Drug resistance is a well-known and key phenomenon that has impacted the effectiveness of medications such as some antibiotics and antihelminthics for treating poultry, livestock, and humans (Mohamed et al., 2022; Malik et al., 2022; Qamar and Alkheraije, 2023; Li et al., 2023). Resistance is defined as a significant increase in the frequency and unresponsiveness of individuals in a susceptible population to a compound (Prichard et al., 1980 ; Coles and Kinoti, 1997; Greenberg, 2013). Unlike tolerance, resistance is heritable and due to a population’s previous drug exposure (Prichard et al., 1980; Greenberg, 2013).

Emerging drug resistance against the broad-spectrum antihelminthic drug praziquantel (PZQ) ( Figure 1 ) has been a growing public health concern (Berger et al., 2021; Cotton and Doyle, 2022). There has been much discussion as to whether PZQ resistance is imminent or widespread (Danso-Appiah and De Vlas, 2002; Botros et al., 2005; Melman et al., 2009; Crellen et al., 2016; Fukushige et al., 2021). Following its discovery in the 1970s by the pharmaceutical companies Merck and Bayer, PZQ has become the drug of choice to treat schistosomiasis, the second most debilitating tropical disease after malaria (Abdel Aziz et al., 2022). The causative schistosomes, or blood flukes, are also responsible for approximately 200,000 annual deaths and affect over 250 million people globally, making them the most important helminthic infectious agents (World Health Organization, 2021).

Schistosomiasis is caused by three main species: Schistosoma mansoni is the most widespread and is the only species known to exist in the Western Hemisphere, S. haematobium is found in Africa and the Middle East, and S. japonicum is found in regions of Southeast Asia (World Health Organization, 2023a). Schistosomes have a complex life cycle that involves two hosts—a mammalian definitive host and a freshwater snail from the genus Biomphalaria as an intermediate host. Schistosoma eggs are released from either the feces or urine of an infected individual, depending on the species of schistosome (Centers for Disease Control and Prevention, 2024). The larvae, called miracidia, infect the suitable snail host for two generations to produce free-swimming larval cercariae. These cercariae then shed their tails, penetrate the skin of the mammalian host, and become schistosomulae (Centers for Disease Control and Prevention, 2024). Following infection, the schistosomulae mature and undergo sexual reproduction. The adult females lay 300 – 3,000 eggs daily until the end of the worm’s lifespan—about three to five years (Cahill, 2011). Some of the eggs build up in the host’s tissue, causing inflammation and a host immune response that results in the disease’s morbidities (Burke et al., 2009; Colley et al., 2014). Other eggs are passed through the intestinal or bladder mucosa and are expelled in the feces or urine, completing the cycle (Cahill, 2011).

In endemic areas, MDA of PZQ is essential for schistosomiasis control as a form of preventative chemotherapy due to the drug’s affordability, availability, minimal side effects, and effectiveness against human infections of trematodes and cestodes (Cioli et al., 2014; Crellen et al., 2016; Nogueira et al., 2022; Villamizar-Monsalve et al., 2024). This extensive use has raised concerns about emerging drug resistance, which may develop following prolonged and repeated application, such as in MDA (Coles and Kinoti, 1997; Geerts et al., 1997).

Laboratory-induced resistance to PZQ have been successful, and there have been multiple reports of reduced PZQ efficacy in the field following continuous drug exposure (Ismail et al., 1994; Fallon, 1998; Ismail et al., 1999; Melman et al., 2009; Couto et al., 2011; Li et al., 2011; Lotfy et al., 2015; Crellen et al., 2016). However, it has also been observed that reduced PZQ sensitivity characteristics have dissipated after several generations, even in the presence of drug pressure (Botros et al., 2005; Melman et al., 2009). In addition, multiple areas have endured several years of PZQ treatment, and the efficacy rates remain high (Seto et al., 2011; Mduluza et al., 2020; Tetteh-Quarcoo et al., 2020).

This review draws together previous and recent literature about PZQ efficacy across the three main schistosome species in the context of emerging PZQ resistance. Brief updates on the PZQ mechanism of action, proposed mechanism of resistance, impacts of MDA on schistosome genetic diversity, PZQ alternatives, and schistosomiasis vaccine development are also covered.

