High-throughput analysis of antimalarial susceptibility data by the WorldWide Antimalarial Resistance Network (WWARN) in vitro analysis and reporting tool.

Assessment of in vitro susceptibility is a fundamental component of antimalarial surveillance studies, but wide variations in the measurement of parasite growth and the calculation of inhibitory constants make comparisons of data from different laboratories difficult. Here we describe a Web-based, high-throughput in vitro analysis and reporting tool (IVART) generating inhibitory constants for large data sets. Fourteen primary data sets examining laboratory-determined susceptibility to artemisinin derivatives and artemisinin combination therapy partner drugs were collated from 11 laboratories. Drug concentrations associated with half-maximal inhibition of growth (IC50s) were determined by a modified sigmoid Emax model-fitting algorithm, allowing standardized analysis of 7,350 concentration-inhibition assays involving 1,592 isolates. Examination of concentration-inhibition data revealed evidence of apparent paradoxical growth at high concentrations of nonartemisinin drugs, supporting amendment of the method for calculating the maximal drug effect in each assay. Criteria for defining more-reliable IC50s based on estimated confidence intervals and growth ratios improved correlation coefficients for the drug pairs mefloquine-quinine and chloroquine-desethylamodiaquine in 9 of 11 and 8 of 8 data sets, respectively. Further analysis showed that maximal drug inhibition was higher for artemisinins than for other drugs, particularly in ELISA (enzyme-linked immunosorbent assay)-based assays, a finding consistent with the earlier onset of action of these drugs in the parasite life cycle. This is the first high-throughput analytical approach to apply consistent constraints and reliability criteria to large, diverse antimalarial susceptibility data sets. The data also illustrate the distinct biological properties of artemisinins and underline the need to apply more sensitive approaches to assessing in vitro susceptibility to these drugs.

Mapping the aetiology of non-malarial febrile illness in Southeast Asia through a systematic review--terra incognita impairing treatment policies.

BACKGROUND: An increasing use of point of care diagnostic tests that exclude malaria, coupled with a declining malaria burden in many endemic countries, is highlighting the lack of ability of many health systems to manage other causes of febrile disease. A lack of knowledge of distribution of these pathogens, and a lack of screening and point-of-care diagnostics to identify them, prevents effective management of these generally treatable contributors to disease burden. While prospective data collection is vital, an untapped body of knowledge already exists in the published health literature. METHODS: Focusing on the Mekong region of Southeast Asia, published data from 1986 to 2011 was screened to for frequency of isolation of pathogens implicated in aetiology of non-malarial febrile illness. Eligibility criteria included English-language peer-reviewed studies recording major pathogens for which specific management is likely to be warranted. Of 1,252 identified papers, 146 met inclusion criteria and were analyzed and data mapped. RESULTS: Data tended to be clustered around specific areas where research institutions operate, and where resources to conduct studies are greater. The most frequently reported pathogen was dengue virus (n = 70), followed by Orientia tsutsugamushi and Rickettsia species (scrub typhus/murine typhus/spotted fever group n = 58), Leptospira spp. (n = 35), Salmonella enterica serovar Typhi and Paratyphi (enteric fever n = 24), Burkholderia pseudomallei (melioidosis n = 14), and Japanese encephalitis virus (n = 18). Wide tracts with very little published data on aetiology of fever are apparent. DISCUSSION AND CONCLUSIONS: This mapping demonstrates a very heterogeneous distribution of information on the causes of fever in the Mekong countries. Further directed data collection to address gaps in the evidence-base, and expansion to a global database of pathogen distribution, is readily achievable, and would help define wider priorities for research and development to improve syndromic management of fever, prioritize diagnostic development, and guide empirical therapy.