Lepr Rev (2019) 90, 456–459 CASE REPORT Successful treatment of rifampicin resistant case of leprosy by WHO recommended ofloxacin and minocycline regimen MALLIKA LAVANIAa, JOYDEEPA DARLONGb, ABHISHEK REDDYb, MADHVI AHUJAa, ITU SINGHa, R.P. TURANKARa & U. SENGUPTAa aStanley Browne Laboratory, The Leprosy Mission Community Hospital, Nand Nagri, New Delhi 110093, India bThe Leprosy Mission Hospital, Purulia, West Bengal 723101, India Accepted for publication 15 July 2019 Summary A 25-year-old male treated for leprosy at the age of 15, with MDT, visited TLM Purulia Hospital in July 2017. He was provisionally diagnosed as a lepromatous relapse with ENL reaction. A biopsy was done to test for drug resistance. Drug resistance testing showed resistance to rifampicin. Second line drug regimen recommended by WHO for rifampicin-resistance was started. Within 6 months of taking medication the clinical signs and symptoms improved rapidly and the BI dropped by 1·66 log within 6 months. This case highlights the need for investigations in cases of relapse and the efficacy of WHO recommended second line drug regimen treatment in rifampicin-resistant leprosy cases. Keywords: leprosy, rifampicin-resistance, second-line treatment Introduction Leprosy, also known as Hansen’s disease (HD), is a chronic infectious disease caused by the bacterium Mycobacterium leprae or Mycobacterium lepromatosis.1,2 Leprosy is curable with administration of a rifampicin, clofazimine and dapsone known as multidrug therapy (MDT). Since the introduction of MDT in 1983 the prevalence of leprosy has fallen significantly from 54 cases/10 000 in 1983 to ,1 case/10 000 in 2005 in India. However, from 2005 onwards the annual new case detection rate has remained somewhat static, with only a slight decline.3 While treatment for paucibacillary (PB) leprosy is with dapsone and rifampicin for six months,2 treatment for multibacillary (MB) leprosy is with the combination of rifampicin, dapsone, and clofazimine for 12 months.2 Regular reports of relapse in patients after Correspondence to: Mallika Lavania, Stanley Browne Laboratory, Nand Nagri, New Delhi, India (e-mail: [email protected], [email protected]) 456 0305-7518/19/064053+04 q Lepra Treatment of a rifampicin-resistant case 457 completion of a full course of MDT suggest the possibility of either reinfection, or the emergence of resistant strains of M. leprae under drug pressure. Drug resistance is a potential disrupter for any communicable disease control/elimination program. Although the number of leprosy samples so far tested globally is low,4 the results suggest that drug resistance may pose a serious threat to leprosy control. In recent studies especially from The Leprosy Mission (TLM) Trust India, we reported the emergence of primary rifampicin resistance as well as multidrug resistance cases5,6 from endemic regions of India. This report presents a case of rifampicin resistance and its management with the administration of alternative drug combinations. Case Summary A 25-year-old male treated for MB leprosy at the age of 15, with WHO MDT, visited TLM Hospital, Purulia in July 2017 with complaints of painful swelling on legs and a history of fever on and off for 2 weeks. There was no history of joint pains, red eyes or painful eruptions in the past. His family was of lower socioeconomic status and he worked as an apprentice in a garage. His mother has been treated for leprosy 10 years ago and his father and two brothers were also diagnosed cases of leprosy. He was of average height and moderate nutritional status and his systemic examination was normal. He was afebrile and had numerous flesh coloured nodules and papules on the extensor surfaces of hands and feet. They were painless and unnoticed by the patient. There were also a few subcutaneous nodules on the lower leg that were painful and reddish. There was grade 1 pitting oedema on both feet. Routine investigation revealed mild anaemia, Hb 9 gm/dl. Ziehl-Nelson staining of the slit skin smear was positive, with a bacteriological index (BI) of 5·66þ. He was provisionally diagnosed as having Erythema Nodosum Leprosum (ENL), complicating relapsed lepromatous leprosy. A skin biopsy was done for histopathology and polymerase chain reaction (PCR) for drug resistance testing. Histopathology reports confirmed active lepromatous leprosy with necrotizing ENL reaction. Sections showed atrophy of the epidermis. The dermis had a diffuse granulomatous inflammatory cell collection consisting of foamy macrophages, lymphocytes and neutrophils around blood vessels, along neuro vascular bundles and around one hair follicle. Granuloma fraction was <10%. Acid fast stain showed presence of numerous bacilli in both solid and fragmented forms. The BI of the granuloma was 5þ. Drug resistance testing by PCR sequencing was performed for gene targets rpoB, folP and gyrA pertaining to the drugs rifampicin, dapsone and ofloxacin respectively, followed by DNA sequencing (Figure 1). The M. leprae