Biology subjects

Dooley, K. E.

Publications and source records attributed to Dooley, K. E..

3 recordsLinked to original sources

bioRxiv2021

Novel regimens of bedaquiline-pyrazinamide combined with moxifloxacin, rifabutin, delamanid and/or OPC-167832 in murine tuberculosis models

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin and isoniazid (PZMH) to be non-inferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. Addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.

microbiology↗

bioRxiv2021

In vitro activity of bedaquiline and imipenem against actively growing, nutrient-starved, and intracellular Mycobacterium abscessus

Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multi-drug regimen with at least 3 active drugs, preferably including a {beta}-lactam (imipenem or cefoxitin). These regimens are lengthy, toxic, and have limited efficacy. The search for more efficacious regimens led us to evaluate bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed in vitro time-kill experiments to evaluate the activity of bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, bedaquiline was bactericidal, while imipenem was not, and bedaquiline drove the activity of the combination. In an intracellular infection model, bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of bedaquiline. Overall, these results show that bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus, where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.

microbiology↗

bioRxiv2020

Preserved efficacy and reduced toxicity with intermittent linezolid dosing in combination with bedaquiline and pretomanid in a murine TB model

The novel regimen of bedaquiline, pretomanid, and linezolid (BPaL) is highly effective against drug resistant tuberculosis, but linezolid toxicities are frequent. We hypothesized that, for a similar total weekly cumulative dose, thrice-weekly administration of linezolid would preserve efficacy while reducing toxicity compared to daily dosing, in the context of the BPaL regimen.Using C3HeB/FeJ and BALB/c mouse models of tuberculosis disease, thrice-weekly linezolid dosing was compared to daily dosing, with intermittent dosing introduced (a) from treatment initiation or (b) following an initial period of daily dosing. In all animals, BPa was dosed daily throughout treatment. Blood counts were used to assess hematologic toxicity. Following unexpected findings of apparent antagonism, we conducted additional experiments to investigate strain-to-strain differences in the contribution of linezolid to regimen efficacy comparing each 1- and 2-drug component to the BPaL regimen in BALB/c mice infected with Mycobacterium tuberculosis H37Rv or HN878.Giving linezolid daily for 1-2 months achieved the greatest efficacy, but following that, results were similar if the drug was stopped, dosed thrice-weekly, or continued daily. Erythrocyte counts were lower with daily than thrice-weekly dosing. Linezolid had additive effects with BPa against M. tuberculosis H37Rv but antagonistic effects with BPa against M. tuberculosis HN878. However, overall efficacy of BPaL was high and similar against both strains.Dosing linezolid daily for the first two months, then less frequently thereafter, may optimize its therapeutic margin. Linezolid’s contribution to BPaL regimens may depend on M. tuberculosis strain.View Full Text

pharmacology and toxicology↗