Abstract
Background: Mycobacterium tuberculosis [Mtb] could be present in different metabolic population in the lung lesions, and nonreplicating persisters [NRP], associated with latent tuberculosis [TB], are the most difficult to kill. Objective: Test the combination of tedizolid, moxifloxacin, and faropenem for activity against NRP using Mtb SS18b in the hollow fiber model [HFS-TB]. Methods: Tedizolid and moxifloxacin were tested as, first, two-drug combination against log-phase growth [LPG] and, second, slowly replicating bacilli [SRB] under acidic condition and with faropenem to create a three-drug combination regimen. Finally, standard regimen [isoniazid-rifampin-pyrazinamide] was used as comparator in the HFS-TB experiment with NRP Mtb. HFS-TB units were sampled for drug-concentration measurement as well as for estimation of bacterial burden using solid agar and mycobacterial growth indicator tube [MGIT] method. Linear regression was used to calculate the kill slopes with each treatment regimen and analysis of variance (ANOVA) to compare the regimen. Results: Tedizolid at standard dose in combination with high-dose moxifloxacin killed 3.05 log10 CFU/ml LPG Mtb and 7.37 log10 CFU/ml SRB in the bactericidal and sterilizing activity HFS-TB experiments, respectively. There was no statistical difference between tedizolid-moxifloxacin-faropenem combination and the standard regimen as both killed 7.35 log10 CFU/ml NRP Mtb in 21 days. There was no emergence of resistance to any of the drugs studied in the three HFS-TB experiments. Conclusion: The experimental regimen of tedizolid, moxifloxacin, and faropenem could effectively kill NRP population of Mtb, and given the efficacy against different metabolic population of Mtb could serve as a pan-TB regimen. Clinical studies are warranted to validate the in vitro findings.
Highlights
Explaining the basic mechanism of antituberculosis chemotherapy, Prof
Mandal et al (2019) recently published a review summarizing the problem of persisters in tuberculosis and the difficulties they posed to the tuberculosis drug discovery as well as potential role of pyrazinamide against this metabolic population
In order to access the extent of kill of NRP with three of the above-mentioned antibiotics, namely, tedizolid, moxifloxacin, and faropenem, that we found to be effective against log-phase growth [LPG] and semidormant bacilli [SRB] growing under acidic condition as well as against intracellular M. tuberculosis, we performed pharmacokinetics/pharmacodynamics studies using the hollow fiber model system of tuberculosis [HFS-TB] (Gumbo et al, 2009; Srivastava and Gumbo, 2011; Deshpande et al, 2016a; Swaminathan et al, 2016; Srivastava et al, 2018)
Summary
Explaining the basic mechanism of antituberculosis chemotherapy, Prof. Denis Mitchison in 1979 proposed the special population hypothesis, where each drug in the combination therapy had efficacy against a specific metabolic population of Mycobacterium tuberculosis [Mtb] (Mitchison, 1979). Mtb can enter a dormant or latent state that is characterized by limited growth and metabolism and, consistent with Prof. Mitchison’s hypothesis, this metabolic state displays phenotypic resistance to many of the commonly used drugs for treating tuberculosis [TB] (Chan and Flynn, 2004; Boshoff et al, 2005). This allows Mtb to persist indefinitely in the human host. Mycobacterium tuberculosis [Mtb] could be present in different metabolic population in the lung lesions, and nonreplicating persisters [NRP], associated with latent tuberculosis [TB], are the most difficult to kill
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