Molecular Evaluation of Fluoroquinolone Resistance in Serial Mycobacterium tuberculosis Isolates from Individuals Diagnosed with Multidrug-Resistant Tuberculosis

ABSTRACTFluoroquinolones (FQ) are crucial components of multidrug-resistant tuberculosis (MDR TB) treatment. Differing levels of resistance are associated with specific mutations within the quinolone-resistance-determining region (QRDR) of gyrA. We sequenced the QRDR from serial isolates of MDR TB patients in the Preserving Effective TB Treatment Study (PETTS) with baseline FQ resistance (FQR) or acquired FQ resistance (FQACQR) using an Ion Torrent Personal Genome Machine (PGM) to a depth of 10,000× and reported single nucleotide polymorphisms in ≥1% of reads. FQR isolates harbored 15 distinct alleles with 1.3 (maximum = 6) on average per isolate. Eighteen alleles were identified in FQACQR isolates with an average of 1.6 (maximum = 9) per isolate. Isolates from 78% of FQACQR individuals had mutant alleles identified within 6 months of treatment initiation. Asp94Gly was the predominant allele in the initial FQ-resistant isolates followed by Ala90Val. Seventy-seven percent (36/47) of FQACQR group patients had isolates with FQ resistance alleles prior to changes to the FQ component of their treatment. Unlike the individuals treated initially with other FQs, none of the 21 individuals treated initially with levofloxacin developed genotypic or phenotypic FQ resistance, although country of residence was likely a contributing factor since 69% of these individuals were from a single country. Initial detection of phenotypic resistance and genotypic resistance occurred simultaneously for most; however, phenotypic resistance occurred earlier in isolates harboring mixtures of alleles of very low abundance (<1% of reads), whereas genotypic resistance often occurred earlier for alleles associated with low-level resistance. Understanding factors influencing acquisition and evolution of FQ resistance could reveal strategies for improved treatment success.

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Effectiveness of Shorter Treatment Regimen in Multidrug-Resistant Tuberculosis Patients in Pakistan: A Multicenter Retrospective Record Review

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.20-1134 ◽

2021 ◽

Author(s):

Abudl Wahid ◽

Nafees Ahmad ◽

Abdul Ghafoor ◽

Abdullah Latif ◽

Fahad Saleem ◽

...

Keyword(s):

Treatment Failure ◽

Success Rate ◽

Treatment Success ◽

Multidrug Resistant ◽

Retrospective Record Review ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Record Review

In Pakistan, the treatment of multidrug-resistant tuberculosis (MDR-TB) with a shorter treatment regimen (STR), that is, 4–6 months of amikacin, moxifloxacin (Mfx), ethionamide, clofazimine (Cfz), pyrazinamide (Z), ethambutol (E), and high-dose isoniazid, followed by 5 months of Mfx, Cfz, Z, and E, was initiated in 2018. However, there is a lack of information about its effectiveness in Pakistani healthcare settings. Therefore, this retrospective record review of MDR-TB patients treated with STR at eight treatment sites in Pakistan aimed to fill this gap. Data were analyzed using SPSS 23. Multivariate binary logistic regression (MVBLR) analysis was conducted to find factors associated with death and treatment failure, and lost to follow-up (LTFU). A P-value < 0.05 was considered statistically significant. Of 912 MDR-TB patients enrolled at the study sites, only 313 (34.3%) eligible patients were treated with STR and included in the current study. Of them, a total of 250 (79.9%) were cured, 12 (3.8%) completed treated, 31 (9.9%) died, 16 (5.1%) were LTFU, and four (1.3%) were declared as treatment failures. The overall treatment success rate was 83.7%. In MVBLR analysis, patients’ age of 41–60 (odds ratio [OR] = 4.9, P-value = 0.020) and > 60 years (OR = 3.6, P-value = 0.035), being underweight (OR = 2.7, P-value = 0.042), and previous TB treatment (OR = 0.4, P-value = 0.042) had statistically significant association with death and treatment failure, whereas patients’ age of > 60 years (OR = 5.4, P-value = 0.040) and previous TB treatment (OR = 0.2, P-value = 0.008) had statistically significant association with LTFU. The treatment success rate of STR was encouraging. However, to further improve the treatment outcomes, special attention should be paid to the patients with identified risk factors.

