Secondary Bacterial Infections of Buruli Ulcer Lesions Before and After Chemotherapy with Streptomycin and Rifampicin

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Abstract
Buruli ulcer (BU), caused by Mycobacterium ulcerans is a chronic necrotizing skin disease. It usually starts with a subcutaneous nodule or plaque containing large clusters of extracellular acid-fast bacilli. Surrounding tissue is destroyed by the cytotoxic macrolide toxin mycolactone produced by microcolonies of M. ulcerans. Skin covering the destroyed subcutaneous fat and soft tissue may eventually break down leading to the formation of large ulcers that progress, if untreated, over months and years. Here we have analyzed the bacterial flora of BU lesions of three different groups of patients before, during and after daily treatment with streptomycin and rifampicin for eight weeks (SR8) and determined drug resistance of the bacteria isolated from the lesions. Before SR8 treatment, more than 60% of the examined BU lesions were infected with other bacteria, with Staphylococcus aureus and Pseudomonas aeruginosa being the most prominent ones. During treatment, 65% of all lesions were still infected, mainly with P. aeruginosa. After completion of SR8 treatment, still more than 75% of lesions clinically suspected to be infected were microbiologically confirmed as infected, mainly with P. aeruginosa or Proteus miriabilis. Drug susceptibility tests revealed especially for S. aureus a high frequency of resistance to the first line drugs used in Ghana. Our results show that secondary infection of BU lesions is common. This could lead to delayed healing and should therefore be further investigated. Buruli ulcer (BU) can lead to large ulcerative lesions due to extensive skin loss caused by the necrotizing effect of the main virulence factor mycolactone. For a long time the general perception was that BU lesions are not infected by other bacteria because of a postulated antimicrobial effect of the macrolide toxin, mycolactone. In this study, we analyzed laboratory confirmed BU lesions before, during, and after streptomycin/rifampicin treatment. Contrary to popular belief, our findings show that BU lesions are frequently co-colonized with other potential bacterial pathogens before, during, and after antibiotic treatment. For example, 75% of cases that were clinically indicative of being infected after treatment were microbiologically confirmed as infected. Most microbiologically infected cases were also confirmed by histopathological analysis. The most prominent bacterial species isolated included Pseudomonas aeruginosa, S. aureus, and P. mirabilis. When we tested the isolates against first line drugs used in Ghana, the isolates were found to be resistant to most of these drugs. This study indicates that wound care practices need to be improved and that wound infection may be a common cause of wound healing delay in BU.

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