Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization.

BACKGROUND: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization. METHODS AND FINDINGS: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts. CONCLUSIONS: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.

Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives.

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.

Esophagorespiratory fistula without stricture: palliative treatment with a barbed covered metallic stent in the central airway.

PURPOSE: To compare the clinical safety and efficacy of airway placement of barbed and nonbarbed metallic stents in the treatment of esophagorespiratory fistula (ERF) without stricture. MATERIALS AND METHODS: The authors prospectively evaluated the clinical results of 10 patients who underwent fluoroscopically guided placement of barbed, fully covered, retrievable metallic stents in the trachea or main bronchus for treatment of ERF without stricture in the esophagus and central airway between 2007 and 2009. The authors compared these outcomes with retrospectively evaluated clinical outcomes in seven patients who underwent airway placement of nonbarbed, fully covered, metallic stents for treatment of ERF without stricture between 1998 and 2001. Study end points included stent migration and clinical success, defined as effective closure of the fistula with improved aspiration symptoms, or improvement of dyspnea, within 7 days after stent placement. RESULTS: Clinical success was observed in nine of ten (90%) of patients who received barbed stents, compared with two of seven (29%) who were treated with nonbarbed stents (P = .035). Stent migration within 5 days occurred in zero of ten and five of seven (57%) patients, respectively (P = .015). CONCLUSIONS: Placement of barbed, covered metallic stents in the central airway is safe and effective for closure of ERF without strictures. The barbed design is effective in preventing stent migration.

Efficacy comparison between (18)F-FDG PET/CT and bone scintigraphy in detecting bony metastases of non-small-cell lung cancer.

BACKGROUND: We compared the efficacies of integrated whole-body (18)F-FDG PET/CT (PET/CT) and (99m)Tc-DPD bone scintigraphy (bone scan) for the detection of bone metastases in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between April 2004 and May 2007, the database at our institution was retrospectively reviewed to identify all patients with newly diagnosed NSCLC and who underwent staging with both PET/CT and bone scan prior to the initiation of therapy. Presence of bone metastases was confirmed by considering all available clinical information. This search identified 1000 patients, 265 women and 735 men (age range, 18-89 years; median age, 65 years). RESULTS: Bone metastases were confirmed in 105 (10.5%) patients. The respective accuracy, sensitivity, and specificity of PET/CT and bone scan in detecting bone metastases were 98.3% and 95.1% (p<0.001), 94.3% and 78.1% (p=0.001), and 98.8% and 97.4% (p=0.006). PET/CT also showed lower incidence of false positive (1.2% vs. 2.9%) and false-negative results (5.7% vs. 21.9%) than bone scan. Agreement between PET/CT and bone scan findings was good with calculated kappa=0.732. CONCLUSIONS: PET/CT was superior to bone scan in the detection of bone metastases of NSCLC with the lower incidence of false-positive as well as false-negative results.

Chromosomal instability is a risk factor for poor prognosis of adenocarcinoma of the lung: Fluorescence in situ hybridization analysis of paraffin-embedded tissue from Korean patients.

BACKGROUND: In this study, we sought to evaluate the prognostic importance of chromosomal instability (CIN) in adenocarcinoma (AC) of the lung. The relationship between CIN detected by fluorescence in situ hybridization (FISH) and survival in AC patients was examined. METHODS: Sixty-three surgical specimens of lung AC were analyzed. To identify tumors with CIN, p16 and multi-target DNA FISH assays for c-myc, chromosome 6, EGFR, and chromosome 5 (LAVysion, Vysis) were performed on nuclei extracted from paraffin-embedded tumor tissues. Survival rates were compared in terms of sex, age, histology, T factor, N factor, CIN, and smoking status. A sample was classified as CIN-positive if at least three of the five chromosomes were positive. RESULTS: Out of the 63 specimens, 32 (39.7%) were CIN-positive. The 5-year overall disease-free survival rate was 58.7% as a whole, 46.9% for CIN-positive patients and 71.0% for the CIN-negative patients [hazard ratio (HR), 2.34; 95% confidence interval (CI), 1.04-5.26; p = 0.04]. The 5-year overall survival rate was 81.0%, 68.7% for CIN-positive patients and 93.5% for the CIN-negative patients (HR, 5.64; 95% CI, 1.23-25.70; p = 0.026). In multivariate analysis after adjusting for pathologic nodal staging, tumor staging, sex, age, and smoking history, compared with the CIN-negative patients, the CIN-positive status remained significantly associated with decreased overall survival (HR, 8.48; 95% CI, 1.66-43.42; p = 0.010). CONCLUSIONS: CIN can be effectively detected in primary AC of lung using FISH analysis. CIN is associated with poor prognosis for AC, and may thus be utilized as an independent prognostic factor for the disease.

Treatment of tracheobronchial obstruction with a polytetrafluoroethylene-covered retrievable expandable nitinol stent.

