scholarly journals Clinical Impact on Tuberculosis Treatment Outcomes of Discordance Between Molecular and Growth-Based Assays for Rifampin Resistance, California 2003–2013

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Neha S. Shah ◽  
SY Grace Lin ◽  
Pennan M. Barry ◽  
Yi-Ning Cheng ◽  
Gisela Schecter ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Demographic Data ◽  
Clinical Importance ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Successful Outcome ◽  
Treatment Regimens ◽  
Initial Regimen ◽  
Rpob Mutation ◽  
Poor Outcomes

Abstract Background.  Data from international settings suggest that isolates of Mycobacterium tuberculosis with rpoB mutations testing phenotypically susceptible to rifampin (RIF) may have clinical significance. We analyzed treatment outcomes of California patients with discordant molecular-phenotypic RIF results. Methods.  We included tuberculosis (TB) patients, during 2003–2013, whose specimens tested RIF susceptible phenotypically but had a rpoB mutation determined by pyrosequencing. Demographic data were abstracted from the California TB registry. Phenotypic drug-susceptibility testing, medical history, treatment, and outcomes were abstracted from medical records. Results.  Of 3330 isolates tested, 413 specimens had a rpoB mutation (12.4%). Of these, 16 (3.9%) had molecular-phenotypic discordant RIF results. Seven mutations were identified: 511Pro, 516Phe, 526Asn, 526Ser (AGC and TCC), 526Cys, and 533Pro. Fourteen (88%) had isoniazid (INH) resistance, 6 of whom were also phenotypically resistant to ethambutol (EMB) and/or pyrazinamide (PZA). Five patients (25%), 1 with 511Pro and 4 with 526Asn, relapsed or failed treatment. The initial regimen for 3 patients was RIF, PZA, and EMB; 1 patient received RIF, PZA, EMB, and a fluoroquinolone (FQN); and 1 patient received RIF, EMB, FQN, and some second-line medications. Upon retreatment with an expanded regimen, 3 (75%) patients completed treatment, 1 patient moved before treatment completion, and 1 patient continues on treatment. The remaining 11 patients had a successful outcome with 9 having received a FQN and/or a rifamycin. Conclusions.  Rifampin molecular-phenotypic discordance was rare, and most isolates had INH resistance. Patients who did not receive an expanded regimen had poor outcomes. These mutations may have clinical importance, and expanded treatment regimens should be considered.

Multidrug-resistant tuberculosis in the Kharkiv Region, Ukraine

2020 ◽  
Vol 24 (5) ◽  
pp. 485-491
Author(s):  
D. Butov ◽  
C. Lange ◽  
J. Heyckendorf ◽  
I. Kalmykova ◽  
T. Butova ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Poor Treatment ◽  
Mdr Tb ◽  
Observational Cohort

OBJECTIVE: To document the level of drug resistance in MDR-TB patients and to characterize management capacities for their medical care and MDR-TB treatment outcomes in the Kharkiv region of Ukraine. This area has one of the highest frequencies of MDR-TB worldwide.METHODS: A retrospective observational cohort study was performed on registry data from the regional anti-TB dispensary in Kharkiv. All microbiologically confirmed MDR-TB patients registered in 2014 were included. Diagnostic, treatment and post-treatment follow-up data were analysed.RESULTS: Of 169 patients with MDR-TB, 55.0% had pre-extensively drug-resistant (pre-XDR) or XDR resistant patterns. Rapid molecular diagnosis by GeneXpert and liquid M. tuberculosis cultures were only available for 66.9% and 56.8% of patients, respectively. Phenotypic drug-susceptibility testing (DST) for high priority TB drugs (bedaquiline, linezolid, clofazimine) were not available. DST for later generation fluroquinolones was available only in 53.2% of patients. 50.9% of patients had less than 4 drugs in the treatment regimen proven to be effective by DST. More than 23.1% of patients with MDR-TB failed their treatment and only 45.0% achieved a cure.CONCLUSION: The high prevalence of MDR-TB and poor MDR-TB treatment outcomes in the Kharkiv region, is associated with substantial shortages in rapid molecular and phenotypic DST, a lack of high priority MDR-TB drugs, poor treatment monitoring and follow-up capacities.

