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

ABSTRACT: 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.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.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.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.

SUBMITTER: Klis S

PROVIDER: S-EPMC3953024 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Klis Sandor S Stienstra Ymkje Y Phillips Richard O RO Abass Kabiru Mohammed KM Tuah Wilson W van der Werf Tjip S TS

PLoS neglected tropical diseases 20140313 3

<h4>Background</h4>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.<h4>Methods</h4>Former patients ...[more]

PMID: 24625583

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Project description:BackgroundHypertension is a major risk factor for peripheral artery disease (PAD). Little is known about relative efficacy of antihypertensive treatments for preventing PAD.ObjectivesTo compare, by randomized treatment groups, hospitalized or revascularized PAD rates and subsequent morbidity and mortality among participants in the Antihypertensive and Lipid-Lower Treatment to Prevent Heart Attack Trial (ALLHAT).DesignRandomized, double-blind, active-control trial in high-risk hypertensive participants.ParticipantsEight hundred thirty participants with specified secondary outcome of lower extremity PAD events during the randomized phase of ALLHAT.Interventions/eventsIn-trial PAD events were reported during ALLHAT (1994-2002). Post-trial mortality data through 2006 were obtained from administrative databases. Mean follow-up was 8.8 years.Main measuresBaseline characteristics and intermediate outcomes in three treatment groups, using the Kaplan-Meier method to calculate cumulative event rates and post-PAD mortality rates, Cox proportional hazards regression model for hazard ratios and 95 % confidence intervals, and multivariate Cox regression models to examine risk differences among treatment groups.Key resultsFollowing adjustment for baseline characteristics, neither participants assigned to the calcium-channel antagonist amlodipine nor to the ACE-inhibitor lisinopril showed a difference in risk of clinically advanced PAD compared with those in the chlorthalidone arm (HR, 0.86; 95 % CI, 0.72-1.03 and HR, 0.98; 95 % CI, 0.83-1.17, respectively). Of the 830 participants with in-trial PAD events, 63 % died compared to 34 % of those without PAD; there were no significant treatment group differences for subsequent nonfatal myocardial infarction, coronary revascularizations, strokes, heart failure, or mortality.ConclusionsNeither amlodipine nor lisinopril showed superiority over chlorthalidone in reducing clinically advanced PAD risk. These findings reinforce the compelling need for comparative outcome trials examining treatment of PAD in high-risk hypertensive patients. Once PAD develops, cardiovascular event and mortality risk is high, regardless of type of antihypertensive treatment.

Project description:BackgroundBuruli ulcer caused by Mycobacterium ulcerans is an infection of the subcutaneous tissue leading to chronic necrotising skin ulcers. The pathogenesis is associated with the cytocidal and immunosuppressive activities of a macrolide toxin. Histopathological hallmark of progressing disease is a poor inflammatory response despite of clusters of extracellular bacilli. While traditionally wide excision of the infected tissue was the standard treatment, provisional WHO guidelines now recommend an eight week pre-treatment with streptomycin and rifampicin.Methodology/principal findingsWe conducted a detailed immunohistochemical analysis of tissue samples from Buruli patients who received antibiotic treatment. Cellular immune response along with bacterial load and distribution were monitored. We demonstrate that this treatment leads to the development of highly organized cellular infiltration surrounding areas of coagulative necrosis. Diffuse infiltrates, granulomas and dense lymphocyte aggregation close to vessels were observed. Mycobacterial material was primarily located inside mononuclear phagocytes and microcolonies consisting of extracellular rod-shaped mycobacteria were no longer found. In observational studies some patients showed no clinical response to antibiotic treatment. Corresponding to that, one of five lesions analysed presented with huge clusters of rod-shaped bacilli but no signs of infiltration.Conclusions/significanceResults signify that eight weeks of antibiotic treatment reverses local immunosuppression and leads to an active inflammatory process in different compartments of the skin. Structured leukocyte infiltrates with unique signatures indicative for healing processes developed at the margins of the lesions. It remains to be analysed whether antibiotic resistance of certain strains of M. ulcerans, lacking patient compliance or poor drug quality are responsible for the absent clinical responses in some patients. In future, analysis of local immune responses could serve as a suitable surrogate marker for the efficacy of alternative treatment strategies.

Project description:PURPOSE:Chest wall (CW) pain and rib fractures are frequently diagnosed after stereotactic body radiation therapy (SBRT) for malignant lung tumors. We hypothesize that multiple risk factors, including bone mineral density (BMD), are associated with CW toxicity, and that CW pain and rib fractures often evolve into chronic clinical problems. METHODS AND MATERIALS:A total of 118 lung tumors treated with SBRT in 100 patients with a minimum follow-up period of 2 years were retrospectively analyzed. The incidence, clinical course, and related demographic, clinical, and dosimetric factors of CW pain and rib fractures were analyzed. In addition, BMD was assessed, and the radiographic appearance of radiation-induced rib fractures and their healing process were characterized. RESULTS:The median follow-up was 49 months (range, 24-106 months). CW pain developed in 33 of 118 treatments (28%) after, on average, 12.5 months (range, 0-50 months), and was more common in women (P = .04). The mean duration of CW pain was 25 months (range, 2-63 months), and 36% of patients never had resolution of CW pain. A total of 34 of 118 treatments (29%) resulted in rib fractures at a mean time of 22 months (range, 3-46 months); rib fractures were more common in women, African Americans, upper/middle lobe tumors, and patients with lower BMD (P < .05). The mean duration of rib fractures was 25 months (range, 5-41 months), and only 16 rib fractures (47%) healed. Shorter CW planning target volume distance resulted in a higher risk for both rib fractures and CW pain (P = .01). Sixty-seven percent of fractures developed surrounding soft tissue fibrosis, and 62% (21 of 34 fractures) heterotopic ossification. Diabetes, body mass index, and steroid use were not associated with CW pain or rib fracture. CONCLUSIONS:Several factors were associated with a higher risk of SBRT-related CW toxicity. Optimal CW sparing (eg, volumetric modulated arc therapy, lower dose per fraction) should be considered in this patient group without compromising tumor control. SBRT-induced rib fractures commonly heal abnormally and result in potential chronic CW pain.

Dataset Information

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

Publications

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

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