Amoxicillin-Clavulanic Acid for Treating Drug-Resistant Mycobacterium tuberculosis

Nadler, Jeffrey P.; Berger, Judith; Nord, Jill A.; Cofsky, Richard; Saxena, Mridula

doi:10.1378/chest.99.4.1025

Cited by 103 publications

(55 citation statements)

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“…Amoxicillinclavulanic acid has been used to successfully treat two patients with multi-drug-resistant tuberculosis when it was administered along with second-line drugs (18). Further evaluation of the clinical usefulness of amoxicillin-clavulanic acid alone or in combination with ethambutol in the treatment of mycobacterial infections is warranted.…”

Section: Discussionmentioning

confidence: 99%

“…Amoxicillin-clavulanic acid in combination with antimycobacterial agents has been used successfully to treat two patients with multiple-drug-resistant M. tuberculosis infections (18). Preliminary data demonstrate that amoxicillin-clavulanic acid MICs for M. tuberculosis obtained with the BACTEC system were 8/4 or 16/8 g/ml (17), and for 20 M. avium complex isolates screened, MICs were Յ 8/4 g/ml for 10 isolates, and MICs were Յ 4/2 g/ml for 8 isolates (28).…”

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Susceptibilities of nontuberculosis mycobacterial species to amoxicillin-clavulanic acid alone and in combination with antimycobacterial agents

Utrup

Moore

Actor

et al. 1995

Antimicrob Agents Chemother

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Neither amoxicillin nor clavulanic acid used alone was active at the highest level tested, i.e., 256.0 g/ml, in vitro against 24 isolates of Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium marinum. However, the MIC of an amoxicillin-clavulanic acid combination of 2:1 was <8.0/4.0 g/ml for 50 percent of the isolates tested, with all isolates being inhibited in the range of 4.0/2.0 to 32.0/16.0 g/ml, respectively. Titration of amoxicillin-clavulanic acid with a fixed 2-g/ml concentration of ethambutol resulted in synergistic activity against 3 of 9 isolates of M. fortuitum, 10 of 10 isolates of M. kansasii, and 5 of 5 isolates of M. marinum. This observation was confirmed in a checkerboard analysis in which fractional inhibitory concentrations were <0.5 for 20 of the 24 isolates. Synergistic activity was observed against the other four isolates in one of two trials. On the other hand, titration of amoxicillin-clavulanic acid in the presence of either one or two fixed concentrations of isoniazid, rifampin, cycloserine, tetracycline, or amikacin failed to result in synergism.There has been a resurgence of mycobacterial infections in the United States mainly attributed to the spread of AIDS in large metropolitan areas (4). A significant number of the mycobacterial isolates causing disease are nontuberculosis mycobacteria (NTM) (29,32). Of these organisms, Mycobacterium avium complex, which represents more than 60% of the NTM isolates, is by far the most common cause of opportunistic NTM infection in patients with AIDS (23, 32). Among other NTM isolates capable of causing infection are M. fortuitum complex (19%) and M. kansasii (10%), with the remaining 10% being other mycobacterial species (13,21). In addition to disseminated infections in patients with AIDS, NTM cause pulmonary, postoperative, soft tissue, and bone and joint infections (29,30).NTM tend to be resistant to a wide variety of antimicrobial agents including many of the ␤-lactam antibiotics (2). Resistance to ␤-lactam antibiotics has been attributed to an interplay between ␤-lactamase activity and cell permeability as well as a low affinity to penicillin-binding proteins (12,15). ␤-Lactamase production by mycobacteria is likely to be an important factor in the expression of resistance to ␤-lactam antibiotics (11, 12). Indeed, ␤-lactams in combination with either clavulanic acid or other ␤-lactamase inhibitors have in vitro activity against mycobacteria not observed with either agent alone (5,7,8,31).Amoxicillin-clavulanic acid in combination with antimycobacterial agents has been used successfully to treat two patients with multiple-drug-resistant M. tuberculosis infections (18). Preliminary data demonstrate that amoxicillin-clavulanic acid MICs for M. tuberculosis obtained with the BACTEC system were 8/4 or 16/8 g/ml (17), and for 20 M. avium complex isolates screened, MICs were Յ 8/4 g/ml for 10 isolates, and MICs were Յ 4/2 g/ml for 8 isolates (28).Since antimycobacterial agents are usually used in combination for the treatment of my...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Susceptibilities of nontuberculosis mycobacterial species to amoxicillin-clavulanic acid alone and in combination with antimycobacterial agents

Utrup

Moore

Actor

et al. 1995

Antimicrob Agents Chemother

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“…However, the effectiveness of b-lactam/b-lactamase inhibitor combinations has been shown in vitro for M. tuberculosis (Chambers et al, 1995;Cynamon & Palmer, 1983;Segura et al, 1998;Sorg & Cynamon, 1987), M. avium (Casal et al, 1987), M. fortuitum (Utrup et al, 1995;Wong et al, 1988) and M. smegmatis (Yabu et al, 1985). Clinical evidence suggests that b-lactam antibiotics in combination with b-lactamase inhibitors may be useful in the treatment of M. tuberculosis infection (Chambers et al, 1998;Nadler et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of the β-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to β-lactam antibiotics

