Moxifloxacin target site concentrations in patients with pulmonary TB utilizing microdialysis: a clinical pharmacokinetic study.

Background: Moxifloxacin is a second-line anti-TB drug that is useful in the treatment of drug-resistant TB. However, little is known about its target site pharmacokinetics. Lower drug concentrations at the infection site (i.e. in severe lung lesions including cavitary lesions) may lead to development and amplification of drug resistance. Improved knowledge regarding tissue penetration of anti-TB drugs will help guide drug development and optimize drug dosing. Methods: Patients with culture-confirmed drug-resistant pulmonary TB scheduled to undergo adjunctive surgical lung resection were enrolled in Tbilisi, Georgia. Five serum samples per patient were collected at different timepoints including at the time of surgical resection (approximately at Tmax). Microdialysis was performed in the ex vivo tissue immediately after resection. Non-compartmental analysis was performed and a tissue/serum concentration ratio was calculated. Results: Among the seven patients enrolled, the median moxifloxacin dose given was 7.7 mg/kg, the median age was 25.2 years, 57% were male and the median creatinine clearance was 95.4 mL/min. Most patients (71%) had suboptimal steady-state serum Cmax (total drug) concentrations. The median free moxifloxacin serum concentration at time of surgical resection was 1.23 µg/mL (range = 0.12-1.80) and the median free lung tissue concentration was 3.37 µg/mL (range = 0.81-5.76). The median free-tissue/free-serum concentration ratio was 3.20 (range = 0.66-28.08). Conclusions: Moxifloxacin showed excellent penetration into diseased lung tissue (including cavitary lesions) among patients with pulmonary TB. Moxifloxacin lung tissue concentrations were higher than those seen in serum. Our findings highlight the importance of moxifloxacin in the treatment of MDR-TB and potentially any patient with pulmonary TB and severe lung lesions.

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

Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary (n = 6 patients), mass-like (n = 3 patients), or consolidative (n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 µg/ml. The median lung tissue free pyrazinamide concentration was 20.96 µg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis (R = -0.66, P = 0.04) and acid-fast bacilli (R = -0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens.

Cavitary penetration of levofloxacin among patients with multidrug-resistant tuberculosis.

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 (Cmax) was 6.5 µg/ml, and it was <2 µg/ml in 3 (25%) patients. Among 11 patients with complete data, the median cavitary concentration of levofloxacin was 4.36 µg/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.

Additional drug resistance in Mycobacterium tuberculosis isolates from resected cavities among patients with multidrug-resistant or extensively drug-resistant pulmonary tuberculosis.

The pathogenesis of increasing drug resistance among patients with multidrug-resistant or extensively drug-resistant tuberculosis undergoing treatment is poorly understood. Increasing drug resistance found among Mycobacterium tuberculosis recovered from cavitary isolates compared with paired sputum isolates suggests pulmonary cavities may play a role in the development of worsening tuberculosis drug resistance.

Adjunctive surgery versus medical treatment among patients with cavitary multidrug-resistant tuberculosis.

OBJECTIVES: Surgical resection is recommended as adjunctive treatment for multidrug-resistant (MDR) tuberculosis (TB) in certain scenarios; however, data are limited. We sought to evaluate the impact of surgery by comparing TB outcomes among patients with cavitary disease who received medical versus combined medical and surgical treatment. METHODS: A cohort of all patients with cavitary MDR or extensively drug-resistant (XDR) TB treated in Tbilisi, Georgia, between 2008 and 2012. Patients meeting indications for surgery underwent adjunctive resection in addition to medical treatment. We compared TB outcomes (proportions achieving cure/complete) among patients who received adjunctive surgery to those who received medical treatment alone using an adjusted robust Poisson regression. RESULTS: Among 408 patients, 299 received medical treatment alone and 109 combined medical and surgical treatment. Patients in the non-surgical group were older and had higher rates of tobacco and alcohol use and bilateral disease compared to the surgical group. Patients in the surgical group had higher rates of XDR disease (28% vs 15%). Favourable outcomes were higher among the surgical versus non-surgical group cohort (76% vs 41%). After adjusting for multiple factors, the association between adjunctive resection and favourable outcome remained (adjusted risk ratio 1.6, 95% confidence interval 1.3-2.0); the relationship was also observed in secondary models that excluded patients with bilateral disease (contraindication for surgery) and patients receiving <6 months of treatment. Major postoperative complications occurred among 8 patients (7%) with no postoperative mortality. CONCLUSIONS: Adjunctive surgery is safe and may improve the effectiveness of treatment among select patients with cavitary MDR- and XDR-TB.

