Clarithromycin antibacterial activity

Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47). Clarithromycin also has activity against M leprae and Toxoplasma gondii. Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin. 

Clarithromycin is metabolized in the liver. The major metabolite is 14-hydroxyclarithromycin, which also has antibacterial activity. A portion of active drug and this major metabolite is eliminated in the urine, and dosage reduction (eg, a 500-mg loading dose, then 250 mg once or twice daily) is recommended for patients with creatinine clearances less than 30 mL/min. Clarithromycin has drug interactions similar to those described for erythromycin. 

Clarithromycin has a spectrum of antibacterial activity similar to that of erythromycin, but is also effective against Haemophilus influenzae. Its activity against intracellular pathogens such as Chlamydia. Legionella and Ureaplasma is higher than that of erythromycin (Figure 31.9). 

Macrolide antibiotics are a homogeneous group of antimicrobial drugs that have been used to treat clinical infections for several decades. The most clinically useful classification of the macrolides is based on the size of the lactone ring that forms the chemical nucleus of each macrolide molecule [1, 2]. The 14- and 15-membered macrolides include erythromycin, clarithromycin, dirithromycin, roxithromycin, and azithromycin. Erythromycin is the oldest and still the most important of the macrolide antibiotics because it is a useful alternative to penicillin G. It is one of the safest antibiotics available. Clarithromycin and azithromycin have shown some advantages over erythromycin in their antibacterial activity,... 

Erythromycin is active against gram-positive cocci with the exception of enterococci. Erythromycin is also active against Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia pneumoniae, and Borrelia burgdorferi. Clarithromycin and azithromycin have antibacterial spectra similar to that of erythromycin except that they have enhanced activity against H. influenzae. 

The antibacterial spectrum of these macrolides is broader. For example, the clinical modification at C6 [e.g., O-methylation (clarithromycin)] or at C9 [e.g., some 9-ether oxime derivatives (roxithromycin and dirithromycin)] stabilizes 14-membered lactone rings in acidic media, even when the modified drugs have been orally administered. Drugs with an expanded erythromycin A-lactone ring (e.g., azithromycin) are also more stable in acidic media and display better antigram-negative activity than does erythromycin A. 

Erythromycin is a known inhibitor of the cytochrome P450 isoenzyme CYP3A4. However, this isoenzyme has only a minor role in the metabolism of warfarin , (p.358), specifically the less active R-isomer of warfarin. Consequently, only minor increases in the levels of warfarin have been seen in pharmacokinetic studies, which would generally not be expected to be clinically relevant. However, it is possible that even these small changes might be important in a very few patients, particularly those with a low prothrombin complex aetivity. Other macrolides (azithromycin, clarithromycin, dirithromycin, roxithromycin) have less effect on CYP3A4 than erythromycin, and consequently would be expected to have even less effect on the pharmacokinetics of warfarin or acenocoumarol, which is borne out in the few studies available. Nevertheless, cases of interactions have been reported for nearly all these macrolides. Moreover, one cohort study found that clarithromycin increased the risk of an interaction and erythromycin did not. It is possible that there is some other, as yet unidentified, mechanism involved. Alternatively, it is equally possible that the relatively few cases just represent idiosyncratic effects attributable to other factors, and not to any interaction (see also Coumarins -i- Antibacterials , p.365). 

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