Background The association between Tuberculosis (TB) and Diabetes Mellitus (DM) have always been an area of interest for decades. Many studies have reported the impact of DM on the development and prognosis of TB and vice versa. There is a major research gap in the area of drug-drug interactions between anti-TB drugs and anti-diabetic drugs. Hence, this study investigated the drug-drug interactions between first-line anti-TB and anti-diabetic drugs in patients with TB and DM. Methodology A prospective study was undertaken in three groups of adult patients, namely, TB, DM and DMTB from May 2018 to February 2020. Plasma concentrations of RMP, INH, PZA, MET, GLB, GLP and GLM were estimated by high-performance liquid chromatography (HPLC). Result 21 TB, 76 DMTB and 51 DM patients with subgroups in both DM and DMTB were recruited. It was observed that plasma levels of anti-diabetic drugs were altered in DMTB patients receiving first-line anti-TB drugs. However, the levels of anti-TB drugs were not altered in the presence of DM and irrespective of the DM status, sub-therapeutic rifampicin concentration was detected. Conclusion This study provided the roadmap to study the impact of anti-diabetic drug interactions on anti-TB drugs and vice versa. Our study is the first of its kind to explore this puzzle.

Background Drug-resistant tuberculosis (DR-TB) is one of the challenging forms of TB to treat, not only in adults but also in children and adolescents. Further, there is a void in the treatment strategy exclusively for children due to various reasons, including paucity of pharmacokinetic (PK) data on anti-TB drugs across the globe. In this context, the present study aimed at assessing the PK of some of the anti-TB drugs used in DR-TB treatment regimens.Method A multicentre observational study was conducted among DR-TB children and adolescents (n = 200) aged 1-18 years (median: 12 years; IQR: 9-14) treated under programmatic settings in India. Steady-state PK (intensive: n = 89; and sparse: n = 111) evaluation of moxifloxacin, levofloxacin, cycloserine, ethionamide, rifampicin, isoniazid and pyrazinamide was carried out by measuring plasma levels using HPLC methods.Results In the study population, the frequency of achieving peak plasma concentrations ranged between 13% (for rifampicin) to 82% (for pyrazinamide), whereas the frequency of suboptimal peak concentration for pyrazinamide, cycloserine, moxifloxacin, levofloxacin and rifampicin was 15%, 19%, 29%, 41% and 74%, respectively. Further, the frequency of supratherapeutic levels among patients varied between 3% for pyrazinamide and 60% for isoniazid. In the below-12 years age category, the median plasma maximum concentration and 12 h exposure of moxifloxacin were significantly lower than that of the above-12 years category despite similar weight-adjusted dosing.Conclusions Age significantly impacted the plasma concentration and exposure of moxifloxacin. The observed frequencies of suboptimal and supratherapeutic concentrations underscore the necessity for dose optimization and therapeutic drug monitoring in children and adolescents undergoing DR-TB treatment.

Background:To evaluate the effect of metformin on the plasma levels of rifampicin, isoniazid, and pyrazinamide in patients with drug-sensitive pulmonary tuberculosis being treated with first-line antituberculosis treatment (ATT) and to assess the influence of gene polymorphisms on the metabolic pathway of metformin and plasma levels of antitubercular drugs.Methods:Nondiabetic adults aged 18-60 years with pulmonary tuberculosis were randomized to either the standard ATT (ATT group) or ATT plus metformin (METRIF group) groups in a phase IIB clinical trial. An intensive pharmacokinetic study with blood collection at 0 hour (predosing), followed by 1, 2, 4, 6, 8, and 12 hours after dosing was conducted during the first month of treatment in a subset of 60 study participants after a minimum of 14 doses. Plasma concentrations of rifampicin, isoniazid, pyrazinamide, and metformin were measured by high-performance liquid chromatography using validated methods, and pharmacokinetic parameters and OCT1 and MATE1 gene polymorphisms were compared between the groups.Results:Significant increases in the clearance of rifampicin, isoniazid, and pyrazinamide were observed in patients in the METRIF group (n = 29) compared with those in the ATT group (n = 31). The AA genotypes of the single-nucleotide polymorphism of rs2289669 (MATE1) in the METRIF group showed a significantly decreased area under the concentration-time curve to the last observation point and increased clearance of rifampicin.Conclusions:Metformin altered rifampicin and isoniazid plasma concentrations in patients receiving antituberculosis treatment for pulmonary tuberculosis with little effect on sputum conversion at the end of treatment. Studies with larger sample sizes are needed to understand host drug-drug interactions.