scholarly journals A Retrospective Analysis of Isoniazid-Monoresistant Tuberculosis: Among Iranian Pulmonary Tuberculosis Patients

2014 ◽  
Vol 8 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Mohammad Varahram ◽  
Mohammad Javad Nasiri ◽  
Parissa Farnia ◽  
Mohadese Mozafari ◽  
Ali Akbar Velayati
Keyword(s):  
Risk Factors ◽  
Control Program ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Clinical Samples ◽  
Chi Square ◽  
Tb Control ◽  
Treatment Regimens ◽  
Chi Square Test ◽  
Associated Risk Factors

Background and objectives:Isoniazid (INH) is one of the most potent anti-tuberculosis (TB) drugs. The spread and transmission of INH- resistant bacilli are likely to pose a significant problem for National TB control Program (NTP). In this study, we aimed to determine the trend of INH-monoresistant TB in Iran.Methods:The susceptibility patternsof Mycobacterium tuberculosis(MTB) strains that were isolated from clinical samples were retrospectively analyzed (January 2003-December 2011). Identification and drug susceptibility testing (DST) were performed using both conventional and molecular methods. The associated risk factors were assessed using the Chi-square test.Results:Out of 4825 culture-positive isolates, 6.1% were resistant to INH, with an increasing trend over the study period. The INH-monoresistance from 4.4 in 2003 reached to 9.4% in 2011. Among the studied risk factors, age was significantly associated with INH-monoresistance (p < 0.05).Conclusions:The increased trend in INH-monoresistance underlines the need for greater enforcement of national TB control programs. In this regard, better management of TB cases, establishing advanced diagnostic facilities and use of standard treatment regimens are recommended to avoid further emergence of INH resistant cases.

scholarly journals Pediatric Tuberculosis in Young Children in India: A Prospective Study

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Sanjay K. Jain ◽  
Alvaro Ordonez ◽  
Aarti Kinikar ◽  
Nikhil Gupte ◽  
Madhuri Thakar ◽  
...  
Keyword(s):  
Young Children ◽  
Small Sample Size ◽  
Tertiary Hospital ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Small Sample ◽  
Vulnerable Population ◽  
Poor Outcomes ◽  
Pediatric Tuberculosis ◽  
A Prospective Study

Background. India has one of the highest tuberculosis (TB) burdens globally. However, few studies have focused on TB in young children, a vulnerable population, where lack of early diagnosis results in poor outcomes.Methods. Young children (≤5 years) with suspected TB were prospectively enrolled at a tertiary hospital in Pune, India. Detailed clinical evaluation, HIV testing, mycobacterial cultures, and drug susceptibility testing were performed.Results. 223 children with suspected TB were enrolled. The median age was 31 months, 46% were female, 86% had received BCG, 57% were malnourished, and 10% were HIV positive. 12% had TB disease (definite or probable), 35% did not have TB, while TB could not be ruled out in 53%. Extrapulmonary disease was noted in 46%, which was predominantly meningeal. Tuberculin skin test (TST) was positive in 20% of children with TB. Four of 7 (57%) children with culture-confirmed TB harbored drug-resistant (DR) strains of whom 2 (50%) were multi-DR (MDR). In adjusted analyses, HIV infection, positive TST, and exposure to household smoke were found to be significantly associated with children with TB (P≤0.04). Mortality (at 1 year) was 3 of 26 (12%) and 1 of 79 (1%), respectively, in children with TB and those without TB (P< 0.05).Conclusions. Diagnosis of TB is challenging in young children, with high rates of extra-pulmonary and meningeal disease. While the data on DR-TB are limited by the small sample size, they are however concerning, and additional studies are needed to more accurately define the prevalence of DR strains in this vulnerable population.