PURPOSE: To evaluate the clinical effectiveness of polytetrafluoroethylene (PTFE)-covered retrievable expandable nitinol stents in tracheobronchial strictures. MATERIALS AND METHODS: With fluoroscopic guidance, PTFE-covered retrievable expandable nitinol stents were placed in 15 symptomatic patients with benign (n = 6) or malignant (n = 9) tracheobronchial strictures. Complications and improvement in respiratory status were evaluated. Stents were removed electively 6 months after placement in benign strictures or if complications occurred. Membrane degradation or separation from the wire mesh was evaluated in removed stents. RESULTS: A total of 17 stents were successfully placed and were well tolerated in all patients. Sputum retention, stent migration, and tissue hyperplasia occurred in 23.5% (n = 4), 17.6% (n = 3), and 17.6% (n = 3) of stents, respectively. A total of 11 stents were successfully removed electively 6 months after placement (n = 4) or when complications occurred (n = 7). All 11 such stents were removed without difficulty with use of standard techniques, antecedent balloon dilation being necessary in two cases as a result of tissue hyperplasia. No removed stent showed signs of membrane degradation, and two removed stents showed signs of membrane separation from the mesh. CONCLUSIONS: PTFE-covered retrievable expandable nitinol stents were effective in the treatment of tracheobronchial strictures. Stent removal was easy with use of standard techniques, and no removed stent showed evidence of membrane degradation.

Clinical characteristics of acute pulmonary thromboembolism in Korea.

BACKGROUND: Acute pulmonary thromboembolism (APTE) remains an important cause of morbidity and mortality in Western countries. In Korea, both the incidence and the mortality rate of APTE were thought to be low compared to Western countries. We performed the present study to investigate the current status of APTE in Korea. METHODS: Eight hundred and eight registry patients with APTE were analyzed with respect to clinical symptoms and signs, the presence of underlying diseases or predisposing factors, diagnostic methods, treatment and clinical course. RESULTS: The most common risk factors were prolonged immobilization (22.9%), deep venous thrombosis (22.0%), a recent operation (19.2%), and cancer (15.8%). The most common symptoms were dyspnea (78.6%), and chest pain (26.9%). The most common abnormality on chest radiography was effusion. The overall mortality rate at 3 months was 11.0%. Multivariate logistic regression analysis demonstrated that increased mortality risk was independently associated with the following baseline factors: onset in hospital (OR 1.88; 95% CI 1.03-3.42; p=0.03), lung cancer (OR 9.20; 95% CI 1.96-43.27; p=0.005), tachycardia (OR 3.50; 95% CI 1.86-6.60; p=0.0001), cardiogenic shock (OR 6.74; 95% CI 2.73-16.64; p=0.0001), and cyanosis (OR 3.45; 95% CI 1.27-9.44; p=0.01). CONCLUSIONS: Some differences did exist for the risk factors, symptoms, chest X-ray findings, mortality rate and prognostic factors as compared with those for Western patients. These results can prove especially helpful in the diagnosis as well as for the treatment of patients with APTE.

The effects of methylene blue on hemodynamic parameters and cytokine levels in refractory septic shock.

BACKGROUND: Endogenous nitric oxide (NO) induces the peripheral vasodilation via the activation of guanylate cyclase in patients with septic shock. The purpose of this study was to assess the acute effects of methylene blue (MB), which is an inhibitor of guanylate cyclase, on the hemodynamics and on the production of pro-inflammatory cytokines and nitric oxide (NO) in patients with refractory septic shock. METHODS: Twenty consecutive patients with refractory septic shock, which was defined as shock refractory to a dopamine infusion of more than 20 microg/kg/min with the appropriate use of antibiotics and adequate volume replacement, received MB infusion of 1 mg/kg intravenously. The hemodynamic and respiratory variables were measured at baseline, 30, 60 and 120 min after an infusion of MB (1 mg/kg). The blood levels of NO, IL-1, IL-10 and TNF-alpha were measured at baseline, 30 and 120 min after MB infusion. RESULTS: The administration of MB induced an increase in the systemic vascular resistance (SVR) that resulted in an increase of the mean arterial pressure (MAP) in patients with refractory septic shock, and this was without a decrease in cardiac output. The administered MB induced an increase in pulmonary vascular resistance (PVR) that resulted in an increase of pulmonary arterial pressure (PAP), without any deterioration of gas exchange. However, the increases in SVR and PVR were not associated with the alteration of endogenous production of NO, IL-1, IL-10 and TNF- alpha. CONCLUSION: MB transiently elevated the MAP by increasing the SVR without altering the endogenous productions of NO, IL-1, IL-10 and TNF- alpha during the study period in patients with refractory septic shock.

Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs.

RATIONALE: In cigarette smoking-induced chronic obstructive pulmonary disease, structural and functional derangements are characterized by parenchymal destruction and pulmonary hypertension. Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase inhibitors that have been used as lipid-lowering agents. These drugs also have additional pharmacologic properties, including antiinflammation, scavenging reactive oxygen species, restoring endothelial function, and antithrombogenesis, all of which can counteract the harmful effects of cigarette smoking. OBJECTIVE: We performed assays to determine whether simvastatin could attenuate lung damage induced by chronic cigarette smoking in rats. METHODS: In Sprague-Dawley rats exposed to cigarette smoke for 16 weeks, morphologic changes in the lungs and pulmonary arterial pressure were examined. MAIN RESULTS: Simvastatin inhibited lung parenchymal destruction and development of pulmonary hypertension, and also inhibited peribronchial and perivascular infiltration of inflammatory cells and induction of matrix metalloproteinase-9 activity in lung tissue. Simvastatin additionally prevented pulmonary vascular remodeling and the changes in endothelial nitric oxide synthase expression induced by smoking. In human lung microvascular endothelial cells, simvastatin increased expression of endothelial nitric oxide synthase mRNA. CONCLUSIONS: Simvastatin ameliorated the structural and functional derangements of the lungs caused by cigarette smoking, partly by suppressing inflammation and matrix metalloproteinase-9 induction and preventing pulmonary vascular abnormality. These findings indicate that statins may play a role in the treatment of cigarette smoking-induced chronic obstructive pulmonary disease.