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Antimicrobial Agents and Chemotherapy, June 2001, p. 1637-1644, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1637-1644.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Treatment of Tuberculosis Using a Combination of Sustained-Release Rifampin-Loaded Microspheres and Oral Dosing with Isoniazid

Debra C. Quenelle,1,dagger Gary A. Winchester,2 Jay K. Staas,2 Esther L. W. Barrow,3,Dagger and William W. Barrow3,*

Infectious Disease Animal Models Group,1 Drug Delivery Group,2 and Mycobacteriology Research Unit,3 Southern Research Institute, Birmingham, Alabama

Received 4 August 2000/Returned for modification 14 September 2000/Accepted 5 March 2001

Previously, we reported on the use of rifampin-loaded microspheres to effectively treat Mycobacterium tuberculosis-infected macrophages and mice. Using similar biocompatible polymeric excipients of lactide and glycolide copolymers, we have increased the rifampin loading of small microsphere formulations (1 to 10 µm) by fourfold. Improved formulations were evaluated individually and in combination with oral regimens of isoniazid for the treatment of Mycobacterium tuberculosis H37Rv-infected mice. Groups (10 mice per group) consisted of mice that received (i) oral dosages of isoniazid (25 to 0.19 mg/kg of body weight/day), (ii) two intraperitoneal injections of rifampin-loaded microspheres on days 0 and 7, (iii) a combination of small rifampin-loaded microspheres on days 0 and 7 and isoniazid orally for 25 days (12.5 to 0.39 mg/kg/day), (iv) placebo injections, and (v) no treatment. Treatment with rifampin-loaded microspheres alone resulted in significant reductions in the numbers of CFU in the lungs and spleens by day 26. A bioassay revealed that plasma rifampin levels from the microspheres exceeded the MICs by more than twofold throughout the 26-day experimental period. Susceptibility testing demonstrated continued sensitivity to rifampin during the treatment period. Whereas isoniazid alone significantly reduced the numbers of CFU for dosages ranging from 12.5 to 1.56 mg/kg, combination therapy with rifampin-loaded microspheres increased the effective range to 0.39 mg/kg. In many cases, complete elimination of CFU was obtained with the combination therapy, something not achieved with most of the single therapies. These results demonstrate the ability to use small microsphere formulations alone to achieve significant results in a murine tuberculosis model and also the ability to use them safely in combination with another antimycobacterial agent.

* Corresponding author. Present address: Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078-2007. Phone: (405) 744-6745. Fax: (405) 744-5275.

dagger Present address: Department of Pediatrics, Division of Infectious Diseases, The University of Alabama at Birmingham, Birmingham, AL 35294-2170.

Dagger Present address: Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078-2007.

Antimicrobial Agents and Chemotherapy, June 2001, p. 1637-1644, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1637-1644.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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