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A sterilizing tuberculosis treatment regimen is associated with faster clearance of bacteria in cavitary lesions in marmosets.

ABSTRACT: Shortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treated Mycobacterium tuberculosis-infected marmosets with two drug regimens known to differ in their relapse rates in human clinical trials: the standard four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) that has very low relapse rates and the combination of isoniazid and streptomycin that is associated with higher relapse rates. As early as 2 weeks, the more sterilizing regimen significantly reduced the volume of lung disease by computed tomography (P = 0.035) and also significantly reduced uptake of [(18)F]-2-fluoro-2-deoxyglucose by positron emission tomography (P = 0.049). After 6 weeks of therapy, both treatments caused similar reductions in granuloma bacterial load, but the more sterilizing, four-drug regimen caused greater reduction in bacterial load in cavitary lesions (P = 0.009). These findings, combined with the association in humans between cavitary disease and relapse, suggest that the basis for improved sterilizing activity of the four-drug combination is both its faster disease volume resolution and its stronger sterilizing effect on cavitary lesions. Definitive data from relapse experiments are needed to support this observation.

SUBMITTER: Via LE

PROVIDER: S-EPMC4468655 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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A sterilizing tuberculosis treatment regimen is associated with faster clearance of bacteria in cavitary lesions in marmosets.

Via Laura E LE England Kathleen K Weiner Danielle M DM Schimel Daniel D Zimmerman Matthew D MD Dayao Emmanuel E Chen Ray Y RY Dodd Lori E LE Richardson Mike M Robbins Katherine K KK Cai Ying Y Hammoud Dima D Herscovitch Peter P Dartois Véronique V Flynn JoAnne L JL Barry Clifton E CE

Antimicrobial agents and chemotherapy 20150504 7

Shortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treated Mycobacterium tuberculosis-infected marmosets with two drug regimens known to differ in their relapse rates in human clinical trials: the standard four-drug combination of isonia ...[more]

PMID: 25941223

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Project description:Cavitary pulmonary tuberculosis (TB) is associated with poor outcomes, treatment recurrence, higher transmission rates, and the development of drug resistance. However, reports on its clinical characteristics, associated factors, and treatment outcomes are lacking. Hence, this study sought to evaluate the clinical factors associated with cavitary pulmonary TB and its treatment outcomes. We retrospectively evaluated 410 patients with drug-susceptible pulmonary TB in a university hospital in Korea between 2014 and 2019. To evaluate the factors associated with cavitary TB, multivariable logistic regression was performed with adjustments for potential confounders. We also compared the treatment outcomes between patients with cavitary TB and those without cavitary TB. Of the 410 patients, 244 (59.5%) had non-cavitary TB and 166 (40.5%) had cavitary TB. Multivariable logistic analysis with forward selection method showed that body mass index (BMI) (adjusted OR = 0.88, 95% CI: 0.81-0.97), previous history of TB (adjusted OR = 3.45, 95% CI: 1.24-9.59), ex- or current smoker (adjusted OR = 1.77, 95% CI: 1.01-3.13), diabetes mellitus (adjusted OR = 2.72, 95% CI: 1.36-5.44), and positive results on the initial sputum acid-fast bacilli (AFB) smear (adjusted OR = 2.24, 95% CI: 1.26-3.98) were significantly associated with cavitary TB. Although treatment duration was significantly longer in patients with cavitary TB than in those with non-cavitary TB (248 (102-370 days) vs. 202 (98-336 days), p < 0.001), the recurrence rate after successful treatment was significantly higher in the patients with cavitary TB than in those with non-cavitary TB (0.4% vs. 3.0% p = 0.042). In conclusion, ex- or current smoker, lower BMI, previous history of TB, diabetes mellitus, and positivity of the initial AFB smear were associated with cavitary TB. The patients with cavitary TB had more AFB culture-positive results at 2 months, longer treatment duration, and higher recurrence rates than those with non-cavitary TB.

Project description:BackgroundSince a meta-analysis showed little or no effect of second-line injectables on treatment success, and using injectables may induce ototoxicity, injectable-free rifampicin-resistant tuberculosis (RR-TB) treatment regimens are recommended. However, acquired resistance preventing activity was overlooked. No previous study assessed the effect of shortening the duration of kanamycin administration to 2 months during the intensive phase of the RR-TB shorter treatment regimen (STR).MethodsRetrospective cohort study of the effect of using 2 months of kanamycin instead of the standard 4(+) months (extension if lack of smear conversion at 4 months) on recurrence (either treatment failure or relapse) and fluoroquinolone acquired drug resistance, in patients treated with a gatifloxacin-based STR in Damien Foundation supported clinics in Bangladesh. Logistic regression was used to estimate associations.ResultsFive of 52 (9.6%) treated with a STR containing two months of kanamycin had recurrence, compared to 21 of 738 (2.8%) patients treated with the standard STR containing 4(+) months of kanamycin (OR 3.7; 95%CI:1.5-10.3). In those with initially fluoroquinolone-susceptible TB, acquired resistance to fluoroquinolone was detected in none of 639 patients treated with 4(+) months of kanamycin and two (4.5%) of 44 treated with two months of kanamycin (OR 75.2; 95%CI:3.6-1592.1).ConclusionTwo months of kanamycin was insufficient to prevent recurrence with acquired resistance to gatifloxacin, the core drug of the most effective RR-TB STR. Injectable mediated resistance prevention is important to reach high effectiveness, to safeguard all treatment options after recurrence, and to prevent the spread of resistant TB. Studies on all-oral regimens should also assess the effect of regimen composition on resistance acquisition. Until evidence shows that other drugs can assure at least the same strong resistance preventing activity of the injectables, it seems wise to continue using this group of drugs, and adapt the regimen if any ototoxicity is detected.

Dataset Information

A sterilizing tuberculosis treatment regimen is associated with faster clearance of bacteria in cavitary lesions in marmosets.

Publications

A sterilizing tuberculosis treatment regimen is associated with faster clearance of bacteria in cavitary lesions in marmosets.

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