Azithromycin And Clarithromycin Update

The median MICs (minimum inhibitory concentrations) against Mycobacterium-avium-M. intracellulars complex was found to be 8 ng/ml for azithromycin and <2 ng/ml for clarithromycin (55). The MIC value for clarithromycin against 46 strains of M. ulerans ranged from 0.125-2 ng/ml at pH 6.6 and from 0.125-0.5 ng/ml at pH 7.4 (56). The MICgo value for clarithromycin tested against Actinobacillus actinomycetem-comitans is < 2 ng/ml (57). The susceptibility of Coxiella burnetii, the etiologic agent for Q fever, to clarithromycin was found to have an MIC value ranging from 2-4 ng/mi (58). The pH effect of carbon dioxide on the susceptibility testing of azithromycin and clarithromycin against 178 clinical isolates from the lower respiratory tract of patients with chronic obstructive pulmonary disease were studied. The MICs measured in air alone were lower than those measured in 5% carbon dioxide. However, testing of isolates in 5% carbon dioxide on pH-adjusted medium (pH 8.4) reduced the loss of activity (59). Molecular investigation of the postantibiotic effects of clarithromycin on S. aureus cells indicated the reduction of the number of 50S ribosomal subunits to 13% of the untreated control while the 30S subunit formation was not affected (60).

A simple assay using infected J774 cells for the quantitation of activities of clarithromycin and azithromycin against intracellular Legionella pneumophila has been developed (61). This MTT assay system permits comparative and quantitative evaluation of intracellular activities of macrolides and processing a large number of samples efficiently. A model of continuous Chlamydia pneumoniae infections in vitro closely resembling to the actual events in vivo was developed (62). HEp-2 cells inoculated with CM-1 and TW-183 strains have been persistently infected for a periods of over 1.5 and 2 years, respectively. Using this model, azithromycin was found to reduce but not to completely eliminate the organism. This observation is in agreement with the failure of antibiotic therapy against C. pneumoniae infection in humans. A liquid chromatographic method using a cyanopropyl column with electrochemical detection for the determination of macrolides was reported (63).

A study of the pharmacodynamics of clarithromycin and azithromycin on their efficacy against pulmonary H. influenzae infection in rats suggested that duration of therapy should be considered as a key parameter in the evaluation of macrolide efficacy (64). The serum area under the curve when the drug concentration in serum is plotted against time was found to be the best predictor of the in vivo efficacy of macrolides in a mouse thigh model (65). The effects on interaction of macrolides and other chemical substances were reported. Using a chemostat continuous-culture system against slow-growing H. pylori, combination of amoxicillin and clarithromycin was found to be bactericidal at pHs 6.5 and 7.0 (66). The combination of azithromycin-lansoprazole was found to be synergic on 60% of H. pylori strains (67). The combination of azithromycin and rifampin produced good activity and higher rates of eradication of C. pneumoniae from lung tissues than azithromycin alone in experimental mouse pneumonitis (68). Atovaquone was found to interact pharmacokinetically with azithromycin in human immunodeficiency virus-infected children. At steady-state, the values of azithromycin's area under the concentration-time curve from 0 to 24 hour and maximum concentration in serum were consistently lower than azithromycin administered alone (69). Administration of grapefruit juice increased the time to peak concentration of both clarithromycin and 14-hydroxylclarithromycin, but did not affect other pharmacokinetic parameters (70). Oral administration of cimetidine, however, prolonged clarithromycin absorption (71). Although zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically significant pharmacokinetic effect on azithromycin, clarithromycin or 14-hydroxy-clarithromycin (72).

Several clinical studies on macrolides have been reported. Due to their safety profile, macrolides represent one of the few potential therapeutic options for pregnant women and children infected with Orientia tsutsugamushi, the etiologic agent of scrub typhus. Azithromycin administered to two pregnant women infected with drug-resistant strains of 0. tsutsugamushi in northern Thailand rapidly abated the symptoms, signs and fever in these patients (73). A comparative trial between azithromycin and ciprofloxacin for treatment of uncomplicated typhoid fever in Egypt on 123 adults infected with or without multidrug resistance strains of Salmonella typhi showed that both azithromycin and ciprofloxacin were similarly effective, clinically and bacteriologically (74). A prospective, open-label, randomized study of azithromycin in acute otitis media in children was conducted. Bacteriologic failure after 3 to 4 days of treatment occurred in high proportion (53%) of culture-positive patients, especially in those infected with H. influenzae. It was suggested that the current susceptibility breakpoint for azithromycin for H. influenzae should be considerably lowered for acute otitis media caused by H. influenzae (75). The pharmacokinetic study on serum and leukocyte exposure following oral azithromycin, given over 3- or 5- day in healthy subjects indicated that the exposures of serum and both types of WBCs were similar with both regimens and that azithromycin can be administered over either 3 or 5 days (76). The intracellular disposition of clarithromycin and azithromycin in AIDS patients requiring Mycobacterium avium complex (MAC) prophylaxis was investigated. Both drugs displayed sustained intracellular concentrations in mononuclear and polymorphonuclear leukocytes exceeding their MICs for MAC for the entire dosing period (77). A multicenter, randomized, dose-ranging study on azithromycin for treating disseminated MAC patients with AIDS produced symptomatic improvement on patients with both 600 and 1,200 mg daily dose regimens (78).

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