ANTIMICROBIAL DEVELOPMENT AND DRUG RESISTANCE (A PAKYZ, SECTION EDITORS) Triple Combination Therapy and Drug Cycling—Tangential Strategies for Countering Artemisinin Resistance Bhattacharjee Dipanjan 1 & G. Shivaprakash 1 & O. Balaji 1 Published online: 6 June 2017 # Springer Science+Business Media New York 2017 Abstract Purpose of Review This review attempts to understand the reasons for the successes and failures of the two novel strate- gies that have slowly begun to emerge as potential counters for anti-malarial drug resistance—“Triple Combination Therapy” and “Drug Cycling.” Recent Findings Recent reports have suggested that increas- ing the heterogeneity within the parasite’ s environment, both at an individual and the population level, may help raise the probabilistic barrier of development of resistance in the para- site. The encouraging results following the implementation of a few experimental triple combination therapies like atovaquone – proguanil – artesunate along with the re- emergence of chloroquine sensitive Plasmodium falciparum parasites in the sub-Saharan African nations have re-kindled mankind’ s hope of curbing anti-malarial drug resistance. Summary The addition of a third drug with traits like a medium half-life and benign safety profile is crucial to achieving SERCAP (single encounter radical cure and preventive therapy), the principle of a triple combination therapy. Simultaneously, the plausible reasons behind the re-emergence of chloroquine sensi- tive Plasmodium falciparum malaria in the high transmission regions could be the re-expansion of an existing chloroquine susceptible parasite reservoir and a greater predisposition to- wards the development of polyclonal infections. Another poten- tial reason for this observation could be an impaired deoxyribonucleic acid (DNA) repair mechanisms in the south- east Asian Plasmodium falciparum parasites. These strategies may potentially emerge as the key players in warding off anti- malarial drug resistance in the near future. However, their imple- mentation would be dictated by a host of factors like the epide- miological knowledge, population pharmacokinetics, drug- resistance patterns, cost, availability, and ease of adherence. Keywords Drug resistance . Combination therapy . Environmental heterogeneity . Malaria . Chloroquine renaissance Introduction At the turn of the millennium, barring artemisinin and its de- rivatives, the majority of the anti-malarial drugs had been rendered ineffective in the face of mounting anti-malarial drug resistance. Given the staccato nature of the new drug pipeline, the scenario seemed to worsen further. It is here that that the World Health Organization (WHO) finally came up with the idea of combining antimalarial drugs, which lent itself to the introduction of artemisinin combination therapy (ACT) glob- ally in 2001 [1]. ACT, by introducing two chemically different drugs with completely different sets of mechanisms of action and resistance development within the parasite’ s surround- ings, intended to exploit the parasite’ s innately low potential of undergoing mutations in the face of heterogeneity within its surroundings [2–5]. The dramatic reductions in reported ma- laria associated mortality and parasite prevalence are a testi- mony to its efficacy [6]. But, as history has been witness to it on a multitude of occasions, resistance build-up within the parasite to artemisinin and its derivatives was inevitable, as evidenced by reports of the increased clearance times of Plasmodium This article is part of the Topical Collection on Antimicrobial Development and Drug Resistance * G. Shivaprakash sivag1977@gmail.com 1 Department of Pharmacology, Kasturba Medical College, Manipal Campus, Manipal University, Manipal, Karnataka 576104, India Curr Infect Dis Rep (2017) 19: 25 DOI 10.1007/s11908-017-0579-4