Background & objectives In gastrointestinal stromal tumour (GIST), not only genetic abnormalities are responsible for adverse clinical events, but epigenetic modifications also play a crucial role. MicroRNA (miRNA) dysregulation plays a significant role in carcinogenesis as miRNAs serve as natural silencer for their targets. Our study aimed to explore the miRNAs expression and its association with molecular and histopathological characteristics of GIST. Methods Fifty GIST samples, including 45 formalin fixed paraffin embedded (FFPE) and fresh tissues were included. Peripheral non-tumour tissues were used as controls. All the cases were confirmed using immunohistochemistry. RNA was extracted using miRNA-specific kit, and the expression was performed using RT-qPCR. The data were evaluated using AriaMx software version 1.5 (Agilent, US). MiRNAs expression was analyzed by using the relative quantification method (ΔΔCT). Results miR-221, miR-222, miR-494 and miR-34a showed significant down-regulation in tumours relative to non-tumour tissues. The expression levels of these miRNAs were significantly down-regulated in c-KIT (proto-oncogene encoding the tyrosine kinase transmembrane receptor)-positive tumours compared to c-KIT-negative. Further analysis revealed that reduced expression was associated with spindle subtypes and gastric localization. However, there was no significant correlation with other histological features. Additionally, miR-221/222, and miR-494 were down-regulated in most of the KIT exon 11 mutant subtypes, while miRNA-34a was associated with platelet derived growth factor receptor alpha (PDGFRA) mutations. Interpretation & conclusions The present study showed that the down-regulation of these miRNAs may help better molecular classification and characterization of GISTs. Our results offer new insight into the association between miRNAs and histological features, enabling a more thorough understanding of GISTs at the molecular level.

This study was carried out to assess the role of therapeutic drug monitoring of crucial first-line anti-tubercular drugs: rifampicin (R) and isoniazid (H) among 75 non-responding proven drug-sensitive tuberculosis patients on treatment followed by intervention in field conditions. The intervention was done in the form of either an increase in the dosage of R and H in patients with minimally low drug levels or a modification of the regimen in a certain group of patients with significantly low drug levels by augmenting it with three or four second-line drugs in addition to standard first-line drugs. This study also aimed to determine the relationship between the measured plasma concentration of anti-tubercular drugs and various demographic, microbiological, radiological, and malabsorption factors and the presence of co-morbidities affecting them. The study also focused on the clinical impact of the intervention for low plasma levels of anti-TB drugs on TB treatment outcomes. In our study overall, 85.5% of patients had low levels of any drug. In 85.3% of patients, R levels were low, and in 39.1%, H levels were low. On univariate analysis, low body mass index (BMI), hypoalbuminemia, bilateral disease on chest X-rays, and the presence of cavities were found to be significantly associated with low drug levels, while none of the factors were independently significantly associated. Low BMI, pulmonary tuberculosis and disseminated tuberculosis, far-advanced disease and bilateral disease on chest X-ray, presence of cavities, and only low R levels were associated with unfavorable outcomes, with none of the factors found to be significant on multivariate analysis. In our study, it was seen that the treatment outcome was favorable in 59.6% of patients in whom this intervention was done by augmenting the treatment regimen with three/four second-line drugs along with increasing the dose of R and H. To conclude, various factors may be associated with low plasma levels of anti-tubercular drugs. If such patients show clinical non-response after >6 months of treatment and have significantly low drug levels, with an absence of drug resistance, their treatment regimen may need augmentation with three/four second-line drugs along with an increase in the dose of R and H, which may lead to a favorable outcome.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h ) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

Introduction: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors. Anemia is a common finding in GIST, but the relationship between tumor volume and anemia severity is not well established. Methods: This study aimed to investigate the correlation between the severity of anemia and various factors, mainly tumor volume, in GIST patients who underwent surgical resection. The study included 20 patients with GIST who underwent surgical resection at a tertiary care center. Demographic data, clinical presentation, hemoglobin level, radiological findings, surgical procedure, tumor characteristics, pathological findings, and immunohistochemical analysis were recorded. The tumor volume was calculated from the final resected tumor dimensions. Results: The mean age of the patients was 53.8 ± 12 years. Eleven were males, and nine were females. The most common presentation was upper gastrointestinal bleeding (50%), followed by pain in the abdomen (35%). The most common tumor location was the stomach (75%). The mean hemoglobin level was 10.29 ± 1.9 g/dL. The mean tumor volume was 470.8 ± 1269.07 cc. R0 resection was achieved in 18 (90%) patients. There was no significant correlation between tumor volume and hemoglobin level (r=0.227, p=0.358). Conclusion: This study found no significant correlation between tumor volume and the severity of anemia in patients with GIST. Further studies with larger sample sizes are needed to validate these findings.

