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      All-Oral Antibiotic Treatment for Buruli Ulcer: A Report of Four Patients

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          Abstract

          The Cases Buruli ulcer (BU) was treated primarily with wide surgical excision until recent studies confirmed the efficacy of oral rifampicin combined with intramuscular streptomycin. Whether all-oral antibiotic regimens will be equally effective is unknown. This report describes four patients with Mycobacterium ulcerans infection, all of whom received rifampicin-based oral antibiotic therapy followed by surgical resection (three patients) or oral antibiotics alone (one patient). Following oral antibiotics for between 4 and 8 weeks, viable M. ulcerans was not detectable by culture in three of the patients, or by histology in a fourth patient from whom no specimen for culture was obtained. All cases spent time in a BU-endemic area in coastal Victoria, Australia. Baseline characteristics, diagnosis, treatment received, and histopathology of resected specimens are detailed in Table 1. Clinical photographs are shown in Figures 1– 4. All patients gave informed consent for publication. 10.1371/journal.pntd.0000770.g001 Figure 1 Thirty-eight-year-old male with culture confirmed Buruli ulcer before, during, and after treatment. 10.1371/journal.pntd.0000770.g002 Figure 2 Thirty-two-year-old male with culture confirmed Buruli ulcer before, during, and after treatment. 10.1371/journal.pntd.0000770.g003 Figure 3 Twelve-year-old male with culture confirmed Buruli ulcer before, during, and after treatment. 10.1371/journal.pntd.0000770.g004 Figure 4 Three-year-old female with culture confirmed Buruli ulcer before, during, and after treatment. 10.1371/journal.pntd.0000770.t001 Table 1 Baseline Characteristics, Diagnosis, Treatment Received, and Histopathology and Microbiology of Resected Specimens. Case 1 Case 2 Case 3 Case 4 Age 38-year-old male 32-year-old male 12-year-old male 3-year-old female Location of lesion Right lateral malleolus Right elbow Lower back Left thigh/buttock Clinical form, size, and WHO category of lesion [17] Ulcer, 2cm diameter, category 1 Ulcer, 2cm diameter, srcategory 1 Pre-ulcerative form, 4cm diameter of induration, category 1 Ulcer, 2cm diameter, category 1 Region exposed Bellarine Peninsula Bellarine Peninsula Bellarine Peninsula Bellarine Peninsula Specimen collected for diagnosis Dry swab Dry swab Saline-moistened swab Dry swab Basis of diagnosis PCR and culture PCR and culture PCR and culture PCR and culture Date of laboratory diagnosis November 2006 October 2008 November 2008 November 2009 Principal drug Rifampicin 600 mg daily Rifampicin 600 mg daily Rifampicin 450 mg daily reduced to 600 mg 3× week after day 7 Rifampicin 10mg/kg daily Secondary drug Moxifloxacin 400 mg daily Moxifloxacin 400 mg daily Clarithromycin 250 mg twice daily reduced to 250 mg twice daily, alternate days after day 7 Clarithromycin 15mg/kg daily in divided doses Duration of oral drug therapy prior to excision 6 weeks 6 weeks 4 weeks 8 weeks (lesion not excised) Outcome (follow-up period) No recurrence (36 months) No recurrence (13 months) No recurrence (12 months) Improved to match head sized palpable nodule Histology/microbiology summary of excised specimen (cases 1–3; no excision case 4) No AFB, culture negative, chronic granulomatous inflammation without necrosis No AFB, chronic necrotizing granulomatous inflammation, culture not performed AFB seen, culture negative, necrosis to edges of excision Spontaneous discharge 4 weeks after ceasing antibiotics, AFB seen, PCR positive, culture negative Comment Doses and duration reduced due to drug intolerance Apparent relapse due to a culture negative “paradoxical” reaction [22] In all patients, the diagnosis of M. ulcerans was confirmed by positive polymerase chain reaction (PCR) and isolation of M. ulcerans by culture from