To the Editor: Mitnick and colleagues (Aug. 7 issue)1 have raisedawareness about the clinical management and outcomes of extensivelydrug-resistant tuberculosis in Peru. Although a cure rate of60% is encouraging, we caution against generalizing these findingsto other high-burden settings. Of 95 patients with extensivelydrug-resistant tuberculosis (of whom about 60% were negativefor the human immunodeficiency virus) we identified in CapeTown, South Africa, between 2006 and 2008, only 10% underwentculture conversion, despite intensive inpatient therapy, includingcapreomycin-based regimens. This difference may be due to higherrates of alcohol and drug abuse, smoking, and malnutrition amongour patients, along with differences in strain virulence2 andhost immunity (including underlying profiles of helper T cells).3Another factor may be our minimal use of moxifloxacin (whichwas administered to 72% of the patients in the study by Mitnicket al., as compared with 1% in our cohort). The clinical additivevalue of this agent requires further evaluation, and it wouldbe useful to know the level of cross-resistance between thedifferent quinolone subclasses in the Peruvian study. Thus,in an African setting, treatment outcomes for patients withextensively drug-resistant tuberculosis are poor. This underscoresthe importance of strengthening laboratory capacity, programsfor tuberculosis treatment, and the rollout of rapid diagnostictests.4
Keertan Dheda, Ph.D. Karen Shean, B.Tech. Motasim Badri, Ph.D. University of Cape Town Cape Town 7925, South Africa keertan.dheda{at}uct.ac.za
References
Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008;359:563-574. [Free Full Text]
Nicol MP, Wilkinson RJ. The clinical consequences of strain diversity in Mycobacterium tuberculosis. Trans R Soc Trop Med Hyg 2008;102:955-965. [CrossRef][Web of Science][Medline]
Rook GA, Dheda K, Zumla A. Immune responses to tuberculosis in developing countries: implications for new vaccines. Nat Rev Immunol 2005;5:661-667. [CrossRef][Web of Science][Medline]
Barnard M, Albert H, Coetzee G, O'Brien R, Bosman ME. Rapid molecular screening for multidrug-resistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med 2008;177:787-792. [Free Full Text]
To the Editor: Mitnick et al. emphasize the concept of comprehensivemanagement of extensively drug-resistant tuberculosis for successfuloutcomes. Each patient received tailor-made therapy that rangedfrom a highly efficacious drug regimen (obtained after detailedtesting of drug susceptibility) to nutritional and psychosocialsupport. However, the study raises a practical and ethical question:Is it feasible to implement and sustain such aggressive, multilevelintervention under various conditions in national tuberculosis-controlprograms? Another issue relates to the financial implicationsof executing such a rigorous approach. The estimated costs oftreatment of multidrug-resistant tuberculosis range from $1,979to $8,196 per patient, and costs of treatment of extensivelydrug-resistant tuberculosis range from $6,843 to $15,579 (allin U.S. dollars).1 A further analysis of the study by Mitnicket al. to address the costs per averted death from tuberculosisand per gain in quality-adjusted life-year would throw lighton the monetary implications of carrying out such a complexyet coordinated and complete intervention.
Mani Cheruvu, Ph.D. Satish Bhadriraju, M.D. Memorial University Medical Center Savannah, GA 31404 mani.cheruvu{at}gmail.com
References
The global MDR-TB and XDR-TB response plan 2007-2008. Geneva: World Health Organization, 2007. (Publication no. WHO/HTM/STB/2007.387.)
The authors reply: We agree with Dheda and colleagues aboutthe importance of reinforcing tuberculosis management. New,affordable, and widely available drugs that have proven safetyand efficacy against Mycobacterium tuberculosis are essentialfor the treatment of drug-resistant disease — and thesedrugs include moxifloxacin. Although testing for moxifloxacinsusceptibility was not performed in patients in our study, testingfor resistance to ciprofloxacin and levofloxacin was common(see Table 3 in the Supplementary Appendix of our article).Nearly all patients who received moxifloxacin had confirmedresistance to ciprofloxacin; 31% had documented resistance tolevofloxacin (Table 1 in the Supplementary Appendix of our article).Limitations in the data and susceptibility testing, however,preclude evaluation of the effectiveness of moxifloxacin inthese patients. Additional research on cross-resistance amongthe fluoroquinolones and the clinical implications of such resistanceremains critical.
Possible reasons for the difference in patient outcomes betweenthe two settings are myriad and may be related to the strain,the host, the composition of the therapy regimen and other supportiveelements, or the environment. The common objective in all sites,however, is the implementation of the types of therapy and supportthat yield optimal results. The elucidation of such generalizableapproaches can best be accomplished through multisite randomizedtrials, for which large-scale, long-term financing must be secured.1
Cheruvu and Bhadriraju question the practicality of replicatingthe conditions in our study. As noted by Raviglione2 in an editorialaccompanying our article, the components of the interventionin Peru conform to the standard of care recommended by boththe Stop TB strategy of the World Health Organization and thecurrent guidelines for the treatment of drug-resistant tuberculosis.3,4Although more modest approaches have been deemed cost-effective,at least one did not cure even 50% of patients with multidrug-resistanttuberculosis.5 In the meantime, the estimated global incidenceof multidrug-resistant tuberculosis nearly doubled between 2000and 2006, and extensively drug-resistant tuberculosis emergedin at least 49 countries. Cost-effectiveness studies that donot evaluate the effect of interventions on further developmentof resistance through transmission and amplification are oflimited value. It would be neither ethical nor practical torely on a cost-effective approach that does not consider thesedevelopments. A cost analysis of the intervention in Peru isunder way to permit the "clear planning, financial commitmentand adequate resources" that Raviglione recommends for scale-upof these appropriately complex interventions.
Carole D. Mitnick, Sc.D. Harvard Medical School Boston, MA 02115
Jaime Bayona, M.D. Socios En Salud Lima 6, Peru
Mercedes C. Becerra, Sc.D. Harvard Medical School Boston,MA 02115
References
Mitnick CD, Castro KG, Harrington M, Sacks LV, Burman W. Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PLoS Med 2007;4:e292-e292. [CrossRef][Medline]
Raviglione MC. Facing extensively drug-resistant tuberculosis -- a hope and a challenge. N Engl J Med 2008;359:636-638. [Free Full Text]
Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva: World Health Organization, 2006.
Suárez PG, Floyd K, Portocarrero J, et al. Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002;359:1980-1989. [CrossRef][Web of Science][Medline]
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