Effectiveness of Various Anthelmintics in the Treatment of Moniliformiasis in Experimentally Infected Wistar Rats

Abstract

Humans occasionally become infected with acanthocephalans, particularly Moniliformis moniliformis. Although several anthelmintics have been used, no controlled studies have been conducted to assess the efficacy of common anthelmintics in the treatment of moniliformiasis. The effectiveness of pyrantel pamoate, ivermectin, praziquantel, niclosamide, thiabendazole, and mebendazole was evaluated in the treatment of moniliformiasis in laboratory-infected female Wistar rats. Pyrantel pamoate and ivermectin were wholly unsuccessful in the treatment of moniliformiasis. A single dose of thiabendazole lead to a 40% reduction and two doses lead to a 57% reduction of worm burden after 2 weeks. The most effective drug in the treatment of moniliformiasis in rats was mebendazole, for which two doses resulted in a 69% reduction in worm burden after 2 weeks; however, 50% of the rats receiving the treatment died within 2 weeks after first administration of the drug. Two surviving rats that had been treated with mebendazole exhibited evidence of hepatic dysfunction characterized by extremely elevated levels of alkaline phosphatase in conjuction with depressed serum albumin levels. It is hypothesized that Mo. moniliformis may metabolize the drug and release a metabolite that is highly toxic to the host. On the basis of these data, thiabendazole is recommended as the drug of choice for the treatment of human acanthocephaliasis until more extensive testing can be conducted.

Introduction

H umans occasionally become infected with acanthocephalans (Beck 1959, Pradatsundarasar and Pechranond 1965, Sahba et al. 1970, Moayedi et al. 1971, Goldsmid et al. 1974, Kliks et al. 1974, Al-Rawas et al. 1977, Dingley and Beaver 1985, Counselman et al. 1989, Radomyos et al. 1989, Prociv et al. 1990, Mao 1991, Ikeh et al. 1992, Anosike et al. 2000, Vienn et al. 2000, Sahar et al. 2006, Berenji et al. 2007, Salehabadi et al. 2008). Seven species of acanthocephalans have been documented from humans (Schmidt 1971), but, by far, the most common are Moniliformis moniliformis and Macracanthorhynchus spp.

Adults of Mo. moniliformis are normally found in the small intestine of rats. Eggs are passed in the feces. Cockroaches serve as intermediate host and become infected by ingesting eggs in rat feces. Cystacanths are the infective stage to the definitive host and may be found in the roach hemocoel after 6 weeks (Moore 1946). Representatives of the genus Macracanthorhynchus exhibit a similar life cycle. Adult Macracanthorhynchus hirudinaceous occur in swine (Pradatsundarasar and Pechranond 1965, Kliks et al. 1974, Radomyos et al. 1989, Prociv et al. 1990, Mao 1991) and Macracanthorhynchus ingens occurs in raccoons (Dingley and Beaver 1985, Vienn et al. 2000). Both occasionally infect humans. Each uses various beetles as intermediate hosts. Humans may become infected with acanthocephalans by ingesting the cystacanth in an infected intermediate host. Most human infections occur in infants and toddlers, although infection of adults does occur.

Of 27 case reports of moniliformiasis presented in the literature (Grassi and Calandruccio 1888, Beck 1959, Sahba et al. 1970, Moayedi et al. 1971, Goldsmid et al. 1974, Al-Rawas et al. 1977, Counselman et al. 1989, Prociv et al. 1990, Anosike et al. 2000), 33% were asymptomatic. When present, the most common symptoms were mild to severe abdominal pain (39%), diarrhea (22%), tinnitus/dizziness (22%), and anorexia (17%). Other clinical manifestations noted in 11% of patients were mild fever, abdominal distension, physical retardation, and nausea and vomiting (Richardson 2003). Too few case reports of infection with Macracanthorhynchus spp. exist to provide a summary of symptoms; however, existing information (Pradatsundarasar and Pechranond 1965, Kliks, et al. 1974, Dingley and Beaver 1985, Radomyos et al. 1989, Vienn et al. 2000) suggests symptomology similar to that evoked by Mo. moniliformis (Richardson 2003). Diagnosis is made by observation of worms or eggs in stools (Richardson 2003).

