Effectiveness of the macrolide clarithromycin in the treatment ofMycobacterium avium complex infection in HIV-infected patients

MICs of clarithromycin, amikacin, isoniazid, rifabutin, ciprofloxacin, sparfloxacin, ethambutol, and clofazimine were determined for six isolates of Mycobacterium avium complex (MAC) from AIDS patients both by the radiometric method and by an ex vivo model of infection in human macrophages. The median MICs in macrophages were similar or slightly lower than values found in broth, except for amikacin, which had slightly higher MICs inside the cells. Combinations of clarithromycin with other antimicrobial agents showed that clarithromycin-clofazimine and clarithromycin-rifabutin were synergistic on five of six strains while clarithromycin-amikacin and clarithromycin-isoniazid were antagonistic on one and two strains, respectively. The addition of amikacin made the combinations of clarithromycin-clofazimine and clarithromycin-ethambutol synergistic against all the MAC strains. In the macrophage model, the combination of clarithromycinclofazimine (mean survival, 21%) and clarithromycin-rifabutin (mean survival, 29%) showed a strong reduction in viable counts compared with single drugs, while clarithromycin-amikacin was less active than single drugs alone. In general, the addition of amikacin did not improve the activity of the combinations, except for clarithromycin-isoniazid-amikacin (mean survival, 19%), which was significantly more active than either clarithromycin-isoniazid or clarithromycin-amikacin. The use of the macrophage model can suggest new combinations of antimicrobial agents with anti-MAC activity which, on the basis of their in vitro effectiveness, would probably be disregarded for assay in animal models.Mycobacterium avium complex (MAC) infections are very common in AIDS patients, with an estimated prevalence of 43% in the 2 years following the diagnosis of AIDS (25). Therapy for MAC diseases usually involves the combination of several drugs, not only to obtain a greater antimycobacterial effect but also to decrease the probability of selecting resistant mutants (13,15). In some studies, the efficacy of different antimicrobial combinations has been evaluated in vitro (12,34), while in others the activity has been investigated with human macrophages (MP) (33,35,37) or in the murine MP cell line J774 (33,35,36). The Public Health Service Task Force on Prophylaxis and Therapy for MAC recently recommended clarithromycin (CLA)-containing regimens for therapy for disseminated infections by these organisms in AIDS patients (20). At the present time, only for a few reports has the activity of CLA-containing combinations been studied, by in vitro and ex vivo methods, on the same strains (27,28).In this study, we assessed the susceptibility of MAC strains isolated in Italy from AIDS patients (7) by determining the MICs of eight antimicrobial agents both by the radiometric method (11) and by a model of human monocyte-derived MP infection (22,23). This was adopted to evaluate the relationship between the extracellular and intracellular activities of drugs with different capacities for accumulating within MP (31)....

Section: Discussionmentioning

confidence: 99%

In vitro and ex vivo activities of antimicrobial agents used in combination with clarithromycin, with or without amikacin, against Mycobacterium avium

Fattorini

Piersimoni

et al. 1995

“…A double-blind clinical trial showed that within 6 weeks, monotherapy with clarithromycin produced a dramatic decrease in the number of viable bacteria in the blood of patients with AIDS and disseminated MAC infection (3). However, it was simultaneously noted that monotherapy with clarithromycin can lead to drug resistance (21).…”

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confidence: 99%

Identification of mutations in 23S rRNA gene of clarithromycin-resistant Mycobacterium intracellulare

