Pharmacokinetics of extended-release clarithromycin in patients with Mycobacterium ulcerans infection.

Clarithromycin extended-release (CLA-ER) was used as companion drug to rifampicin (RIF) for Mycobacterium ulcerans infection in the intervention arm of a WHO drug trial. RIF enhances CYP3A4 metabolism, thereby reducing CLA serum concentrations, and RIF concentrations might be increased by CLA co-administration. We studied the pharmacokinetics of CLA-ER at a daily dose of 15 mg/kg combined with RIF at a dose of 10 mg/kg in a subset of trial participants, and compared these to previously obtained pharmacokinetic data. Serial dried blood spot samples were obtained over a period of ten hours, and analyzed by LC-MS/MS in 30 study participants-20 in the RIF-CLA study arm, and 10 in the RIF-streptomycin study arm. Median CLA Cmax was 0.4 mg/L-and median AUC 3.9 mg*h/L, following 15 mg/kg CLA-ER. Compared to standard CLA dosed at 7.5 mg/kg previously, CLA-ER resulted in a non-significant 58% decrease in Cmax and a non-significant 30% increase in AUC. CLA co-administration did not alter RIF Cmax or AUC. Treatment was successful in all study participants. No effect of CLA co-administration on RIF pharmacokinetics was observed. Based on our serum concentration studies, the benefits CLA-ER over CLA immediate release are unclear.

Former Buruli Ulcer Patients' Experiences and Wishes May Serve as a Guide to Further Improve Buruli Ulcer Management.

BACKGROUND: Buruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical disease frequently leading to permanent disabilities. The ulcers are treated with rifampicin and streptomycin, wound care and, if necessary surgical intervention. Professionals have exclusively shaped the research agenda concerning management and control, while patients' perspective on priorities and preferences have not explicitly been explored or addressed. METHODOLOGY/PRINCIPAL FINDINGS: To get insight into patient perception of the management and control of Buruli ulcer a mixed methods research design was applied with a questionnaire and focus group discussions among former BU patients. Data collection was obtained in collaboration with a local team of native speakers in Ghana. A questionnaire was completed by 60 former patients and four focus group discussions were conducted with eight participants per group. Former patients positively evaluated both the effectiveness of the treatment and the financial contribution received for the travel costs to the hospitals. Pain experienced during treatment procedures, in particular wound care and the streptomycin injections, and the side-effects of the treatment were negatively evaluated. Former patients considered the development of preventive measures and knowledge on the transmission as priorities. Additionally, former patients asked for improved accessibility of health services, counselling and economic support. CONCLUSIONS: These findings can be used to improve clinical management and to guide the international research agenda.

The Application of Modern Dressings to Buruli Ulcers: Results from a Pilot Implementation Project in Ghana.

Buruli ulcer (BU) is a tropical, infectious skin disease. The resulting ulcer can take a long time to heal, and a high standard of wound care is essential. Currently, the only dressing used for BU wound care is gauze, and its removal causes pain and bleeding. We performed a pilot implementation project using HydroTac(®) (HARTMANN, Heidenheim, Germany), a modern dressing combining foam with a hydrogel component. For future BU treatment, we recommend to use a more absorbent dressing than the HydroTac dressing used in the current project. However, we show that modern dressings can be applied to BUs and that HydroTac dressings yield clean, healing wounds, and prevent the pain and bleeding associated with gauze dressings. Wound care is a vital but to date neglected aspect of BU management.

Genetic Susceptibility and Predictors of Paradoxical Reactions in Buruli Ulcer.