Several anthelmintics have been used in the treatment of acanthocephalan infection, including mebendazole (Goldsmid et al. 1974, Counselman et al. 1989, Prociv et al. 1990, Sahar et al. 2006), thiabendazole (Moayedi et al. 1971), pyrantel pamoate (Goldsmid et al. 1974, Counselman et al. 1989, Prociv et al. 1990), ivermectin (Anosike 2000), niclosamide (Sahba et al. 1970, Prociv et al. 1990, Ikeh et al. 1992), levamisole (Berenji et al. 2007), piperazine citrate (Salehabadi et al. 2008), and Telmex (Sahba et al. 1970). All information regarding putative successful and unsuccessful treatment is anecdotal. No controlled studies have been conducted to assess the effectiveness of commonly used anthelmintics for the treatment of acanthocephalan infection.

The purpose of this study was to assess the effectiveness of pyrantel pamoate, ivermectin, praziquantel, niclosamide, thiabendazole, and mebendazole in the treatment of laboratory rats experimentally infected with Mo. moniliformis.

Materials and Methods

Three trials were conducted to assess the efficacy of various drugs for the treatment of moniliformiasis. In each instance, female Wistar rats (24–28 days old) were each infected with 20 Mo. moniliformis cystacanths obtained from laboratory-infected cockroaches (Periplaneta americana). The cockroaches were dissected and cystacanths were pooled and administered to rats with an eyedropper. At 6 weeks postinfection (PI), infection of each rat was confirmed by observation of eggs in feces in a fecal smear.

Trial I

Thirty-five rats were divided into seven groups of five rats each. Groups I and II were designated control groups. Rats in groups III–VII were each treated with a single dose of a different anthelmintic at week 6 PI. Proper rat dosages for each anthelmintic was determined by reference to Hillyer and Quesenberry (1996) and/or Harkness and Wagner (1995). Average rat weight was determined to be ∼250 g; thus, dosages were calculated for 250 g. All drugs were administered in suspension by gavage. Rats of control group I were given 250 μL of water by gavage. No procedure was performed on rats of control group II. Rats of groups III–VII were treated as follows:

Rats in Group III were each given 250 μL of a 50 mg/mL aqueous suspension of pyrantel pamoate for a dosage of 50 mg/kg.

Rats in Group IV were each given 200 μL of a 50 μg/μL aqueous suspension of ivermectin for a dosage of 400 μg/kg.

Rats in Group V were each given 250 μL of an 11.4 mg/mL suspension of praziquantel in glycerin for a dosage of 11.4 mg/kg.

Rats in Group VI were each given 250 μL of a 100 mg/mL suspension of niclosamide in glycerin for a dosage of 100 mg/kg.

Rats in Group VII were each given 250 μL of a 200 mg/mL suspension of thiabendazole in glycerin for a dosage of 200 mg/kg.

Four days after treatment, all rats were killed by carbon dioxide narcosis, small intestines were removed and longitudinally dissected, and the worm burden for each rat was determined. Effect of gavaging on worm burden was examined by comparing mean worm intensities between Control Group I and Control Group II using a two-tailed Student's t-test. The effectiveness of each anthelmintic in reducing worm burden was assessed by comparing the mean worm intensity for each group to that of the control group(s) using a two-tailed Student's t-test. Significant differences assume p ≤ 0.05.

Trail II

Thirty-six rats were divided into four groups. Group I consisted of 10 rats designated as a control group. Group II–IV were treated as follows.

Group II consisted of 10 rats that were each given 250 μL of a 100 mg/mL aqueous suspension of pyrantel pamoate for a dosage of 100 mg/kg (twice the normal dosage) at weeks 6 and 7 PI.

Group III consisted of six rats that were each given an intramuscular injection of ivermectin at 800 μg/kg (twice the normal dosage) at weeks 6 and 7 PI.

