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Impacts of dosing frequency of the combination rifampin-streptomycin on its bactericidal and sterilizing activities against Mycobacterium ulcerans in mice.

ABSTRACT: Because of operational limitations, a significant proportion of the health centers at the peripheral level are able to provide treatment to Buruli ulcer patients with the combination rifampin (rifampicin)-streptomycin (RIF-STR) only five times weekly (5/7) instead of seven times weekly (7/7), as recommended. The objective of this experiment is to assess the impacts of various dosing frequencies of the combination on its bactericidal and sterilizing activities against Mycobacterium ulcerans in mice. The results demonstrate that the bactericidal activities did not differ significantly among five dosing frequencies of the combination, ranging from seven times to twice weekly, whereas the sterilizing activities differed widely. RIF-STR 7/7 was the only regimen that was able to sterilize the infection after 4 to 8 weeks of treatment; the sterilizing activities associated with reduced dosing frequencies were significantly diminished, and 8 weeks of 5/7 administration yielded a relapse rate greater than the generally accepted level of 5%. We recommend that the duration of treatment with 5/7 administration be prolonged beyond 8 weeks and that additional experiments with mice be carried out, with sufficient statistical power to compare the relapse rates of M. ulcerans infection between 8 weeks of 7/7 administration and 10 and 12 weeks of 5/7 administration of RIF-STR.

SUBMITTER: Ji B

PROVIDER: S-EPMC2704658 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Impacts of dosing frequency of the combination rifampin-streptomycin on its bactericidal and sterilizing activities against Mycobacterium ulcerans in mice.

Ji Baohong B Chauffour Aurélie A Aubry Alexandra A Robert Jérome J Ibrahim Murad M Jarlier Vincent V

Antimicrobial agents and chemotherapy 20090413 7

Because of operational limitations, a significant proportion of the health centers at the peripheral level are able to provide treatment to Buruli ulcer patients with the combination rifampin (rifampicin)-streptomycin (RIF-STR) only five times weekly (5/7) instead of seven times weekly (7/7), as recommended. The objective of this experiment is to assess the impacts of various dosing frequencies of the combination on its bactericidal and sterilizing activities against Mycobacterium ulcerans in mi ...[more]

PMID: 19364857

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Project description:Treatment of Buruli ulcer, or Mycobacterium ulcerans disease, has shifted from surgical excision and skin grafting to antibiotic therapy usually with 8 weeks of daily rifampin (RIF) and streptomycin (STR). Although the results have been highly favorable, administration of STR requires intramuscular injection and carries the risk of side effects, such as hearing loss. Therefore, an all-oral, potentially less toxic, treatment regimen has been sought and encouraged by the World Health Organization. A combination of RIF plus clarithromycin (CLR) has been successful in patients first administered RIF+STR for 2 or 4 weeks. Based on evidence of efficacy of clofazimine (CFZ) in humans and mice with tuberculosis, we hypothesized that the combination of RIF+CFZ would be effective against M. ulcerans in the mouse footpad model of M. ulcerans disease because CFZ has similar MIC against M. tuberculosis and M. ulcerans. For comparison, mice were also treated with the gold standard of RIF+STR, the proposed RIF+CLR alternative regimen, or CFZ alone. Treatment was initiated after development of footpad swelling, when the bacterial burden was 4.64±0.14log10 CFU. At week 2 of treatment, the CFU counts had increased in untreated mice, remained essentially unchanged in mice treated with CFZ alone, decreased modestly with either RIF+CLR or RIF+CFZ, and decreased substantially with RIF+STR. At week 4, on the basis of footpad CFU counts, the combination regimens were ranked as follows: RIF+STR>RIF+CLR>RIF+CFZ. At weeks 6 and 8, none of the mice treated with these regimens had detectable CFU. Footpad swelling declined comparably with all of the combination regimens, as did the levels of detectable mycolactone A/B. In mice treated for only 6 weeks and followed up for 24 weeks, there were no relapses in RIF+STR treated mice, one (5%) relapse in RIF+CFZ-treated mice, but >50% in RIF+CLR treated mice. On the basis of these results, RIF+CFZ has potential as a continuation phase regimen for treatment of M. ulcerans disease.

Project description:BackgroundBuruli ulcer (BU) is a skin neglected tropical disease (NTD) caused by Mycobacterium ulcerans. WHO-recommended treatment requires 8-weeks of daily rifampicin (RIF) and clarithromycin (CLA) with wound care. Treatment compliance may be challenging due to socioeconomic determinants. Previous minimum Inhibitory Concentration and checkerboard assays showed that amoxicillin/clavulanate (AMX/CLV) combined with RIF+CLA were synergistic against M. ulcerans. However, in vitro time kill assays (TKA) are a better approach to understand the antimicrobial activity of a drug over time. Colony forming units (CFU) enumeration is the in vitro reference method to measure bacterial load, although this is a time-consuming method due to the slow growth of M. ulcerans. The aim of this study was to assess the in vitro activity of RIF, CLA and AMX/CLV combinations against M. ulcerans clinical isolates by TKA, while comparing four methodologies: CFU enumeration, luminescence by relative light unit (RLU) and optical density (at 600 nm) measurements, and 16S rRNA/IS2404 genes quantification.Methodology/principal findingsTKA of RIF, CLA and AMX/CLV alone and in combination were performed against different M. ulcerans clinical isolates. Bacterial loads were quantified with different methodologies after 1, 3, 7, 10, 14, 21 and 28 days of treatment. RIF+AMX/CLV and the triple RIF+CLA+AMX/CLV combinations were bactericidal and more effective in vitro than the currently used RIF+CLA combination to treat BU. All methodologies except IS2404 quantitative PCR provided similar results with a good correlation with CFU enumeration. Measuring luminescence (RLU) was the most cost-effective methodology to quantify M. ulcerans bacterial loads in in vitro TKA.Conclusions/significanceOur study suggests that alternative and faster TKA methodologies can be used in BU research instead of the cumbersome CFU quantification method. These results provide an in vitro microbiological support to of the BLMs4BU clinical trial (NCT05169554, PACTR202209521256638) to shorten BU treatment.

Dataset Information

Impacts of dosing frequency of the combination rifampin-streptomycin on its bactericidal and sterilizing activities against Mycobacterium ulcerans in mice.

Publications

Impacts of dosing frequency of the combination rifampin-streptomycin on its bactericidal and sterilizing activities against Mycobacterium ulcerans in mice.

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