INTRODUCTION: Buruli ulcer (BU) is the third most frequent mycobacterial disease in immunocompetent persons after tuberculosis and leprosy. During the last decade, eight weeks of antimicrobial treatment has become the standard of care. This treatment may be accompanied by transient clinical deterioration, known as paradoxical reaction. We investigate the incidence and the risks factors associated with paradoxical reaction in BU. METHODS: The lesion size of participants was assessed by careful palpation and recorded by serial acetate sheet tracings. For every time point, surface area was compared with the previous assessment. All patients received antimicrobial treatment for 8 weeks. Serum concentration of 25-hydroxyvitamin D, the primary indicator of vitamin D status, was determined in duplex for blood samples at baseline by a radioimmunoassay. We genotyped four polymorphisms in the SLC11A1 gene, previously associated with susceptibility to BU. For testing the association of genetic variants with paradoxical responses, we used a binary logistic regression analysis with the occurrence of a paradoxical response as the dependent variable. RESULTS: Paradoxical reaction occurred in 22% of the patients; the reaction was significantly associated with trunk localization (p = .039 by Χ(2)), larger lesions (p = .021 by Χ(2)) and genetic factors. The polymorphisms 3'UTR TGTG ins/ins (OR 7.19, p < .001) had a higher risk for developing paradoxical reaction compared to ins/del or del/del polymorphisms. CONCLUSIONS: Paradoxical reactions are common in BU. They are associated with trunk localization, larger lesions and polymorphisms in the SLC11A1 gene.

Buruli ulcer control in a highly endemic district in Ghana: role of community-based surveillance volunteers.

Buruli ulcer (BU) is an infectious skin disease that occurs mainly in West and Central Africa. It can lead to severe disability and stigma because of scarring and contractures. Effective treatment with antibiotics is available, but patients often report to the hospital too late to prevent surgery and the disabling consequences of the disease. In a highly endemic district in Ghana, intensified public health efforts, mainly revolving around training and motivating community-based surveillance volunteers (CBSVs), were implemented. As a result, 70% of cases were reported in the earliest-World Health Organization category I-stage of the disease, potentially minimizing the need for surgery. CBSVs referred more cases in total and more cases in the early stages of the disease than any other source. CBSVs are an important resource in the early detection of BU.

Good quality of life in former Buruli ulcer patients with small lesions: long-term follow-up of the BURULICO trial.

BACKGROUND: Buruli Ulcer is a tropical skin disease caused by Mycobacterium ulcerans, which, due to scarring and contractures can lead to stigma and functional limitations. However, recent advances in treatment, combined with increased public health efforts have the potential to significantly improve disease outcome. OBJECTIVES: To study the Quality of Life (QoL) of former Buruli Ulcer patients who, in the context of a randomized controlled trial, reported early with small lesions (cross-sectional diameter <10 cm), and received a full course of antibiotic treatment. METHODS: 127 Participants of the BURULICO drug trial in Ghana were revisited. All former patients aged 16 or older completed the Dermatology Life Quality Index (DLQI) and the abbreviated World Health Organization Quality of Life scale (WHOQOL-BREF). The WHOQOL-BREF was also administered to 82 matched healthy controls. Those younger than 16 completed the Childrens' Dermatology Life Quality Index (CDLQI) only. RESULTS: The median (Inter Quartile Range) score on the DLQI was 0 (0-4), indicating good QoL. 85% of former patients indicated no effect, or only a small effect of the disease on their current life. Former patients also indicated good QoL on the physical and psychological domains of the WHOQOL-BREF, and scored significantly higher than healthy controls on these domains. There was a weak correlation between the DLQI and scar size (ρ = 0.32; p<0.001). CONCLUSIONS: BU patients who report early with small lesions and receive 8 weeks of antimicrobial therapy have a good QoL at long-term follow-up. These findings contrast with the debilitating sequelae often reported in BU, and highlight the importance of early case detection.

Wound care in Buruli ulcer disease in Ghana and Benin.

Buruli ulcer (BU) is a disease affecting the skin, subcutaneous fat, and bone tissues. Wound care is important in the prevention of disabilities. Awareness of current wound care practices in BU-endemic regions is necessary for future wound care interventions. Thirty-one health care workers in Ghana and Benin were interviewed with a semi-structured interview, complemented by structural observations. Quantitative data were analyzed through t tests and one-way analysis of variance, and qualitative data through descriptive statistics. There appeared to be a general understanding of wound assessment. A large variety of different topical antiseptics was reported to be used, pressure irrigation was never reported. Gauze was the main dressing type and a moist environment was preferred, but could not be maintained. Bleeding and pain were observed frequently. Standard of wound care differed importantly between health care personnel and between institutions and adherence to World Health Organization guidelines was low.