PZQ treatment efficacy is commonly measured by the egg reduction rate (ERR), which compares the pre-treatment and post-treatment number of eggs shed in the urine or feces. Another prevalent method is the cure rate (CR), which compares the number of infected individuals who become negative for schistosomiasis post-treatment (Fukushige et al., 2021).

Due to its effectiveness as an antiparasitic, PZQ is on the WHO’s list of essential medicines, and in 2017, approximately 100 million individuals received PZQ treatment for schistosomiasis (Park and Marchant, 2020). However, PZQ is less effective against juvenile worms or schistosomulae (Pica-Mattoccia and Cioli, 2004; Villamizar-Monsalve et al., 2024). It is thought that ATP-binding cassette (ABC) transporters, which can export toxins, play a role in this protection, as juvenile worms have about two and a half times the number of ABC transporters as the adult form (Kasinathan et al., 2010). In addition, PZQ must be administered in higher than recommended doses to efficiently kill schistosome eggs (Richards et al., 1989). Therefore, a follow-up dose 4 to 6 weeks after the initial dose may be necessary to prevent reinfection after any juvenile worms have matured (Gryseels et al., 2006).

Several laboratory studies have successfully induced PZQ resistance in schistosomes, particularly S. mansoni. In 1994, an in vitro study subjected a population of S. mansoni-infected mice to increasing PZQ drug pressure. By the seventh generation, 93% of the resistant schistosomes survived three PZQ doses of 300 mg/kg, which killed 89% of the control group (Fallon, 1998; Vale et al., 2017). Another study showed that resistance to the therapeutic dose of PZQ can be induced in following generations of S. mansoni in mice through successive subcurative doses (Ismail et al., 1994). A simpler and less expensive technique was later developed to induce PZQ resistance in S. mansoni through successively treating infected Biomphalaria glabrata snails with 100 mg/kg of PZQ (Couto et al., 2011). More recently, a study in 2015 induced resistance in an Egyptian strain of S. mansoni through treating multiple subcurative doses of Biomphalaria alexandrina snails (Lotfy et al., 2015). Regarding S. japonicum, an unsuccessful attempt was made in 1990 to experimentally induce resistance using drug pressure through infected mice (Yue et al., 1990). Induction of resistance in S. japonicum in the three life stages—adult, cercaria, and miracidia— was later achieved (Li et al., 2011). These studies demonstrate that schistosomes are capable of developing resistance under PZQ drug pressure of subcurative doses. There is currently no knowledge of laboratory-induced resistance to PZQ in S. haematobium.

The first significant instance of reported PZQ resistance on the field occurred in 1994 during an S. mansoni infection outbreak in Senegal (Stelma et al., 1995). The standard single-dose treatment of 40 mg/kg resulted in alarmingly low cure rates of 18-36% rather than the usual 60-90% (Doenhoff et al., 2008; Stelma et al., 1995). However, a 20 mg/kg dose of oxamniquine, an alternative anthelminthic drug, showed a typical cure rate (Stelma et al., 1997). It has been suggested that the low cure rate of PZQ was due to an intense initial infection, as the average egg counts were notably high in patients (Stelma et al., 1995; Utzinger et al., 2000; Danso-Appiah and De Vlas, 2002). PZQ is less effective against juvenile schistosomes and eggs, which may have survived the initial treatment and matured into adults after treatment (Richards et al., 1989; Danso-Appiah and De Vlas, 2002; Pica-Mattoccia and Cioli, 2004).

Another early report of apparent S. mansoni field resistance to PZQ was in villages in the Nile Delta region of Egypt (Ismail et al., 1996). All patients were treated with the standard dose of 40 mg/kg followed by a second 40 mg/kg dose or a third 60 mg/kg dose if necessary (Ismail et al., 1996). Although the PZQ cure rate was 98.4%, eggs isolated from the uncured patients generated PZQ infections in mice that were 3-5 times less sensitive to PZQ, raising concerns about resistance to PZQ in the parent worms (Ismail et al., 1996, 1999). When treated with PZQ in vitro, the isolates from the uncured patients showed decreased muscle contraction, decreased tegumental disruption, and decreased calcium influx, all of which are well-characterized PZQ actions on schistosomes (Ismail et al., 1999; William et al., 2001; William and Botros, 2004; Eyoh et al., 2019; Nogueira et al., 2022). Although these results were concerning, a study conducted in the same villages using the same dosing regimen ten years after the initial studies revealed no resistance to PZQ despite a decade of continued and broad use of the drug. It is worth noting that the infections initially present for the follow-up study were generally light. In addition, detecting a change from the previous 98.4% cure rate was not possible due to the sample size (Botros et al., 2005).