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Determination of MIC Breakpoints for Second-Line Drugs Associated with Clinical Outcomes in Multidrug-Resistant Tuberculosis Treatment in China

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03008-15 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4786-4792 ◽

Cited By ~ 14

Author(s):

Xubin Zheng ◽

Rongrong Zheng ◽

Yi Hu ◽

Jim Werngren ◽

Lina Davies Forsman ◽

...

Keyword(s):

Treatment Outcome ◽

Treatment Success ◽

Multidrug Resistant ◽

Classification And Regression Tree ◽

Second Line ◽

Cart Analysis ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

ABSTRACTOur study aims to identify the clinical breakpoints (CBPs) of second-line drugs (SLDs) above which standard therapy fails in order to improve multidrug-resistant tuberculosis (MDR-TB) treatment. MICs of SLDs were determined forM. tuberculosisisolates cultured from 207 MDR-TB patients in a prospective cohort study in China between January 2010 and December 2012. Classification and regression tree (CART) analysis was used to identify the CBPs predictive of treatment outcome. Of the 207 MDR-TB isolates included in the present study, the proportion of isolates above the critical concentration recommended by WHO ranged from 5.3% in pyrazinamide to 62.8% in amikacin. By selecting pyrazinamide as the primary node (CBP, 18.75 mg/liter), 72.1% of sputum culture conversions at month four could be predicted. As for treatment outcome, pyrazinamide (CBP, 37.5 mg/liter) was selected as the primary node to predict 89% of the treatment success, followed by ofloxacin (CBP, 3 mg/liter), improving the predictive capacity of the primary node by 10.6%. Adjusted by identified confounders, the CART-derived pyrazinamide CBP remained the strongest predictor in the model of treatment outcome. Our findings indicate that the critical breakpoints of some second-line drugs and PZA need to be reconsidered in order to better indicate MDR-TB treatment outcome.

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Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan

ERJ Open Research ◽

10.1183/23120541.00537-2020 ◽

2020 ◽

pp. 00537-2020

Author(s):

Philipp du Cros ◽

Khamraev Atadjan ◽

Tigay Zinaida ◽

Tleubergen Abdrasuliev ◽

Jane Greig ◽

...

Keyword(s):

Treatment Failure ◽

Treatment Success ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Fluoroquinolone Resistance ◽

Second Line ◽

Serious Adverse Events ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

BackgroundIn 2016, WHO guidelines conditionally recommended standardised shorter 9–12 month regimens for multidrug-resistant tuberculosis (MDR-TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan.MethodsConsecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between 1st September 2013 and 31st March 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion.ResultsOf 146 enrolled, 128 patients were included: 67 female (52.3%), median age 30.1 (IQR 23.8–44.4) years. At the end of treatment, 71.9% (92/128) patients achieved treatment success, with 68% (87/128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failure with fluoroquinolone resistance amplification in 8 patients (8/22, 36.4%); 12 (9.4%) loss to follow-up; 2 (1.5%) deaths. Recurrence occurred in one patient. 14 patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (aOR 6.13, 95% CI 2.01;18.63) and adherence<95% (aOR 5.33, 95% CI 1.73;16.36) were associated with unsuccessful outcome in multivariable logistic regression.ConclusionsOverall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of DST-confirmed susceptibility.

