Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis

Abstract

Background. Levofloxacin is used for the treatment of multidrug-resistant tuberculosis; however the optimal dose is unknown. Methods. We used the hollow fiber system model of tuberculosis (HFS-TB) to identify 0-24 hour area under the concentration-time curve (AUC 0-24) to minimum inhibitory concentration (MIC) ratios associated with maximal microbial kill and suppression of acquired drug resistance (ADR) of Mycobacterium tuberculosis (Mtb). Levofloxacin-resistant isolates underwent whole-genome sequencing. Ten thousands patient Monte Carlo experiments (MCEs) were used to identify doses best able to achieve the HFS-TBderived target exposures in cavitary tuberculosis and tuberculous meningitis. Next, we used an ensemble of artificial intelligence (AI) algorithms to identify the most important predictors of sputum conversion, ADR, and death in Tanzanian patients with pulmonary multidrug-resistant tuberculosis treated with a levofloxacin-containing regimen. We also performed probit regression to identify optimal levofloxacin doses in Vietnamese tuberculous meningitis patients. Results. In the HFS-TB, the AUC 0-24 /MIC associated with maximal Mtb kill was 146, while that associated with suppression of resistance was 360. The most common gyrA mutations in resistant Mtb were Asp94Gly, Asp94Asn, and Asp94Tyr. The minimum dose to achieve target exposures in MCEs was 1500 mg/day. AI algorithms identified an AUC 0-24 /MIC of 160 as predictive of microbiologic cure, followed by levofloxacin 2-hour peak concentration and body weight. Probit regression identified an optimal dose of 25 mg/kg as associated with >90% favorable response in adults with pulmonary tuberculosis. Conclusions. The levofloxacin dose of 25 mg/kg or 1500 mg/day was adequate for replacement of high-dose moxifloxacin in treatment of multidrug-resistant tuberculosis.

d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

“…First, we did not examine d-cycloserine in combination with other drugs for synergistic effects, which could potentially lower the exposures of d-cycloserine needed. Second, in contrast to our work with gatifloxacin, levofloxacin, and ethionamide, we had no clinical data to validate the doses or susceptibility breakpoints we identified [18,51,55]. Third, we relied on the Sensititre assay, which is not endorsed by WHO and could differ from conventional media, to define a tentative ECOFF.…”

“…Second, d-cycloserine had impressive kill rates against Mtb in the HFS-TB, which rivaled some of the first-line compounds and fluoroquinolones [18,36,51]. Thus the drug is not "static, " as has been traditionally thought.…”

Evaluation of Saliva as a Potential Alternative Sampling Matrix for Therapeutic Drug Monitoring of Levofloxacin in Patients with Multidrug-Resistant Tuberculosis

“…Furthermore, a trend toward moderately positive correlation (r s ϭ 0.379; P ϭ 0.021) was observed when Lfx C min in saliva was evaluated to predict its AUC 0 -24 in plasma (r ϭ 0.38; estimated linear regression equation). When the saliva C min was Ͻ2 mg/liter, a proportion of patients had a plasma AUC 0 -24 below the desired level, 146, given the MIC was 1 mg/liter (12).…”

“…Therefore, measuring Lfx concentrations in plasma or other alternative matrices (saliva and dried blood spots) could help clinicians make informed dosing decisions, especially now, as the TB treatment marches toward individualization, therapeutic drug monitoring (TDM) using saliva sampling might become a game changer in TB treatment due to specific advantages over plasma sampling, in low-resource settings (10,11). The efficacy of Lfx is predicted by AUC 0 -24 and MIC (12). Given as a monotherapy, the hollow-fiber infection model on TB recently established a Lfx target of 146 for maximum bacterial kill (80% effective concentration) and 360 for the prevention of acquired drug resistance (12).…”

“…The efficacy of Lfx is predicted by AUC 0 -24 and MIC (12). Given as a monotherapy, the hollow-fiber infection model on TB recently established a Lfx target of 146 for maximum bacterial kill (80% effective concentration) and 360 for the prevention of acquired drug resistance (12). Therefore, a plasma AUC 0 -24 above 75 (if the MIC is 0.5 mg/liter) or 146 (if the MIC is 1 mg/liter) will be needed to attain the optimal target exposure for efficacy.…”