Reduced sensitivity to PZQ was later reported in Kenya among isolates of S. mansoni gathered from patients who had been previously treated with PZQ but whose occupations continuously exposed them to infection. The study also analyzed an isolate from a patient who had been treated with PZQ 18 times and never fully cured (KCW). This isolate was significantly less susceptible to PZQ both in vivo and in vitro. However, one KCW sub-isolate retained its resistant characteristics through 6 generations without any PZQ treatment. Meanwhile, another KCW sub-isolate returned to PZQ sensitivity after retesting for 8 generations. Such an occurrence may inform the results of the Nile Delta villages studies, suggesting that reduced PZQ susceptibility is not a stable trait in schistosomes and may require a biological cost (Botros et al., 2005; Melman et al., 2009; Greenberg, 2013).

A repeated cross-sectional study in Uganda found statistically reduced PZQ efficacy against S. mansoni among children from schools that had received 8 or 9 rounds of mass drug administration (MDA) than children from schools that had received 5 rounds or 1 round. Interestingly, a whole-genome sequencing study of the miracidia collected revealed that genomic diversity remained varied and unstructured despite long-term PZQ use. Therefore, the previously reported low PZQ efficacy may have been due to factors other than resistance (Crellen et al., 2016; Berger et al., 2021).

Concern for PZQ resistance in wild-type S. japonicum had received discussion due to its heavy use in endemic areas of China (Yu et al., 2001; Wu et al., 2011; Wang et al., 2012). Field studies have tested the efficacy of PZQ to S. japonicum in areas of varying endemicities throughout China using a single oral dose of 40 mg/kg (Liang et al., 2001; Wang et al., 2012). The results suggest that despite thirty years of heavy and expanded chemotherapy, sensitivity to PZQ in S. japonicum has not significantly decreased in China (Liang et al., 2001; Wang et al., 2012). In another study, the efficacy of PZQ against S. japonicum was compared between an area with repeated PZQ chemotherapy and a newly identified endemic area. The results indicated that the efficacy between the two areas were not significantly different (Yu et al., 2001). A cross-sectional study across 33 villages in Sichuan Province was organized to evaluate PZQ efficacy against S. japonicum (Seto et al., 2011). Out of 185 cases, only one remained uncured after receiving two doses of 40 mg/kg of PZQ, indicating that PZQ remains an effective treatment for S. japnonicum in China (Seto et al., 2011).

Regarding S. haebatobium, a recent study in Ghana detected no sign of its resistance to PZQ and attributed the more persistent schistosomiasis cases to reinfection (Tetteh-Quarcoo et al., 2020). Occasionally, there have been isolated reports of failed standard treatment of S. haematobium in travelers returning from endemic areas (Herwaldt et al., 1995; da Silva et al., 2005; Alonso et al., 2006). Various possible explanations exist for these instances, including the presence of a concurrent infection and the therapeutic failure of a single 40 mg/kg dose of PZQ (Herwaldt et al., 1995; da Silva et al., 2005). Since PZQ acts in synergy with the host immune system, it has been hypothesized that some individuals originating from non-endemic areas may lack the necessary immunological factor to overcome the infection (Wu et al., 2011; Vale et al., 2017).

A meta-analysis and systematic review article in 2023 have reported that PZQ efficacy has remained high, and there is no consistent evidence for the emergence of PZQ resistance in schistosomes (Fukushige et al., 2021; Aboagye and Addison, 2023). However, care should be taken to attempt to prevent schistosome resistance on the field, such as avoiding treatment with subcurative doses of PZQ, as this has been shown to experimentally induce resistance in S. mansoni and S. japonicum (Fallon, 1998; Li et al., 2011; Wang et al., 2012). Focus should also be placed on alternative methods of schistosomiasis control, such as snail control, clean tap water, health education, and building latrines (Wang et al., 2012; Villamizar-Monsalve et al., 2024). In addition, drug quality should continue to be monitored to ensure the effectiveness of praziquantel and detect further cases of suspected resistance (Wang et al., 2012; World Health Organization, 2022).