Influence of pH on the antimicrobial activity of clarithromycin and 14-hydroxyclarithromycin against Haemophilus influenzae using an in vitro pharmacodynamic model.

Clarithromycin activity can be influenced by the pH of the surrounding environment. Evidence supports a reduced pH of middle ear fluid (MEF) and lung tissues in patients with otitis media and pneumonia, respectively. To evaluate the influence of pH on clarithromycin activity, an in vitro pharmacodynamic chamber model (PDCM) was used to generate bacterial time-kill curves for clarithromycin and a 2:1 ratio of clarithromycin and 14-hydroxyclarithromycin (HC) against Haemophilus influenzae at three different pH values: 7.2, 6.8, 6.4. Concentrations observed in MEF and lung tissues were simulated for clarithromycin alone and clarithromycin plus HC. Differences in activity at each pH were identified by comparing initial kill curve slopes and total log reduction. Experiments with amoxicillin-clavulanate were conducted as a reference. In simulated MEF regimens at pH 7.2, activity of clarithromycin alone improved by adding HC (additional 2 log10 reduction at 8 h); however, at pH values of 6.8 and 6.4, kill curves resembled growth controls. In simulated lung regimens, differences between clarithromycin alone and clarithromycin plus HC were insignificant; both produced a 2 log10 reduction at pH 7.2, and activity dramatically dropped to < 0.4 log10 as pH declined. In contrast, amoxicillin-clavulanate consistently produced a 3 log10 reduction over each pH value with more rapid initial kill relative to all clarithromycin regimens. These findings suggest the activity of clarithromycin against H. influenzae may be significantly compromised in respiratory tract infections involving a reduced pH. Trials with emphasis on clinical outcomes analysis will assist further in determining the significance of these experimental findings.