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      Increased Moxifloxacin Dosing Among Patients With Multidrug-Resistant Tuberculosis With Low-Level Resistance to Moxifloxacin Did Not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India

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          Abstract

          Background

          Mycobacterium tuberculosis ( Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available.

          Methods

          We conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes.

          Results

          Of 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6–2.4]) or adjusted (HR, 0.8 [95% CI, .5–1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2–8.8]).

          Conclusions

          In a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test–based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.

          Abstract

          In a large observational cohort, adding high-dose moxifloxacin at 600 mg daily to a susceptibility testing–based regimen for multidrug-resistant tuberculosis (MDR-TB) with low-level moxifloxacin resistance did not improve overall outcomes and should be avoided for treatment of moxifloxacin-resistant MDR-TB.

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          Most cited references21

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          Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis

          Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis.
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            A simple, valid, numerical score for grading chest x-ray severity in adult smear-positive pulmonary tuberculosis.

            The grading of radiological severity in clinical trials in tuberculosis (TB) remains unstandardised. The aim of this study was to generate and validate a numerical score for grading chest x-ray (CXR) severity and predicting response to treatment in adults with smear-positive pulmonary TB. At a TB clinic in Papua, Indonesia, serial CXRs were performed at diagnosis, 2 and 6 months in 115 adults with smear-positive pulmonary TB. Radiographic findings predictive of 2-month sputum microscopy status were used to generate a score. The validity of the score was then assessed in a second data set of 139 comparable adults with TB, recruited 4 years later at the same site. Relationships between the CXR score and other measures of TB severity were examined. The estimated proportion of lung affected and presence of cavitation, but not cavity size or other radiological findings, significantly predicted outcome and were combined to derive a score given by percentage of lung affected plus 40 if cavitation was present. As well as predicting 2-month outcome, scores were significantly associated with sputum smear grade at diagnosis (p<0.001), body mass index, lung function, haemoglobin, exercise tolerance and quality of life (p<0.02 for each). In the validation data set, baseline CXR score predicted 2-month smear status significantly more accurately than did the proportion of lung affected alone. In both data sets, CXR scores decreased over time (p<0.001). This simple, validated method for grading CXR severity in adults with smear-positive pulmonary TB correlates with baseline clinical and microbiological severity and response to treatment, and is suitable for use in clinical trials.
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              Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling.

              Moxifloxacin is a quinolone antimicrobial that has potent activity against Mycobacterium tuberculosis. To optimize moxifloxacin dose and dose regimen, pharmacodynamic antibiotic-exposure targets associated with maximal microbial kill and complete suppression of drug resistance in M. tuberculosis must be identified. We used a novel in vitro pharmacodynamic infection model of tuberculosis in which we exposed M. tuberculosis to moxifloxacin with a pharmacokinetic half-life of decline similar to that encountered in humans. Data obtained from this model were mathematically modeled, and the drug-exposure breakpoint associated with the suppression of drug resistance was determined. Monte-Carlo simulations were performed to determine the probability that 10,000 clinical patients taking different doses of moxifloxacin would achieve or exceed the drug-exposure breakpoint needed to suppress resistance to moxifloxacin in M. tuberculosis. The ratio of the moxifloxacin-free (non-protein-bound) area under the concentration-time curve from 0 to 24 h to the minimum inhibitory concentration associated with complete suppression of the drug-resistant mutant population was 53. For patients taking moxifloxacin doses of 400, 600, or 800 mg/day, the calculated target-attainment rates to suppress drug resistance were 59%, 86%, and 93%, respectively. A moxifloxacin dose of 800 mg/day is likely to achieve excellent M. tuberculosis microbial kill and to suppress drug resistance. However, tolerability of this higher dose is still unknown.
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                Author and article information

                Journal
                Open Forum Infect Dis
                Open Forum Infect Dis
                ofid
                Open Forum Infectious Diseases
                Oxford University Press (US )
                2328-8957
                February 2022
                23 December 2021
                23 December 2021
                : 9
                : 2
                : ofab615
                Affiliations
                [1 ] Center for Clinical Global Health Education, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland, USA
                [2 ] Department of Respiratory Medicine, P. D. Hinduja National Hospital and Medical Research Centre , Mumbai, Maharashtra, India
                [3 ] Department of Laboratory Medicine, P. D. Hinduja National Hospital and Medical Research Centre , Mumbai, Maharashtra, India
                [4 ] Johns Hopkins University School of Medicine , Baltimore, Maryland, USA
                [5 ] Johns Hopkins University–India Office (Center for Clinical Global Health Education) , Pune, Maharashtra, India
                [6 ] Department of International Health, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, USA
                [7 ] Department of Microbiology, P. D. Hinduja National Hospital and Medical Research Centre , Mumbai, Maharashtra, India
                Author notes
                Correspondence: Zarir F. Udwadia, MD, DNB, FRCP, FCCP, P. D. Hinduja National Hospital and Medical Research Centre, Veer Savarkar Road, Mahim, Mumbai, Maharashtra 400016, India ( zfu@ 123456hindujahospital.com ).
                Author information
                https://orcid.org/0000-0002-1566-4622
                https://orcid.org/0000-0001-7036-2718
                Article
                ofab615
                10.1093/ofid/ofab615
                8794589
                35097152
                db859632-fdd3-4022-ad52-840d6bae94d2
                © The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 13 September 2021
                : 01 December 2021
                : 30 November 2021
                : 27 January 2022
                Page count
                Pages: 9
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases, DOI 10.13039/100000060;
                Funded by: National Institutes of Health, DOI 10.13039/100000002;
                Award ID: K23AI135102
                Award ID: R21AI122922
                Award ID: R01AI134430
                Award ID: UM1AI069465
                Funded by: Office of AIDS Research through the Fogarty Global Health Fellows Program Consortium;
                Award ID: R25TW009340
                Funded by: Johns Hopkins University School of Medicine Clinician Scientist Career Development Award;
                Funded by: NIH/Department of Biotechnology;
                Funded by: Regional Prospective Observational Research in Tuberculosis;
                Funded by: Ujala Foundation;
                Funded by: Gilead Foundation, DOI 10.13039/100008799;
                Funded by: Wyncote Foundation, DOI 10.13039/100009456;
                Funded by: Frederick Mulder Foundation;
                Funded by: Pogge Tong Foundation;
                Categories
                Major Article
                AcademicSubjects/MED00290
                Editor's Choice

                drug resistance,drug susceptibility testing,india,mdr-tb,moxifloxacin

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