Epidemiology of first- and second-line drugs-resistant pulmonary tuberculosis in Iran: Systematic review and meta-analysis.

Drug resistance among Mycobacterium tuberculosis (MTB) strains is a growing concern in developing countries. We conducted a comprehensive search for relevant studies in Iran on PubMed, Scopus, and Embase until June 12, 2020. Our study focused on determining the prevalence of antibiotic resistance in MTB isolates, with subgroup analyses based on year, location, and drug susceptibility testing (DST) methods. Statistical analyses were performed using STATA software. Our meta-analysis included a total of 47 articles. Among new TB cases, we found the following prevalence rates: Any-resistance to first-line drugs: 31 % (95 % CI, 24-38), mono-drug resistance: 15 % (95 % CI, 10-22), and multidrug resistance to first-line drugs: 6 % (95 % CI, 4-8). There was a significant variation in the rate of MDR among new TB cases based on the year of publication, location, and DST methods (P < 0.0001). We observed substantial variability in multidrug-resistant TB rates among new cases across the studies. Stratified analyses revealed that publication years and DST methods significantly affected resistance rates. Studies from southern and central Iran reported higher any-drug resistance rates, suggesting regional differences. Among retreatment cases, the prevalence rates were as follows: Any resistance: 68 % (95 % CI 58-78), mono-resistance: 19 % (95 % CI 7-34), multidrug resistance: 28 % (95 % CI 15-43). Our study revealed that the prevalence of drug-resistant TB (DR-TB) among TB cases in Iran is higher than the global average. Particularly, MDR-TB among retreatment TB cases is a significant public health issue.

Extrapulmonary and Drug-Resistant Childhood Tuberculosis: Unveiling the Disease to Adopt the Optimal Treatment Strategy.

Paediatric tuberculosis (TB) is a substantial threat among infectious diseases, particularly considering the high risk of extrapulmonary tuberculosis (EPTB), severe forms of the disease, and the spreading of drug-resistant strains. Describing the characteristics of children with EPTB and those with drug-resistant tuberculosis (DR-TB) and analysing the role of second-line drugs could facilitate the management of these cases. This retrospective study was conducted on 271 children diagnosed with active TB disease (44 EPTB cases, 9 DR-TB cases), originating from diverse geographic areas, who were referred to the infectious disease unit at Meyer Children's Hospital, Florence, Italy, from 2006 to 2022. In most patients, the management of therapies was complicated by the impossibility to obtain drug susceptibility testing (DST) results, which improved over the years: 17/154 (11.04%) children had DST results between 2006 and 2013, and 50/117 (42.73%, p < 0.001) between 2014 and 2022. Second-line drugs were not exclusively administered to DR-TB cases, but also to EPTB cases (20/44, 45.45%). Drugs were generally well tolerated; adverse events occurred in 13 children (13/271, 4.80%) and were generally mild and reversable. Therapies were successful in 267 children (98.52%) considered cured, while 4 (1.48%) presented sequelae. Both univariate and multivariate logistic regression analyses were conducted to investigate factors associated with EPTB, DR-TB, and second-line drugs administration. Originating from Asia emerged as a risk factor associated with both EPTB and DR-TB (p = 0.013 and p = 0.045, respectively). The introduction of GeneXpert tests has significantly improved TB diagnosis and the obtaining of DST results. The administration of second-line therapies should be limited primarily to DR-TB cases, but it is possible that these drugs may also be beneficial in selected EPTB cases.

A Systematic Review of Second-Line Treatments in Antiviral Resistant Strains of HSV-1, HSV-2, and VZV.

