Pharmacology Consult

Not all 3GCs are created equal: Oral antibiotic selection in pediatric pneumococcal infections

Community-acquired pneumonia (CAP), otitis media (OM) and acute bacterial rhinosinusitis (ABRS) are common childhood illnesses. Although OM is more typically a childhood infection, CAP and ABRS are also common in adults. However, important differences exist in pathogenesis and treatment. Causative pathogens differ between children and adults. Streptococcus pneumoniae remains the predominant pathogen, and Haemophilus influenzae causes CAP less frequently in children than in adults, although this continues to evolve with the introduction of pneumococcal vaccines and may yield future changes to recommended empiric therapy. Additionally, Mycoplasma pneumoniae is the primary atypical pathogen in pediatric CAP but usually only in certain age groups with specific presenting features, and therefore it does not warrant universal empiric coverage.

Leah Molloy

Although beta-lactams are mainstays of IV treatment in the hospital setting for both children and adults, adult patients often complete treatment with oral fluoroquinolones or doxycycline, which have limited utility in children and are not preferred as first-line agents. Oral beta-lactams are therefore used frequently for outpatient management of pediatric respiratory infections, and proper selection of agent and dose are important and common sources of error.

Understanding both antibiotic resistance mechanisms and pharmacokinetic characteristics are necessary to choose the best antibiotic. Beta-lactam resistance among S. pneumoniae is mediated by penicillin-binding proteins (PBPs) altered through genetic recombination with existing streptococcal PBPs, which may be overcome with high drug concentrations. In contrast, PBP mutations in MRSA entail a novel PBP unable to bind to any beta-lactam at any concentration, except ceftaroline. Additionally, S. pneumoniae does not produce the same near-universal beta-lactamase as Staphylococcus. aureus, negating any advantage of beta-lactamase inhibitors like sulbactam, or broad-spectrum agents like cephalosporins that are stable against beta-lactamase. For these reasons, IV ampicillin is typically used as first-line treatment in the hospital setting, although ceftriaxone is preferred for children who are unvaccinated or in the setting of high local pneumococcal resistance to penicillin. The advantage of ceftriaxone lies not in its activity against gram-negative pathogens or its stability against beta-lactamases because neither of these is of consequence in pneumococcal infections. Rather, its IV route of administration and long half-life allow for optimal drug exposure, even against penicillin-resistant S. pneumoniae. A common but incorrect assumption at the time of conversion to oral therapy is that an oral third-generation cephalosporin — or 3GC — should be selected to best mimic the therapy received intravenously. However, amoxicillin is more active than oral cephalosporins, particularly against strains of S. pneumoniae with elevated minimum inhibitory concentrations — generally up to 2 mg/L — owing to differences in pharmacokinetic profiles. To optimize drug concentration at the site of infection, an orally administered drug must be well absorbed from the gut and eliminated slowly from the body. In contrast to commonly prescribed oral cephalosporins, amoxicillin administered at high doses undergoes more complete absorption and slower elimination (see Table).

Dosing strategy is important to get full benefit of amoxicillin. Although moderately dosed amoxicillin (40-50 mg/kg per day) may be considered for OM and ABRS treatment among children without serious illness or risk factors for penicillin-nonsusceptible S. pneumoniae (PNSP), optimal exposure with extended activity against PNSP with a MIC of up to 2 µg/mL requires doses of 80 to 100 mg/kg per day, divided every 12 hours. When H. influenzae is suspected in addition to S. pneumoniae, amoxicillin/clavulanate is preferred because 30% to 50% of H. influenzae produce beta-lactamase and will not be susceptible to amoxicillin alone. Regarding a high-dose strategy for amoxicillin/clavulanate, only the 600-mg/5-mL formulation should be used because it holds clavulanate in a lower ratio to amoxicillin than other formulations, which allows for maximal amoxicillin dosing without excessive amounts of clavulanate.

For pneumococcal infections, reluctance to “step down” from IV ceftriaxone to high-dose oral amoxicillin is unfounded, and antibiotic selection should prioritize favorable pharmacokinetic profiles over a broader spectrum of activity and similarity in antibiotic class and generation. Consideration of concomitant pathogens and changing pathogenesis owing to pneumococcal vaccination warrant continued evolution of treatment guidelines.

