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INTERNATIONAL JOURNAL OF CURRENT ZOOLOGICAL RESEARCH
RESEARCH ARTICLE
International Journal of Current Zoological Research - Vol. 1, Issue, 1, pp.014 - 016, January, 2013
CHEMOTHERAPY TREATMENT OF RIFAMPICIN AND CLARITHROMYCIN IN BURULI ULCER
DISEASE

Sakthivel, K 1*., Niraimathi, S1., Govindarajan ,M 2, and Angelina glorita parimala, S3

1PG & Research Department of Biochemistry, RVS College of Arts and Science, Karaikal-609 609, Tamilnadu, India
2Division of Vector Biology and phytochemistry, Department of Zoology, Annamalai University, Annamalainagar-
608 002, India
3Department of Zoology, A.D.M College for women, Nagapattinam- 611 001, Tamilnadu, India
A R T I C L E I N F O
A B S T R A C T
Article History:
Mycobacterium ulcerans is the causative agent of Buruli ulcer, an emerging
Received 10th December, 2012
tropical disease marked by devastating skin lesions. Mycobacterium ulcerans Received in revised form 20th, December, 2012 infection is responsible for severe skin lesions in Nagapattinam rural areas . We enrolled 30 patients with Buruli ulcers in study to evaluate efficacy of an oral chemotherapy using rifampicin plus clarithromycin during an 8-week period. The treatment was well tolerated, and all patients were healed by 12months after
Key words:
Mycobacterium, Buruli ulcer, disease Copy Right, IJCZR, 2013, Academic Journals. All rights reserved. INTRODUCTION
and is better tolerated than streptomycin, which requires daily injections and is associated with adverse events, such Mycobacterium ulcerans is the causative agent of Buruli as vestibular toxicity (which occurs in 0.5%–5%of ulcer, an emerging tropical disease marked by devastating patients) and nephrotoxicity (which occurs in 5%–10%) [5]. skin lesions [1]. Buruli ulcer affects mainly children in rural A clarithromycin-based oral treatment would be more areas, where access to health care is often delayed and easily administered, better accepted by patients, and where lengthy hospital stays are problematic. Until contribute to limiting the number of injections in the recently, surgery was the only treatment for Buruli ulcer. developing world [6]. Implementation of an oral R 1 C Significant progress has been made in the past 5 years with chemotherapy is supported by recent evidence of its the demonstration of the efficacy of rifampicin plus bactericidal activity in vivo [7, 8] and by several clinical streptomycin (R 1 S) Chemotherapy [2]. Its routine successes [9, 10]. Here, we report a pilot study involving 30 implementation has dramatically improved healing while patients with Buruli ulcer disease treated using an oral reducing the frequency of relapses [3]. However, combination of rifampicin and clarithromycin over an 8- streptomycin is an inject able drug, and the lack of an week period. All patients were successfully healed, and no efficacious oral treatment remains one of the main obstacles to decentralizing care at local level. A recently published randomized controlled trial from Nagapattinam MATERIALS AND METHODS
rural area showed no significant difference in the This study was realized at the Centre of Nagapattinam proportion of patients who achieved cure after receiving government hospitals.Eligible patients had laboratory- the World Health Organization (WHO)–recommended 8- confirmed cases of Buruli ulcer, were at least 5 years of week course of R 1 S chemotherapy compared with the age, presented with lesions <10 cm in diameter that had proportion who achieved cure after receiving a treatment appeared within the past 6 months, agreed to be consisting of 4 weeks of R 1 S followed by 4 weeks of hospitalized during treatment, and were likely to be rifampicin 1 clarithromycin (R 1 C) [4]. This study followed up for 18 months (ie, had stable habitation). represents a significant step to improve Buruli ulcer Written informed consent was obtained from the patient treatment. Indeed, clarithromycin is orally administered and from the patient’s parent or guardian if the patient was International Journal of Current Zoological Research - Vol. 1, Issue, 1, pp.014-016, January, 2013 under 18 years of age. No inclusion criteria were lesions Nine patients presented with non ulcerative lesions, and 21 .10 cm in diameter, multiple lesions, lesions located over a presented with ulcerative lesions. Buruli ulcer diagnosis joint, history of treatment with anti mycobacterial drugs, was confirmed by PCR for all patients, and 13 patients receipt of macrolide or quinolone antibiotics during the (43%) had a positive culture result at enrolment. Treatment previous month, allergy to rifampicin or clarithromycin, was well tolerated, and no adverse events were reported. pregnancy, or human immunodeficiency