This study involves the in-vitro and in-vivo anti-TB potency and in-vivo safety of Transitmycin (TR) (PubChem CID:90659753)- identified to be a novel secondary metabolite derived from Streptomyces sp (R2). TR was tested in-vitro against drug resistant TB clinical isolates (n = 49). 94% of DR-TB strains (n = 49) were inhibited by TR at 10μg ml-1. In-vivo safety and efficacy studies showed that 0.005mg kg-1 of TR is toxic to mice, rats and guinea pigs, while 0.001mg kg-1 is safe, infection load did not reduce. TR is a potent DNA intercalator and also targets RecA and methionine aminopeptidases of Mycobacterium. Analogue 47 of TR was designed using in-silico based molecule detoxification approaches and SAR analysis. The multiple targeting nature of the TR brightens the chances of the analogues of TR to be a potent TB therapeutic molecule even though the parental compound is toxic. Analog 47 of TR is proposed to have non-DNA intercalating property and lesser in-vivo toxicity with high functional potency. This study attempts to develop a novel anti-TB molecule from microbial sources. Though the parental compound is toxic, its analogs are designed to be safe through in-silico approaches. However, further laboratory validations on this claim need to be carried out before labelling it as a promising anti-TB molecule.

Abstract Background Treatment success rates for multidrug-resistant tuberculosis (MDR-TB) remain low globally. Availability of newer drugs has given scope to develop regimens that can be patient-friendly, less toxic, with improved outcomes. We proposed to determine the effectiveness of an entirely oral, short-course regimen with bedaquiline and delamanid in treating MDR-TB with additional resistance to fluoroquinolones (MDR-TBFQ+) or second-line injectable (MDR-TBSLI+). Methods We prospectively determined the effectiveness and safety of combining 2 new drugs with 2 repurposed drugs—bedaquiline, delamanid, linezolid, and clofazimine—for 24–36 weeks in adults with pulmonary MDR-TBFQ+ and/or MDR-TBSLI+. The primary outcome was a favorable response at end of treatment, defined as 2 consecutive negative cultures taken 4 weeks apart. The unfavorable outcomes included bacteriologic or clinical failure during the treatment period. Results Of the 165 participants enrolled, 158 had MDR-TBFQ+. At the end of treatment, after excluding 12 patients due to baseline drug susceptibility and culture negatives, 139 of 153 patients (91%) had a favorable outcome. Fourteen patients (9%) had unfavorable outcomes: 4 deaths, 7 treatment changes, 2 bacteriological failures, and 1 withdrawal. During treatment, 85 patients (52%) developed myelosuppression, 69 (42%) reported peripheral neuropathy, and none had QTc(F) prolongation >500 ms. At 48 weeks of follow-up, 131 patients showed sustained treatment success with the resolution of adverse events in the majority. Conclusions After 24–36 weeks of treatment, this regimen resulted in a satisfactory favorable outcome in pulmonary MDR-TB patients with additional drug resistance. Cardiotoxicity was minimal, and myelosuppression, while common, was detected early and treated successfully. Clinical Trials Registration ClinicalTrials Registry of India (CTRI/2019/01/017310).

Iatrogenic colonic barotrauma is a well-documented entity, mostly due to endoscopic procedures. Compressed air pressure colorectal injury is less frequent, and the exact mechanism is not defined clearly to date. We present our experience of managing high transanal barotrauma to the colorectum in two similar cases presented with massive pneumoperitoneum, pneumothorax, and pneumomediastinum, a rare presentation in emergency departments, with an accident being the common etiology, where both the patients presented with massive abdominal distension and respiratory distress with diffuse subcutaneous emphysema. A huge amount of gas was noted in the peritoneal cavity on radiographs; the FAST examination was inconclusive and attributed to emphysema impeding the diagnosis. A big gush of air was noted during temporary pneumoperitoneum decompression and laparotomy. Multiple seromuscular tears with perforation in the transverse colon were identified and primarily repaired in the first patient, and the second one had perforation at the rectosigmoid junction, which was brought out as a stoma. The restoration of the stoma was done after ensuring adequate anal tone, with both patients doing well in the follow-up period.

BackgroundSuboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.MethodsWe systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24andCmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide.N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants ofCmaxwere generally similar to those for AUC0–24.ConclusionsThis study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Background & objectives: The National Tuberculosis (TB) Control Programme has transitioned from thrice-weekly to daily drug treatment regimens in India. This preliminary study was conceived to compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in TB patients being treated with daily and thrice weekly anti-TB treatment (ATT). Methods: This prospective observational study was undertaken in 49 newly diagnosed adult TB patients receiving either daily ATT (n=22) or thrice-weekly ATT (n=27). Plasma RMP, INH and PZA were estimated by high-performance liquid chromatography. Results: The peak concentration (Cmax) of RMP was significantly higher (RMP: 8.5 μg/ml vs. 5.5 μg/ml; P=0.003) and Cmax of INH was significantly lower (INH: 4.8 μg/ml vs. 10.9 μg/ml; P<0.001) in case of daily dosing compared to thrice-weekly ATT. Cmax of drugs and doses was significantly correlated. A higher proportion of patients had subtherapeutic RMP Cmax (8.0 μg/ml) during thrice-weekly compared to daily ATT (78% vs. 36%; P=0.004). Multiple linear regression analysis showed that Cmax of RMP was significantly influenced by the dosing rhythm, pulmonary TB and Cmax of INH and PZA by the mg/kg doses. Interpretation & conclusions: RMP concentrations were higher and INH concentrations were lower during daily ATT, suggesting that INH doses may need to be increased in case of a daily regimen. Larger studies are, however, required using higher INH doses when monitoring for adverse drug reactions and treatment outcomes.

Introduction: Eosinophilic enteritis is a rare cause of gastric outlet obstruction and if not recognized early can be very difficult to manage. Endoscopic ultrasound (EUS) guided gastrojejunostomy (GJ) is most often used for malignant disorders. However, it can act as a very effective temporary tool in benign disorders for effective medical therapy to take its course. Case Description/Methods: A 49-year-old man presented to us with features of recurrent vomiting and pain abdomen for 5 months. He had alcohol-related chronic calcific pancreatitis. Three years prior to current presentation he had features of gastric outlet obstruction for which he underwent oesophagogastroduodenoscopy (EGD) revealing a circumferential ulcer in antropyloric region with swelling. He underwent truncal vagotomy with antecolic gastrojejunostomy. Biopsy from the specimen had revealed eosinophilic gastroenteritis (EE). He again had some symptoms of obstruction 2 months after surgery which responded to proton pump inhibitors. He remained apparently well with regular follow up for chronic pancreatitis. Now he was symptomatic with progressive symptoms of gastric outlet obstruction since last 4 months. On endoscopy he was found to have both afferent and efferent loop strictures. He was also having a few geographic ulcers and psuedopolyps near stricture mouth. He underwent balloon dilatation twice upto 13.5 mm but symtoms did not improve. Repeat biopsies were taken from the ulcer and stricture site revealed EE with eosinophilic abscesses. Barium meal follow-through and Contrast enhanced CT was done for evaluation of stricture. A nasoduodenal (ND) tube of 10 french was negotiated over guidewire through the stricture using a cannula. It was used to continue enteral feeding. Surgical consultation was taken and poor surgical outcome was predicted in view of both loop involvement. He was started on oral budesonide and planned for an endoscopic bypass procedure. The ND tube was used to distend the normal jejunal loops beyond stricture and endoscopic ultrasound was used for gastrojejunostomy using a lumen apposing metal stent. Discussion: EUS-GJ is a viable option for gastric outlet obstruction even in benign cases for bridging for further surgical or medical therapy. Post-surgery complications may be difficult to manage and EUS-GJ appears more lucrative for the short time period. It requires a carefully selected patient with preset managment plan and a learning curve for successful implementation. Watch the video at https://tinyurl.com/ACGAbstractS355