swabs obtained prior to treatment. Three patients had ulcerative lesions (Table 1: cases 1, 2, and 4; Figures 1, 2, and 4) and one had a pre-ulcerative lesion (Table 1: case 3 and Figure 3) from which a saline-moistened swab of the lesion yielded a positive PCR and culture. For the two adults (Table 1: cases 1 and 2), rifampicin was combined with moxifloxacin for 6 weeks prior to resection. The two children (Table 1: cases 3 and 4) received rifampicin combined with clarithromycin for either 4 weeks prior to resection (Table 1: case 3) or 8 weeks without resection (Table 1: case 4). In cases 1 and 3, resection specimens were culture-negative, and culture was not performed in case 2, although histology showed resolving inflammation and no acid-fast bacilli (AFB) by Ziehl-Neelsen staining. In case 3, a Ziehl-Neelsen stained section showed persistent AFB but culture was negative. He had received a reduced dose of rifampicin due to gastrointestinal and neurological side effects and underwent earlier excision than planned at 4 weeks. Inflammation of surrounding skin and the size of the lesion reduced during antibiotic therapy in all four patients (Figures 1–4). PCR was not performed on surgical excision specimens (cases 1–3). Excision and primary closure, rather than grafting, was achieved in case 2 and 3, which had not been considered possible initially. Antibiotic treatment was continued after surgery in all patients. Total treatment duration was 7 weeks for case 3 and 12 weeks for cases 1 and 2. Case 4 was a 3-year-old girl who was treated with oral combination antibiotics without surgery. After 8 weeks of rifampicin and clarithromycin syrup, the ulcer had reduced to a very small palpable nodule. However, 4 weeks after ceasing antibiotic therapy the lesion became inflamed and discharged pus. Acid-fast bacilli were seen and PCR for M. ulcerans was positive. However, subsequent culture was negative at 3-months, suggesting an immune-mediated “paradoxical reaction” driven by residual but dead mycobacterial cells, rather than a true failure of oral antibiotic therapy. Following spontaneous discharge only a small blind ending sinus remained. Discussion BU is a slowly progressive and destructive soft tissue infection, with the potential for severe scarring and disability [1], [2]. The main burden of disease occurs in sub-Saharan Africa [1], although in Australia, there are also active foci in coastal Victoria, the Daintree region in the far north, and near Rockhampton, Queensland [3]–[6]. Until recently, the practice of wide surgical excision followed by grafting has been the mainstay of treatment [2]. High relapse rates [7], prohibitive cost, and limited access to surgery in endemic areas in Africa led to a renewal of interest in antibiotic therapy, which had not appeared effective when first studied in field trials [8]–[10]. Based on promising experiments in the mouse footpad model [11]–[15], a small pilot study established that the combination of oral rifampicin and intramuscular (IM) streptomycin for 8 weeks was able to sterilize early BU lesions in humans. In this small study of 21 pre-ulcerative patients in Ghana, even 4 weeks of rifampicin and streptomycin led to culture negativity when lesions were surgically excised after antibiotic treatment of varying durations [16]. Based on this result, WHO introduced and promoted a new protocol of initial therapy with 8 weeks of daily oral rifampicin and IM streptomycin for all patients with BU, although it was expected that many would still require surgery [17]. Subsequently, Chauty et al. reported a case series of 224 patients with pre-ulcerative and ulcerative BU who were treated with this regimen [18]. Of the 215 patients whose lesions healed, 47% were treated only with antibiotics and did not require surgery. Although there were no microbiological studies, recurrence of M. ulcerans infection occurred in only two patients treated with