Evidence Against Rapid Emergence of Praziquantel Resistance in Schistosoma haematobium, Kenya

Charles H. King, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, USA; Eric M. Muchiri, John H. Ouma, Ministry of Health, Nairobi, Kenya

Disclosures

Emerging Infectious Diseases. 2000;6(6) 

In This Article

Materials and Methods

The overall goal of the community study was to treat urinary schistosomiasis in schoolchildren (initial N = 3,196) in a nine-village area in Kwale District, Coast Province, Kenya. After oral informed consent was obtained under a human investigations protocol approved by the institutional review boards of University Hospitals of Cleveland and the Ministry of Health, Kenya, case-finding was performed by school-based and follow-up village surveys. Details of the protocols have been published[25,26,27]. In 1984, the initial treatment year, S. haematobium-infected children were randomly assigned to groups for treatment with either praziquantel (Biltricide, Bayer, Leverkusen, Germany), 40 mg/kg once a year, or metrifonate (Bilarcil, Bayer), 10 mg/kg three times a year. In years 2 and 3, the initial treatment was repeated, independent of parasitologic findings. New entrants to the study were assigned randomly to either the praziquantel or metrifonate treatment groups, according to the original 1984 protocol. In 1987, half the 1984 cohort, treated either with praziquantel or with metrifonate, was randomized to receive a single dose of metrifonate, 10 mg/kg, as a "consolidation" treatment. After a 2-year hiatus, annual treatment was resumed in 1989 to 1991; during this period, only children in whose urine samples eggs were identified (egg-positive children) were treated with praziquantel alone.

Infection status was determined by Nuclepore (Whatman, Kent, UK) filtration of two 10-mL samples from stirred midday urine specimens. Infection-associated disease was determined by physical examination, dipstick urine examination for hematuria and proteinuria, and ultrasound examination of the kidneys and bladder[25]. Clinical and parasitologic testing was performed each year. Results were coded and entered for analysis in databases at Case Western Reserve University and the Kenyan Ministry of Health.

Results of annual treatments were scored as "cure" for patients whose status changed from egg-positive to egg-negative, "noncure" for those whose status remained egg-positive, and "infected or reinfected" for those whose status changed from egg-negative to egg-positive between yearly examinations. Because of the skewed distribution of egg counts in the infected population, the effects of treatment on average intensity of infection were assessed by determining the change in geometric mean egg count between examinations. Differences between outcome rates were assessed by the chi-square test with Yates' correction or Fisher's exact test.

The potential for development of praziquantel resistance in the study population was first estimated by the Hardy-Weinberg equilibrium analysis[28]. We then used a deterministic, simultaneous differential equation model of helminth resistance (Appendix,[29]). This more advanced model takes into account the skewed (negative binomial) distribution of number of worms in human populations, the obligate sexual reproduction of the parasites, and a possible decrease in fecundity as a result of parasite crowding in heavily infected humans. The model provides estimates of average level of infection in the study population, as well as the prevalence and density of resistant worms over time. Results are shown as three-dimensional graphs of mean numbers of worms over time (20 years), as a function of annual community drug use (p), and the reproductive fitness of resistant parasites. Treatment efficacy and aggregation constants for infection (k) were derived from our study area.

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