<i>In Vitro</i>
            and
            <i>In Vivo</i>
            Efficacy of β-Lactams against Replicating and Slowly Growing/Nonreplicating Mycobacterium tuberculosis

129

Recent clinical studies indicate that meropenem, a ␤-lactam antibiotic, is a promising candidate for therapy of drug-resistant tuberculosis. However, meropenem is chemically unstable, requires frequent intravenous injection, and must be combined with a ␤-lactamase inhibitor (clavulanate) for optimal activity. Here, we report that faropenem, a stable and orally bioavailable ␤-lactam, efficiently kills Mycobacterium tuberculosis even in the absence of clavulanate. The target enzymes, L,D-transpeptidases, were inactivated 6-to 22-fold more efficiently by faropenem than by meropenem. Using a real-time assay based on quantitative time-lapse microscopy and microfluidics, we demonstrate the superiority of faropenem to the frontline antituberculosis drug isoniazid in its ability to induce the rapid cytolysis of single cells. Faropenem also showed superior activity against a cryptic subpopulation of nongrowing but metabolically active cells, which may correspond to the viable but nonculturable forms believed to be responsible for relapses following prolonged chemotherapy. These results identify faropenem to be a potential candidate for alternative therapy of drug-resistant tuberculosis.

Section: Es E+p E+ssupporting

confidence: 74%

Rapid Cytolysis of Mycobacterium tuberculosis by Faropenem, an Orally Bioavailable β-Lactam Antibiotic

Dhar

Dubée

Ballell

et al. 2015

129

“…We determined the effects of combining AZD5847 with several TB drugs through the use of a checkerboard titration, which has been previously described (17). Briefly, using 96-well microtiter plates, we diluted one drug vertically (rows A to H) and a second drug horizontally (columns 1 to 10) to obtain various combinations of the two drugs in a final volume of 100 l for each well.…”

Section: Methodsmentioning

confidence: 99%

“…We then added to each well 100 l of H37Rv-infected 7H9 to provide an inoculum of approximately 5 ϫ 10 5 CFU/ml. The plates were incubated for 7 days, and the MIC was interpreted as described earlier (17). To evaluate whether the paired combinations of agents had additive efficacy in inhibiting M. tuberculosis (i.e., no interaction) or inhibitory efficacy more or less than the sum of their effects alone (synergy versus antagonism), we calculated the fractional inhibitory concentration index (⌺FIC) using the following formula:…”

Section: Methodsmentioning

confidence: 99%

Bactericidal Activity and Mechanism of Action of AZD5847, a Novel Oxazolidinone for Treatment of Tuberculosis

Balasubramanian

Solapure

Iyer

et al. 2014

Self Cite

Treatment of tuberculosis (TB) is impaired by the long duration and complexity of therapy and the rising incidence of drug resistance. There is an urgent need for new agents with improved efficacy, safety, and compatibility with combination chemotherapies. Oxazolidinones offer a potential new class of TB drugs, and linezolid-the only currently approved oxazolidinone-has proven highly effective against extensively drug-resistant (XDR) TB in experimental trials. However, widespread use of linezolid is prohibited by its significant toxicities. AZD5847, a novel oxazolidinone, demonstrates improved in vitro bactericidal activity against both extracellular and intracellular M. tuberculosis compared to that of linezolid. Killing kinetics in broth media and in macrophages indicate that the rate and extent of kill obtained with AZD5847 are superior to those obtained with linezolid. Moreover, the efficacy of AZD5847 was additive when tested along with a variety of conventional TB agents, indicating that AZD5847 may function well in combination therapies. AZD5847 appears to function similarly to linezolid through impairment of the mycobacterial 50S ribosomal subunit. Future studies should be undertaken to further characterize the pharmacodynamics and pharmacokinetics of AZD5847 in both in vitro and animal models as well is in human clinical trials.T uberculosis (TB), caused by Mycobacterium tuberculosis, continues to pose an enormous threat to global public health (1). In 2010, nearly 9 million people were infected with M. tuberculosis and 1.4 million died from the disease (1, 2). While the vast majority of cases of drug-sensitive TB are curable with appropriate drug therapy, rates of treatment success have stagnated due to the long duration and complexity of therapy and the rising incidence of drug resistance (1, 3, 4). Standard TB therapy alone involves four drugs taken for at least 6 months, and treatment for multidrugresistant (MDR) and extensively drug-resistant (XDR) TB requires administration of more toxic antibiotics-including at least one injectable-for durations of 1 to 2 years (5). Often, patients are coinfected with HIV, which further complicates treatment due to deleterious potential drug-drug interactions between TB medications and antiretrovirals (6). Despite the limitations of current treatment options, only one new class of TB drugs has been approved in the past 40 years (7). There is an urgent need for new TB drugs with greater efficacy, reduced toxicities, and improved compatibility with antiretrovirals.Recent evidence demonstrates that linezolid, the only member of the oxazolidinone class of antimicrobials currently on the market, has efficacy against MDR TB (8-11). The potential of linezolid for the treatment of TB is limited due to the incidence of serious adverse effects, including cytopenias, neuropathies, lactic acidosis, and rhabdomyolysis (12, 13). Risk increases with increasing dose and duration, which is particularly problematic, given the typical extended course of chemotherapy for TB. A numbe...

“…They are poor substrates for BlaC and are not affected by its ␤-lactamase activity (5). Recent reports have demonstrated that carbapenems exhibit high antimicrobial potency against M. tuberculosis; therefore, they may be considered for treatment of tuberculosis (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Carbapenems and Rifampin Exhibit Synergy against Mycobacterium tuberculosis and Mycobacterium abscessus

Kaushik

Makkar

Pandey

et al. 2015

108

113

cAn effective regimen for treatment of tuberculosis (TB) is comprised of multiple drugs that inhibit a range of essential cellular activities in Mycobacterium tuberculosis. The effectiveness of a regimen is further enhanced if constituent drugs act with synergy. Here, we report that faropenem (a penem) or biapenem, doripenem, or meropenem (carbapenems), which belong to the ␤-lactam class of antibiotics, and rifampin, one of the drugs that forms the backbone of TB treatment, act with synergy when combined. One of the reasons (carba)penems are seldom used for treatment of TB is the high dosage levels required, often at the therapeutic limits. The synergistic combination of rifampin and these (carba)penems indicates that (carba)penems can be administered at dosages that are therapeutically relevant. The combination of faropenem and rifampin also limits the frequency of resistant mutants, as we were unable to obtain spontaneous mutants in the presence of these two drugs. The combinations of rifampin and (carba)penems were effective not only against drug-sensitive Mycobacterium tuberculosis but also against drugresistant clinical isolates that are otherwise resistant to rifampin. A combination of doripenem or biapenem and rifampin also exhibited synergistic activity against Mycobacterium abscessus. Although the MICs of these three drugs alone against M. abscessus are too high to be of clinical relevance, their concentrations in combinations are therapeutically relevant; therefore, they warrant further evaluation for clinical utility to treat Mycobacterium abscessus infection, especially in cystic fibrosis patients.