The Potential Impact of Density Dependent Fecundity on the Use of the Faecal Egg Count Reduction Test for Detecting Drug Resistance in Human Hookworms

Current efforts to control human soil-transmitted helminth (STH) infections involve the periodic mass treatment of people, particularly children, in all endemic areas, using benzimidazole and imidothiazole drugs. Given the fact that high levels of resistance have developed to these same drugs in roundworms of livestock, there is a need to monitor drug efficacy in human STHs. The faecal egg count reduction test (FECRT), in which faecal egg output is measured pre- and post-drug treatment, is presently under examination by WHO as a means of detecting the emergence of resistance. We have examined the potential impact of density dependent fecundity on FECRT data. Recent evidence with the canine hookworm indicates that the density dependent egg production phenomenon shows dynamic properties in response to drug treatment. This will impact on measurements of drug efficacy, and hence drug resistance. It is likely that the female worms that survive a FECRT drug treatment in some human cases will respond to the relaxation of density dependent constraints on egg production by increasing their egg output significantly compared to their pre-treatment levels. These cases will therefore underestimate drug efficacy in the FECRT. The degree of underestimation will depend on the ability of the worms within particular hosts to increase their egg output, which will in turn depend on the extent to which their egg output is constrained prior to the drug treatment. As worms within different human cases will likely be present at quite different densities prior to a proposed FECRT, there is potential for the effects of this phenomenon on drug efficacy measurements to vary considerably within any group of potential FECRT candidates. Measurement of relative drug efficacy may be improved by attempting to ensure a consistent degree of underestimation in groups of people involved in separate FECRTs. This may be partly achieved by omission of cases with the heaviest infections from a FECRT, as these cases may have the greatest potential to increase their egg output upon removal of density dependent constraints. The potential impact of worm reproductive biology on the utility of the FECRT as a resistance detection tool highlights the need to develop new drug resistance monitoring methods which examine either direct drug effects on isolated worms with in vitro phenotypic assays, or changes in worm genotypes.Author Summary: Current efforts to control soil-transmitted helminth (STH) infections in humans in endemic countries involve the mass administration of drugs. The use of these same drugs for many years to control livestock nematodes has resulted in the emergence of significant levels of resistance. Hence, there is a need to manage the use of drugs against human STHs in order to reduce the likelihood of resistance developing. An important component of managing drug use will be an ability to detect drug resistance should it emerge. WHO and the World Bank are presently supporting initiatives to develop tools for detecting drug resistance in human STHs. The tool to be assessed in the short term is the faecal egg count reduction test (FECRT). We have examined literature on an aspect of worm reproductive biology with potential to impact significantly on the FECRT. We describe the potential effects that density dependent egg production by female hookworms may have on interpretation of FECRT data. This study highlights a potential weakness in reliance on the FECRT for assessment of drug resistance in human hookworms, hence emphasising the need to develop more advanced worm bioassay and molecular methods.