BACKGROUND:The role of ascitic and serum levels of various tumour biomarkers in the discrimination of cause of ascites is not well established.OBJECTIVE:To evaluate the role of serum and ascitic levels of tumor biomarkers (CA 72-4, CA 19-9, CEA and CA 125) in discrimination of cause of ascites.METHODS:A prospective study was conducted in consecutive patients presenting with ascites. Serum and ascitic levels of CA 19-9, CA 125, CA 72-4 and carcinoembryonic antigen (CEA) were determined at the presentation. The patients with cirrhotic ascites, tuberculous peritonitis (TBP) and peritoneal carcinomatosis (PC) were eventually included in analysis.RESULTS:Of the 93 patients (58 males, mean age 47 years) included, the underlying cause was cirrhosis in 31, PC in 42 and peritoneal tuberculosis in 20. The best cutoff for discriminating benign and malignant ascites for serum CEA, CA 19-9 and CA 72-4 were 6.7 ng/mL, 108 IU/mL and 8.9 IU/mL, respectively. The best cutoff for discriminating benign and malignant ascites for ascitic CA 125, CEA, CA 19-9 and CA 72-4 were 623 IU/mL, 8.7 ng/mL, 33.2 IU/mL and 7 IU/mL, respectively.CONCLUSION:The performance of single biomarker for the prediction of underlying PC is low but a combination of serum CA 19-9 and CA 72-4 best predicted the presence of peritoneal carcinomatosis.

BACKGROUND:Patients with concurrent diabetes mellitus (DM) and tuberculosis (TB) pose an increased risk of treatment failure in TB and management of DM is complicated. Anti-diabetic and anti-TB drugs may interact with on another other when co-administered. The role of anti-TB drugs on the excretion of metformin in urine has not been studied. Therefore, we carried out a study in DM patients with and without TB to compare the percentage of metformin excreted in urine. METHODS:A total of 52 DMTB and 17 DM patients were recruited in this study from the Chennai Corporation Centres. DM and DM - TB patients were administered the prescribed anti-TB and anti-diabetic drugs (metformin (MET), glipizide (GLP),glimepiride (GLM),glibenclamide (GLB),rifampicin (RMP),isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). DM and DMTB patients received metformin (MET) alone and in combination with sulphonylureas as diabetic drugs. The urine samples were collected from 0 to 8 hours after drug administration. Urine MET excreted in DM and DMTB patients were estimated by high performance liquid chromatography (HPLC) and percent dose was calculated. RESULTS:The percent dose of MET excreted in urine in DMTB patients was significantly higher when compared to DM patients. There is significant difference in the percent dose of MET excreted among DM patients with and without sulphonylureas, values being 23.3 and 17.7% respectively (p = 0.044). CONCLUSION:This is the first study to report on the percent dose of MET excretion in urine in patients with DM and DMTB receiving MET along with anti-TB drugs.

BACKGROUND: Surgical site infection continues to be a major problem after laparotomy for perforation peritonitis, as it increases morbidity and hospital stay and decreases the quality of life. Intra-abdominal drain placement is a routine practice in perforation peritonitis. The aim of our study is to compare the incidence of surgical site infection in two groups of patients who were operated for perforation peritonitis: The first group received the intraperitoneal drain, while no drain was placed in the second group. METHODS: The present single-center, prospective, non-randomized study was conducted in the Department of General Surgery at the Postgraduate Institute of Medical Education and Research, India. A total of 122 patients underwent exploratory laparotomy for gastroduodenal and small bowel perforation peritonitis, of which 100 participants were included in this study, based on specified criteria for inclusion and exclusion. A total of 50 participants each were included in the drain group and the no drain group, respectively. A drain was placed in every alternate patient with perforation peritonitis who received primary closure or resection anastomosis. Patients with diabetes, renal failure, and hemodynamic instability and those who presented more than 72 h since symptom onset were excluded from the study. Peritoneal fluids were cultured. The primary endpoint was to identify the incidence of surgical site infections (SSIs) in the two groups. We also compared the time taken for the return of bowel movements, duration for which a nasogastric tube was inserted, whether any intervention was performed under local or general anesthesia within 30 days of surgery, the duration of hospital stay, and the ease of diagnosing repair leak in the post-operative period in both the groups. RESULTS: Demographics of participants in both the groups were matched. No significant difference was observed between the drain and no-drain groups with respect to the incidence of surgical site infection (p=0.779). The duration of surgery and length of hospital stay were significantly lower in the no drain group. A significant difference was observed between the two groups concerning the peritoneal culture growth, and increased bacterial growth was seen in the drain group. No significant difference in morbidity was noted between the two groups, which was classified according to the Clavien-Dindo classification. CONCLUSION: Routine use of intra-abdominal drains was not found to be effective in preventing SSIs, but a selection bias cannot be ruled out. Patients with no drains had a significantly shorter duration of hospital stay.