scholarly journals Comparative Performance of Genomic Methods for the Detection of Pyrazinamide Resistance and Heteroresistance in Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Michael G. Whitfield ◽  
David M. Engelthaler ◽  
Christopher Allender ◽  
Megan Folkerts ◽  
Tim H. Heupink ◽  
...  
Keyword(s):  
Diagnostic Accuracy ◽  
Susceptibility Testing ◽  
High Sensitivity ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Comparative Performance ◽  
Treatment Regimens ◽  
Resistant Tuberculosis ◽  
Targeted Deep Sequencing ◽  
Phenotypic Methods

Background: Pyrazinamide is an important component of both drug-susceptible and drug-resistant tuberculosis treatment regimens. Although approximately 50% of rifampicin resistant isolates are also resistant to pyrazinamide, pyrazinamide susceptibility testing is not routinely performed due to the challenging nature of the assay. We investigated the diagnostic accuracy of genotypic and phenotypic methods, and explored the occurrence of pyrazinamide heteroresistance. Methods: We assessed pyrazinamide susceptibility among 358 individuals enrolled in the South African EXIT-RIF cohort using Sanger and targeted deep sequencing (TDS) of the pncA gene, whole genome sequencing (WGS), and phenotypic drug-susceptibility testing. We calculated the diagnostic accuracy of the different methods, and investigated the prevalence and clinical impact of pncA heteroresistance. True pyrazinamide susceptibility status was assigned to each isolate using the Koser classification and expert rules. Results: We observed 100% agreement across genotypic methods for detection of pncA fixed mutations, only TDS confidently identified three isolates (0.8%) with minor variants. For the 355 (99.2%) isolates that could be assigned true pyrazinamide status with confidence, phenotypic DST had a sensitivity of 96.5% (95% CI: 93.8-99.3%) and specificity of 100% (95% CI: 100-100%); both Sanger sequencing and WGS had a sensitivity of 97.1% (95% CI: 94.6-99.6%) and specificity of 97.8% (95% CI: 95.7-99.9%); and TDS, sensitivity of 98.8% (95% CI: 97.2-100%) and specificity of 97.8% (95% CI: 95.7-99.9%). Conclusions: We demonstrate high sensitivity and specificity for pyrazinamide susceptibility testing among all assessed genotypic methods. The prevalence of pyrazinamide heteroresistance in Mtb isolates was lower than that identified for other first-line drugs.

scholarly journals Detection of pyrazinamide heteroresistance in Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Jim Werngren ◽  
Mikael Mansjö ◽  
Mikaela Glader ◽  
Sven Hoffner ◽  
Lina Davies Forsman
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Diagnostic Tools ◽  
Resistant Bacteria ◽  
Published Data ◽  
Treatment Regimens ◽  
Traditional Drug ◽  
Clinical Awareness

Heteroresistance is defined as the coexistence of both susceptible and resistant bacteria in a bacterial population. Previously published data show that it may occur in 9-57% of Mycobacterium tuberculosis isolates for various drugs. Pyrazinamide (PZA) is an important first-line drug used for treatment of both drug-susceptible and PZA-susceptible multidrug-resistant TB. Clinical PZA resistance is defined as a proportion of resistant bacteria in the isolate exceeding 10%, when the drug is no longer considered clinically effective. The capability of traditional drug susceptibility testing techniques to detect PZA heteroresistance has not yet been evaluated. The aim of this study was to compare the capacity of BACTEC MGIT 960, Wayne’s test and whole genome sequencing (WGS) to detect PZA resistant subpopulations in bacterial suspensions prepared with different proportions of mutant strains. Both BACTEC MGIT 960 and WGS were able to detect the critical level of 10% PZA heteroresistance whereas Wayne’s test failed to do so, with the latter falsely reporting highly resistant samples as PZA susceptible. Failure to detect drug resistant subpopulations may lead to inadvertently weak treatment regimens if ineffective drugs are included, with the risk of treatment failure with the selective growth of resistant subpopulations. We need clinical awareness of heteroresistance as well as evaluation of new diagnostic tools in their capacity in detecting heteroresistance in TB.