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

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.

Predictors for persistence of functional somatic symptoms in adolescents.

OBJECTIVE: To identify risk factors for persistence of functional somatic symptoms (FSS; ie, somatic symptoms that cannot be sufficiently explained by underlying organic pathology). STUDY DESIGN: The first (N = 2230, mean age = 11.1 years [SD 0.6], 50.8% girls), second (N = 2149, mean age = 13.7 years [SD 0.5], 51.0% girls), and third (N = 1816, mean age = 16.3 years [SD 0.7], 52.3% girls) assessment waves of the general population study TRacking Adolescents' Individual Lives Survey were used. FSS were assessed with the Youth Self-Report and the Child Behavior Checklist. Growth mixture models were used to identify different subgroups of adolescents on the basis of the developmental trajectory of their symptoms. Adolescents with persistent symptoms were compared with adolescents with decreasing symptoms with a multivariable logistic regression analysis. RESULTS: In our general population cohort, 4.1% of adolescents suffered from persistent FSS. Risk factors for persistent FSS were being a girl (OR 4.69, 95% CI 2.17-10.12), suffering from depressive symptoms (OR 5.35, 95% CI 1.46-16.62), poor self-rated health (OR 1.56, 95% CI 1.02-2.39), and high parent-reported FSS (OR 4.03, 95% CI 1.20-13.54). Anxiety, parental overprotection, school absenteeism, and diversity of symptoms did not predict persistence of FSS. CONCLUSIONS: This study identified risk factors for persistence of FSS in adolescents. Future studies might study effects of coping strategies and iatrogenic factors on symptom persistence.

Towards rational use of antibiotics for suspected secondary infections in Buruli ulcer patients.

BACKGROUND: The emerging disease Buruli ulcer is treated with streptomycin and rifampicin and surgery if necessary. Frequently other antibiotics are used during treatment. METHODS/PRINCIPAL FINDINGS: Information on prescribing behavior of antibiotics for suspected secondary infections and for prophylactic use was collected retrospectively. Of 185 patients that started treatment for Buruli ulcer in different centers in Ghana and Bénin 51 were admitted. Forty of these 51 admitted patients (78%) received at least one course of antibiotics other than streptomycin and rifampicin during their hospital stay. The median number (IQR) of antibiotic courses for admitted patients was 2 (1, 5). Only twelve patients received antibiotics for a suspected secondary infection, all other courses were prescribed as prophylaxis of secondary infections extended till 10 days on average after excision, debridement or skin grafting. Antibiotic regimens varied considerably per indication. In another group of BU patients in two centers in Bénin, superficial wound cultures were performed. These cultures from superficial swabs represented bacteria to be expected from a chronic wound, but 13 of the 34 (38%) S. aureus were MRSA. CONCLUSIONS/SIGNIFICANCE: A guide for rational antibiotic treatment for suspected secondary infections or prophylaxis is needed. Adherence to the guideline proposed in this article may reduce and tailor antibiotic use other than streptomycin and rifampicin in Buruli ulcer patients. It may save costs, reduce toxicity and limit development of further antimicrobial resistance. This topic should be included in general protocols on the management of Buruli ulcer.

Depression and posttraumatic stress disorder among HIV-infected Gambians on antiretroviral therapy.

