Antimicrobial resistance in Haemophilus influenzae

Abstract

Haemophilus influenzae is a major community-acquired pathogen causing significant morbidity and mortality worldwide. Meningitis and bacteremia due to type b strains occur in areas where the protein-conjugated type b vaccine is not in use, whereas nontypeable strains are major causes of otitis media, sinusitis, acute exacerbations of chronic bronchitis, and pneumonia. Antibiotic resistance in this organism is more diverse and widespread than is commonly appreciated. Intrinsic efflux resistance mechanisms limit the activity of the macrolides, azalides, and ketolides. beta-Lactamase production is highly prevalent worldwide and is associated with resistance to ampicillin and amoxicillin. Strains with alterations in penicillin binding proteins, particularly PBP3 (beta-lactamase negative ampicillin resistant and beta-lactamase positive amoxicillin-clavulanate resistant), are increasing in prevalence, particularly in Japan, with increasing resistance to ampicillin, amoxicillin, amoxicillin-clavulanate, and many cephalosporins, limiting the efficacy of expanded-spectrum cephalosporins against meningitis and of many oral cephalosporins against other diseases. Most strains remain susceptible to the carbapenems, which are not affected by penicillin binding protein changes, and the quinolones. The activity of many oral agents is limited by pharmacokinetics achieved with administration by this route, and the susceptibility of isolates based on pharmacokinetic and pharmacodynamic parameters is reviewed.

FIG. 1.

Correlation between β-lactam resistance mechanisms and susceptibility of H. influenzae to ampicillin, cefotaxime, and meropenem. Data were adapted from Hasegawa et al. (57) and Sanbongi et al. (125). The figure was created by M. Jacobs.

FIG. 2.

MIC distributions of selected β-lactam antimicrobial agents for H. influenzae. Arrows indicate PK/PD breakpoints. The two arrows shown for amoxicillin and amoxicillin-clavulanate indicate breakpoints applicable to lower (left) and higher (right) dosing regimens. The two arrows shown for cefuroxime indicate breakpoints applicable to oral (left) and parenteral (right) dosing regimens. The figure was created by M. Jacobs.

FIG. 3.

MIC distributions of selected non-β-lactam antimicrobial agents for H. influenzae. Arrows indicate PK/PD breakpoints. The figure was created by M. Jacobs.