Drug-resistant variants of herpes simplex viruses (HSV) have been reported that are not effectively treated with first-line antiviral agents. The objective of this study was to evaluate available literature on the possible efficacy of second-line treatments in HSV and the use of second-line treatments in HSV strains that are resistant to first-line treatments. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a final search was conducted in six databases on November 5, 2021 for all relevant literature using terms related to antiviral resistance, herpes, and HSV. Eligible manuscripts were required to report the presence of an existing or proposed second-line treatment for HSV-1, HSV-2, or varicella zoster virus (VZV); have full-text English-language access; and potentially reduce the rate of antiviral resistance. Following screening, 137 articles were included in qualitative synthesis. Of the included studies, articles that examined the relationship between viral resistance to first-line treatments and potential second-line treatments in HSV were included. The Cochrane risk-of-bias tool for randomized trials was used to assess risk of bias. Due to the heterogeneity of study designs, a meta-analysis of the studies was not performed. The dates in which accepted studies were published spanned from 2015-2021. In terms of sample characteristics, the majority (72.26%) of studies used Vero cells. When looking at the viruses on which the interventions were tested, the majority (84.67%) used HSV-1, with (34.31%) of these studies reporting testing on resistant HSV strains. Regarding the effectiveness of the proposed interventions, 91.97% were effective as potential managements for resistant strains of HSV. Of the papers reviewed, nectin in 2.19% of the reviews had efficacy as a second-line treatments in HSV, amenamevir in 2.19%, methanol extract in 2.19%, monoclonal antibodies in 1.46%, arbidol in 1.46%, siRNA swarms in 1.46%, Cucumis melo sulfated pectin in 1.46%, and components from Olea europeae in 1.46%. In addition to this griffithsin in 1.46% was effective, Morus alba L. in 1.46%, using nucleosides in 1.46%, botryosphaeran in 1.46%, monoterpenes in 1.46%, almond skin extracts in 1.46%, bortezomib in 1.46%, flavonoid compounds in 1.46%, andessential oils were effective in 1.46%, but not effective in 0.73%. The available literature reviewed consistently supports the existence and potentiality of second-line treatments for HSV strains that are resistant to first-line treatments. Immunocompromised patients have been noted to be the population most often affected by drug-resistant variants of HSV. Subsequently, we found that HSV infections in this patient population are challenging to manage clinically effectively. The goal of this systematic review is to provide additional information to patients on the potentiality of second-line treatment in HSV strains resistant to first-line treatments, especially those who are immunocompromised. All patients, whether they are immunocompromised or not, deserve to have their infections clinically managed in a manner supported by comprehensive research. This review provides necessary information about treatment options for patients with resistant HSV infections and their providers.

First and Second-Line Anti-Tuberculosis Drug-Resistance Patterns in Pulmonary Tuberculosis Patients in Zambia.

BACKGROUND: Drug-resistant tuberculosis has continued to be a serious global health threat defined by complexity as well as higher morbidity and mortality wherever it occurs, Zambia included. However, the paucity of information on drug-susceptibility patterns of both first-line and second-line anti-tuberculosis (anti-TB) drugs, including the new and repurposed drugs used in the management of drug-resistant tuberculosis in Zambia, was the major thrust for conducting this study. METHODS: A total of 132 bacteriologically confirmed TB isolates were collected from patients with pulmonary TB during the period from April 2020 to December 2021 in Southern and Eastern Provinces of Zambia. Drug-resistance profiles were determined according to four first-line and five second-line anti-TB drugs. Standard mycobacteriological methods were used to isolate and determine phenotypic drug susceptibility. Data on the participants' social-demographic characteristics were obtained using a pre-test checklist. RESULTS: Overall, the prevalence of resistance to one or more anti-TB drugs was 23.5% (31/132, 95% CI: 16.5-31.6%). A total of 9.8% (13/132, 95% CI: 5.3-16.2%) of the patients had multidrug-resistant TB and 1.2% were new cases, while 25.5% had a history of being previously treated for TB. Among those with mono-resistant TB strains, isoniazid (INH) resistance was the highest at 9.8% (13/132, 95% CI: 5.3-16.2%). Two (2/31) (6.5%) XDR-TB and one (1/31) (3.2%) pre-XDR-TB cases were identified among the MDR-TB patients. Previously treated patients were 40 times more likely (OR; 40.3, 95% CI: 11.1-146.5%) to have drug-resistant TB than those who had no history of being treated for TB. CONCLUSION: This study has established a high rate of multidrug-resistant TB and has further identified both pre-XDR- and XDR-TB. There is a need to intensify surveillance of MDR- and XDR-TB to inform future guidelines for effective treatment and monitoring.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis: Neuropsychiatric and Multidisciplinary Approach to a Patient Not Responding to First-Line Treatment.

