Abstract
Rifamycins are integral part of the combination regimen for treatment of pulmonary Mycobacterium avium-complex [MAC] infection, but different practitioners prefer different rifamycins. The objective of the study was to compare microbial kill and resistance emergence of rifamycins using principles of pharmacokinetics/pharmacodynamics. First, we identified rifamycin MICs in 20 MAC isolates from patients followed by concentration-response studies in test-tubes. Next, we examined efficacy and resistance suppression of three doses of each rifamycin in the hollow fiber system model of pulmonary MAC [HFS-MAC], mimicking human like concentration-time profile of the drugs. HFS-MAC units were repetitively sampled for total and drug-resistant MAC burden and for drug concentration measurements. Inhibitory sigmoid E max model, linear regression, and analysis of variance was used for data analysis. For rifabutin 90% of isolates had MIC ≤ 0.125 mg/L while for both rifampin and rifapentine this was ≤2.0 mg/L. There was no statistically significant difference (p > 0.05) in maximal kill and effective concentration mediating 50% of the bacterial kill among three rifamycins in the static concentration experiment. In the HFS-MAC, the bactericidal kill (day 0–4) for rifampin was 0.89 (95% Confidence Interval (CI): 0.43–1.35), for rifapentine was 1.05 (95% CI: 0.08–1.23), and for rifabutin was 0.92 (95% CI: 0.61–1.24) log10 CFU/ml, respectively. Rifamycins monotherapy failed after just 4-days of treatment and entire MAC population was drug resistant on day 26 of the study. There was no dose dependent difference in MAC kill or resistance suppression among the three rifamycins tested in the HFS-MAC. Therefore, replacing one rifamycin, due to emergence of drug-resistance, with other may not be beneficial in clinical setting.
Highlights
Nontuberculous mycobacteria (NTM), especially species of the Mycobacterium avium complex (MAC), are among the most difficult to treat pulmonary infection (Cowman et al, 2019)
We have developed a pre-clinical hollow fiber system model of pulmonary MAC (HFS-MAC), that can mimic the human like PK of the drugs (Deshpande et al, 2010a; Deshpande et al, 2010b; Deshpande and Gumbo, 2011; Deshpande et al, 2016b; Deshpande et al, 2017a; Deshpande et al, 2017b; Deshpande et al, 2017c; Deshpande et al, 2017d; Srivastava et al, 2017a; Srivastava et al, 2017b)
The MIC of the MAC laboratory strain used for all subsequent pharmacokinetics/ pharmacodynamic (PK/PD) studies was 0.032 mg/L for either rifampin, or rifapentine, or rifabutin, in two separate experiments with two replicate each
Summary
Nontuberculous mycobacteria (NTM), especially species of the Mycobacterium avium complex (MAC), are among the most difficult to treat pulmonary infection (Cowman et al, 2019). A recent retrospective study showed that between 2008 to 2015, the annual NTM lung disease incidence increased from 3.13 to 4.73 per 100,000 person, and the annual prevalence changed from 6.78 to 11.7 (Winthrop et al, 2020). Rifamycins for Pulmonary MAC from 9.63 to 16.7 per 100,000, while among those 65 years or older it increased from 30.27 to 47.48 per 100,000 (Winthrop et al, 2020). Just as clinicians use different macrolides (azithromycin or clarithromycin], they use different rifamycins [rifampin or rifabutin). It is unclear which rifamycin is better; how rifapentine would fare in treatment of pulmonary MAC is currently unclear. We compared the three rifamycins head-to-head using pharmacokinetics/ pharmacodynamic (PK/PD) study design
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