Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model

L Garcia-Contreras; J Fiegel; M J Telko; K Elbert; A Hawi; M Thomas; J VerBerkmoes; W A Germishuizen; P B Fourie; A J Hickey; D Edwards

doi:10.1128/AAC.01164-06

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Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model

Journal article

Open access

Peer reviewed

Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model

L Garcia-Contreras, J Fiegel, M J Telko, K Elbert, A Hawi, M Thomas, J VerBerkmoes, W A Germishuizen, P B Fourie, A J Hickey, …

Antimicrobial agents and chemotherapy, Vol.51(8), pp.2830-2836

08/2007

DOI: 10.1128/AAC.01164-06

PMCID: PMC1932523

PMID: 17517845

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Abstract

Capreomycin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-aerosol-inoculum guinea pig model of TB. Capreomycin particles were manufactured by spray drying and characterized in terms of size and drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling capreomycin in a novel powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify drug delivery by eliminating injections and might reduce adverse effects through lowering the dose.

Drug Delivery Systems

Drug Design

Administration, Inhalation

Animals

Antibiotics, Antitubercular - administration & dosage

Antibiotics, Antitubercular - pharmacokinetics

Antibiotics, Antitubercular - therapeutic use

Capreomycin - administration & dosage

Capreomycin - pharmacokinetics

Capreomycin - therapeutic use

Guinea Pigs

Humans

Lung - metabolism

Lung - microbiology

Lung - pathology

Mycobacterium tuberculosis

Particle Size

Spleen - microbiology

Spleen - pathology

Treatment Outcome

Tuberculosis, Pulmonary - drug therapy

Tuberculosis, Pulmonary - microbiology

Details

Title: Subtitle: Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model
Creators: L Garcia-Contreras - University of North Carolina, Chapel Hill, NC 27599-7360, USA
J Fiegel - Harvard University
M J Telko - University of North Carolina at Chapel Hill
K Elbert - Harvard University
A Hawi - Medicine in Need, 104 Mt. Auburn St., Suite 3, Cambridge, Massachusetts 02138
M Thomas - Harvard University
J VerBerkmoes - Harvard University
W A Germishuizen - Harvard University
P B Fourie - Medicine in Need, 104 Mt. Auburn St., Suite 3, Cambridge, Massachusetts 02138
A J Hickey - University of North Carolina at Chapel Hill
D Edwards - Harvard University
Resource Type: Journal article
Publication Details: Antimicrobial agents and chemotherapy, Vol.51(8), pp.2830-2836
DOI: 10.1128/AAC.01164-06
PMID: 17517845
PMCID: PMC1932523
NLM abbreviation: Antimicrob Agents Chemother
ISSN: 0066-4804
eISSN: 1098-6596
Grant note: 5 U01 61336-02 / PHS HHS
Language: English
Date published: 08/2007
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Chemical and Biochemical Engineering
Record Identifier: 9984197257802771

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