virus infection. All patients had reached 18 months of follow-up by All no included patients were treated according to WHO September 2010. All 30 patients were successfully treated, guidelines. The primary end point was defined as healing with complete re epithelialization of wounds 12 months of the wound at 12 months, without recurrence 18 months after treatment initiation, and no patient experienced after initiation of chemotherapy. Patients were treated relapse during follow-up. The median duration of healing using an oral combination of rifampicin (10 mg/kg) and was 104 days (range, 30–212 days; see Table 1 and clarithromycin (12 mg/kg) administered simultaneously, once daily, over 8 weeks. During treatment, patients were Microbiological follow-up was performed at week 4, 6, hospitalized and attended to daily by nursing staff, who and 8 on lesions that remained open. Culture results dispensed chemotherapy with a fatty snack and monitored became negative for all sampled patients except 1 after 4 patients for adverse effects during a 1-hours period after weeks; no culture was positive after 6 weeks. PCR follow- treatment intake. Clarithromycin was administered as 250- up of lesions that remained open showed that negative mg tablets completed with syrup to achieve exact dose. PCR results were rarely obtained before scarring Nursing staff cleansed the wound using physiological (supplementary Table 1). Among those 30 patients, 15 solution and renewed the wound dressing using simple (50%) healed after chemotherapy without any additional sterile dressings. Every week, patients were examined by a intervention (Table 1), and 11 (37%) of the patients doctor, who also collected samples at week 4, 6, and 8 if underwent limited surgical procedures, such as curettage the lesion had not healed, using swabs or aspiration. These (n 5 9) or excision (n 5 2). These procedures were mainly samples were sent for Mycobacterium ulcerans culture undertaken without suspicion of failure to promote a faster and polymerase chain reaction (PCR) analysis. After the and more regular scaring of lesions presenting excessive wound closed, patients were discharged from the hospital granulation or risks of functional incapacities. Four and were followed-up every 3 months up to 18 months patients, 6–8 years of age, underwent extensive surgical after starting treatment. Limited surgery was defined as excision followed by skin grafting. Three patients curettage of the lesion or a minor excision to remove presented with category 2 lesions that were large for their excess granulation tissue and to deride ulcer margins. body size and either worsened or showed no improvement Extensive surgery was defined as major excision followed (supplementary Table 1). One patient who had previously by skin-grafting. Surgery was undertaken if: (1) no healed without surgery experienced trauma at the site of the scar and required secondary extensive surgery. As characteristics was observed at week 4 of chemotherapy or observed in our routine experience of R 1 S chemotherapy after, (2) indurations persisted 12 weeks after initiation of [3], R 1 C chemotherapy was also sufficient to cure most (8 chemotherapy, (3) the lesion started bleeding at any time, or of 10) patients with category 1 ulcerative lesions and to (4) the lesion showed signs of improper scaring and risks of cure 5 of 11 patients who presented with larger ulcerative functional incapacities at any time. Excised tissue was sent lesions. A majority of no ulcerative lesions (7 of 9) for histological analysis, as well as Mycobacterium required additional surgical procedures. Tissue specimens ulcerans culture and PCR. All biological samples were were collected from the 15 patients who underwent collected and handled identically according to WHO surgery. Of 14 samples analyzed in culture, none was positive for M. ulcerans. However, 13 patients had a mycobacterial material, as described by others [2]. Patients were enrolled consecutively from December 2009 through February 2011. Included patients represented one- Table 1. Outcome and Additional Care received in 30 third of eligible patients who received a diagnosis during Patients with Buruli Ulcer Disease Treated with Oral this period. The main reason for nonparticipation was Rifampicin plus Clarithromycin (R 1 C) Chemotherapy refusal of hospitalization. Twelve of the patients were male, and 18 were female; 11 were .15 years of age. Table 1 Outcome and Additional Care received in 30 Patient
s with Buruli Ulcer Disease Treated with Oral Rifampicin plus Clarithromycin (R 1 C) Chemotherapy over an 8 wee With limited
With excision
Median time
Lesion type
and skin-grafting
to healing (days)
International Journal of Current Zoological Research - Vol. 1, Issue, 1, pp.014-016, January, 2013 DISCUSSION