Group IV consisted of 10 rats that were each given 250 μL of a 200 mg/mL suspension of thiabendazole in glycerin for the normal dosage of 200 mg/kg at weeks 6 and 7 PI.

At week 8 PI, all rats were killed by carbon dioxide narcosis, small intestines were removed and longitudinally dissected, and the worm burden for each rat was determined. The effectiveness of each anthelmintic in reducing worm burden was assessed by comparing the mean worm intensity for each group to that of the control group using a two-tailed Student's t-test. Significant differences assume p ≤ 0.05.

Trial III

Twenty-four rats were divided into two groups of 12 each. Group I was designated a control group. Rats in Group II were each given 250 μL of a 50 mg/mL suspension of mebendazole in glycerin for the normal dosage of 50 mg/kg at weeks 6 and 7 PI. At week 8 PI, all rats were killed by carbon dioxide narcosis, small intestines were removed and longitudinally dissected, and the worm burden for each rat was determined. Rats in group II that died between weeks 6 and 8 PI were necropsied at the time of death and their worm burden was determined. The effectiveness of mebendazole in reducing worm burden was assessed by comparing the mean worm intensity of rats in group II to those of the control group using a two-tailed Student's t-test. Significant differences assume p ≤ 0.05.

When necropsied at 8 weeks PI, blood was collected from representative rats in each group by cardiac puncture and placed into a serum separator collection tube. After 30 min, the samples were centrifuged at ∼1000 g for 20 min (Aiello 1998). Sera were immediately shipped to Antech Diagnostics (Middletown, CT) for determination of blood chemistry profiles. In addition to blood samples from representative rats in groups I and II, samples were taken from female Wistar rats of the same age that were not infected with Mo. moniliformis that were being utilized in a separate investigation. The following parameters were examined in the hematological analysis: glucose, urea nitrogen, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, alanine aminotransferase a.k.a. serum glutamic-pyruvic transaminase, aspartate transaminase a.k.a. serum glutamic-oxaloacetate transaminase, cholesterol, calcium, phosphorous, sodium, potassium, chloride, albumin/globulin ratio, blood urea nitrogen/creatinine ratio, globulin, and creatine phosphokinase.

Results

Trial I

All rats were infected with Mo. moniliformis after treatment. No significant difference was detected in mean worm intensity between the two control groups; thus, it was concluded that gavaging had no effect on worm burden. The control groups were combined for subsequent comparisons to each of the experimental groups. The mean number of worms for the combined control group (±standard error [SE]) was 11.7 (±1.3). No significant differences were detected in the mean worm intensities between any experimental group and that of the control group (combined groups I and II). Data are summarized in Table 1.

Table 1.

Summary of Results of Trial I

Treatment	Mean intensity (±SE) of Moniliformis moniliformis {range}	t versus control	p-Value
Control	11.7 (±1.3) {3–17}	—	—
Pyrantel Pamoate 50 mg/kg once	10.8 (±1.7) {7–17}	0.404	0.69
Ivermectin 400 μg/kg once	14.2 (±3.0) {4–20}	0.902	0.38
Praziquantel 11.4 mg/kg once	12.2 (±2.4) {3–17}	0.200	0.84
Niclosamide 100 mg/kg once	8.0 (±1.7) {3–12}	1.680	0.12
Thiabendazole 200 mg/kg once	7.0 (±1.9) {1–12}	2.040	0.06

SE, standard error.

Although no significant reduction in worm burden was detected within a 95% confidence interval, the mean worm burden for rats treated with thiabendazole was 40% lower than that of the control group (Table 1) with a t-value of 2.040 (p < 0.06). Further, it was qualitatively observed that worms from the rats treated with thiabendazole were not as robust as worms from other rats in Trial I.

Trial II

The mean number of worms in the control group (±SE) was 14.8 (±1.3). No significant difference was detected between the mean intensity of the control group, group I, with that of group II or III. Mean worm intensity (±SE) of rats in Group IV was 6.3 (±1.4), significantly lower than that of the control group (t = 4.627; p < 0.001). Data are summarized in Table 2.

Table 2.