antibiotics alone. In a recent randomized trial of 151 patients, the majority of whom also did not have surgery, Nienhuis et al. demonstrated that oral rifampicin plus IM streptomycin for 4 weeks then oral rifampicin plus oral clarithromycin for 4 weeks was as effective as 8 weeks of oral rifampicin plus IM streptomycin [19], indicating that a shorter duration of IM streptomycin is also effective. In Australia, surgery is widely accessible and remains the main treatment modality for BU, although often in combination with oral antibiotics. As a result, the efficacy of surgery alone compared with oral antibiotics alone is difficult to establish, although relapses may be less when both modalities are used [6], [20], [21]. Australian consensus guidelines [6], now 4 years old, recommend surgery alone for small lesions or surgery combined with antibiotic therapy for more extensive disease. These guidelines include the use of IV amikacin for severe disease, but in practice amikacin is rarely used due to concerns about ototoxicity. Other oral antibiotics that appear to be active against M. ulcerans in mice include moxifloxacin and clarithromycin [11]. Clarithromycin is preferred in children due to its established safety record. There are unpublished accounts of successful treatment of BU with oral rifampicin alone (W. Meyers, personal communication), and the first published report of successful use of oral antibiotics was of a North Queensland farmer with acute, oedematous M. ulcerans disease who received oral rifampicin, clarithromycin, and ethambutol for 12 weeks immediately following extensive but incomplete surgical excision [20]. The surgical resection margin showed AFB, but further biopsies taken after 3 weeks of antibiotics due to concern about relapse were smear and culture negative. In retrospect, this apparent clinical deterioration may have been a “paradoxical reaction” [22] and the case demonstrated the principle that oral antibiotics are able to prevent relapse after incomplete surgical excision, even in a severe form of BU. In the four patients we have described here, combination oral antibiotic therapy prior to excision led to the inability to recover M. ulcerans by culture in the three cases from whom a second specimen was submitted for culture, confirming that oral combinations of antibiotics are capable of sterilizing lesions in humans, as Etuafal et al. demonstrated for rifampicin plus IM streptomcyin. Two of the three patients we described received oral antibiotics for a total of 12 weeks. However, negative culture results at excision (4 weeks for case 3, 6 weeks for case 1) suggest that shorter periods may be effective as suggested for the combination of rifampicin and streptomycin [16], [17]. Dossou et al. also reported clinical improvement after 8 weeks of oral rifampicin and clarithromycin [23] in a pregnant patient. However, in all patients we have described, the clinical appearance of the lesions only improved slowly over several weeks. As experience with antibiotics increases it has become apparent that healing is slow but continues long after the treatment course is completed [18], [19]. Although this is a small clinical case series of Category I BU, oral rifampicin in combination with clarithromycin or moxifloxacin shows promise and should be further investigated. Key Learning Points Treatment of patients with limited BU prior to surgery using rifampicin-based oral antibiotics resulted in culture-negative resection specimens. Clinical healing is slow despite the microbiological activity of oral antibiotics. Apparent relapses that occur during or after treatment may be due to immunologically driven paradoxical reactions rather than primary treatment failure. Rifampicin-based oral antibiotic therapy for the treatment of M. ulcerans infection followed by delayed surgery appears to simplify management by allowing excision and closure in one step without relapse.

