The vitro efficacy of β-lactam and β-lactamase inhibitors against multidrug resistant clinical strains of Mycobacterium tuberculosis

Dinçer, Irem; Ergin, Alper; Kocagoz, Tanil

doi:10.1016/j.ijantimicag.2003.09.023

Cited by 27 publications

(18 citation statements)

References 14 publications

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“…Other b-lactam-b-lactamase inhibitor combinations have also shown similar in vitro activity [134], but clinical efficacy data are limited [135,136]. Imipenem/ cilastatin is active against MDR and XDR strains M. tuberculosis in vitro [137].…”

Section: Sustained Political Commitmentmentioning

confidence: 99%

Treatment of tuberculosis: update 2010

Yew¹,

Lange²,

Leung³

2010

Eur Respir J

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Currently, the standard short-course chemotherapy for tuberculosis comprises a 6-month regimen, with a four-drug intensive phase and a two-drug continuation phase. Alternative chemotherapy using more costly and toxic drugs, often for prolonged durations generally .18 months, is required for multidrug-resistant and extensively drug-resistant tuberculosis. Directly observed treatment, as part of a holistic care programme, is a cost-effective strategy to ensure high treatment success and curtail development of drug resistance in tuberculosis. New antituberculosis drugs are urgently needed to improve the present standard short-course and alternative chemotherapies, by shortening administration durations and increasing cure rates, through the greater potency of these agents. At the same time, the role of adjunctive surgery for drug-resistant tuberculosis has to be better defined. Immunotherapy might improve treatment outcomes of both drug-susceptible and -resistant tuberculosis, and warrants further exploration.

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Section: Sustained Political Commitmentmentioning

confidence: 99%

Treatment of tuberculosis: update 2010

Yew¹,

Lange²,

Leung³

2010

Eur Respir J

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“…Several lines of evidence, however, suggest it is premature to discount the value of β-lactams for treatment of tuberculosis. Deletion of the gene encoding BlaC increases sensitivity of Mtb to β-lactams 4 and, in combination with inhibitors of β-lactamase, β-lactams show bactericidal activity against numerous strains of M. tuberculosis ( Mtb ), including multidrug-resistant (MDR) strains 5 . Moreover, a combination of amoxicillin and clavulanate shows some efficacy in patients with tuberculosis 6 , and meropenem in combination with clavulanate is potent against both aerobically and anaerobically grown strains of Mtb , as well as laboratory strains of MDR and XDR Mtb 7 , and improves survival of mice infected with Mtb H37Rv 8 .…”

Section: Introductionmentioning

confidence: 99%

The Role of the β5–α11 Loop in the Active-Site Dynamics of Acylated Penicillin-Binding Protein A from Mycobacterium tuberculosis

Fedarovich

Nicholas

Davies

2012

Journal of Molecular Biology

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Penicillin-binding protein A (PBPA) is a class B penicillin-binding protein that is important for cell division in M. tuberculosis. We have determined a second crystal structure of PBPA in apo form and compared it with an earlier structure of the apo enzyme. Significant structural differences in the active site region are apparent, including increased ordering of a β-hairpin loop and a shift of the SxN active site motif such that it now occupies a position that appears catalytically competent. Using two assays, including one that uses the intrinsic fluorescence of a tryptophan residue, we have also measured second-order acylation rate constants for the antibiotics, imipenem, penicillin G and ceftriaxone. Of these, imipenem, which has demonstrable antitubercular activity, shows the highest acylation efficiency. Crystal structures of PBPA in complex with the same antibiotics were also determined and all show conformational differences in the β5-α11 loop near the active site, but these differ for each β-lactam and also for each of the two molecules in the crystallographic asymmetric unit. Overall, these data reveal the β5-α11 loop of PBPA as a flexible region that appears important for acylation and provide further evidence that PBPs in apo form can occupy different conformational states.

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“…␤-Lactam antibiotics have little intrinsic activity against M. tuberculosis (18-21), but are effective in vitro when combined with a ␤-lactamase inhibitor (18,(20)(21)(22)(23). The combination of ␤-lactam antibiotics and ␤-lactamase inhibitors has shown anti-TB effect in humans (24,25), rodents (26), within macrophages (10), and against nonreplicating M. tuberculosis in vitro (8).…”

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confidence: 99%

Meropenem-Clavulanic Acid Has High In Vitro Activity against Multidrug-Resistant Mycobacterium tuberculosis

Forsman

Giske

Bruchfeld

et al. 2015

Antimicrob Agents Chemother

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We investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68 Mycobacterium tuberculosis isolates. We included predominantly multi-and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/ liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB. Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is unrelentingly increasing worldwide. As MDR/XDR-TB is notoriously difficult to treat, already approved drugs, such as trimethoprim-sulfamethoxazole, are being investigated as treatment options (1). The activity of penicillin against Mycobacterium tuberculosis was investigated in the 1940s (2), but ␤-lactams were deemed ineffective. However, it was later shown that the ␤-lactamase BlaC causes the hydrolysis of ␤-lactam antibiotics (3-6). This hydrolysis can be inhibited by the ␤-lactamase inhibitor clavulanic acid (CLA), which irreversibly inactivates BlaC (6, 7). Meropenem (MEM) is a ␤-lactam antibiotic of the carbapenem group. Even though MEM is a relatively poor substrate for BlaC (8), MEM on its own shows conflicting evidence regarding antituberculous activity (9-12). Hence, the combination meropenem-clavulanic acid (MEM-CLA) is an interesting treatment alternative for drug-resistant TB, but there is a lack of in vitro and in vivo studies for this combination. The aim of this study was to investigate the in vitro effect of MEM-CLA against M. tuberculosis, predominantly MDR/XDR-TB isolates.Using Middlebrook 7H10, 94 M. tuberculosis isolates were studied. The isolates consisted of clinical isolates and isolates submitted to the Public Health Agency of Sweden for proficiency drug susceptibility testing, with all isolates being globally sourced. A total of 68 isolates showed sufficient growth to be studied further, and they were categorized into three resistance groups consisting of 36 MDR-TB, 13 XDR-TB, and 19 with mixed resistance patterns (non-MDR/XDR-TB). Strain H37Rv (ATCC 27294) was used as the control. Middlebrook 7H10 agar (Becton Dickinson AB, Stockholm, Sweden) enriched with 10% oleic acid-albumindextrose-catalase (OADC) and 5% glycerol was prepared in 14-cm petri dishes, each dish containing 60 ml of agar. A stock solution was prepared by diluting MEM with water, and then applied in serial two-step dilutions, reaching a final antibiotic concentration range of 0.002 to 512 mg/liter of MEM. CLA was added to all dishes at a concentration of 64 mg/liter in order to ensure a sufficient concentration of the ␤-lactamase inhibitor throughout the whole experiment. Due to the short half-life of CLA in solid media (1.4 days) (13), the concentration of CLA after the first week of our experiment was expected to be around 2 mg/liter, similar to the concentration of CLA seen in seru...

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The vitro efficacy of β-lactam and β-lactamase inhibitors against multidrug resistant clinical strains of Mycobacterium tuberculosis

Cited by 27 publications

References 14 publications

Treatment of tuberculosis: update 2010

Treatment of tuberculosis: update 2010

The Role of the β5–α11 Loop in the Active-Site Dynamics of Acylated Penicillin-Binding Protein A from Mycobacterium tuberculosis

Meropenem-Clavulanic Acid Has High In Vitro Activity against Multidrug-Resistant Mycobacterium tuberculosis

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