Summary of Results of Trial II

Treatment	Mean intensity (±SE) of Mo. moniliformis {range}	t versus control	p-Value
Control	14.8 (±1.3) {7–20}	—	—
Pyrantel Pamoate 100 mg/kg at weeks 6 and 7 PI	11.4 (±2.3) {1–26}	1.297	0.21
Ivermectin 800 μg/kg at weeks 6 and 7 PI	11.8 (±3.2) {3–25}	1.036	0.32
Thiabendazole 200 mg/kg at weeks 6 and 7 PI	6.3 (±1.4) {0–13}	4.627	0.0002

PI, postinfection.

Trial III

The mean number of worms in the control group (±SE) was 10.6 (±1.7) with a range of 2 to 19 worms. Six of the 12 rats in group II died subsequent to initiation of treatment at 6 week PI: 2 rats on day 6 after the first treatment, 1 rat on day 5 after the second treatment, 2 rats on day 6 after the second treatment, and 1 rat on day 7 after the second treatment. The mean number of worms in group II (±SE) was 3.3 (±0.9) with a range of 0 to 10 worms (two rats had no worms). There was a significant difference in the mean intensity of worms between groups I and II (t = 3.89; p = 0.0008).

Results of hematological analyses conducted on uninfected untreated rats, infected untreated rats, and infected rats treated with mebendazole are summarized in Table 3. No consistently remarkable hematological changes were associated with treatment with mebendazole. However, two (50%) of the rats in the treated group exhibited extremely elevated levels of alkaline phosphatase in conjunction with depressed albumin levels.

Table 3.

Summary of Hematological Findings of Uninfected Rats, Rats Infected with Moniliformis moniliformis, and Infected Rats Treated with Mebendazole

Parameter	Normal range	Uninfected rats (mean ± SE)	Infected rats (mean ± SE)	Treated infected rats (mean ± SE)
Glucose	50–207 mg/dL	160–260 (219.7 ± 30.4)	185–288 (249.3 ± 32.4)	66–289 (183.5 ± 46.7)
Urea nitrogen	6–24 mg/dL	32–36 (33.7 ± 1.2)	16–21 (19.3 ± 1.7)	18–29 (24.3 ± 2.3)
Creatinine	0.2–0.8 mg/dL	0.8 (0.8 ± 0.0)	0.6–0.7 (0.7 ± 0.0)	0.6–0.7 (0.7 ± 0.0)
Total protein	4.7–7.8 g/dL	6.5–6.9 (6.7 ± 0.1)	6.5–7.4 (7.0 ± 0.3)	5.8–7.4 (6.8 ± 0.4)
Albumin	3.4–4.8 g/dL	4.0–4.3 (4.2 ± 0.1)	3.7–4.1 (3.9 ± 0.1)	2.2–4.2 (3.3 ± 0.5)
Total bilirubin	0.2–0.6 mg/dL	0.1–0.2 (0.1 ± 0.0)	0.1 (0.1 ± 0.0)	0.1–0.2 (0.2 ± 0.0)
Alkaline phosphatase	16–125 U/L	3–64 (43.0 ± 20.0)	74–97 (89.0 ± 7.5)	63–482 (213.5 ± 92.3)
ALT (SGPT)	16–89 U/L	42–49 (44.3 ± 2.3)	34–38 (35.7 ± 1.2)	13–32 (26.0 ± 4.4)
AST (SGOT)	10–90 U/L	180–219 (203 ± 11.8)	73–89 (79.3 ± 4.9)	62–250 (131.8 ± 42.3)
Cholesterol	40–130 mg/dL	50–142 (93.7 ± 26.7)	63–80 (73.7 ± 5.4)	42–146 (92.5 ± 24.7)
Calcium	5.3–13 mg/dL	9.8–12.2 (11.3 ± 0.8)	11.9–13.5 (12.6 ± 0.5)	9.0–12.8 (11.2 ± 1.1)
Phosphorous	5.3–8.3 mg/dL	8.9–9.9 (9.5 ± 0.6)	8.9–9.9 (9.6 ± 0.6)	8.6–12.5 (11.0 ± 1.2)
Sodium	135–155 mEq/L	142–145 (143.3 ± 0.9)	147–148 (147.7 ± 0.3)	144–154 (147.3 ± 2.4)
Potassium	4–8 mEq/L	7.5–8.3 (8.0 ± 0.3)	6.3–7.4 (6.8 ± 0.3)	7.4–8.6 (8.2 ± 0.3)
Chloride	90–110 mEq/L	105–107 (106.0 ± 0.6)	106–115 (110.3 ± 2.6)	98–112 (106.8 ± 3.1)
Globulin	1.3–3.0 g/dL	2.3–2.7 (2.5 ± 0.1)	2.8–3.4 (3.1 ± 0.2)	3.1–4.3 (3.6 ± 0.3)
Creatinine phosphokinase—U/L		865–1293 (1096.7 ± 124.8)	101 – 318 (184.7 ± 67.4)	128 – 442 (280.3 ± 71.7)