scholarly journals Correlation between GyrA Substitutions and Ofloxacin, Levofloxacin, and Moxifloxacin Cross-Resistance in Mycobacterium tuberculosis

2015 ◽  
Vol 59 (9) ◽  
pp. 5427-5434 ◽  
Author(s):  
Melisa Willby ◽  
R. David Sikes ◽  
Seidu Malik ◽  
Beverly Metchock ◽  
James E. Posey
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Concentration ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Cross Resistance ◽  
Content Type ◽  
Treatment Regimens ◽  
Testing Susceptibility ◽  
Proportion Method ◽  
Reflex Testing

ABSTRACTThe newer fluoroquinolones moxifloxacin (MXF) and levofloxacin (LVX) are becoming more common components of tuberculosis (TB) treatment regimens. However, the critical concentrations for testing susceptibility ofMycobacterium tuberculosisto MXF and LVX are not yet well established. Additionally, the degree of cross-resistance between ofloxacin (OFX) and these newer fluoroquinolones has not been thoroughly investigated. In this study, the MICs for MXF and LVX and susceptibility to the critical concentration of OFX were determined using the agar proportion method for 133 isolates ofM. tuberculosis. Most isolates resistant to OFX had LVX MICs of >1 μg/ml and MXF MICs of >0.5 μg/ml. The presence of mutations within thegyrAquinolone resistance-determining regions (QRDR) correlated well with increased MICs, and the level of LVX and MXF resistance was dependent on the specificgyrAmutation present. Substitutions Ala90Val, Asp94Ala, and Asp94Tyr resulted in low-level MXF resistance (MICs were >0.5 but ≤2 μg/ml), while other mutations led to MXF MICs of >2 μg/ml. Based on these results, a critical concentration of 1 μg/ml is suggested for LVX and 0.5 μg/ml for MXF drug susceptibility testing by agar proportion with reflex testing for MXF at 2 μg/ml.

Minimum Inhibitory Concentrations of Fluoroquinolones and Pyrazinamide Susceptibility Correlate to Clinical Improvement in Multidrug-resistant Tuberculosis Patients: A Nationwide Swedish Cohort Study Over 2 Decades

2018 ◽  
Vol 69 (8) ◽  
pp. 1394-1402 ◽  
Author(s):  
Lina Davies Forsman ◽  
Jerker Jonsson ◽  
Charlotta Wagrell ◽  
Jim Werngren ◽  
Mikael Mansjö ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Critical Concentration ◽  
Demographic Data ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Outcome Data ◽  
Tuberculosis Patients ◽  
Successful Treatment Outcome ◽  
Unsuccessful Treatment

Abstract Background Minimum inhibitory concentration (MIC) testing, unlike routine drug susceptibility testing (DST) at a single critical concentration, quantifies drug resistance. The association of MICs and treatment outcome in multidrug-resistant (MDR)–tuberculosis patients is unclear. Therefore, we correlated MICs of first- and second-line tuberculosis drugs with time to sputum culture conversion (tSCC) and treatment outcome in MDR-tuberculosis patients. Methods Clinical and demographic data of MDR-tuberculosis patients in Sweden, including DST results, were retrieved from medical records from 1992 to 2014. MIC determinations were performed retrospectively for the stored individual Mycobacterium tuberculosis (Mtb) isolates using broth microdilution in Middlebrook 7H9. We fitted Cox proportional hazard models correlating MICs, DST results, and clinical variables to tSCC and treatment outcome. Results Successful treatment outcome was observed in 83.5% (132/158) of MDR-tuberculosis patients. Increasing MICs of fluoroquinolones, diabetes, and age >40 years were significantly associated with unsuccessful treatment outcome. Patients treated with pyrazinamide (PZA) had a significantly shorter tSCC compared to patients who were not (median difference, 27 days). Conclusions Increasing MICs of fluoroquinolones were correlated with unsuccessful treatment outcome in MDR-tuberculosis patients. Further studies, including MIC testing and clinical outcome data to define clinical Mtb breakpoints, are warranted. PZA treatment was associated with shorter tSCC, highlighting the importance of PZA DST.

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