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The activity of 14-hydroxy clarithromycin, alone and in combination with clarithromycin, against penicillin- and
S J Martin1, C G Garvin, C R McBurney
1The Infectious Diseases Research Laboratory at The University of Toledo, College of Pharmacy, 2801 W. Bancroft Street, Toledo, OH 43606, USA. smartin2@pop3.utoledo.edu
Abstract:
There are no data regarding the activity of clarithromycin's active metabolite, 14-hydroxy clarithromycin, against penicillin-intermediate, penicillin-resistant or erythromycin-resistant Streptococcus pneumoniae. Agar dilution MICs were determined for clarithromycin, 14-hydroxy clarithromycin (henceforth called 'metabolite'), azithromycin, erythromycin and clarithromycin/metabolite (2:1 and 1:1 ratio) against 24 penicillin-intermediate and 14 penicillin-resistant strains, including 13 erythromycin-resistant clinical strains and one ATCC strain of S. pneumoniae. The interaction between clarithromycin and its metabolite was determined using an agar chequerboard assay against all isolates, and time-kill tests were performed against five penicillin-intermediate (macrolide-susceptible) and five penicillin-resistant (two macrolide-resistant) strains of S. pneumoniae using all antibiotics alone at simulated peak serum concentrations, and clarithromycin/metabolite in a 2:1 ratio (physiological). MICs were as follows: clarithromycin, 0.008-->64 mg/L; metabolite, 0.015-->64 mg/L; erythromycin, 0.015-->64 mg/L; azithromycin, 0.125-->64 mg/L; clarithromycin/metabolite (1:1 and 2:1 combinations), 0.001-->64 mg/L. The MIC of the clarithromycin/metabolite combination was one or more tube dilution lower than the MIC of clarithromycin in 28 of the isolates tested. In chequerboard testing, 13 strains (seven erythromycin susceptible and six erythromycin resistant) demonstrated synergy, 18 additivity and seven indifference. In time-kill testing, bacterial eradication below detection limits occurred with clarithromycin and metabolite in seven of 10 organisms. The combination of parent and metabolite was more rapidly bactericidal than clarithromycin alone in six of the seven isolates (P = 0.026). The metabolite has potent activity against S. pneumoniae and enhances the activity of the parent compound against this organism. The metabolite's activity must be considered in evaluating clarithromycin in vitro to avoid underestimation of clarithromycin's activity against the pneumococcus.
Insights
The active metabolite of clarithromycin, 14-hydroxy clarithromycin, shows potent activity against Streptococcus pneumoniae. Combining clarithromycin with its metabolite enhances antibacterial efficacy, especially against resistant strains.
Area of Science:
- Pharmacology and Microbiology
- Antimicrobial Resistance
- Drug Metabolism
Background:
- Limited data exist on the activity of 14-hydroxy clarithromycin against resistant Streptococcus pneumoniae strains.
- Understanding clarithromycin's metabolite activity is crucial for accurate in vitro susceptibility testing.
- Penicillin-intermediate and resistant Streptococcus pneumoniae pose significant therapeutic challenges.
Purpose of the Study:
- To evaluate the in vitro activity of 14-hydroxy clarithromycin against various Streptococcus pneumoniae strains.
- To assess the synergistic or additive effects of combining clarithromycin with its metabolite.
- To determine the bactericidal activity of the clarithromycin-metabolite combination.
Main Methods:
- Agar dilution Minimum Inhibitory Concentrations (MICs) were determined for clarithromycin, its metabolite, azithromycin, and erythromycin.
- Agar chequerboard assays assessed drug interactions, and time-kill tests evaluated bactericidal activity.
- Testing included penicillin-intermediate, penicillin-resistant, and erythromycin-resistant Streptococcus pneumoniae isolates.
Main Results:
- 14-hydroxy clarithromycin demonstrated potent activity against Streptococcus pneumoniae isolates.
- Clarithromycin/metabolite combinations showed lower MICs than clarithromycin alone in many strains.
- Synergy was observed in 13 strains, and the combination was more rapidly bactericidal than clarithromycin alone in most tested isolates.
Conclusions:
- 14-hydroxy clarithromycin possesses significant intrinsic activity against Streptococcus pneumoniae.
- The metabolite enhances the activity of clarithromycin, particularly against resistant strains.
- In vitro susceptibility testing should account for the metabolite's activity to avoid underestimating clarithromycin's efficacy.