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.

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 ϭ 6 patients), mass-like (n ϭ 3 patients), or consolidative (n ϭ 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of Յ5.5. 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 g/ml. The median lung tissue free pyrazinamide concentration was 20.96 g/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 ϭ Ϫ0.66, P ϭ 0.04) and acid-fast bacilli (R ϭ Ϫ0.75, P ϭ 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.

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 ...

Background New approaches are needed in the treatment of multi- 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 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 WHO recommendations. Results 80 patients (55 MDR, 25 XDR) with PTB underwent adjunctive thoracic surgery. Median age was 30 years and average duration of preoperative M/XDR-PTB medical therapy was 350 days. The following surgical procedures were performed: pneumonectomy (10%), lobectomy (51%), segmentectomy (33%), and thoracoplasty (6%). Mean postoperative follow up time was 372 days. Of 77 patients with evaluable outcomes, 64 (83%) had favorable outcomes including 90% of MDR and 68% 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 cavitary 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.

Modulation of immunity and disease by glycans is increasingly recognized. However, how host glycosylation shapes and is shaped by tuberculosis remains poorly understood. We show that deficiency in the glucosaminyl (N-acetyl) transferase 1 (Gcnt1), a key enzyme for core-2 O-glycans biosynthesis, drives susceptibility to Mycobacterium tuberculosis infection. The increased susceptibility of Gcnt1 deficient mice was characterized by extensive lung immune pathology, mechanistically related to neutrophils. Uninfected Gcnt1 deficient mice presented bone marrow, blood and lung neutrophilia, which further increased with infection. Blood neutrophilia required Gcnt1 deficiency in the hematopoietic compartment, relating with enhanced granulopoiesis, but normal cellular egress from the bone marrow. Interestingly, for the blood neutrophilia to translate into susceptibility to M. tuberculosis infection, Gnct1 deficiency in the stroma was also necessary. Complete Gcnt1 deficiency associated with increased lung expression of the neutrophil chemoattractant CXCL2. Lastly, we demonstrate that the transcript levels of various glycosyltransferase-encoding genes were altered in whole blood of active tuberculosis patients and that sialyl Lewis x, a glycan widely present in human neutrophils, was detected in the lung of tuberculosis patients. Our findings reveal a previously unappreciated link between Gcnt1, neutrophilia and susceptibility to M. tuberculosis infection, uncovering new players balancing the immune response in tuberculosis.