg/dose PO/NG bid × 5 days (2 weeks-1 year old) Oseltamivir 30 mg PO/NG bid × 5 days (>1 year old and <15 kg body weight) Oseltamivir 45 mg PO/NG bid × 5 days (15-23 kg body weight) Oseltamivir 60 mg PO/NG bid × 5 days (23-40 kg body weight) Oseltamivir 75 mg PO/NG bid × 5 days (>40 kg body weight)
Herpes simplex or zoster		Acyclovir (250 mg/m₂/8 h) (IV) (20 mg/kg/8 h) OR Foscarnet (60 mg/kg/8 h) (IV)
Cytomegalovirus		Ganciclovir 2.5 mg/kg/8 h initial (IV) 5 mg/kg/12 h (2-3 weeks) or foscarnet
Fungi		Amphotericin B (1 mg/kg/day) Liposomal amphotericin B (3 mg/kg/day) or fluconazole (6 mg/kg/day)
MIC, minimum inhibitory concentration.