I am currently working on two mycobacterial human pathogens Mycobacterium tuberculosis and Mycobacterium ulcerans.
M. tuberculosis is the causative agent of tuberculosis. One of the major threats towards control of tuberculosis is drug resistance, the main reasons for which are inadequate provision of combination chemotherapy and poor patient adherence. Both of these factors are affected by the long duration of TB treatment and the need to administer drugs in combination to prevent emergence of drug resistance. My work involves studying the interaction of various available anti-TB drugs with new drugs when administered in combination for treatment of M. tuberculosis infection in the murine model. This will enable us to administer both new and available drugs in ways that will improve efficacy and limit the selection of resistance. The second objective is the study of single drug administration to prevent the emergence of resistance. Recent work includes a validation of the mutation prevention concentration (MPC) of moxifloxacin in vivo. The MPC is the concentration of a particular drug that will prevent emergence of single step resistance mutants in vitro. Theoretically, drugs administered to provide concentrations at or above the MPC for some proportion of the dosing interval may not select for resistant mutants despite being used as monotherapy in tuberculosis. In a practical sense, use of drug doses optimized to prevent selection of resistant mutants should help to prevent the emergence of resistance even when treatment interruptions or non-adherence occurs during combination chemotherapy.
M. ulcerans is the causative agent of Buruli ulcer. This is an emerging ulcerative skin disease seen predominantly in parts of Africa and Australia. Although rarely lethal, it may cause significant functional disability and disfigurement. Our major objective is to establish reliable murine models for experimental chemotherapy studies of this disease. We are currently using the mouse footpad model to identify new effective oral and partially oral drug regimens and to evaluate the role of BCG vaccination in prevention of disease.
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1. Rosenthal, I. M., M. Zhang, D. Almeida, J. H. Grosset, and E. L. Nuermberger. 2008. Isoniazid or moxifloxacin in rifapentine-based regimens for experimental tuberculosis? Am J Respir Crit Care Med 178:989-93.
2. Nuermberger, E., S. Tyagi, R. Tasneen, K. N. Williams, D. Almeida, I. Rosenthal, and J. H. Grosset. 2008. Powerful bactericidal and sterilizing activity of a regimen containing PA-824, moxifloxacin, and pyrazinamide in a murine model of tuberculosis. Antimicrob Agents Chemother 52:1522-4.
3. Rodrigues, C. S., S. V. Shenai, D. Almeida, M. A. Sadani, N. Goyal, C. Vadher, and A. P. Mehta. 2007. Use of Bactec 460 TB system in the diagnosis of tuberculosis. Indian J Med Microbiol 25:32-6.
4. Rodrigues, C., D. Almeida, S. Shenai, N. Goyal, and A. Mehta. 2007. Dedicated decontamination: a necessity to prevent cross contamination in high throughput mycobacteriology laboratories. Indian J Med Microbiol 25:4-6.
5. Almeida, D., E. Nuermberger, S. Tyagi, W. R. Bishai, and J. Grosset. 2007. In vivo validation of the mutant selection window hypothesis with moxifloxacin in a murine model of tuberculosis. Antimicrob Agents Chemother.
6. Nuermberger, E., I. Rosenthal, S. Tyagi, K. N. Williams, D. Almeida, C. A. Peloquin, W. R. Bishai, and J. H. Grosset. 2006. Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis. Antimicrob Agents Chemother 50:2621-5.
7. Almeida, D., C. Rodrigues, T. F. Ashavaid, A. Lalvani, Z. F. Udwadia, and A. Mehta. 2005. High incidence of the Beijing genotype among multidrug-resistant isolates of Mycobacterium tuberculosis in a tertiary care center in Mumbai, India. Clin Infect Dis 40:881-6.
8. Krishnamurthy, A., D. Almeida, C. Rodrigues, and A. Mehta. 2004. Comparison of pyrazinamide drug susceptibility of M. tuberculosis by radiometric Bactec and enzymatic pyrazinamidase assay. Indian J Med Microbiol 22:166-8.
9. Almeida, D., C. Rodrigues, Z. F. Udwadia, A. Lalvani, G. D. Gothi, P. Mehta, and A. Mehta. 2003. Incidence of multidrug-resistant tuberculosis in urban and rural India and implications for prevention. Clin Infect Dis 36:e152-4.
10. Almeida, D., Z. F. Udwadia, C. Rodrigues, and A. Mehta. 2002. Drug-resistant tuberculosis in India. Int J Tuberc Lung Dis 6:1033.