Pulmonary function and respiratory health after successful treatment of drug-resistant tuberculosis.

BACKGROUND: Post-treatment morbidity among subjects with drug-resistant tuberculosis (DR-TB) is unclear. METHODS: This was a cross-sectional study of patients from Tbilisi, Georgia with cavitary DR-TB and an outcome of cure. Participants had a chest X-ray (CXR), St. George Respiratory Quality (SGRQ) survey, and pulmonary function tests (PFTs) performed. Correlations between SGRQ and PFT results and factors associated with pulmonary impairment were examined. RESULTS: Among 58 subjects (median age 31 years), 40% used tobacco, 59% had prior TB, and 47% underwent adjunctive surgical resection. The median follow-up time was 41 months. Follow-up CXR revealed fibrosis in 30 subjects (52%) and bronchiectasis in seven (12%). The median forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio was 0.72, with 24 subjects (41%) having a ratio of ≤0.70. Significant correlations existed between PFT measures and overall and component SGRQ scores. In linear regression, age, prior TB, and CXR fibrosis or bronchiectasis were significantly associated with decreased pulmonary function. Adjunctive surgery was significantly associated with a higher percent predicted FEV1 and FVC. CONCLUSIONS: A high proportion of DR-TB subjects had residual pulmonary impairment, particularly with recurrent TB and severe radiological disease. The association of surgical resection with improved lung function deserves further study. PFTs and SGRQ may both be useful to evaluate lung health.

Favorable outcomes for multidrug and extensively drug resistant tuberculosis patients undergoing surgery.

BACKGROUND: New approaches are needed in the treatment of multidrug-resistant and extensively drug-resistant pulmonary tuberculosis (M/XDR-PTB). We evaluated the role of adjunctive surgical therapy in the treatment of M/XDR-PTB in the setting of directly observed treatment strategy (DOTS)-Plus implementation. METHODS: We conducted an observational cohort study consisting of M/XDR-PTB patients who underwent thoracic surgery at the National Tuberculosis Center in Tbilisi, Georgia between October 2008 and February 2011. Indications for surgery included presence of M/XDR-PTB, localized pulmonary disease, fit to undergo surgery, and either medical treatment failure or such extensive drug resistance that failure was likely. Second-line anti-tuberculosis medical therapy was administered per World Health Organization (WHO) recommendations. RESULTS: Seventy-five patients (51 MDR, 24 XDR) with PTB underwent adjunctive thoracic surgery. Median age was 30 years and average duration of preoperative M/XDR-PTB medical therapy was 342 days. The following surgical procedures were performed: pneumonectomy (11%), lobectomy (54%), and segmentectomy (35%). Mean postoperative follow-up time was 372 days. Of 72 patients with evaluable outcomes, 59 (82%) had favorable outcomes including 90% of MDR and 67% of XDR-TB patients. There was no postoperative mortality; postoperative complications occurred in 7 patients (9%). Risk factors for poor treatment outcomes in univariate analysis included bilateral disease, XDR, increasing effective drugs received, positive preoperative sputum culture, and major postoperative surgical complication. CONCLUSIONS: Patients with M/XDR-PTB undergoing adjunctive thoracic surgery had high rates of favorable outcomes, no surgical-related mortality, and low rates of complications. Adjunctive surgery appears to play an important role in the treatment of select patients with M/XDR-PTB.