Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters

Abstract

Most drugs demonstrated efficacy against M. tuberculosis . When these MICs are compared with the published pharmacokinetic/pharmacodynamic profiles of the respective drugs in humans, trimethoprim/sulfamethoxazole, meropenem/clavulanate, linezolid, clofazimine and nitazoxanide appear promising and warrant further clinical investigation.

Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis

“…Overall, the results of the studies identified in this review, which used a variety of experimental methods to test clinical and laboratory strains of M. tuberculosis for susceptibility to carbapenems, are consistent. Carbapenems are more active against M. tuberculosis if used in combination with clavulanate, a BLaC inhibitor (8,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). In line with these in vitro studies, the addition of clavulanate improved the survival rate in mice (33).…”

“…Multiple studies reported that meropenem in the presence of clavulanate is active in vitro against clinical and laboratory strains H37Rv and H37Ra of M. tuberculosis, showing MICs of Յ1 mg/liter. In vitro studies reporting susceptibility to meropenem of M. tuberculosis reference strains and clinical isolates showed MICs of between 1 and 32 mg/liter (8,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). Meropenem in combination with clavulanic acid was shown to have MICs of between 0.063 and 32 mg/liter (31-33, 36, 41).…”

“…Subsequently, studies addressing the inactivation mechanism of LDT provided the underlying evidence to support the hypothesis of activity of carbapenems against M. tuberculosis (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). In spite of this, a series of in vitro studies have been carried out, some of which detected an effect and some of which did not (8,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). Only later was it recognized that these confusing results are probably explained by the chemical instability of carbapenems in culture media at the temperatures typically used in in vitro studies, and many previously published in vitro studies are likely to have reported falsely high MICs (43).…”

“…Eight patients achieved sputum conversion after 6 months, while two patients died (57). Pharmacokinetic parameters of 1 g meropenem-clavulanate given intravenously over 5 min showed a serum peak of 112 mg/ml and a concentration of 28.6 mg • h/liter (37). In an observational retrospective cohort study, efficacy and safety were evaluated in 96 patients treated with regimens containing meropenem-clavulanate and compared with the data for 168 controls.…”

Cytoplasmic RNA Sensor Pathways and Nitazoxanide Broadly Inhibit Intracellular Mycobacterium tuberculosis Growth

“…NTZ has been reported to inhibit the growth of diverse strains of MTb cultured in cell-free media (Cavanaugh et al., 2017, de Carvalho et al., 2009, de Carvalho et al., 2011, Harausz et al., 2016, Odingo et al., 2017, Piccaro et al., 2013, Shigyo et al., 2013). In one study using an H37Rv-luciferase reporter MTb strain, NTZ inhibited MTb replication in THP-1 cells when measured at 24, 48, and 72 h after infection (Lam et al., 2012).…”