Means with differences significantly different from control are designated by italic bold print.

Several significant differences were noted in hematological parameters between infected and uninfected rats. Infected rats exhibited significantly lower level of urea nitrogen than did uninfected rats. Infected rats exhibited significantly lower levels of creatinine than did uninfected rats. Infected rats exhibited significantly lower levels of alanine aminotransferase (serum glutamic-pyruvic transaminase) than did uninfected rats. Infected rats exhibited significantly higher levels of aspartate transaminase (serum glutamic-oxaloacetate transaminase) than did uninfected rats. Infected rats exhibited significantly higher levels of sodium and globulin than did uninfected rats. Infected rats exhibited significantly lower levels of creatine phosphokinase than did uninfected rats.

Discussion

Of anthelmintics used for the treatment of human moniliformiasis, pyrantel pamoate (Counselman et al. 1989) and ivermectin (Anosike et al. 2000) have been reported to be the most successful; however, no controlled studies have been carried out to assess the effectiveness of either drug.

Counselman et al. (1989) reported that pyrantel pamoate was used successfuly in the treatment of a 15-month-old male infected with Mo. moniliformis based on the observation that worms and eggs were passed over a 6-week course of treatment with pyrantel pamoate, but in decreasing numbers. Counselman et al. (1989) determined that initial treatment with mebendazole was ineffective after the child continued to pass eggs after a 3-day course of treatment. The findings of Counselman et al. (1989) were in direct contradiction with those of Goldsmid et al. (1974), who determined that treatment with mebendazole effected a cure after treatment with pyrantel pamoate had failed.

Goldsmid et al. (1974) subjected a 12-month-old female infected with Mo. moniliformis to a 3-day course of treatment with mebendazole. Initially, upon observing worms in the stool, the mother subjected the child to a 2-day course of treatment with pyrantel pamoate. The child continued to pass eggs over the next 3 to 4 weeks after treatment, leading Goldsmid et al. (1974) to conclude that pyrantel pamoate had been ineffective in clearing the infection. It was at that point that treatment with mebendazole was initiated. The child continued to pass worms for a period of 2 weeks post-treatment. No eggs were detected in the stool at 2 and 4 weeks post-treatment, leading to the conclusion that treatment with mebendazole had cleared the infection.

The Red Book (Pickering et al. 2000) lists pyrantel pamoate as the drug of choice for the treatment of moniliformiasis.

The duration of infection in the rat, normal definitive host, is about 5–6 months (Crompton et al. 1972). It may be much shorter in humans, an abnormal host for this parasite. Thus, the reduction in worm and egg burden as well as the eventual clearance of infection observed by Counselman et al. (1989) and Goldsmid et al. (1974) may have represented the normal course of infection of Mo. moniliformis in humans and not a result of treatment. In each instance of putative successful treatment listed above, treatment was initiated well into the infection. This might further explain the contradictions in their assertions. In each case, the last drug utilized appeared to have worked.