2) Etuaful S, Carbonnelle B, Grosset J, et al. In this pilot study, 30 patients with confirmed Buruli ulcer Mycobacterium ulcerans in early lesions of Buruli chemotherapy. Microbiological results indicate that ulcer in humans. Antimicrob Agents Chemother persistence of viable mycobacteria was unlikely, even when extensive surgery was required. Histological analysis 3) Chauty A, Ardant M, Adeye A, et al. Promising supports this point, showing that 10 of 11 samples clinical efficacy of streptomycin- rifampin analyzed presented evidence of massive inflammatory combination for treatment of buruli ulcer infiltration. Local inflammatory reactions and the (Mycobacterium ulcerans disease). Antimicrob development of ectopic lymphoid tissue have been observed in Buruli ulcer lesions during healing while 4) Nienhuis WA, Stienstra Y, Thompson WA, et al. receiving chemotherapy [11, 12]. This most likely results Antimicrobial treatment for early, limited from mycobacterial antigens and immune stimulators Mycobacterium ulcerans infection: a randomized released during chemotherapy. In our experience, as controlled trial. Lancet 2010; 375:664–672. confirmed by others [13], this reaction is associated with good response to treatment and occurs irrespective of the interactions of antimycobacterial therapy. Clin chemotherapy used (A.C., unpublished data). We advocate that additional chemotherapy efficacy studies should rely 6) Hutin Y, Hauri A, Chiarello L, et al. Best on an improved definition of treatment failure that includes infection control practices for intradermal, microbiological evidence of viable, treatment-resistant mycobacteria and histological assessment of inflammatory injections. Bull World Health Organ 2003; reaction. Clinical criteria do not provide a clear rule to 7) Ji B, Chauffour A, Robert J, Jarlier V. chemotherapy failure and patients who successfully clear Bactericidal sterilizing activities of several orally the infection but require surgery to expedite the healing process. In the Ghanaian trial, treatment failure was defined according to clinical criteria, such as lesion size Antimicrob Agents Chemother 2008; 52:1912– progression or the need for extensive surgery, for all but one of the patients who experienced treatment failure [4]. 8) Ji B, Chauffour A, Robert J, Lefrancxois S, Jarlier The subjective component of such clinical criteria makes it V. Orally administered combined regimens for difficult to compare results across different studies. In our treatment of Mycobacterium ulcerans infection in study, 3 patients required extensive surgery, but none presented persistence of viable mycobacteria. Positive cultures were obtained in Ghana after treatment 9) O’Brien DP, Hughes AJ, Cheng AC, et al. completion in 5 patients who belonged to the 4 weeks of R Outcomes for Mycobacterium ulcerans infection 1 S followed by 4 weeks of R 1 C arm [4]. This result is with combined surgery and antibiotic therapy: difficult to interpret without information on drug resistance findings from a south-eastern Australian case or possible reinfections. In our study, viable mycobacteria were not observed after 6 weeks of treatment. We 10) Dossou AD, Sopoh GE, Johnson CR, et al. hypothesize that our higher dosage of clarithromycin was more efficient at clearing the infection, without causing infection in a pregnant woman in Benin using more adverse effects. In conclusion, this study provides rifampicin and clarithromycin. Med J Aust 2008; compelling evidence to support a future randomized controlled trial that compares the standard regimen (8 11) Schu¨tte D, Um-Boock A, Mensah-Quainoo E, weeks of R 1 S) with the complete oral regimen (8 weeks Itin P, Schmid P, Pluschke G. Development of of R 1 C). Proving the efficacy of the R 1 C combination highly organized lymphoid structures in Buruli could lead to a simpler, less invasive, and less painful ulcer lesions after treatment with rifampicin and treatment that is easier to implement at the local level. streptomycin. PLoS Negl Trop Dis 2007; 1:e2. Surgery is likely to remain necessary for severe lesions, 12) Schu¨tte D, Pluschke G. Immunosuppression but a large proportion of patients can be cured through oral treatment-associated inflammatory response in chemotherapy alone, which is a great boon to the rural patients with Mycobacterium ulcerans infection communities most affected by Buruli ulcer. (Buruli ulcer). Expert Opin Biol Ther 2009; References
13) O’Brien DP, Robson ME, Callan PP, McDonald 1) Wansbrough-Jones M, Phillips R. Buruli ulcer: AH. ‘‘Paradoxical’’ immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success, not failure. Med J Aust 2009; 191:564–566.

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