Evidence Against Rapid Emergence of Praziquantel Resistance in Schistosoma haematobium, Kenya - Statistical Data Included

Emerging Infectious Diseases, Nov, 2000 by Charles H. King, Eric M. Muchiri, John H. Ouma

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Praziquantel failure on initial treatment in S. mansoni-endemic areas of Senegal suggests primary resistance to praziquantel (16,18) and a high prevalence of resistance genes in the local S. mansoni strain (21,33,34). More recent reports indicate, however, that in this area of Senegal, retreatment after 40 days adequately reduces infection levels and achieves better cure rates (19). The latter results suggest that immature schistosomes, which are known not to be susceptible to praziquantel, are typically present in Senegalese patients at the time of treatment. If the treated patient has been recently exposed to infection ([is less than or equal to] 6 weeks ago) in an area with continuous--rather than seasonal--transmission, apparent treatment failure may be observed when unaffected juvenile worms reach maturity and pass eggs several weeks after praziquantel treatment (14). Annual reinfection rates for S. haematobium may be high in some areas, such as Niger (35), and post-treatment infection detected after a single round of therapy should not be immediately interpreted as evidence of praziquantel resistance.

Nevertheless, animal studies of S. mansoni strains from Senegal indicate they are less sensitive to praziquantel than strains from other parts of the world (21,33,34). There is another explanation for an apparent low-level prevalence of drug resistance that fails to predominate in the parasite population: if a praziquantel-resistance mutation compromises reproductive fitness, the homozygous, fully resistant worm will never predominate. Instead, under the pressure of continued treatment, the resistance gene will achieve a stable-equilibrium share of the worm population, at a level dependent on its lower survival efficiency relative to that of the praziquantel-sensitive genotype (Figure 4c). This situation is analogous to the effect of the sickle cell-hemoglobin gene in human populations exposed to malaria.

Another possible factor likely to be slowing the emergence of praziquantel resistance in Schistosoma is the parasite's obligate diecious sexual reproduction. Unlike drug-resistant bacteria, praziquantel-resistant schistosomes must find a mate of the opposite sex to reproduce, which requires a sufficient density of human infection. In a disease-endemic area where most of the population has been treated, the initial heavy loss of susceptible worms (>80%) may actually reduce mean number of worms sufficiently (i.e., to fewer than one male and one female per host) to prevent most resistant worms from finding suitable mates (29). Worm distribution is highly aggregated in the human population, with most (75%) patients having light infections and a small proportion (approximately 5%) having heavy infections. Heavy infection can result in reduced worm fecundity, slowing the production of eggs and thus the transmission of genes from a resistant worm, even though the chances of mating are enhanced. After treatment, the reduced number of worms in a heavily infected human could increase fecundity, so the net effect of treatment on praziquantel-resistance gene transmission would be difficult to predict. In an age-targeted program such as ours, praziquantel-sensitive parasites would also persist in the untreated adult and infant human subpopulations, slowing the dominance of drug resistance gene(s). This would occur by allowing interbreeding of resistant and susceptible worms in host locations not having the environmental pressure (i.e., praziquantel treatment) that favors the resistance gene.