Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a MALDI mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside1. In contrast, moxifloxacin which is active in vitro against persisters, a sub-population of Mycobacterium tuberculosis that persists in specific niches under drug pressure, and achieved treatment shortening in mice2, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We also suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration contributes to treatment outcome has wide implications for TB.

Pyrazinamide has played a critical role in shortening therapy against drug-sensitive, drug-resistant, active, and latent tuberculosis (TB). Despite widespread recognition of its therapeutic importance, the sterilizing properties of this 60-year-old drug remain an enigma given its rather poor activity in vitro. Here we revisit longstanding paradigms and offer pharmacokinetic explanations for the apparent disconnect between in vitro activity and clinical impact. We show substantial host-mediated conversion of prodrug pyrazinamide (PZA) to the active form, pyrazinoic acid (POA), in TB patients and in animal models. We demonstrate favorable penetration of this pool of circulating POA from plasma into lung tissue and granulomas, where the pathogen resides. In standardized growth inhibition experiments, we show that POA exhibits superior in vitro potency compared to PZA, indicating that the vascular supply of host-derived POA may contribute to the in vivo efficacy of PZA, thereby reducing the apparent discrepancy between in vitro and in vivo activity. However, the results also raise the possibility that subinhibitory concentrations of POA generated by the host could fuel the emergence of resistance to both PZA and POA. In contrast to widespread expectations, we demonstrate good oral bioavailability and exposure in preclinical species in pharmacokinetic studies of oral POA. Baseline exposure of oral POA can be further increased by the xanthine oxidase inhibitor and approved gout drug allopurinol. These promising results pave the way for clinical investigations of oral POA as a therapeutic alternative or an add-on to overcome PZA resistance and salvage this essential TB drug.

No abstract

No abstract

ObjectiveTo investigate the efficacy of systemic pulmonary rehabilitation (PR) after lung resection in patients with lung cancer.MethodsForty-one patients undergoing lung resection were enrolled and classified into the experimental (n=31) and control groups (n=10). The experimental group underwent post-operative systemic PR which was conducted 30 min/day on every hospitalization day by an expert physical therapist. The control group received the same education about the PR exercises and were encouraged to self-exercise without supervision of the physical therapist. The PR group was taught a self-PR program and feedback was provided regularly until 6 months after surgery. We conducted pulmonary function testing (PFT) and used a visual analog scale (VAS) to evaluate pain, and the modified Borg Dyspnea Scale (mBS) to measure perceived respiratory exertion shortly before and 2 weeks, 1, 3, and 6 months after surgery.ResultsA significant improvement on the VAS was observed in patients who received systemic PR >3 months. Significant improvements in forced vital capacity (FVC) and mBS score were observed in patients who received systemic PR >6 months (p<0.05). Other PFT results were not different compared with those in the control group.ConclusionPatients who received lung resection suffered a significant decline in functional reserve and increases in pain and subjective dyspnea deteriorating quality of life (QoL). Systemic PR supervised by a therapist helped improve reduced pulmonary FVC and QoL and minimized discomfort during the postoperative periods in patients who underwent lung resection.