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.


CONCLUSIONS
Against H. influenzae, the antibacterials most likely to achieve optimal in vivo exposures in children are cefpodoxime, ceftibuten, and amoxicillin/clavulanic acid.
Pichichero
Michael E
ME
Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, USA. michael_pichichero@urmc.rochester.edu
Doern
Gary V
GV
Kuti
Joseph L
JL
Nicolau
David P
DP
D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002648:Child; D006192:Haemophilus Infections / Q000188:drug therapy*; D006193:Haemophilus influenzae / Q000187:drug effects*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D010033:Otitis Media / Q000188:drug therapy; D012141:Respiratory Tract Infections / Q000188:drug therapy; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000378:metabolism; D047090:beta-Lactams / Q000008:administration & dosage / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D001618:beta-Lactamases