The understanding of anti-NMDA (N-methyl-D-aspartate) receptor encephalitis, recognized by Dalmau and colleagues in 2007, has come a long way in helping clinicians to recognize the significance of rapidly progressive psychiatric symptoms in patients who are actually suffering from autoimmune disease. This subtype of autoimmune encephalitis manifests from antibodies that target the NR1 and/or NR2 subunits of NMDA receptors in serum or cerebrospinal fluid. Since gaining notoriety among neurologists, it has shown an etiologic predilection for children, adolescents, and young adult females, often associated with ovarian teratomas. Conversely, it affects young males as well, though it is rarer to find co-occurring tumors. It is a multistage disorder, initially presenting with psychiatric symptoms that progress in varying fashion, including headache, fever, nuchal rigidity, emesis, seizure, autonomic instability, auditory and visual hallucinations, delusional ideation, agitation, altered sensorium, and motor disturbances (i.e. dyskinesia, catatonia, etc.). Early diagnosis is critical due to the relatively high (25%) mortality rate. In this case, we present the case of a 30-year-old male who presented to our institution's Comprehensive Psychiatric Emergency Program (CPEP) exhibiting bizarre behavior and visual hallucinations, and was later confirmed to have anti-NMDA receptor encephalitis. The case report highlights the risk factors, disease course, and treatment modalities of anti-NMDA receptor encephalitis with special emphasis on the subsect of patients who may not respond to first-line therapies.

Novel rrs mutations in second-line injectable drug-resistant clinical isolates of Mycobacterium tuberculosis from the Punjab province of Pakistan.

INTRODUCTION: Phenotypic drug susceptibility testing is the most common approach to assess drug-resistant isolates; however, molecular methods of drug susceptibility testing are fast, accurate hence, offer less time for transmission during the diagnosis period. As data on the molecular methods regarding injectable drug resistance in the Punjab province of Pakistan is limited, therefore in this study, we aimed to analyze the mutations in the rrs gene behind second-line injectable drug resistance. MATERIAL AND METHODS: Mycobacterium tuberculosis isolates were collected from the sputum of 5362 TB suspects. The strains confirmed for resistant to injectable drugs through drug susceptibility testing were further proceeded. The 1537bp rrs gene was amplified with the help of three sets of primers with overlapping regions and DNA sequencing was performed. Obtained sequences were aligned with reference sequence to find mutations. RFLP-PCR method was also optimized for rapid detection of a common (143bp and 205bp) rrs gene mutation. RESULTS: Among 172 rifampicin resistance isolates, 163(95%) were resistant to both rifampicin and isoniazid, and 9 (5%) were resistant to only rifampicin. Among the resistant samples, 12 (6.9%) samples were resistant to all three injectable drugs. Sixty out of 172 (34.9%) samples showed resistance to at least one drug and 10 (5.8%) samples were resistant to two drugs among the 3 s-line drugs. Sequencing analysis showed novel mutations in different samples at positions 443InsC, 19DelT, 29G>A, 48C>T, 50G>C, 265InsT, 423T>G, 476InsA, 446A>G, 563DelA, 695G>A, 805DelA, 900G>A, and 1510A>G, while some already reported mutations at position 1401A>G, 1402A>G, and 1484G>T were also observed. MIC of novel rrs gene mutations in KAN, CAP, and AMK resistant isolates were found between 2.5 mg/L-3.05 mg/L, 2.08 mg/L-3.0 mg/L, and 2.1 mg/L-2.7 mg/L respectively. CONCLUSION: Novel mutations in the rrs gene reported in this study may confer second-line injectable drugs resistance in Mtb. This molecular insight into second-line injectable drug resistance is useful for better management of resistance Mtb in high burden countries.

Access to quality diagnosis and rational treatment for tuberculosis: real-world evidence from China-Gates Tuberculosis Control Project Phase III.

