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

Mathematical Modeling

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.

Results

Yearly Efficacy of Praziquantel

During 1984 to 1992, we observed substantial year-to-year variations in cure rates (conversion from egg-positive to egg-negative status on urine Nuclepore filtration examination) for both praziquantel and metrifonate (Table 1). The response to metrifonate treatment declined each year, from 79% in 1984 to 47% in 1987 (p [is less than] 0.001, Figure 1); in contrast, we observed no consistent downward trend in response to praziquantel treatment, despite repeated use of the drug in many patients (Figures 1 and 2). However, the response to praziquantel varied significantly from year to year (p [is less than] 0.001), from a cure rate of 96% in 1990 (year 7 of the project) to a cure rate of 65% in 1986 (year 3, p [is less than] 0.001). This level of efficacy was within the previous range of S. haematobium cure rates, both in Coast Province and elsewhere in Africa (Table 2). In suppression of infection intensity, the praziquantel-mediated reduction of mean S. haematobium egg counts was consistently [is greater than or equal to] 83% for all years of observation.

[Figures 1-2 ILLUSTRATION OMITTED]

Table 1. Effectiveness of praziquantel in eliminating Schistosoma haematobium infection, Msambweni, Coast Province, Kenya, 1984-1992

                               Prevalence of infection
                                  at 12 months after
                                      treatment
                                (interval change in
                               geometric mean of (egg
                                count   1) for group)

                               Year treated with PZQ or
                                     metrifonate

Patient's
infection and
treatment status                 1984          1985

Egg-positive urine,               17%           12%
Given PZQ, never              (97 to 1.5)   (33 to 1.5)
previously treated              n = 981       n = 51

Egg-positive urine,               --            13%
Given PZQ, had [is greater                  (10 to 1.5)
than or equal to 1]                           n = 111
PZQ treatments

All egg-positive,                 17%           13%
PZQ-treated patients          (97 to 1.5)   (15 to 1.5)
                                n = 981       n = 162

Infection rate                    15%           9%
(egg - to egg   conversion)

All patients, treated and         18%           12%
untreated                      n = 3,196     n = 2,498

                               Prevalence of infection at 12 months
                                          after treatment
                               (interval change in geometric mean
                                  of (egg count   1) for group)

                               Year treated with PZQ or metrifonate

Patient's
infection and
treatment status                 1986         1987         1989

Egg-positive urine,               34%          --           15%
Given PZQ, never              (29 to 3.7)               (18 to 1.5)
previously treated              n = 82                    n = 352

Egg-positive urine,               38%          --           10%
Given PZQ, had [is greater    (16 to 2.6)               (19 to 1.1)
than or equal to 1]             n = 47                    n = 68
PZQ treatments

All egg-positive,                 35%          --           14%
PZQ-treated patients          (24 to 3.3)               (19 to 1.4)
                                n = 129                   n = 420

Infection rate                    11%          11%          13%
(egg - to egg   conversion)

All patients, treated and         14%          19%          14%
untreated                      n = 2,372    n = 1,968    n = 1,398

                               Prevalence of infection
                                  at 12 months after
                                      treatment
                                (interval change in
                               geometric mean of (egg
                                count   1) for group)

                              Year treated with PZQ or
                                      metrifonate

Patient's
infection and
treatment status                 1990          1991

Egg-positive urine,               4%            35%
Given PZQ, never              (22 to 1.1)    (24 to 4)
previously treated              n = 292       n = 274

Egg-positive urine,               29%           2%
Given PZQ, had [is greater    (13 to 2.8)   (14 to 1.0)
than or equal to 1]             n = 64        n = 73
PZQ treatments

All egg-positive,                 4%            34%
PZQ-treated patients          (20 to 1.1)   (22 to 3.8)
                                n = 365       n = 338

Infection rate                    10%           21%
(egg - to egg   conversion)

All patients, treated and         13%           24%
untreated                      n = 2,579     n = 1,938