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, respect ively. To evaluate the influence of pH on clarithromycin activity, an in vitro pharmacodynamic chamber model (PDCM) was used to generate bac terial time-kill curves for clarithromycin and a 2:1 ratio of clarithr omycin and 14-hydroxyclarithromycin (HC) against Haemophilus influenza e at three different pH values: 7.2, 6.8, 6.4. Concentrations observed in MEF and lung tissues were simulated for clarithromycin alone and c larithromycin plus HC. Differences in activity at each pH were identif ied by com paring initial kill curve slopes and total log reduction. E xperiments 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 log(10) reduction at 8 h); howeve r, 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 log(1 0) reduction at pH 7.2, and activity dramatically dropped to <0.4 log( 10) as pH declined. In contrast, amoxicillin-clavulanate consistently produced a 3 log(10) reduction over each pH value with more rapid init ial kill relative to all clarithromycin regimens. These findings sugge st the activity of clarithromycin against H. influenzae may be signifi cantly compromised in respiratory tract infections involving a reduced pH. Trials with emphasis on clinical outcomes analysis will assist fu rther in determining the significance of these experimental findings. (C) 1997 Elsevier Science Inc.