Correspondence

Emergence of Extensive Drug Resistance during Treatment for Multidrug-Resistant Tuberculosis

N Engl J Med 2008; 359:2398-2400November 27, 2008

Article

To the Editor:

We report the development of fluoroquinolone-resistant tuberculosis and extensively drug-resistant tuberculosis during second-line treatment for multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan. Eighty-seven patients were treated with a regimen containing at least five drugs to which the infecting strain was presumed to be susceptible, according to recommendations from the World Health Organization.1,2 We performed drug-susceptibility testing and DNA fingerprinting on Mycobacterium tuberculosis isolates collected at baseline and during treatment.

None of the 87 patients had ofloxacin resistance at baseline, yet ofloxacin resistance developed during treatment in 18 patients (21%), and 10 patients (11%) were classified as having extensively drug-resistant tuberculosis.3 Only 5 (28%) of the 18 patients with ofloxacin resistance were successfully treated. Isolates from 13 patients had identical DNA fingerprints throughout treatment, probably reflecting the induction and amplification of ofloxacin resistance. A mixed infection, with two strains at baseline, was found in one patient, whereas the isolates obtained from four patients during treatment had DNA fingerprints that differed from those of the baseline isolates, indicating potential reinfection (Figure 1Figure 1Ofloxacin Resistance during Treatment among 87 Patients with Multidrug-Resistant Tuberculosis at the Start of Treatment.).

Among the 13 patients with identical strains at baseline and during treatment, second-line resistance and a severe clinical condition at baseline were significantly associated with the development of ofloxacin resistance on univariate analysis (P=0.002 and P=0.03, respectively) (see the Supplementary Appendix, available with the full text of this letter at www.nejm.org). Both factors remained significantly associated with fluoroquinolone resistance in a multivariate model (P=0.007 and P=0.03, respectively). Interestingly, 9 of the 13 patients were infected with a multidrug-resistant tuberculosis clone that is highly prevalent in this region, suggesting a higher propensity of particular strains to acquire resistance. A reduction in population diversity caused by clonal expansion of particular multidrug-resistant strains also renders strain differentiation based on IS6110 fingerprints more difficult. Thus, some of the presumed amplification might represent reinfection with a fluoroquinolone-resistant variant of the same strain.

This study shows that exogenous reinfection with extensively drug-resistant M. tuberculosis strains may occur during second-line treatment of multidrug-resistant tuberculosis. The reinfecting strains from three patients showed DNA fingerprint patterns and resistance profiles that were identical to those of M. tuberculosis strains obtained from patients who stayed in the same hospital during the same time. These data point to the risk of nosocomial transmission of extensively drug-resistant tuberculosis strains in high-incidence settings, even with the implementation of the best available and sustainable infection-control measures, which in this case included limiting the number of patients in each room and restricting patient congregation to well-ventilated communal areas. Ultraviolet lights installed initially proved to be unworkable over time, for safety reasons, and it was difficult to provide sufficient ventilation in subzero temperatures.

The emergence of fluoroquinolone resistance and extensively drug-resistant tuberculosis during treatment of multidrug-resistant tuberculosis with currently recommended protocols, under well-controlled conditions, has significant implications for the scale-up of multidrug-resistant tuberculosis treatment internationally. With an estimated 489,000 new cases of multidrug-resistant tuberculosis emerging each year, the need to scale up treatment is undeniable.4 However, the risk of creating and transmitting highly resistant M. tuberculosis strains highlights the need to optimize treatment regimens and develop strategies for administering these regimens safely and effectively.5

Helen S. Cox, M.P.H., Ph.D.
Burnet Institute for Medical Research and Public Health, Melbourne, VIC 3001, Australia

Caterina Sibilia, M.D.
Silke Feuerriegel, M.Sc., Ph.D.
Forschungszentrum Borstel, 23845 Borstel, Germany

Stobdan Kalon, M.B., B.S., M.P.H.
Jonny Polonsky, M.Sc.
Médecins sans Frontières, 742000 Nukus, Uzbekistan

Atadjan K. Khamraev, M.D.
Ministry of Health, 742000 Nukus, Uzbekistan

Sabine Rüsch-Gerdes, M.Sc., Ph.D.
Forschungszentrum Borstel, 23845 Borstel, Germany

Clair Mills, M.B., Ch.B., M.Sc.
Médecins sans Frontières, 1018 DD Amsterdam, the Netherlands

Stefan Niemann, M.Sc., Ph.D.
Forschungszentrum Borstel, 23845 Borstel, Germany
sniemann@fz-borstel.de

The Karakalpakstan MDR-TB treatment program is funded by Médecins Sans Frontières (Amsterdam). The National Reference Center for Mycobacteria, in Borstel, Germany, is supported by the German Ministry of Health.

This letter (10.1056/NEJMc0805644) was updated on October 20, 2010, at NEJM.org.

5 References

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   Scott K Heysell, Eric R Houpt. (2012) The future of molecular diagnostics for drug-resistant tuberculosis. Expert Review of Molecular Diagnostics 12:4, 395-405
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   Cagri Ozcaglar, Amina Shabbeer, Scott L. Vandenberg, Bülent Yener, Kristin P. Bennett. (2012) Epidemiological models of Mycobacterium tuberculosis complex infections. Mathematical Biosciences 236:2, 77-96
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   Elizabeth M. Streicher, Borna Müller, Violet Chihota, Charmaine Mlambo, Marisa Tait, Manormoney Pillay, Andre Trollip, Kim G.P. Hoek, Frederick A. Sirgel, Nicolaas C. Gey van Pittius, Paul D. van Helden, Thomas C. Victor, Robin M. Warren. (2011) Emergence and treatment of multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in South Africa. Infection, Genetics and Evolution
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   Paul M. Kelly. (2010) Commentary on ‘Reminder Systems and Late Patient Tracers in the Diagnosis and Management of Tuberculosis’. Evidence-Based Child Health: A Cochrane Review Journal 5:3, 1248-1250
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5. 5

   Keertan Dheda, Robin M. Warren, Alimuddin Zumla, Martin P. Grobusch. (2010) Extensively Drug-resistant Tuberculosis: Epidemiology and Management Challenges. Infectious Disease Clinics of North America 24:3, 705-725
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