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Predicting the Outcomes of New Short-Course Regimens for Multidrug-Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modeling

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01487-18 ◽

2018 ◽

Vol 62 (12) ◽

Cited By ~ 2

Author(s):

Tan N. Doan ◽

Pengxing Cao ◽

Theophilus I. Emeto ◽

James M. McCaw ◽

Emma S. McBryde

Keyword(s):

Treatment Duration ◽

Treatment Success ◽

Empirical Evaluation ◽

Multidrug Resistant ◽

Pharmacodynamic Modeling ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Short Course ◽

Mdr Tb

ABSTRACT Short-course regimens for multidrug-resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug bedaquiline (BDQ) may have the potential to shorten MDR-TB treatment to less than 6 months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modeling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modeling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (4 months) while still maintaining a very high treatment success rate (100% for daily BDQ for 2 weeks, or 95% for daily BDQ for 1 week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes, then we anticipate clear cost savings and a subsequent improvement in the efficiency of national TB programs.

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National treatment outcome and predictors of death and treatment failure in multidrug-resistant tuberculosis in Ethiopia: a 10-year retrospective cohort study

BMJ Open ◽

10.1136/bmjopen-2020-040862 ◽

2021 ◽

Vol 11 (8) ◽

pp. e040862

Author(s):

Habteyes Tola ◽

K Holakouie-Naieni ◽

Mohammad Ali Mansournia ◽

Mehdi Yaseri ◽

Dinka Fikadu Gamtesa ◽

...

Keyword(s):

Treatment Outcome ◽

Treatment Failure ◽

Treatment Success ◽

Multidrug Resistant ◽

The Past ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

ObjectivesTreatment success rate in patients treated for multidrug-resistant tuberculosis (MDR-TB) is low, but predictors of treatment failure and death have been under-reported. Thus, we aimed to determine the national proportion of treatment success rate in the past 10 years and factors that predict treatment failure and death in patients with MDR-TB in Ethiopia.SettingA retrospective cohort study with a 10-years follow-up period was conducted in 42 MDR-TB treatment-initiating centres in Ethiopia.ParticipantsA total of 3395 adult patients with MDR-TB who had final treatment outcome and who were treated under national TB programme were included. Data were collected from clinical charts, registration books and laboratory reports. Competing risk survival analysis model with robust standard errors (SE) was used to determine the predictors of treatment failure and death.Primary and secondary outcomesTreatment outcome was a primary outcome whereas predictors of treatment failure and death were a secondary outcome.ResultsThe proportion of treatment success was 75.7%, death rate was 12.8%, treatment failure was 1.7% and lost to follow-up was 9.7%. The significant predictors of death were older age (adjusted hazard ratio (AHR)=1.03; 95% CI 1.03 to 1.05; p<0.001), HIV infection (AHR=2.0; 95% CI 1.6 to 2.4; p<0.001) and presence of any grade of anaemia (AHR=1.7; 95% CI 1.4 to 2.0; p<0.001). Unlike the predictors of death, all variables included into multivariable model were not significantly associated with treatment failure.ConclusionIn the past 10 years, although MDR-TB treatment success in Ethiopia has been consistently favourable, the proportion of patients who died is still considerable. Death could be attributed to advanced age, HIV infection and anaemia. Prospective cohort studies are necessary to further explore the potentially modifiable predictors of treatment failure.

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Genetic characterization of N-acetyltransferase 2 variants in acquired multidrug-resistant tuberculosis in Indonesia

Pharmacogenomics ◽

10.2217/pgs-2020-0163 ◽

2021 ◽

Author(s):

Rika Yuliwulandari ◽

Kinasih Prayuni ◽

Intan Razari ◽

Retno W Susilowati ◽

Yenni Zulhamidah ◽

...

