Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Abstract

A better understanding of second-line drug (SLD) pharmacokinetics, including cavitary penetration, may help optimize SLD dosing. Patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) undergoing adjunctive surgery were enrolled in Tbilisi, Georgia. Serum was obtained at 0, 1, 4, and 8 h and at the time of cavitary removal to measure levofloxacin concentrations. After surgery, microdialysis was performed using the ex vivo cavity, and levofloxacin concentrations in the collected dialysate fluid were measured. Noncompartmental analysis was performed, and a cavitary-to-serum levofloxacin concentration ratio was calculated. Twelve patients received levofloxacin for a median of 373 days before surgery (median dose, 11.8 mg/kg). The median levofloxacin concentration in serum (C max ) was 6.5 g/ml, and it was <2 g/ml in 3 (25%) patients. Among 11 patients with complete data, the median cavitary concentration of levofloxacin was 4.36 g/ml (range, 0.46 to 8.82). The median cavitary/ serum levofloxacin ratio was 1.33 (range, 0.63 to 2.36), and 7 patients (64%) had a ratio of >1. There was a significant correlation between serum and cavitary concentrations (r ‫؍‬ 0.71; P ‫؍‬ 0.01). Levofloxacin had excellent penetration into chronic cavitary TB lesions, and there was a good correlation between serum and cavitary concentrations. Optimizing serum concentrations will help ensure optimal cavitary concentrations of levofloxacin, which may enhance treatment outcomes.T he emergence of multidrug-resistant tuberculosis (MDR-TB) remains a major barrier to global TB control (1). The treatment course for MDR-TB (with resistance to isoniazid and rifampin) consists of 18 to 24 months of second-line antituberculosis drugs (SLDs), including a fluoroquinolone and an injectable agent (amikacin, kanamycin, or capreomycin). A 2009 meta-analysis of MDR-TB treatment outcomes found an overall success rate of 62% with a range of 36 to 79% (2). The most recent World Health Organization (WHO) global TB report reported an overall successful outcome rate of 48%, again with a wide range (3). These data show that we are far from the goal of a Ͼ75% successful outcome treatment rate among MDR-TB patients; however, the broad range of successful outcomes suggests that we may be able to more effectively maximize existing SLD regimens. A better knowledge of how to optimize available SLD regimens could improve outcomes and provide important principles for the efficacious use of new drugs.The clinical pharmacology of SLDs has been a neglected area of research (4). Pharmacokinetic studies among patients with drugsusceptible TB demonstrate that low concentrations of first-line drugs are associated with poor clinical outcomes, and simulation studies have found that even with perfect adherence up to 1% of patients would develop further drug resistance during treatment due to variability in drug concentrations (5-7). A recent report on 25 patients with MDR-TB found that plasma SLD concentrations were frequently low and were associated with decreased drug ...

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…The concentrationtime profiles that M tuberculosis will be exposed to are defined by these barriers; these local profiles will either kill the M tuberculosis, amplify acquired drug resistance, or suppress acquired drug resistance. Antituberculosis drug penetration indices into the lung cavity, 434,435 193 showed that entry into the human tuberculosis cavity leads to a concentration gradient map, and they directly linked this gradient to the MICs (and hence resistance) in the different parts of the lung cavity for several antituberculosis drugs that patients were taking. 193 Studies are ongoing that aim to associate this drug penetration at the site of infection to more accessible drug concentrations in media such as the serum, to allow for better therapeutic drug monitoring.…”

Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis

“…Microdialysis (D) was performed ex vivo on resected tissue specimens immediately after surgical removal, as previously described (13). Briefly, a semipermeable D probe with a total length of 10 mm attached to a D infusion pump ( Dialysis AB, Stockholm, Sweden) was inserted into the center of the resected lesion using a slit cannula introducer.…”

“…On the day of surgery, pyrazinamide was given orally with a few milliliters of water. The recommendation to perform adjunctive surgery was made by the NCTLD Drug Resistance Committee, as previously described and following recommendations from international guidelines (13,(23)(24)(25). All participants provided informed consent, and the study was approved by the NCTLD, Emory University, and University of Florida Institutional Review Boards.…”

“…To evaluate the target site concentrations of pyrazinamide, we utilized the technique of microdialysis (D), which allows the measurement of unbound (pharmacologically active) extracellular drug concentrations at the site of disease. We have previously shown this method to be successful in measuring antituberculosis drug concentrations among patients with pulmonary TB (13).…”

Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug-Resistant Tuberculosis Patients

“…LFX has a favorable pharmacokinetic (PK) profile with a very rapid and complete (Ͼ95%) oral absorption, which is hardly influenced by food intake (13). More importantly, LFX is widely distributed throughout the body and showed high penetration into lung tissue, cerebrospinal fluid, and cavitary lesions (14)(15)(16)(17). Despite the general preference for MFX to LFX, earlier studies showed no difference in sputum culture conversion after 3 months of treatment (18,19).…”