Meier

Kirschner

Springer

et al. 1994

184

130

Clarithromycin is a potent macrolide that has been used for treating infections with nontuberculous mycobacteria. Pairs of susceptible and resistant Mycobacterium intracellulare strains were obtained from patients with chronic pulmonary M. intracellulare infections undergoing monotherapy with clarithromycin. Nucleotide sequence comparisons of the peptidyltransferase region in 23S rRNAs from parental and resistant strains revealed that in three of six resistant strains, for which the MIC was >32 ,ug/ml, a single base was mutated (Escherichia coli equivalent, A-2058 ->G, C, or U). As the modification of adenine 2058 by dimethylation is a frequent cause of macrolide resistance in a variety of different bacteria, we suggest that mutation of A-2058 confers acquired resistance to clarithromycin in M. intracellulare.Slowly growing mycobacteria, including Mycobacterium kansasii, M. marinum, M. simiae, M. scrofulaceum, M. szulgai, M. nonchromogenicum, M. intracellulare, and M. avium complex (MAC), have been implicated in various types of human diseases, including skin and soft tissue infections and pulmonary disease. Notably, a common complication in patients with late-stage AIDS is disseminated infection with MAC. In relation to the CD4 cell count, the prevalences of disseminated MAC infection in these patients were reported to be 21% at 1 year and 43% at 2 years following the diagnosis of AIDS (17).Recently, new macrolides, including clarithromycin, roxithromycin, and azithromycin, were synthesized. The in vitro evaluations of these new macrolides as potential therapeutic agents for mycobacterial infections have demonstrated that clarithromycin in particular has activity against isolates of nontuberculous mycobacteria (1, 2, 9). A double-blind clinical trial showed that within 6 weeks, monotherapy with clarithromycin produced a dramatic decrease in the number of viable bacteria in the blood of patients with AIDS and disseminated MAC infection (3). However, it was simultaneously noted that monotherapy with clarithromycin can lead to drug resistance (21).Macrolides are bacteriostatic antibiotics which inhibit the peptidyltransferase region of the 50S ribosomal subunit (for a review, see reference 6). A few years after the introduction of erythromycin for therapy, resistance of Staphylococcus aureus to this drug emerged. For these resistent strains, simultaneous resistance to other macrolides, to lincomycin, and to streptogramin B antibiotics was noted. This is the so-called MLS phenotype (29). Although the exact mechanism of translational inhibition by these drugs is still undetermined, a peptidyltransferase center in a small region of 23S rRNA has been identified by mapping resistance to several transferase inhibitors. In particular, the Escherichia coli equivalent A-2058 (511) 532-4366. 381 implicated in peptidyl transfer (18). The MLS cross-resistance phenotype due to modification of the drug target is widely distributed and has been detected in a number of grampositive and gram-negative bacteria. Clinically ac...

“…Clarithromycin is a recently approved 14-membered macrolide with increased stability in acid and improved pharmacokinetics, including the appearance of a microbiologically active metabolite in humans (8). Clarithromycin possesses broad-spectrum antimicrobial activity, inhibiting a range of gram-positive and gram-negative organisms, some anaerobes, and atypical pathogens (1,3,14,16,25), in many cases with greater in vitro activity than erythromycin.…”

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confidence: 99%

Tight binding of clarithromycin, its 14-(R)-hydroxy metabolite, and erythromycin to Helicobacter pylori ribosomes

Goldman

Zakula

Flamm

et al. 1994

Clarithromycin is a recently approved macrolide with improved pharmacokinetics, antibacterial activity, and efficacy in treating bacterial infections including those caused by Helicobacter pylori, an agent implicated in various forms of gastric disease. We successfully isolated ribosomes from H. pylorz and present the results of a study of their interaction with macrolides. Kinetic data were obtained by using '4C-labeled macrolides to probe the ribosomal binding site. Clarithromycin, its parent compound erythromycin, and its 14-(R)-hydroxy metabolite all bound tightly to H. pylori ribosomes. Kd values were in the range of 2 x 10-10 M, which is the tightest binding interaction observed to date for a macrolide-ribosome complex. This tight binding was due to very slow dissociation rate constants of 7.07 x 10", 6.83 x 10-4, and 16.6 x 10-4 min-' for clarithromycin, erythromycin, and 14-hydroxyclarithromycin, respectively, giving half-times of dissociation ranging from 7 to 16 h, the slowest yet measured for a macrolide-ribosome complex. These dissociation rate constants are 2 orders of magnitude slower than the dissociation rate constants of macrolides from other gram-negative ribosomes.[14C]clarithromycin was bound stoichiometrically to 50S ribosomal subunits following incubation with 70S ribosomes and subsequent separation of the 30S and 50S subunits by sucrose density gradient centrifugation. These data predict that the lower MIC of clarithromycin compared with that of erythromycin for H. pylori is likely due to a faster rate of intracellular accumulation, possibly because of increased hydrophobicity.