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          Most cited references22

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          Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial.

          Surgical debridement was the standard treatment for Mycobacterium ulcerans infection (Buruli ulcer disease) until WHO issued provisional guidelines in 2004 recommending treatment with antimicrobial drugs (streptomycin and rifampicin) in addition to surgery. These recommendations were based on observational studies and a small pilot study with microbiological endpoints. We investigated the efficacy of two regimens of antimicrobial treatment in early-stage M ulcerans infection. In this parallel, open-label, randomised trial undertaken in two sites in Ghana, patients were eligible for enrolment if they were aged 5 years or older and had early (duration <6 months), limited (cross-sectional diameter <10 cm), M ulcerans infection confirmed by dry-reagent-based PCR. Eligible patients were randomly assigned to receive intramuscular streptomycin (15 mg/kg once daily) and oral rifampicin (10 mg/kg once daily) for 8 weeks (8-week streptomycin group; n=76) or streptomycin and rifampicin for 4 weeks followed by rifampicin and clarithromycin (7.5 mg/kg once daily), both orally, for 4 weeks (4-week streptomycin plus 4-week clarithromycin group; n=75). Randomisation was done by computer-generated minimisation for study site and type of lesion (ulceration or no ulceration). The randomly assigned allocation was sent from a central site by cell-phone text message to the study coordinator. The primary endpoint was lesion healing at 1 year after the start of treatment without lesion recurrence or extensive surgical debridement. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00321178. Four patients were lost to follow-up (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, three). Since these four participants had healed lesions at their last assessment, they were included in the analysis for the primary endpoint. 73 (96%) participants in the 8-week streptomycin group and 68 (91%) in the 4-week streptomycin plus 4-week clarithromycin group had healed lesions at 1 year (odds ratio 2.49, 95% CI 0.66 to infinity; p=0.16, one-sided Fisher's exact test). No participants had lesion recurrence at 1 year. Three participants had vestibulotoxic events (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, two). One participant developed an injection abscess and two participants developed an abscess close to the initial lesion, which was incised and drained (all three participants were in the 4-week streptomycin plus 4-week clarithromycin group). Antimycobacterial treatment for M ulcerans infection is effective in early, limited disease. 4 weeks of streptomycin and rifampicin followed by 4 weeks of rifampicin and clarithromycin has similar efficacy to 8 weeks of streptomycin and rifampicin; however, the number of injections of streptomycin can be reduced by switching to oral clarithromycin after 4 weeks. European Union (EU FP6 2003-INCO-Dev2-015476) and Buruli Ulcer Groningen Foundation. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Buruli Ulcer (M. ulcerans Infection): New Insights, New Hope for Disease Control

            Buruli ulcer is a disease of skin and soft tissue caused by Mycobacterium ulcerans. It can leave affected people scarred and disabled. What are the prospects for disease control?
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              Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans.

              Mycobacterium ulcerans disease is common in some humid tropical areas, particularly in parts of West Africa, and current management is by surgical excision of skin lesions ranging from early nodules to extensive ulcers (Buruli ulcer). Antibiotic therapy would be more accessible to patients in areas of Buruli ulcer endemicity. We report a study of the efficacy of antibiotics in converting early lesions (nodules and plaques) from culture positive to culture negative. Lesions were excised either immediately or after treatment with rifampin orally at 10 mg/kg of body weight and streptomycin intramuscularly at 15 mg/kg of body weight daily for 2, 4, 8, or 12 weeks and examined by quantitative bacterial culture, PCR, and histopathology for M. ulcerans. Lesions were measured during treatment. Five lesions excised without antibiotic treatment and five lesions treated with antibiotics for 2 weeks were culture positive, whereas three lesions treated for 4 weeks, five treated for 8 weeks, and three treated for 12 weeks were culture negative. No lesions became enlarged during antibiotic treatment, and most became smaller. Treatment with rifampin and streptomycin for 4 weeks or more inhibited growth of M. ulcerans in human tissue, and it provides a basis for proceeding to a trial of antibiotic therapy as an alternative to surgery for early M. ulcerans disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                November 2010
                30 November 2010
                : 4
                : 11
                : e770
                Affiliations
                [1 ]Department of Infectious Diseases, Austin Health, Melbourne, Australia
                [2 ]Department of Surgery, Box Hill Hospital, Melbourne, Australia
                [3 ]Department of Surgery, Monash University, Melbourne, Australia
                [4 ]Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
                [5 ]WHO Collaborating Centre for Mycobacterium ulcerans (Western Pacific Region) and Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia
                [6 ]Department of Anatomical Pathology, Box Hill Hospital, Melbourne, Australia
                [7 ]Department of Infectious Diseases, Royal Children's Hospital, Melbourne, Australia
                Emory University, United States of America
                Author notes
                Article
                09-PNTD-SM-0733R3
                10.1371/journal.pntd.0000770
                2994921
                21152060
                2c852cbb-40f0-48b4-a713-78cfa4bfd62e
                Gordon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Page count
                Pages: 7
                Categories
                Symposium
                Infectious Diseases/Neglected Tropical Diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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