Long Term Streptomycin Toxicity in the Treatment of Buruli Ulcer: Follow-up of Participants in the BURULICO Drug Trial

Abstract

Background

Buruli Ulcer (BU) is a tropical infectious skin disease that is currently treated with 8 weeks of intramuscular streptomycin and oral rifampicin. As prolonged streptomycin administration can cause both oto- and nephrotoxicity, we evaluated its long term toxicity by following-up former BU patients that had received either 4 or 8 weeks of streptomycin in addition to other drugs between 2006 and 2008, in the context of a randomized controlled trial.

Methods

Former patients were retrieved in 2012, and oto- and nephrotoxicity were determined by audiometry and serum creatinine levels. Data were compared with baseline and week 8 measurements during the drug trial.

Results

Of the total of 151 former patients, 127 (84%) were retrieved. Ototoxicity was present in 29% of adults and 25% of children. Adults in the 8 week streptomycin group had significantly higher hearing thresholds in all frequencies at long term follow-up, and these differences were most prominent in the high frequencies. In children, no differences between the two treatment arms were found. Nephrotoxicity that had been detected in 14% of adults and in 13% of children during treatment, was present in only 2.4% of patients at long term follow-up.

Conclusions

Prolonged streptomycin administration in the adult study subjects caused significant persistent hearing loss, especially in the high frequency range. Nephrotoxicity was also present in both adults and children but appeared to be transient. Streptomycin should be given with caution especially in patients aged 16 or older, and in individuals with concurrent risks for renal dysfunction or hearing loss.

Author Summary

Buruli Ulcer is an infectious skin disease, mainly occurring in West Africa. Previously, the disease was treated exclusively by surgery, but in the last decade, effective treatment with antibiotics has been established. The WHO recommended regimen consists of 8 weeks of oral rifampicin combined with intramuscular streptomycin. However, prolonged use of streptomycin is known to cause permanent ototoxicity and transient nephrotoxicity. To study this, we performed audiometry and measured the serum creatinine in 127 former Buruli ulcer patients who received either 4 or 8 weeks of streptomycin 4 to 6 years ago. Ototoxicity was present in 29% of adults and 25% of children. Adults who received 8 weeks of streptomycin had significantly worse hearing at long term follow-up, and this was most prominent in the high frequencies. In children, no differences between the two groups were found. Nephrotoxicity that had been detected in 14% of adults and in 13% of children during treatment, was present in only 2.4% of patients at long term follow-up. The findings indicate that caution should be exercised when prescribing streptomycin to adults for prolonged periods of time. Treatment regimens for Buruli ulcer that do not contain streptomycin are desirable and should be investigated.