Probability of achieving requisite pharmacodynamic exposure for oral beta-lactam regimens against Haemophilus influenzae in children.

Objective: To define contemporary levels of resistance of Haemophilus influenzae to antibacterials commonly used to treat children for bacterial respiratory infections, and to assess the probability of achieving the requisite pharmacodynamic exposures for regimens against recent respiratory H. influenzae isolates using Monte Carlo simulation.

Methods: 233 H. influenzae isolates obtained from pediatric outpatients with acute otitis media (n = 55), sinusitis (n = 58), or lower respiratory tract infections ( n = 120) from 1 November 2004 to 30 April 2005 were characterized for beta-lactamase production and susceptibility to a panel of 10 beta-lactam antimicrobials. 5000 concentration-time profiles were simulated for US FDA-approved doses of oral amoxicillin, amoxicillin/clavulanic acid, cefpodoxime, cefprozil, ceftibuten, and cefuroxime using pharmacokinetics and weights of 5-year old male children. The probability of attaining free drug concentrations above the minimum inhibitory concentration (MIC) for 50% of the dosing interval (50% fT > MIC) was assessed for each regimen against this population of H. influenzae.

Results: beta-Lactamase production was demonstrated in 67 (28.8%) of the H. influenzae isolates and varied by isolation site (38% acute otitis media, 36% sinusitis, and 21% lower respiratory tract infections). Regarding susceptibility, the rank order of the tested antimicrobials was ceftriaxone = cefixime (100%) > cefpodoxime (99.6%) > ceftibuten = amoxicillin/clavulanic acid (99.1%) > cefdinir (98.7%) > cefuroxime (97.4%) > cefprozil (93.1%) > cefaclor (92.3%) > amoxicillin (63.1%). The most active agents based on pharmacodynamic assessment (50% fT > MIC) were cefpodoxime (98.9%), ceftibuten (95.3%), and high-dose amoxicillin/clavulanic acid (90.4%). Several amoxicillin regimens also achieved a high likelihood of pharmacodynamic target attainment (91.8- 98.6%) when beta-lactamase-positive strains were excluded from the analysis.

Conclusion: Against H. influenzae, the antibacterials most likely to achieve optimal in vivo exposures in children are cefpodoxime, ceftibuten, and amoxicillin/clavulanic acid.