Date Published: October 1, 2008
Publisher: Public Library of Science
Author(s): Andrew C. Kotze, Steven R. Kopp, Jeffrey Bethony
Abstract: 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.
Partial Text: Soil transmitted helminth (STH) infections (Ascaris lumbricoides, Trichuris trichiura, and the hookworms Necator americanus and Ancylostoma duodenale) contribute significantly to morbidity in humans in endemic countries. The major means of controlling these infections is by the periodic administration of anthelmintic drugs . Given the lessons from livestock, where resistance to anthelmintics is widespread , the potential for anthelmintic resistance in human parasites has been recognized . There are a number of differences in drug use patterns between the human and livestock fields which may aid in reducing the rate of resistance development in the former ,, however, the potential for resistance in human parasites is a significant issue .
Figure 1 shows an analysis of the egg output and adult worm numbers for the 4 dogs before and after treatment with pyrantel using the data of Kopp et al. . Dogs 1 and 2 were infected with worms from an isolate with a high level of resistance to the drug, while dogs 3 and 4 were infected with an isolate which showed only a low level of resistance. All four dogs had similar worm burdens before the drug treatment, and all showed very similar rates of egg production per adult worm. Following drug treatment, all dogs showed an increase in their egg output per worm alongside reductions in worm numbers. The change in worm reproductive output was most dramatic for dogs 3 and 4 which increased egg output per worm by 4.2- and 3.6-fold, respectively.
The study by Kopp et al.  suggests that the reproductive behaviour of adult hookworms before and after a drug treatment will likely be far from static. The significant increase in egg production by the worms following drug treatment is most likely a consequence of the relaxation of density dependent constraints on their egg output. The degree to which egg output increased coincided with the extent to which the worm populations were reduced by the drug treatment in the dogs harbouring the two worm isolates showing different levels of resistance to the drug. Given the widespread occurrence of density dependent worm fecundity constraints in human STHs – it is most likely that the phenomenon noted here with the canine hookworm will apply more widely to the human STHs.