2005

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Mycobacteria produce β-lactamases and are intrinsically resistant to β-lactam antibiotics. In addition to the β-lactamases, cell envelope permeability and variations in certain peptidoglycan biosynthetic enzymes are believed to contribute to β-lactam resistance in these organisms. To allow the study of these additional mechanisms, mutants of the major β-lactamases, BlaC and BlaS, were generated in the pathogenic Mycobacterium tuberculosis strain H37Rv and the model organism Mycobacterium smegmatis strain PM274. The mutants M. tuberculosis PM638 (ΔblaC1) and M. smegmatis PM759 (ΔblaS1) showed an increase in susceptibility to β-lactam antibiotics, as determined by disc diffusion and minimal inhibitory concentration (MIC) assays. The susceptibility of the mutants, as assayed by disc diffusion tests, to penicillin-type β-lactam antibiotics was affected most, compared to the cephalosporin-type β-lactam antibiotics. The M. tuberculosis mutant had no detectable β-lactamase activity, while the M. smegmatis mutant had a residual type 1 β-lactamase activity. We identified a gene, blaE, encoding a putative cephalosporinase in M. smegmatis. A double β-lactamase mutant of M. smegmatis, PM976 (ΔblaS1ΔblaE : : res), had no detectable β-lactamase activity, but its susceptibility to β-lactam antibiotics was not significantly different from that of the ΔblaS1 parental strain, PM759. The mutants generated in this study will help determine the contribution of other β-lactam resistance mechanisms in addition to serving as tools to study the biology of peptidoglycan biosynthesis in these organisms.

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“…An example of the former is the use of the beta-lactam-beta-lactamase inhibitor combination amoxicillin-clavulanate, which is active in vitro (3) and has early bactericidal activity in patients with pulmonary tuberculosis (1). Anecdotally, amoxicillin-clavulanate in combination with other second-line agents has been successfully used in selected patients infected with MDR strains (11,19). This approach has met considerable skepticism, and the role, if any, of amoxicillin-clavulanate remains unclear (18).…”

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Imipenem for Treatment of Tuberculosis in Mice and Humans

Chambers

Turner

Schecter

et al. 2005

Antimicrob Agents Chemother

103

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Chemotherapy of tuberculosis caused by multiple-drug-resistant (MDR) strains is problematic because of choices limited to relatively inefficacious and toxic drugs. Some beta-lactam antibiotics are active against Mycobacterium tuberculosis in vitro. We investigated the efficacy of imipenem in a mouse model of tuberculosis and in humans with MDR tuberculosis. Mice infected with M. tuberculosis strain H37Rv were treated with isoniazid or imipenem. Residual organisms in lung and spleen and survival of imipenem-treated mice were compared to those of untreated or isoniazid-treated mice. Ten patients with MDR tuberculosis also were treated with imipenem in combination with other first-or second-line agents; elimination of M. tuberculosis from sputum samples was measured by quantitative culture. Although it was less effective than isoniazid, imipenem significantly reduced the numbers of M. tuberculosis organisms in lungs and spleens and improved survival of mice. Eight of 10 patients with numerous risk factors for poor outcomes responded to imipenem combination therapy with conversion of cultures to negative. Seven remained culture-negative off of therapy. There were two deaths, one of which was due to active tuberculosis. Organisms were eliminated from the sputa of responders at a rate of 0.35 log 10 CFU/ml/week. Relapse upon withdrawal of imipenem and development of resistance to imipenem in a nonresponder suggest that imipenem exerts antimycobacterial activity in humans infected with M. tuberculosis. Imipenem had antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis.Treatment of tuberculosis caused by multiple-drug-resistant (MDR) (i.e., resistant to both isoniazid [INH] and rifampin) strains of Mycobacterium tuberculosis (MDR TB) is a challenge. Second-line antituberculous agents are less efficacious and more toxic than first-line drugs (5, 13). Fluoroquinolones, which can significantly improve response rates, are an important recent addition to the therapeutic armamentarium (13, 17), but other alternatives are desperately needed.Beta-lactams have not been regarded as useful drugs for treatment of tuberculosis because M. tuberculosis is naturally resistant to most of these antibiotics in vitro. Resistance is thought to be mediated by a class A beta-lactamase that hydrolyzes penicillins and cephalosporins (4,6,8). Resistance may be overcome by two means. One is inhibition of the beta-lactamase, and the other is the use of an antibiotic that is not a substrate for it. An example of the former is the use of the beta-lactam-beta-lactamase inhibitor combination amoxicillin-clavulanate, which is active in vitro (3) and has early bactericidal activity in patients with pulmonary tuberculosis (1). Anecdotally, amoxicillin-clavulanate in combination with other second-line agents has been successfully used in selected patients infected with MDR strains (11,19). This approach has met considerable skepticism, and the role, if any, of amoxicillin-clavulanate rem...

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Amoxicillin-Clavulanic Acid for Treating Drug-Resistant Mycobacterium tuberculosis

Cited by 103 publications

References 5 publications

Susceptibilities of nontuberculosis mycobacterial species to amoxicillin-clavulanic acid alone and in combination with antimycobacterial agents

Susceptibilities of nontuberculosis mycobacterial species to amoxicillin-clavulanic acid alone and in combination with antimycobacterial agents

Genetic analysis of the β-lactamases of Mycobacterium tuberculosis and Mycobacterium smegmatis and susceptibility to β-lactam antibiotics

Imipenem for Treatment of Tuberculosis in Mice and Humans

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