Mood disorders are more frequent among people with HIV infection than among non-HIV-infected individuals of the same age, socioeconomic status, and HIV risks. They have been associated with worse adherence and clinical outcomes, yet remain underdiagnosed and undertreated in sub-Saharan Africa. We explored the relationship between mood disorders using the 10-item depression scale of the Centers for Epidemiological Studies (CES-D10) and the 22-item Impact of Events Scale-Revised (IES-R) for posttraumatic stress disorder, and a range of demographic and HIV-related variables among 252 consecutive subjects on antiretroviral therapy (ART). The study was conducted in the Genito-Urinary Medicine Clinic of the Medical Research Council's Gambia Unit. These screening tests were positive in 7% and 30%, respectively, of the patients, with higher scores (more depression or more post-traumatic stress) associated with female gender, more advanced WHO clinical stage, and lower Karnofsky Perfomance Scale rating. Higher CES-D10 scores were also seen among those on their second ART regimen. No relationship was seen with age, time on ART, viral load, or CD4 cell count. Compared to an earlier study at the same site in subjects prior to starting ART, the prevalence of depression in those stabilized on ART was dramatically reduced (by 34%, from 41%) while that of PTSD dropped less (by 13%, from 43%). Integrating the CES-D10 or a similar instrument into patient preparation for ART is recommended in order to identify those who may benefit from further mental health investigations, specific therapy, or closer follow-up during early ART.

Posttraumatic stress and depressive symptoms among people living with HIV in the Gambia.

This study aimed to assess the prevalence and clinical and psychosocial correlates of psychiatric symptoms in a sample of HIV patients in the Gambia. Data from 44 HIV-positive outpatients were collected at a Genito-Urinary Medicine clinic in Fajara, the Gambia. Translated versions of the Impact of Event Scale Revised and the Centre for Epidemiologic Studies Short Depression Scale were used to assess posttraumatic stress disorder (PTSD) symptoms and depressive symptoms, respectively. The Pictorial Representation of Illness and Self Measure revised was used to assess illness perception (IP). All other data (e.g., CD4 counts) were retrieved from medical charts or through standardised questions. The prevalence of PTSD symptoms (43.2%) and depressive symptoms (40.9%) was high. Not having an independent income and having a CD4 count under 200 cells/µl were independent correlates of depressive symptoms. Only IP was an independent correlate of PTSD symptoms. Finally, IP tended to moderate the relationship between CD4 cell counts and depressive symptoms. These findings indicate that routine screening for psychiatric symptoms is both necessary and feasible among HIV patients in the Gambia. In addition, any intervention targeting these symptoms should take IP into account.

Pictorial Representation of Illness and Self Measure Revised II (PRISM-RII): a novel method to assess perceived burden of illness in diabetes patients.

BACKGROUND: The Pictorial Representation of Illness and Self Measure (PRISM) has been introduced as a visual measure of suffering. We explored the validity of a revised version, the PRISM-RII, in diabetes patients as part of the annual review. METHODS: Participants were 308 adult outpatients with either type 1 or type 2 diabetes. MEASURES: (1) the PRISM-RII, yielding Self-Illness Separation (SIS) and Illness Perception Measure (IPM); (2) the Problem Areas in Diabetes (PAID) scale, a measure of diabetes-related distress; (3) the WHO-5 Well-Being Index; (4) and a validation question on suffering (SQ). In addition, patients' complication status, comorbidity and glycemic control values(HbA1c) were recorded. RESULTS: Patients with complications did have marginally significant higher scores on IPM, compared to patients without complications. Type 2 patients had higher IPM scores than Type 1 patients. SIS and IPM showed low intercorrelation (r = -.25; p < .01). Convergent validity of PRISM-RII was demonstrated by significant correlations between IPM and PAID (r = 0.50; p < 0.01), WHO-5 (r = -.26; p < 0.01) and SQ (r = 0.36; p < 0.01). SIS showed only significant correlations with PAID (r = -0.28; p < 0.01) and SQ (r = -0.22; p < 0.01). Neither IPM nor SIS was significantly associated with HbA1c. The PRISM-RII appeared easy to use and facilitated discussion with care providers on coping with the burden of diabetes. CONCLUSION: PRISM-RII appears a promising additional tool to assess the psychological burden of diabetes.