Ertapenem in the treatment of multidrug-resistant tuberculosis: first clinical experience

Tiberi, Simon; D’Ambrosio, Lia; Lorenzo, Saverio De; Viggiani, Pietro; Centis, Rosella; Sotgiu, Giovanni; Alffenaar, J W C; Migliori, Giovanni Battista

doi:10.1183/13993003.01278-2015

Cited by 67 publications

(65 citation statements)

References 14 publications

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“…rtapenem, a ␤-lactam agent of the carbapenem class, has shown promising clinical results and favorable pharmacokinetics against Mycobacterium tuberculosis (1,2). The scourge of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), a global problem, has increased the urgency for the use of carbapenems, such as ertapenem, meropenem, and faropenem (2)(3)(4).…”

mentioning

confidence: 99%

Susceptibility Testing of Antibiotics That Degrade Faster than the Doubling Time of Slow-Growing Mycobacteria: Ertapenem Sterilizing Effect versus Mycobacterium tuberculosis

Srivastava

Rijn

Wessels

et al. 2016

Antimicrob Agents Chemother

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bDrug susceptibility tests (DSTs) for Mycobacterium tuberculosis require at least 7 days of incubation. Drugs that are unstable at 37°C, such as ertapenem, are likely to be degraded before killing or inhibiting slow-growing bacteria. This would alter the MICs of these drugs, including ertapenem, leading to falsely high MICs. Here, we describe a new strategy we developed to perform DSTs and measure MICs for such unstable compounds. E rtapenem, a ␤-lactam agent of the carbapenem class, has shown promising clinical results and favorable pharmacokinetics against Mycobacterium tuberculosis (1, 2). The scourge of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), a global problem, has increased the urgency for the use of carbapenems, such as ertapenem, meropenem, and faropenem (2-4). Recently, the first phase 2 study (NCT02349841) to evaluate early bactericidal activity of meropenem and faropenem was completed, and the results are expected soon.Carbapenems inhibit the peptidase domain of penicillin binding proteins, leading to autolysis and peptidoglycan weakening of the cell wall (5). Degradation of ertapenem on storage following reconstitution and dilution is temperature dependent, and the proposed in-use shelf life is 6 h at room temperature or 24 h at 2°C to 8°C (6). M. tuberculosis has a doubling time of at least 24 h under the best of circumstances (7,8). M. tuberculosis cell division is particularly slow; FtsZ, a protein responsible for initiating cell division and recruiting proteins for formation of new cell walls, is known to have a polymerization rate that is at least 20 times slower in M. tuberculosis than in Escherichia coli, for example (9). In M. tuberculosis at low pH, the replication rate is up to10 to 20 times slower; kill of such semidormant bacteria is defined as a sterilizing effect (7,8,10). Thus, microbial killing and inhibition of growth by the most effective of antibiotics are slow and take place over several days, especially by ␤-lactams that depend on cell wall turnover.Drug susceptibility tests (DSTs) for M. tuberculosis using Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) approved methods require at least 7 days of incubation (11). Drugs such as ertapenem, already appearing unstable at 37°C (2), are likely to be degraded before killing or inhibiting slowgrowing bacteria, especially semidormant M. tuberculosis. This would be expected to alter the MICs of ertapenem, leading to falsely high MICs and false resistance. Here, we saw the rapid decline of ertapenem during DSTs; therefore, we developed a new strategy to perform DSTs and measure MICs for such unstable compounds.Ertapenem (Sigma) was first dissolved in purified water and subsequently diluted in Middlebrook 7H9 broth to the desired drug concentrations of 5.0 and 50 mg/liter, respectively. The two solutions were incubated at 37°C. After 0, 5, 8, 24, 32, and 48 h, three samples were collected from each solution and im...

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confidence: 99%

Susceptibility Testing of Antibiotics That Degrade Faster than the Doubling Time of Slow-Growing Mycobacteria: Ertapenem Sterilizing Effect versus Mycobacterium tuberculosis

Srivastava

Rijn

Wessels

et al. 2016

Antimicrob Agents Chemother

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“…Although it is now a candidate to be a companion drug, there is increasing evidence that it may play a future core drug role [19,40], especially because of its possible good bactericidal activity. Based on the existing evidence, the best carbapenem would probably be meropenem [41,42], although imipenem/cilastatin (often more easily available) [42,43] or ertapenem (given the possibility to administer it once a day intramuscularly, it can act as switch therapy useful for ambulatory/home care) might also have a role [44][45][46]. However, given the need for parenteral administration with carbapenems, delamanid is also a potential choice (needing electrocardiogram monitoring), as discussed previously.…”

Section: Regimen Composition and Possible Alternativesmentioning

confidence: 99%

Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases

et al. 2017

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“…In the direct comparison meropenem performs better than imipenem (37). Initial clinical experience with ertapenem suggests that it can be a valid drug for the home-care phase of MDR-TB treatment, as it can be administered intramuscularly once a day (38).…”

Section: Which Drugs Might Be Upgradedmentioning

confidence: 99%

Classification of drugs to treat multidrug-resistant tuberculosis (MDR-TB): evidence and perspectives

Rendón¹,

Tiberi

Scardigli

et al. 2016

J. Thorac. Dis.

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Ertapenem in the treatment of multidrug-resistant tuberculosis: first clinical experience

Cited by 67 publications

References 14 publications

Susceptibility Testing of Antibiotics That Degrade Faster than the Doubling Time of Slow-Growing Mycobacteria: Ertapenem Sterilizing Effect versus Mycobacterium tuberculosis

Susceptibility Testing of Antibiotics That Degrade Faster than the Doubling Time of Slow-Growing Mycobacteria: Ertapenem Sterilizing Effect versus Mycobacterium tuberculosis

Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases

Classification of drugs to treat multidrug-resistant tuberculosis (MDR-TB): evidence and perspectives

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