Macrolides currently account for 10% to 15% of the worldwide oral antibiotic market.' Erythromycin, the first macrolide antibiotic, was discovered in 1952 from a strain of Streptomyces erythreus obtained from soil samples in the Phillipines. Originally, erythromycin was marketed as an alternative to penicillin because of its activity against gram-positive organisms such as staphylococci, pneumococci, and streptococci. Subsequently, its clinical use broadened to include species of Mycoplasma, Legionella, Campylobacter, and Chlamydia. Although several other macrolides have been marketed in countries other than the United States, they have failed to achieve erythromycin's widespread use. Unfortunately, erythromycin suffers from several drawbacks, including gastrointestinal side effects, a short serum elimination half-life, and only borderline in vitro activity against common gram-negative respiratory pathogens such as Haemophilus influenzae.

Azithromycin and clarithromycin are erythromycin analogues that have recently been approved by the FDA. These drugs inhibit protein synthesis in susceptible organisms by binding to the 50S ribosomal subunit. Alteration in this binding site confers simultaneous resistance to all macrolide antibiotics. Clarithromycin is several-fold more active in vitro than erythromycin against gram-positive organisms, while azithromycin is 2- to 4-fold less potent. Azithromycin has excellent in vitro activity against H influenzae (MIC90 0.5 microgram/ml), whereas clarithromycin, although less active against H influenzae (MIC90 4.0 micrograms/ml) by standard in vitro testing, is metabolized into an active compound with twice the in vitro activity of the parent drug. Both azithromycin and clarithromycin are equivalent to standard oral therapies against respiratory tract and soft tissue infections caused by susceptible organisms, including S aureus, S pneumoniae, S pyogenes, H influenzae, and M catarrhalis. Clarithromycin is more active in vitro against the atypical respiratory pathogens (e.g., Legionella), although insufficient in vivo data are available to demonstrate a clinical difference between azithromycin and clarithromycin. Superior pharmacodynamic properties separate the new macrolides from the prototype, erythromycin. Azithromycin has a large volume of distribution, and, although serum concentrations remain low, it concentrates readily within tissues, demonstrating a tissue half-life of approximately three days. These properties allow novel dosing schemes for azithromycin, because a five-day course will provide therapeutic tissue concentrations for at least ten days. Clarithromycin has a longer serum half-life and better tissue penetration than erythromycin, allowing twice-a-day dosing for most common infections. Azithromycin pharmacokinetics permit a five-day, single daily dose regimen for respiratory tract and soft tissue infections, and a single 1 g dose of azithromycin effectively treats C trachomatis genital infections; these more convenient dosing schedules improve patient compliance. Azithromycin and clarithromycin also are active against some unexpected pathogens (e.g., B burgdorferi, T gondii, M avium complex, and M leprae). Clarithromycin, thus far, appears the most active against atypical mycobacteria, giving new hope to what has become a difficult group of infections to treat. Gastrointestinal distress, a well known and major obstacle to patient compliance with erythromycin, is relatively uncommon with the new macrolides. Further clinical data and experiences may better define and expand the role of these new macrolides in the treatment of infectious diseases.

We compared ciprofloxacin, rifampin, and gentamicin treatments, alone and in combination, for 5 days in the therapy of experimental aortic valve endocarditis in rats caused by a clinical isolate of vancomycin-resistant Enterococcusfaecium. The MICs and MBCs of vancomycin, ciprofloxacin, rifampin, and gentamicin were 250 and >1,000, 3.1 and 6.3, 0.098 and 1.6, and 12.5 and >50 Fg/ml, respectively. Infected rats were sacrificed after completing 5 days of therapy. Additional rats within each treatment group were followed for 5 days beyond the last dose of antibiotic therapy. Although survivals in the different groups were not significantly different after 5 days of therapy, survival was significantly better 5 days beyond the last dose of antibiotic therapy in rats treated with rifampin-containing regimens. The combination of ciprofioxacin and gentamicin was bactericidal in vitro and in vegetations from rats with enterococcal endocarditis. Rifampin alone was similarly bactericidal in vivo, but it was not signifcantly better than rifampin in combination with other antibiotics. Subpopulations resistant to rifampin, but not ciprofloxacin, were detected in the inoculum and in most vegetations during therapy. However, the combination of ciprofloxacin plus both gentamicin and rifampin reduced both the rifampin-susceptible and -resistant population in vegetations of 9 of 10 animals below the level of detection after 5 days of therapy. Nevertheless, a residual enterococcal population apparently remained in numbers of <2 log10 CFU/g after 5 days of therapy, which resulted in relapse. Perhaps a longer course of therapy would have eliminated this residual population and improved efficacy.An aminoglycoside in combination with either penicillin or vancomycin has been the standard regimen for the treatment of serious enterococcal infections such as endocarditis (2). Recently, high-level penicillin resistance (MIC, > 100 Fg/ml) has been described in Enterococcus faecium (3, 21) and t-lactamase production has been described in Enterococcus faecalis (6, 13). High-level aminoglycoside resistance (MIC, >1,000 ,ug/ml) has been described in both species. Vancomycin-resistant enterococci have continued to be reported (8,10,17) with increasing frequency as a cause of nosocomial infections since they were first described by Uttley et al. in 1988 (19). Consequently, treatment of serious enterococcal infections has become problematic. We identified a nosocomial outbreak caused by a vancomycin-resistant E. faecium isolate that was also resistant to penicillin and streptomycin; in vitro data suggested that ciprofloxacin in combination with rifampin and gentamicin was active against this isolate (11). Bacteremic infections in several patients responded clinically and bacteriologically to this antibiotic combination. The purpose of the study described here was to determine the efficacies of ciprofloxacin, rifampin, and gentamicin, each alone and in combination, in a rat model of experimental endocarditis caused by this strain. We also evaluated...

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A man with ventriculitis caused by and carbapenem-resistant was successfully treated with i.v. ceftazidime-avibactam and intrathecal amikacin.