Suspected Artesunate Resistant Malaria in South India.

We report four cases of complicated malaria in Andhra Pradesh-Orissa border between July 2016 and December 2016, with apparent treatment failure with artemisinin drugs, and all showing parasitological clearance after quinine and adjuvant clindamycin therapy. However, one case died due to complications of malaria. We highlight the need for increased monitoring and surveillance to identify artemisinin combination therapy resistance in other parts of India apart from Northeastern states. It is also essential to ensure rationale use of the existing antimalarial drugs.

INTRODUCTION

The emergence and spread of drug-resistant malaria represents a considerable challenge in controlling malaria. The World Health Organization (WHO) recommends use of artemisinin combination therapy (ACT) against Plasmodium falciparum (PF) malaria to ensure high cure rates and prevent development of resistance against artemisinin compounds.[1] However, resistance to artemisinins has emerged in Thai-Cambodian[2] and Thai-Myanmar border.[3] Signs of resistance to the ACT - artesunate sulfadoxine pyrimethamine in PF has been observed in north-eastern states of India.[4] There have been two case reports of artesunate resistance in India, occurring in Kolkata and Mumbai.[56] We describe four cases of suspected artesunate-resistant malaria, of which three survived and one case died. These four cases were encountered over 5-month period, and all were from Andhra Pradesh-Orissa border province.

CASE REPORTS

Case 1

A 13-month-old male child from Koraput district, Orissa, was diagnosed to have malaria with smear positive for PF. He was treated with a 3-day course of oral artesunate-SP. In view of persistent fever and failure of parasite clearance after 3 days, he was administered second course of 3 days oral artesunate-SP. He was referred to our hospital in view of severe anemia and persistence of ring forms of PF in blood smear. He was started on parenteral quinine along with clindamycin and a dose of primaquine was administered. Serial peripheral smears were performed which showed parasitological clearance after 48 h of initiating therapy.

Case 2

An 8-year-old female child from Vizianagaram district, Andhra Pradesh, was admitted with fever for 10 days. PF rapid diagnostic test (RDT) was positive. She received injection artesunate for 3 days and SP was administered on day 2. In view of anemia and persistence of fever, she was referred to our hospital. Her peripheral smear confirmed ring forms of PF. Sickling test was negative. Probable artesunate resistance was suspected. Similar treatment with quinine, clindamycin, and primaquine was given. Smear after 72 h and on 28th day was negative for malarial parasites.

Case 3

A 12-year-old female child hailing from Visakhapatnam district, Andhra Pradesh, was admitted at the referral hospital for fever and icterus. She was started on intravenous (IV) artesunate, clindamycin treatment as RDT was positive for both PF and Plasmodium vivax malaria. She was referred after 3 days of treatment as she developed respiratory distress, hypotension, cola-colored urine, and elevated renal parameters. At admission, her blood smear showed multiple PFand vivax parasites with anemia and thrombocytopenia. Investigations were suggestive of intravascular hemolysis, sepsis with acute kidney injury. Delayed parasite clearance due to occurrence of renal failure was suspected, and hence, she was continued on artesunate. She was also started on quinine along with clindamycin as rescue therapy as we had encountered artesunate-resistant cases previously. Broad-spectrum antibiotics and supportive measures were administered. Her peripheral smear repeated after 48 h showed occasional falciparum ring forms and after 72 h, absent hemoparasites. However, she developed disseminated intravascular coagulation, refractory shock, and acute respiratory distress syndrome and succumbed on 4th day of admission.

Case 4

A 4-year-old female child from Vizianagaram district, Andhra Pradesh, having fever for 5 days was tested positive for PF on smear examination. She was started on IV artesunate as monotherapy. She developed ascites, icterus, severe anemia, and hemoglobinuria requiring multiple blood transfusion. She was referred after 7 days of IV artesunate as she had persistent fever. At admission, her blood smear showed multiple PF. She was started on quinine and clindamycin, along with primaquine. Serial smears were obtained and parasitological clearance was documented after 4 days of therapy.

DISCUSSION

Artemisinin compounds are highly potent, rapidly eliminated drugs and clear parasitemia most rapidly when compared to any other antimalarial. In 2005, the WHO recommended that artemisinin-based combination therapies be used as the first-line treatment for falciparum malaria in all malaria endemic countries. In 2010, India revised its antimalarial policy and recommended ACT for all cases of falciarum malaria.[1]

With widespread use of these drugs, artemisinin resistance has emerged in Cambodia[34] where resistance to previous first-line drugs have emerged. Artemisinin-resistant parasites are spreading from western Cambodia to the Greater Mekong Subregion (GMS) and through India to Africa. Artemisinin resistance has emerged and spread extensively in Southeast Asia,[7] the likely reasons being widespread availability of artemisinin monotherapies, poor quality drugs, unregulated use of antimalarial agents, and unusual genetic structure of parasites. In GMS, high treatment failure rates following treatment with ACT have almost always been observed in areas where there is concomitant resistance to artemisinin and the partner drug. Outside GMS, treatment failure with ACTs has occurred in the absence of artemisinin resistance mainly due to partner drug resistance.[8]

Surrogate measure of artemisinin resistance is slow parasite clearance[4] such as detectable parasitemia by day 3 but is imprecise as parasite clearance depends on several factors such as initial parasite density, host factors including the presence of renal dysfunction, prior splenectomy, and cooccurrence of sickle cell disease.

Resistance to ACT should be suspected if there is no clinical or parasitological response after 72 hours of commencing the treatment and in the absence of vomiting or diarrhoea.[4] Treatment failures with ACT are rare. However, any ACT treatment failure should be treated with quinine plus tetracycline/doxycycline/clindamycin for 7 days[4] and reported to the District Vector Borne Disease Control Officer/State Program Officer/Regional Office for Health and Family Welfare for initiation of therapeutic efficacy studies.

All the four patients belonged to early treatment failure group. The parasitological clearance was achieved by 4 days of quinine with clindamycin in all four cases; however, case 3 died due to complications of malaria. We could not confirm artemisinin resistance in any of these cases due to lack of availability of gene testing in our area.

This report emphasizes the need for increased monitoring and surveillance to identify artemisinin resistance in other parts of India also. There are no new antimalarial drugs which are available to us for several years. Hence, it is essential to ensure rationale use of the few remaining effective drugs such as continued vigil to avoid artemisinin monotherapy, ensure radical cure with primaquine, and documentation of cure by negative smear on day 28.

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Conflicts of interest

There are no conflicts of interest.