BACKGROUND: China has successfully reduced tuberculosis (TB) incidence rate over the past three decades, however, challenges remain in improving the quality of TB diagnosis and treatment. In this paper, we assess the effects of the implementation of "China National Health Commission (NHC) and Gates Foundation TB Prevention and Control Project" on the quality of TB care in the three provinces. METHODS: We conducted the baseline study in 2016 and the final evaluations in 2019 in the 12 selected project counties. We obtained TB patients' information from the TB Information Management System and reviewed medical records of TB cases in the TB designated hospitals. We compared TB diagnosis and treatment services with the national practice guideline and used Student's t-test and Pearson χ2 tests or Fisher's exact tests to compare the difference before and after the project implementation. RESULTS: The percentage of sputum smear-negative (SS-) patients taking culture or rapid molecular test (RMT) doubled between 2015 and 2018 (from 35% to 87%), and the percentage of bacteriologically confirmed pulmonary TB cases increased from 36% to 52%. RMT has been widely used and contributed an additional 20% of bacteriologically confirmed TB cases in 2018. The percentage of TB patients taking drug susceptibility tests (DST) also doubled (from 40% in 2015 to 82% in 2018), and the proportion of TB patients receiving adequate diagnosis services increased from 85% to 96%. Among all SS- TB patients, over 86% received the recommended diagnostic services at the end of the study period, an improvement from 75% prior to the project implementation. However, the proportion of TB patients treated irrationally using second-line anti-TB drugs (SLDs) increased from 12.6% in 2015 to 19.9% in 2018. The regional disparities remained within the project provinces, albeit the gaps between them narrowed down for almost all indicators. CONCLUSIONS: The quality of TB diagnosis services has been improved substantially, which is attributable to the coverage of new diagnosis technology. However, irrational use of SLDs remains a concern after the project implementation.

Medical Management of Trigeminal Neuralgia.

BACKGROUND: Trigeminal neuralgia (TN) is a painful condition, often leading to poor quality of life. OBJECTIVE: The aim of this review was to discuss the various treatment modalities for the medical management of TN. MATERIALS AND METHODS: We reviewed the available literature on TN in clinical databases including PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews, with a specific focus on the pharmacological treatment and newer drugs under development for the treatment of TN. RESULTS: Carbamazepine (CBZ) is the gold standard of treatment for TN. The first-line drugs for the treatment of TN are CBZ and oxcarbazepine (OXC). A proportion of cases (30%) are initially resistant to the first-line drugs. Alternative drugs need to be considered if the first-line drugs are not well tolerated or become ineffective with prolonged therapy. The second-line drugs comprise lamotrigine, baclofen, gabapentin, and pregabalin used as monotherapy or in combination with CBZ/OXC. Botulinum toxin A may be a promising presurgical option. Newer drug like vixotrigine has shown good results in phase two randomized control trials. About 50% of cases develop treatment resistance to oral drugs over the subsequent years of therapy and require surgical options. CONCLUSION: The first-line drugs for the treatment of TN (irrespective of the age group or type) are CBZ and OXC. Combination therapy with second-line or other drugs may become necessary with poor response to CBZ/OXC, or if adverse events occur. Patients should be offered surgical options if there is poor response or tolerance to the medical therapy.

Validation of a novel medium for drug susceptibility testing of Mycobacterium Tuberculosis against First- and Second-Line drugs: AYC.2.2 Agar and AYC.2.1 Broth.

Background: The aim of this study was the validation of AYC.2.2 agar and AYC.2.1 broth for the breakpoint values of first- and second-line drugs for Mycobacterium tuberculosis. Method: A total of 12 isolates including 5 reference strains and 7 well-defined clinical isolates were tested for their antituberculosis susceptibilities. Inhibitory effects of first- and second-line antituberculous drugs including isoniazid, rifampicin, streptomycin, ethambutol, amikacin, capreomycin, kanamycin, para-aminosalicylic acid, ethionamide, rifabutin, ofloxacin, levofloxacin, and moxifloxacin were tested. Results: According to the minimal inhibitory concentration values obtained in 7H10 agar, 7H9-S broth, AYC.2.2 agar, and AYC.2.1 broth, category agreement is 100%, and very major discrepancy (MAD), MAD, and minor discrepancy ratios were determined as 0 for all drugs. Conclusion: It was concluded that breakpoint values by CLSI recommendation for 7H10 agar can be also used for AYC.2.2 agar and AYC.2.1 broth. In addition, further multicenter studies are needed to use the new medium in routine mycobacteriology laboratories.