isolate from the patient was found to be resistant to rifampicin and sensitive to the other two drugs, dapsone and ofloxacin. Second line drug regimen recommended by WHO for rifampicin resistant cases was started from Oct 2017 consisting of minocycline (100 mg), ofloxacin (400 mg) and clofazimine (50 mg) daily for 6 months, followed by clofazimine (50 mg) plus ofloxacin (400 mg) daily for an additional 18 months. Dapsone was also continued. Within 6 months of taking medication the clinical conditions and signs and symptoms improved rapidly. The BI had dropped by 1·66 log to 4þ. 458 M. Lavania et al. Figure 1. Rifampicin resistant patient with mutation in rpoB gene at codon position 456 (Ser456Leu). There were further episodes of severe ENL during the course of his treatment which were treated successfully with steroids and hospitalization. He had gastritis and was treated with proton pump inhibitors. While he was on steroids, his pill burden was large. A general feeling of ill-being was prevalent for the entire course. Prolonged periods of illness prevented him from continuing his job, and he was depressed. This was managed by regular counselling and a supportive family. There was no nerve impairment during the entire treatment period. Discussion As in the cases of other infectious diseases, the relapse rate is a crucial parameter in assessing the long-term efficacy of chemotherapy. Though earlier studies with short-term follow-up have shown a good response, it is the long-term outcome of the treated patients that determines the ultimate utility of the therapeutic regimens.7 In 2017, a total of 35 cases were confirmed as relapse cases in TLM centres, while at national level in India the number was 536. Resistance will not be diagnosed unless it is investigated thoroughly. There must be a high index of suspicion when patients present with new signs and symptoms with a previous history of MDT intake. Clinicians must not hesitate to do histopathological examination and send samples for resistance testing. Protocols for resistant cases must be widely disseminated. The second line drugs for leprosy are essential to address the emerging problem of resistance to MDT, especially rifampicin. Rifampicin has strong bactericidal activities against M. leprae and is the only bactericidal drug in MDT. This drug binds with the b-subunit of RNA polymerase and inhibits RNA synthesis. Emerging reports of rifampicin Treatment of a rifampicin-resistant case 459 resistance stress the need for expansion of surveillance. There is also a need to regulate the global use of antimicrobial agents, as ofloxacin resistance probably develops in relation to the general intake of antibiotics for other infections.8 According to the guidelines of the Global Leprosy Programme for resistant leprosy cases, the patients who were reported to be resistant to dapsone only, standard MB-MDT can be continued, but the patient should be followed at the end of treatment and regularly examined for possible relapse. And for patients with resistance only to quinolones, MDT should be continued. Compliance must be strictly monitored and treatment completion rates must be 100 % in such cases. In cases of laboratory reported rifampicin-resistant M. leprae, second- line treatment consists of 400 mg ofloxacin þ100 mg minocycline þ50 mg clofazimine, daily for 6 months; followed by 400 mg ofloxacin OR 100 mg minocycline þ50 mg clofazimine daily for an additional 18 months. In a previous study, Ji et al.9 observed that gastrointestinal adverse events were mild and transitory among patients treated with the RMP-OFLO-MINO or OFLO-MINO combination, while in our study the patient had recurrent episodes of gastritis, abdominal pain, diarrhoea and vomiting requiring admission and frequent monitoring. Pill burden and loss of workdays caused depression and anxiety. However, there was no disability observed during the duration of treatment. Signs of the infection improved, skin lesions gradually subsided and his bacillary index had dropped by 1·66 log (to 4·0) after 1 year of treatment. To our knowledge, this is the first report of the outcome of second line drug regimen in the management of a rifampicin resistant case. Mono and multi drug resistance has emerged and it requires the expansion of surveillance in country programmes. Though numbers are small, there should be free provision of the alternate drug regimen within the public health system to enable adequate management of such cases. References 1 Hansen’s Disease (Leprosy). Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of High-Consequence Pathogens and Pathology (DHCPP). Archived from the original on 29 May 2019. https://www.cdc.gov/leprosy/index.html. (Accessed 10 February 2017). 2 Suzuki K, Akama T, Kawashima A, Yoshihara A, Yotsu RR, Ishii N. Current status of leprosy: Epidemiology, basic science and clinical perspectives. The J Dermat, 2012; 39(2): 121–129. 3 NLEP Annual Report 2016–17. Available from: http://nlep.nic.in/data.html.