Keyword(s):

Multidrug Resistant ◽

Resistance Rate ◽

Published Data ◽

Drug Induced ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Appropriate Treatment ◽

Acetylator Status ◽

Mdr Tb

Background: Owing to the high resistance rate of tuberculosis (TB) to isoniazid, which is metabolized by N-acetyltransferase 2 (NAT2), we investigated the associations between NAT2 variants and multidrug-resistant (MDR)-TB. Materials & methods: The acetylator status based on NAT2 haplotypes of 128 patients with MDR-TB in Indonesia were compared with our published data from patients with anti-TB drug-induced liver injury (AT-DILI), TB and the general population. Results: NAT2*4 was more frequent in the MDR-TB group than in the AT-DILI group, TB controls and general controls. NAT2*4/*4 was significantly more frequent in patients with MDR-TB than in those with AT-DILI. NAT2*5B/7B, *6A/6A and *7B/*7B were detected at lower frequencies in patients with AT-DILI. Rapid acetylators were significantly more frequent in patients with MDR-TB than in those with AT-DILI. Conclusion: These results provide an initial data for optimizing TB treatment in the Indonesian population, and suggest that NAT2 genotyping may help to select appropriate treatment by predicting TB-treatment effect.

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Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

BioMed Research International ◽

10.1155/2017/4563826 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Y. Hu ◽

L. Xu ◽

Y. L. He ◽

Y. Pang ◽

N. Lu ◽

...

Keyword(s):

Gene Mutations ◽

Multidrug Resistant ◽

Rapid Screening ◽

Second Line ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Improper Use ◽

Mdr Tb

This study aimed to investigate the prevalence of multidrug-resistant tuberculosis (MDR-TB) isolates resistant to the second-line antituberculosis drugs (SLDs) and its association with resistant-related gene mutations inMycobacterium tuberculosis(M.tb) isolates from Southwest of China. There were 81 isolates resistant to at least one of the SLDs among 156 MDR-TB isolates (81/156, 51.9%). The rates of general resistance to each of the drugs were as follows: OFX (66/156, 42.3%), KAN (26/156, 16.7%), CAP (13/156, 8.3%), PTO (11/156, 7.1%), PAS (22/156, 14.1%), and AMK (20/156, 12.8%). Therefore, the most predominant pattern was resistant to OFX compared with other SLDs (P<0.001). The results of sequencing showed that 80.2% OFX-resistant MDR-TB isolates containedgyrAmutation and 88.5% KAN-resistant isolates hadrrsmutations with the most frequent mutation being A1401G. These results suggest that improper use of SLDs especially OFX is a real threat to effective MDR-TB treatment not only in China but also in the whole world. Furthermore the tuberculosis control agencies should carry out SLDs susceptibility testing and rapid screening in a broader population of TB patients immediately and the SLDs should be strictly regulated by the administration in order to maintain their efficacy to treat MDR-TB.

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Treatment outcomes in multidrug-resistant tuberculosis according to pyrazinamide susceptibility

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.19.0314 ◽

2020 ◽

Vol 24 (2) ◽

pp. 233-239

Author(s):

S. Park ◽

K-W. Jo ◽

T. S. Shim

Keyword(s):

Success Rate ◽

Treatment Outcomes ◽

Treatment Success ◽

Multidrug Resistant ◽

Treatment Success Rate ◽

Aminosalicylic Acid ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Effective Drugs

BACKGROUND: Pyrazinamide (PZA) is an important anti-tuberculosis drug for multidrug-resistant tuberculosis (MDR-TB). However, PZA has recently been demoted within the hierarchy of TB drugs used for MDR-TB.METHODS: We conducted a retrospective cohort study to investigate treatment outcomes for simple MDR-TB (susceptible to both second-line injectable drugs and fluoroquinolones) according to PZA susceptibility.RESULTS: Among 216 pulmonary MDR-TB patients included in the study, 68 (31.5%) were PZA-resistant (PZA-R). The mean age was 41.8 years, and 63.4% were male. Baseline characteristics such as comorbidity, previous TB history, acid-fast bacilli (AFB) smear positivity and cavitation were similar in PZA-susceptible (PZA-S) and PZA-R patients. The number of potentially effective drugs was slightly higher among PZA-S patients than among the PZA-R (5.1 vs. 4.8, respectively; P = 0.003). PZA was more frequently used in PZA-S patients (73.0%) than in the PZA-R (14.7%), while para-aminosalicylic acid was more frequently used in PZA-R than in PZA-S patients (76.5% vs. 50.7%). The treatment success rate was similar in PZA-S (77.7%) and PZA-R (75.0%) patients. PZA resistance was not associated with treatment success in multivariate analysis.CONCLUSIONS: PZA-resistant simple MDR-TB patients had the same treatment success rate as the PZA-susceptible group even without using novel anti-TB drugs.