Resistant Tuberculosis: the Latest Advancements of Second-line Antibiotic Inhalation Products.

Drug-resistant tuberculosis (TB) can be considered the man-made result of interrupted, erratic or inadequate TB therapy. As reported in WHO data, resistant Mycobacterium tuberculosis (Mtb) strains continue to constitute a public health crisis. Mtb is naturally able to survive host defence mechanisms and to resist most antibiotics currently available. Prolonged treatment regimens using the available first-line drugs give rise to poor patient compliance and a rapid evolution of strains resistant to rifampicin only or to both rifampicin and isoniazid (multi drug-resistant, MDR-TB). The accumulation of mutations may give rise to extensively drug-resistant strains (XDR-TB), i.e. strains with resistance also to fluoroquinolones and to the injectable aminoglycoside, which represent the second-line drugs. Direct lung delivery of anti-tubercular drugs, as an adjunct to conventional routes, provides high concentrations within the lungs, which are the intended target site of drug delivery, representing an interesting strategy to prevent or reduce the development of drug-resistant strains. The purpose of this paper is to describe and critically analyse the most recent and advanced results in the formulation development of WHO second-line drug inhalation products, with particular focus on dry powder formulation. Although some of these formulations have been developed for other lung infectious diseases (Pseudomonas aeruginosa, nontuberculous mycobacteria), they could be valuable to treat MDR-TB and XDR-TB.

Culture conversion and six months interim outcomes in retreatment cases of pulmonary MDRTB - a six month interim analysis.

OBJECTIVE: To estimate the time to culture conversion and factors associated with failure to culture conversion, six-month interim outcomes and associated risk factors with poor interim outcomes in multi-drug resistant tuberculosis patients previously treated with second-line drugs. METHODS: The prospective clinical case series study was conducted from March 2016 to January 2017 at the Indus Hospital Tuberculosis Clinic and seven other sites that are part of the hospital's Programmatic Management of Drug Resistant Tuberculosis initiative. All bacteriologically confirmed multi-drug resistant tuberculosis retreatment patients were enrolled. Data was collected on age, gender, site of enrollment, detailed history of previous treatment with anti-tuberculosis drugs, medical history, history of first-line drugs, history of second-line drugs, treatment outcomes, baseline sputum smear microscopy and monthly follow-up sputum smear microscopy and culture results. Data was subjected to univariate and multiple logistic regression analyses, and risk factors for failure to culture conversion were assessed using Cox Proportional Hazards Model. RESULTS: Out of 266 patients, 143(53.8%) were males, the overall largest age group was 5-24 years 97(36.5%), and 250 (94%) patients had previous history of treatment with first-line drugs. Overall, 101(40.1%) patients experienced poor interim outcome. Poor interim outcomes were significantly associated with higher number of drugs on the regimen, (odds ratio: 1.27; 95% confidence interval: 1.03-1.58) and high sputum smear grading (odds ratio: 4.56; 95% confidence interval: 3.30-18.71). Besides, 186(70.3%) patients experienced culture conversion within the initial six months of treatment. CONCLUSIONS: The success rate of re-treatment of multi-drug resistant tuberculosis with conventional regimen was found to be unacceptably low.

Isoniazid and Rifampin-Resistance Mutations Associated With Resistance to Second-Line Drugs and With Sputum Culture Conversion.