In carrying out a mass-treatment program in Nigeria, Anosike et al. (2000) treated patients found to have moniliformiasis with a single dose of ivermectin. The patients submitted a follow-up stool sample at least 36 h post-treatment; of the approximately 24,000 samples, 19 were found to contain eggs and/or adults of Mo. moniliformis. Infected individuals were reported to have been successfully treated with subsequent doses of ivermectin. The specific course of treatment was not given, nor was the means of assessment of effectiveness.

In the present study, pyrantel pamoate and ivermectin were wholly unsuccessful in the treatment of moniliformiasis in experimentally infected rats, even when given a dosage twice those normally given to rats.

Moayedi et al. (1971) reported that thiabendazole was effective in the treatment of a case of moniliformiasis in a 4-month-old male. Thiabendazole was administered on 2 successive days. Stool examinations 9 and 12 days post-treatment were negative but another worm was passed 2 weeks after treatment. In the present study, a single dose of thiabendazole lead to a 40% reduction in worm burden after 1 week, and two doses lead to a 57% reduction in worm burden after 2 weeks.

The most effective anthelminic for the treatment of moniliformiasis evaluated in the present study was mebendazole, for which two doses resulted in a 69% reduction in worm burden after 2 weeks; however, 50% of the rats receiving the treatment died within 2 weeks after first administration of the drug. It is hypothesized that Mo. moniliformis may metabolize the drug and release a metabolite that is highly toxic to the host.

Mebendazole, which is probably the most commonly prescribed anthelmintic in North America, is normally considered to be a very safe drug (Marsboom 1973), although rare cases of hepatic dysfunction have been associated with mebendazole toxicity in dogs (Polzin et al. 1981, Van Cauteren et al. 1983). Polzin et al. (1981) observed elevated serum alkaline phosphotase activity in Dachshunds after treatment with mebendazole that was consistent with the apparent hepatic dysfunction observed in treated rats in the present study. Mebendazole is methyl 5-benzoylnenzimidazole-2-carbamate (Medical Economics Co., 1996). Rats have been shown to tolerate doses as high as 40 mg/kg daily for over 2 years (Medical Economics Co., 1996). Mebendazole is considered to be a drug of choice for many intestinal nematodes because it is not readily absorbed from the small intestine. In humans, ∼2% of mebendazole administered is excreted in urine and the remainder is passed in feces. It is the drug itself and not a metabolite that exerts the anthelmintic activity by inhibiting the formation of microtubules, thereby leading to glucose depletion (Medical Economics Co., 1996). After administration of 100 mg twice daily for 3 consecutive days, plasma levels of mebendazole and its primary (host) metabolite, 2-amine, do not exceed 0.03 μg/mL and 0.09 μg/mL, respectively (Medical Economics Co. 1996).

In view of all evidence, thiabendazole should be considered as the drug of choice for treatment of human acanthocephaliasis (Richardson 2003) over pyrantel pamoate and especially over mebendazole. Abramowicz (2002) listed thiabendazole as a potential agent for the treatment of infection with nematodes (Angiostrongylus costaricensis, cutaneous dog and cat hookworms, and Strongyloides stercoralis) although it was pointed out that the drug may be toxic at dosages prescribed for the treatment of strongyloidiasis. In future laboratory studies, effectiveness of drugs with fewer side effects than thiabendazole, such as albendazole, should be assessed to provide viable alternatives for the treatment of moniliformiasis (Richardson 2003).

The several significant hematological differences in infected and uninfected rats suggest that the worms elicit substantial systemic pathophysiological changes in the host. Further studies involving larger samples are warranted to further investigate the pathophysiology of moniliformiasis in rats, particularly in regard to potential reactive metabolites associated with apparent mebendazole toxicity.

Footnotes

Acknowledgments

Brent B. Nickol, University of Nebraska–Lincoln, provided infected cockroaches for the establishment of a laboratory colony of Mo. moniliformis. Holly Clifford, Karen Dionne, Robin LePardo, and Kathryn Vetro, Quinnipiac University, assisted in laboratory aspects of this study. This work was supported by a Quinnipiac University Faculty Research Grant to D.J.R.

Disclosure Statement

No competing financial interests exist.

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