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Multidrug-resistant tuberculosis (MDR-TB) and multidrug-resistant HIV (MDR-HIV) syndemic: challenges in resource limited setting

BMJ Case Reports ◽

10.1136/bcr-2019-230628 ◽

2019 ◽

Vol 12 (8) ◽

pp. e230628 ◽

Cited By ~ 1

Author(s):

Christian Francisco ◽

Mary Ann Lansang ◽

Edsel Maurice Salvana ◽

Katerina Leyritana

Keyword(s):

Psoas Abscess ◽

Multidrug Resistant ◽

Health Concern ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Resource Limited ◽

Persons Living With Hiv ◽

Mdr Tb ◽

Living With Hiv

Tuberculosis (TB) is common among persons living with HIV. This public health concern is aggravated by infection with multidrug-resistant organisms and adverse effects of polypharmacy. There are few published cases of multidrug-resistant tuberculosis (MDR-TB) in multidrug-resistant HIV (MDR-HIV) infected patients. We report a case of a 29-year-old Filipino man with HIV on zidovudine (AZT)-containing antiretroviral therapy (ART) but was eventually shifted to tenofovir due to anaemia. He presented with left flank tenderness, which was found to be due to an MDR-TB psoas abscess, and for which second-line anti-TB treatment was started. HIV genotyping showed MDR-HIV infection susceptible only to AZT, protease inhibitors and integrase inhibitors. Subsequently, he developed neck abscess that grew Mycobacterium avium complex and was treated with ethambutol and azithromycin. ART regimen was revised to AZT plus lamivudine and lopinavir/ritonavir. Erythropoietin was administered for recurrent AZT-induced anaemia. Both abscesses resolved and no recurrence of anaemia was noted.

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Multidisciplinary advisory teams to manage multidrug-resistant tuberculosis: the example of the French Consilium

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.18.0779 ◽

2019 ◽

Vol 23 (10) ◽

pp. 1050-1054

Author(s):

L. Guglielmetti ◽

J. Jaffré ◽

C. Bernard ◽

F. Brossier ◽

N. El Helali ◽

...

Keyword(s):

Multidrug Resistant ◽

New Drugs ◽

World Health ◽

Advisory Committees ◽

Treatment Regimens ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb ◽

Health Organization

SETTING: The World Health Organization (WHO) recommends that multidrug-resistant tuberculosis (MDR-TB) treatment should be managed in collaboration with multidisciplinary advisory committees (consilia). A formal national Consilium has been established in France since 2005 to provide a centralised advisory service for clinicians managing MDR-TB and extensively drug-resistant (XDR-TB) cases.OBJECTIVE: Review the activity of the French TB Consilium since its establishment.DESIGN: Retrospective description and analysis of the activity of the French TB Consilium.RESULTS: Between 2005 and 2016, 786 TB cases or contacts of TB cases were presented at the French TB Consilium, including respectively 42% and 79% of all the MDR-TB and XDR-TB cases notified in France during this period. Treatment regimens including bedaquiline and/or delamanid were recommended for 42% of the cases presented at the French TB Consilium since 2009. Patients were more likely to be presented at the French TB Consilium if they were born in the WHO Europe Region, had XDR-TB, were diagnosed in the Paris region, or had resistance to additional drugs than those defining XDR-TB.CONCLUSION: The French TB Consilium helped supervise appropriate management of MDR/XDR-TB cases and facilitated implementation of new drugs for MDR/XDR-TB treatment.

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