BACKGROUND: Mutations in the genes inhA, katG, and rpoB confer resistance to anti-tuberculosis (TB) drugs isoniazid and rifampin. We questioned whether specific mutations in these genes were associated with different clinical and microbiological characteristics. METHODS: In a multicountry prospective cohort study of multidrug-resistant TB, we identified inhA, katG, and rpoB mutations in sputum isolates using the Hain MTBDRplus line probe assay. For specific mutations, we performed bivariate analysis to determine relative risk of baseline or acquired resistance to other TB drugs. We compared time to sputum culture conversion (TSCC) using Kaplan-Meier curves and stratified Cox regression. RESULTS: In total, 447 participants enrolled from January 2005 to December 2008 from 7 countries were included. Relative to rpoB S531L, isolates with rpoB D516V had less cross-resistance to rifabutin, increased baseline resistance to other drugs, and increased acquired fluoroquinolone resistance. Relative to mutation of katG only, mutation of inhA promoter and katG was associated with baseline extensively drug resistant (XDR) TB, increased acquired fluoroquinolone resistance, and slower TSCC (125.5 vs 89.0 days). CONCLUSIONS: Specific mutations in inhA and katG are associated with differences in resistance to other drugs and TSCC. Molecular testing may make it possible to tailor treatment and assess additional drug resistance risk according to specific mutation profile.

Drug sensitivity patterns in Xpert-positive spinal tuberculosis: an observational study of 252 patients.

PURPOSE: To evaluate the sensitivity patterns of anti-tubercular drugs in Xpert MTB-positive spinal tuberculosis (TB) patients and to formulate the guidelines for early start of empiric anti-tubercular treatment (ATT) in MDR-TB spine based on resistance pattern in this large series. METHODS: It was a cross-sectional observational study of 252 consecutive patients who were Xpert MTB-proven spinal TB cases with retrospective analysis of prospective data. The Xpert MTB/RIF (Mycobacterium tuberculosis/rifampicin) assay was used to diagnose spinal TB and RIF resistance. All patients underwent drug sensitivity testing (DST) to 13 commonly used anti-tubercular drugs using BACTEC MGIT-960 system. The drug sensitivity pattern of primary and secondary anti-tubercular drugs was recorded and compared. RESULTS: The DST study revealed 110 (43.6%) cases of multi-drug resistant (MDR-resistance to both isoniazid and rifampicin) and 24 (9.5%) cases of non-MDR-TB spine. The widespread resistance was found for both isoniazid (91%) and rifampicin (85%), followed by streptomycin (61.9%). The least resistance was found for kanamycin, amikacin and capreomycin and no resistance found for clofazimine. CONCLUSION: The Xpert MTB/RIF assay is an efficient technique for the rapid diagnosis of spinal TB and suspected MDR-TB; however, it is recommended to do culture and DST in all patients with spinal TB to guide the selection of appropriate second-line drugs when required. In cases of non-availability of culture and DST, it is suggested to use data from large series such as this to plan the best empirical ATT regimen. These slides can be retrieved under Electronic Supplementary Material.

Adverse drug reactions in tuberculosis and management.

BACKGROUND: Treatment of drug susceptible tuberculosis (DS-TB) requires regimens containing first line drugs (FLDs') whereas drug resistant tuberculosis (DR-TB) are treated with regimens comprising combination of both second line drugs (SLDs') and few FLDs'. Adverse drug reactions (ADRs') to these anti-tubercular drugs are quite common as they are being used for longer duration. ADRs' may cause associated morbidity and even mortality if not recognized early. There are major concerns regarding treatment of DR-TB patients particularly with SLDs' in that they are expensive, have low efficacy and more toxic as compared to FLDs'. There may be a severe impact on adherence and higher risk of default and treatment failure affecting outcome overall if such ADRs' are not properly managed. METHODS: A search strategy was adopted involving principal electronic databases (Pubmed, EMBASE, Google and Google scholar) of English language articles from 1990 till now, using various terms in combination. All articles with resulting titles, abstract and full text, when available were read and kept for reference. RESULTS: 101 articles including 4 systematic reviews have been identified. The overall prevalence of ADRs' with FLDs' and SLDs' are estimated to vary from 8.0% to 85% and 69% to 96% respectively. Most ADRs' are observed in the intensive phase as compared to continuation phase. No difference in frequency of ADRs' was reported with intermittent or daily intake of anti-tubercular drugs. The occurrence of ADRs' may be influenced by multiple factors and may range from mild gastrointestinal disturbances to serious hepatotoxicity, ototoxicity, nephrotoxicity peripheral neuropathy, cutaneous ADRs', etc. Most of ADRs' are minor and can be managed without discontinuation of treatment. Some ADRs' can be major or severe causing life-threatening experience leading to either modification or discontinuation of regimen and even mortality if not recognized and treated promptly. CONCLUSION: Early recognition by active surveillance and appropriate management of these ADRs' might improve adherence and treatment success.

