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Randomized Controlled Trial
. 2014 Mar 13;8(3):e2739.
doi: 10.1371/journal.pntd.0002739. eCollection 2014 Mar.

Long term streptomycin toxicity in the treatment of Buruli Ulcer: follow-up of participants in the BURULICO drug trial

Sandor Klis  1 , Ymkje Stienstra  1 , Richard O Phillips  2 , Kabiru Mohammed Abass  3 , Wilson Tuah  4 , Tjip S van der Werf  5
Affiliations
Randomized Controlled Trial

Long term streptomycin toxicity in the treatment of Buruli Ulcer: follow-up of participants in the BURULICO drug trial

Sandor Klis et al. PLoS Negl Trop Dis. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Hearing thresholds of adults at long term follow-up.
Mean hearing thresholds of adults (16 or older at the time of treatment) in dB averaged over both ears. The shaded area represents the area used in understanding human speech (Pascoe, 1980) . SR8 = participants in the 8 week Streptomycin/Rifampicin group. SR4/CR4 = participants in the 4 week Streptomycin/Rifampicin plus 4 week Clarithromycin/Rifampicin group. The Differences between the two groups were tested with the Mann-Whitney U test, 1-tailed. * = p<0.05, ** = p<0.001.
Figure 2
Figure 2. Hearing thresholds of children at long term follow-up.
Mean hearing thresholds of children (under 16 at the time of treatment) in dB averaged over both ears. The shaded area represents the area used in understanding human speech (Pascoe, 1980) . SR8 = participants in the 8 week Streptomycin/Rifampicin group. SR4/CR4 = participants in the 4 week Streptomycin/Rifampicin plus 4 week Clarithromycin/Rifampicin group. The Differences between the two groups were tested with the Mann-Whitney U test, all differences were ns.
Figure 3
Figure 3. Serum creatinine levels in adults at long term follow-up.
Mean (SD) serum creatinine concentrations of adults (16 or older at the time of treatment), measured at baseline, after 8 weeks of treatment and at long term follow-up. SR8 = participants in the 8 week Streptomycin/Rifampicin group. SR4/CR4 = participants in the 4 week Streptomycin/Rifampicin plus 4 week Clarithromycin/Rifampicin group. The differences between the two groups at baseline were tested with the students t-test. The differences between the two groups after 8 weeks of treatment and at long-term follow up were tested with an ANCOVA, controlling for serum creatinine concentration at baseline and age. * = p<0.05, others ns (N = 41).
Figure 4
Figure 4. Serum creatinine levels in children at long term follow-up.
Mean (SD) serum creatinine concentrations of children (under 16 at the time of treatment), measured at baseline, after 8 weeks of treatment and at long term follow-up. SR8 = participants in the 8 week Streptomycin/Rifampicin group. SR4/CR4 = participants in the 4 week Streptomycin/Rifampicin plus 4 week Clarithromycin/Rifampicin group. The differences between the two groups were tested with the students t-test. All differences ns (N = 84).
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References

    1. Stienstra Y, van Roest MH, van Wezel MJ, Wiersma IC, Hospers IC, et al. (2005) Factors associated with functional limitations and subsequent employment or schooling in buruli ulcer patients. Trop Med Int Health 10 (12) 1251–1257. - PubMed
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