Fluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose Selection

Abstract

Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted between 1984 and 2015, infected with drug-resistant tuberculosis, and who had received fluoroquinolones for ≥28 days were included. Demographics, sputum cultures and susceptibility, treatment regimens, and serum concentrations were collected. A time-to-event analysis was conducted, and Cox proportional hazards model was used to compare the time to culture conversion. Using additional data from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were performed to assess target attainment for different doses. Overall, 124 patients received fluoroquinolones. The median age was 40 years, and the median weight was 60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones. New-generation fluoroquinolones showed a faster time to culture conversion (median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and clofazimine treatment, patients treated with new-generation fluoroquinolones were more likely to have culture conversion (adjusted hazards ratio, 2.16 [95% confidence interval, 1.28 to 3.64]). We included 178 patients in the pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a one-compartment model with first-order absorption and elimination. At least 1,500 to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill at the current epidemiologic cutoff values. In summary, new-generation fluoroquinolones showed faster time to culture conversion compared to the old generation. For optimal target attainment at the current MIC values, higher doses of levofloxacin and moxifloxacin may be needed.

Pharmacokinetics and pharmacodynamics of levofloxacin in bronchial mucosa and lung tissue of patients undergoing pulmonary operation

“…This result is similar to a PK/PD report of levofloxacin in acutely hospitalized elderly patients (27). A previous study demonstrated that a PK/PD model predicted that 500 mg levofloxacin was not effective for treating multidrug-and drug-resistant tuberculosis (47)(48)(49). By contrast, the fAUC 0-24 /MIC of levofloxacin reached 60 in lung tissue against S. pneumoniae.…”

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

“…However, comparative data are available from a MDR-TB trial (no difference in treatment outcomes when comparing the two drugs; fewer adverse events for M) [23], and rabbit and mouse models (M broadly superior over Lfx) [24,25]. Lfx doses in such studies may have been too low [26,27]. Further RCTs are required.…”

Urine colorimetry for levofloxacin pharmacokinetics and personalized dosing in people with drug-resistant tuberculosis

“…Noncompartmental analysis was performed to estimate the area under the concentration-time curve over 24 h (AUC 0-24 ) using serum concentrations in Phoenix WinNonlin version 8.0 (Certara USA, Princeton, New Jersey). Based on previous studies of PK/PD and treatment outcomes, [ 6 , 7 ] serum levofloxacin C max of 8 μg/mL and AUC 0-24 of 80 μg × h/mL were used as the standard-of-care targets during anti-TB treatment, [ 15 ] as concentrations below these breakpoints have previously predicted poor long-term treatment outcome. To determine the best time interval for the collection of urine samples, serum AUC 0-24 was compared with urine concentrations at 0–4 h, 4–8 h, and 8–24 h using linear correlation.…”

“…[ 5 ] Among people treated for MDR-TB, it has been demonstrated that serum levofloxacin AUC/MIC ratios below certain population targets associate with treatment failure and were in fact the most important predictor of treatment outcome in adjusted analyses. [ 6 , 7 ]…”