Disclosure: Molloy reports no relevant financial disclosures.

Community-acquired pneumonia (CAP), otitis media (OM) and acute bacterial rhinosinusitis (ABRS) are common childhood illnesses. Although OM is more typically a childhood infection, CAP and ABRS are also common in adults. However, important differences exist in pathogenesis and treatment. Causative pathogens differ between children and adults. Streptococcus pneumoniae remains the predominant pathogen, and Haemophilus influenzae causes CAP less frequently in children than in adults, although this continues to evolve with the introduction of pneumococcal vaccines and may yield future changes to recommended empiric therapy. Additionally, Mycoplasma pneumoniae is the primary atypical pathogen in pediatric CAP but usually only in certain age groups with specific presenting features, and therefore it does not warrant universal empiric coverage.

Leah Molloy

Although beta-lactams are mainstays of IV treatment in the hospital setting for both children and adults, adult patients often complete treatment with oral fluoroquinolones or doxycycline, which have limited utility in children and are not preferred as first-line agents. Oral beta-lactams are therefore used frequently for outpatient management of pediatric respiratory infections, and proper selection of agent and dose are important and common sources of error.

Understanding both antibiotic resistance mechanisms and pharmacokinetic characteristics are necessary to choose the best antibiotic. Beta-lactam resistance among S. pneumoniae is mediated by penicillin-binding proteins (PBPs) altered through genetic recombination with existing streptococcal PBPs, which may be overcome with high drug concentrations. In contrast, PBP mutations in MRSA entail a novel PBP unable to bind to any beta-lactam at any concentration, except ceftaroline. Additionally, S. pneumoniae does not produce the same near-universal beta-lactamase as Staphylococcus. aureus, negating any advantage of beta-lactamase inhibitors like sulbactam, or broad-spectrum agents like cephalosporins that are stable against beta-lactamase. For these reasons, IV ampicillin is typically used as first-line treatment in the hospital setting, although ceftriaxone is preferred for children who are unvaccinated or in the setting of high local pneumococcal resistance to penicillin. The advantage of ceftriaxone lies not in its activity against gram-negative pathogens or its stability against beta-lactamases because neither of these is of consequence in pneumococcal infections. Rather, its IV route of administration and long half-life allow for optimal drug exposure, even against penicillin-resistant S. pneumoniae. A common but incorrect assumption at the time of conversion to oral therapy is that an oral third-generation cephalosporin — or 3GC — should be selected to best mimic the therapy received intravenously. However, amoxicillin is more active than oral cephalosporins, particularly against strains of S. pneumoniae with elevated minimum inhibitory concentrations — generally up to 2 mg/L — owing to differences in pharmacokinetic profiles. To optimize drug concentration at the site of infection, an orally administered drug must be well absorbed from the gut and eliminated slowly from the body. In contrast to commonly prescribed oral cephalosporins, amoxicillin administered at high doses undergoes more complete absorption and slower elimination (see Table).

Dosing strategy is important to get full benefit of amoxicillin. Although moderately dosed amoxicillin (40-50 mg/kg per day) may be considered for OM and ABRS treatment among children without serious illness or risk factors for penicillin-nonsusceptible S. pneumoniae (PNSP), optimal exposure with extended activity against PNSP with a MIC of up to 2 µg/mL requires doses of 80 to 100 mg/kg per day, divided every 12 hours. When H. influenzae is suspected in addition to S. pneumoniae, amoxicillin/clavulanate is preferred because 30% to 50% of H. influenzae produce beta-lactamase and will not be susceptible to amoxicillin alone. Regarding a high-dose strategy for amoxicillin/clavulanate, only the 600-mg/5-mL formulation should be used because it holds clavulanate in a lower ratio to amoxicillin than other formulations, which allows for maximal amoxicillin dosing without excessive amounts of clavulanate.

For pneumococcal infections, reluctance to “step down” from IV ceftriaxone to high-dose oral amoxicillin is unfounded, and antibiotic selection should prioritize favorable pharmacokinetic profiles over a broader spectrum of activity and similarity in antibiotic class and generation. Consideration of concomitant pathogens and changing pathogenesis owing to pneumococcal vaccination warrant continued evolution of treatment guidelines.

Disclosure: Molloy reports no relevant financial disclosures.