BACKGROUND:Metformin, by reducing intracellular Mycobacterium tuberculosis growth, can be considered an adjunctive therapy to anti-tuberculosis treatment (ATT). We determined whether metformin with standard ATT reduces time to sputum culture conversion and tissue inflammation in adults with pulmonary tuberculosis (PTB). METHODS:In a randomized, 8-week, clinical trial, newly diagnosed, culture-positive PTB patients were randomized to standard ATT (HREZ = control arm) or standard ATT plus daily 1000 mg metformin (MET-HREZ = Metformin with Rifampicin [METRIF] arm) for 8 weeks during 2018-2020 at 5 sites in India. The primary end point was time to sputum culture conversion by liquid culture during 8 weeks of ATT. Plasma inflammatory markers were estimated in a subset. A Cox proportional hazard model was used to estimate time and predictors of culture conversion. RESULTS:Of the 322 patients randomized, 239 (74%) were male, and 212 (66%) had bilateral disease on chest radiograph with 54 (18%) showing cavitation. The median time to sputum culture conversion by liquid culture was 42 days in the METRIF arm and 41 days in the control arm (hazard ratio, 0.8; 95% confidence interval [CI], .624-1.019). After 8 weeks of ATT, cavitary lesions on X-ray (7, 5.3% vs 18, 12.9%; relative risk, 0.42; 95% CI, .18-.96; P = .041) and inflammatory markers were significantly lower in the METRIF arm. Higher body mass index and lower sputum smear grading were associated with faster sputum culture conversion. CONCLUSIONS:The addition of metformin to standard ATT did not hasten sputum culture conversion but diminished excess inflammation, thus reducing lung tissue damage as seen by faster clearance on X-ray and reduced inflammatory markers. CLINICAL TRIALS REGISTRATION:Clinical Trial Registry of India (CTRI/2018/01/011176).

OBJECTIVE: A high-performance liquid chromatography method for the estimation of Linezolid in human plasma was developed and validated. METHODS: Samples (100µµL) were deproteinized with acetonitrile and analyzed using LiChrospher 100, RP18e column with PDA detection at 254 nm. The flow rate of the isocratic mobile phase comprising of 0.1% formic acid in 1000 ml of water and acetonitrile in the ratio of 60:40 (v/v) was set at 1.0 ml/min. RESULTS: The calibration curve ranged from 0.50 to 20.0 µg/ml and was linear. The recovery ranged from 96% to 101%. The accuracy ranged from 98 to 101% and intra- and inter-day relative standard deviation was <4.58%. The method reliably eliminated interfering materials from plasma and R2 was 0.9973. The method described was applied to the determination of plasma LZD concentration in multi-drug-resistant tuberculosis patients who are treated with a dose of 600 mg LZD once daily. CONCLUSIONS: The developed method is suitable for determination of plasma LZD in routine care and considered feasible in less-resourced settings

BACKGROUND:In TB, therapeutic drug monitoring (TDM) is recommended for linezolid; however, implementation is challenging in endemic settings. Non-invasive saliva sampling using a mobile assay would increase the feasibility of TDM.OBJECTIVES:To validate a linezolid saliva assay using a mobile UV spectrophotometer.METHODS:The saliva assay was developed using NanoPhotometer NP80® and linezolid concentrations were quantified using second-order derivative spectroscopy. Sample preparation involved liquid-liquid extraction of saliva, using saturated sodium chloride and ethyl acetate at 1:1:3 (v/v/v). The assay was validated for accuracy, precision, selectivity, specificity, carry-over, matrix effect, stability and filters. Acceptance criteria were bias and coefficient of variation (CV) <15% for quality control (QC) samples and <20% for the lower limit of quantification (LLOQ).RESULTS:Linezolid concentrations correlated with the amplitude between 250 and 270 nm on the second-order derivative spectra. The linezolid calibration curve was linear over the range of 3.0 to 25 mg/L (R2 = 0.99) and the LLOQ was 3.0 mg/L. Accuracy and precision were demonstrated with bias of -7.5% to 2.7% and CV ≤5.6%. The assay met the criteria for selectivity, matrix effect, carry-over, stability (tested up to 3 days) and use of filters (0.22 μM Millex®-GV and Millex®-GP). Specificity was tested with potential co-medications. Interferences from pyrazinamide, levofloxacin, moxifloxacin, rifampicin, abacavir, acetaminophen and trimethoprim were noted; however, with minimal clinical implications on linezolid dosing.CONCLUSIONS:We validated a UV spectrophotometric assay using non-invasive saliva sampling for linezolid. The next step is to demonstrate clinical feasibility and value to facilitate programmatic implementation of TDM.