Detection of Second Line Drug Resistance among Drug Resistant Mycobacterium Tuberculosis Isolates in Botswana.

The emergence and transmission of multidrug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (M.tb) strains is a threat to global tuberculosis (TB) control. The early detection of drug resistance is critical for patient management. The aim of this study was to determine the proportion of isolates with additional second-line resistance among rifampicin and isoniazid resistant and MDR-TB isolates. A total of 66 M.tb isolates received at the National Tuberculosis Reference Laboratory between March 2012 and October 2013 with resistance to isoniazid, rifampicin or both were analyzed in this study. The genotypes of the M.tb isolates were determined by spoligotyping and second-line drug susceptibility testing was done using the Hain Genotype MTBDRsl line probe assay version 2.0. The treatment outcomes were defined according to the Botswana national and World Health Organization (WHO) guidelines. Of the 57 isolates analyzed, 33 (58%) were MDR-TB, 4 (7%) were additionally resistant to flouroquinolones and 3 (5%) were resistant to both fluoroquinolones and second-line injectable drugs. The most common fluoroquinolone resistance-conferring mutation detected was gyrA A90V. All XDR-TB cases remained smear or culture positive throughout the treatment. Our study findings indicate the importance of monitoring drug resistant TB cases to ensure rapid detection of second-line drug resistance.

Limited Scope of Shorter Drug Regimen for MDR TB Caused by High Resistance to Fluoroquinolone.

Resistance to second-line tuberculosis drugs for patients with multidrug-resistant tuberculosis has emerged globally and is a potential risk factor for unfavorable outcomes of shorter duration drug regimens. We assessed the proportion of patients eligible for a shorter drug regimen in Uttar Pradesh, India, which had the highest rate of multidrug-resistant tuberculosis in India.

Treatment outcomes of the drug resistant tuberculosis cases previously exposed to second line anti Tuberculosis drugs in Pakistan: A multi-center cross-sectional study.

OBJECTIVE: To determine the treatment outcomes of the drug-resistant tuberculosis patients who were previously exposed to second line drugs. METHODS: The retrospective study was conducted at eight Programmatic Management of Drug Resistant Tuberculosis (PMDT) sites in Sindh and Balochistan. Data of patients who were previously exposed to second line drugs and re-enrolled in the drug-resistant tuberculosis register at PMDT sites in Sindh and Balochistan between 2008 and 2016 was included for analysis. Data of those still under treatment or transferred to another treatment site was excluded. Association was explored between treatment outcomes and other independent variables, while in order to identify the risk factors associated with poor treatment outcomes univariate and multivariate logistic regression was used. RESULTS: Overall, there were 3645 patients and 288(8%) were previously exposed to second line drugs. Of them, 95(33%) were excluded, and the final sample stood at 193; 99(51.3%) males and 94(48.7%) females. The median age of the sample was 29 years (inter-quartile range: 22-41 years). The mean duration of treatment was 20}11.14 months. Overall success rate of the re-treatment of previously treated patients was 105(54.4%). Observed relapse rate was 9(4.7%).. CONCLUSIONS: The success rate for re-treatment drug-resistant tuberculosis patients was found to be unacceptably low. New drugs and novel regimens should be made widely available.

Multicentre laboratory validation of the nitrate reductase assay using liquid medium for the rapid detection of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis.

To perform a multicentre study evaluating the performance of the nitrate reductase assay (NRA) using liquid medium for the detection of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis and to establish the MICs and critical concentrations of rifampicin, isoniazid, ofloxacin, amikacin, kanamycin and capreomycin. The study was carried out in three phases. Phase I determined the MIC of each drug. Phase II established the critical concentration of each drug. Phase III validated critical concentrations for the six drugs tested by the NRA using liquid medium compared with the agar proportion method or MGIT 960 system at each site. The critical concentrations for the six drugs used in the NRA are as follows: rifampicin, 1 mg/L; isoniazid, 0.2 mg/L; ofloxacin, 2 mg/L; amikacin, 2 mg/L; kanamycin, 5 mg/L; capreomycin, 2.5 mg/L. Phase III: Excellent agreement was obtained for all drugs tested at the majority of sites. The accuracy was 97%-100% for rifampicin, 96.8%-99.2% for isoniazid, 98%-100% for ofloxacin, 96.8%-98.5% for amikacin, 96.4%-99.5% for kanamycin and 96.8%-100% for capreomycin. Results for NRA using liquid medium were obtained in a median time of 7 days. NRA performed in liquid medium offers a rapid, economical and feasible method for detection of M. tuberculosis resistance to first- and second-line drugs in resource-limited settings.

A study on pattern of resistance to second line anti tubercular drugs among multi drug resistant tuberculosis patients.

AIMS AND OBJECTIVES: To determine the prevalence and pattern of resistance to second line drugs among multi drug resistant (MDR) tuberculosis patients being treated on category IV regimen. METHODOLOGY: This study was conducted at Department of Respiratory Medicine, J.L.N. Medical College, Ajmer in collaboration with IRL, STDC, Ajmer. Second line anti tubercular drug sensitivity for 398 multi drug resistant tuberculosis patients (between June-2015 and June-2016) was done to find out prevalence and pattern of resistance to second line drugs. Second line drug sensitivity was performed at accredited laboratory, Microbiology department, S.M.S. Medical College, Jaipur. RESULTS: Among these 398 patients, 136 (34.17%) were resistant to fluoroquinolones (Ofloxacin) (Pre XDR); 18 (4.52%) were resistant to one of the aminoglycosides (Inj. Kanamycin, Capreomycin, Amikacin) (Pre XDR); while 22 (5.53%) patients were resistant to fluoroquinolones as well as aminoglycosides (XDR). 148 (37.18%) patients were found sensitive to both the drugs. Samples of 41 (10.3%) patients were contaminated and no growth was seen in 33 (8.29%) patients. CONCLUSION: Nearly half of the multi drug resistant (MDR) tuberculosis patients (44.22%) being treated on category IV regimen also have resistance to either fluoroquinolones or aminoglycosides or both i.e. Pre XDR or XDR. This may result in poor outcome of category IV regimen under RNTCP. There is a strong need for provision of culture sensitivity for all first line drugs and at least two second line drugs viz. Fluoroquinolones and aminoglycosides for all the patients registered as smear positive under RNTCP. There is also a need for development of rapid culture technique for sensitivity to second line drugs.

Time to Multidrug-Resistant Tuberculosis Treatment Initiation in Association with Treatment Outcomes in Shanghai, China.

In high tuberculosis (TB)-burden countries such as China, the diagnosis of multidrug-resistant tuberculosis (MDR-TB) using conventional drug susceptibility testing (DST) takes months, making treatment delay inevitable. Poor outcomes of MDR-TB might be associated with delayed, even inappropriate, treatment. The purposes of this study were to investigate the time to MDR-TB treatment initiation and to assess the association between early treatment and treatment outcomes. Between April 2011 and December 2014, this population-based retrospective cohort study collected the demographic and clinical characteristics and the drug susceptibility profiles of all registered MDR-TB patients in Shanghai, China. The dates of TB and MDR-TB diagnoses, DST performance, and treatment initiation were extracted to calculate the times to treatment. In total, 284 of 346 MDR-TB patients were eligible for analysis, and 68.3% (194/284) had favored outcomes. The median time to treatment initiation from TB diagnosis was 172 days among those with favored outcomes and 190 days among those with poor outcomes. Treatments initiated within 60 days after performing DST (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.22 to 5.36) and empirical treatments (OR, 2.09; 95% CI, 1.01 to 4.32) were positively associated with favored outcomes. Substantial delays to MDR-TB treatment were observed when conventional DST was used. Early treatment predicted favored outcomes. Rapid diagnostic methods should be scaled up and improvements should be made in patient management and information linkage to reduce treatment delay.