Ivermectin

Brugia malayi

In an open study from India 21 asymptomatic microfilaria carriers (with counts of 109–6934/ml of blood) were treated with a single oral dose of ivermectin 400 micrograms/kg and a single oral dose of diethylcarbamazine 6 mg/kg for infection with Brugia malayi [ ]. Twelve hours after treatment microfilaria counts fell by 96–100% in all patients and 12 patients had become afilaremic. All had an adverse reaction, lasting up to 48 hours after treatment: fever (n = 20), myalgia (n = 19), headache (n = 17), lethargy (n = 15), chills (n = 13), sweating (n = 11), anorexia (n = 11), sore throat and pharyngeal congestion (n = 10), arthralgia (n = 6), giddiness (n = 4), nausea and vomiting (n = 3), abdominal pain (n = 2), and cough (n = 1). Postural hypotension, lasting 1 day, was noted in two individuals. Transient dilated and painfully inflamed lymphatic channels, which stood out in cords, were seen in two individuals. Most adverse reactions were mild and self-limiting.

Gnathostomiasis

In a prospective open study in 20 Thai patients with cutaneous gnathostomiasis oral ivermectin 50, 100, 150, or 200 micrograms/kg was associated with the following adverse events: malaise (n = 7), myalgia (6), drowsiness (6), pruritus (4), nausea/vomiting (4), dizziness (3), diarrhea (3), a feeling of shortness of breath (2), palpitation (2), constipation (1), anorexia (1), and headache (1) [ ]. These adverse events were self-limiting and there were no serious adverse events. There were laboratory abnormalities in three patients. Transient microscopic hematuria, pyuria, and mildly raised liver enzymes were found in one patient each.

Loa loa

The use of ivermectin and its adverse effects in patients infected with Loa loa have been reviewed [ ]. It was concluded that ivermectin in a single dose of 150–300 micrograms/kg is effective in reducing microfilaria counts by over 90% with suppressed counts to 25% of pretreatment values after 1 year. An even more sustained effect can be reached by more frequent dosing. There is also some evidence that ivermectin in higher doses (400 micrograms/kg twice yearly) can affect the adult Loa loa . Tolerance to ivermectin is generally excellent, but serious adverse effects, especially encephalopathy, can occur, principally in more heavily infected individuals.

Onchocerciasis

The impact of 5 years of annual community treatment with ivermectin on the prevalence of onchocerciasis and onchocerciasis-associated morbidity in the village of Gami (Central African Republic) has been assessed [ ]. Pruritus, onchocercal nodules, and impaired vision were all significantly reduced by annual treatment with ivermectin.

In a study of the effect of ivermectin on adult Onchocerca worms [ ] the following regimens were compared:

• 150 micrograms/kg yearly (reference group; n = 166);

• 400 micrograms/kg then 800 micrograms/kg yearly (n = 172);

• 150 micrograms/kg 3-monthly (n = 161);

• 400 micrograms/kg then 800 micrograms/kg 3-monthly (n = 158).

After 3 years of treatment more female worms had died in those who were treated every 3 months than in the reference group; female worms were also less fertile. There was no difference between the two groups of patients who were treated yearly. There were no serious adverse events, even at high doses. However, subjective complaints of visual disturbances, such as blurred vision, ocular pain, or dyschromatopsia, were more frequent in those who were given 800 micrograms/kg than in those who were given 150 micrograms/kg; the effects lasted less than 1 week. Detailed ocular examination showed no differences between patients from the reference group and the three other groups.

In another study, 890 subjects were interviewed to monitor adverse reactions after repeated ivermectin treatment of onchocerciasis in Nigeria [ ]. After the first treatment round with ivermectin, 202 subjects reported pains in joints, 108 reported fever, 30 reported headache, 18 reported itching, and four reported dizziness. There were no adverse reactions in 528 (59%). After the sixth treatment round, no reactions were reported in 756 subjects (85%). Pains in joints were reported by 76, itching by 26, fever by 24, and dizziness by eight subjects. The relatively mild adverse reactions observed during the first treatment round did not affect future participation in community treatment with ivermectin.

In a study in Uganda, 737 of 1246 patients (59%) with onchocerciasis developed adverse reactions after first treatment with a single oral dose of ivermectin 150 micrograms/kg [ ]. Pain, swelling, and cutaneous reactions were the three most dominant symptoms of adverse effects (in 57%, 50%, and 38% of the 737 symptomatic patients respectively). Ten patients had severe adverse reactions, including severe postural hypotension and high fever. In spite of the fact that many patients had adverse reactions to ivermectin, the drug was well accepted and appreciated by the population.

Severe adverse events (e.g. the Mazzotti reaction, see diethylcarbamazine) can occur after ivermectin treatment in patients with high Loa loa microfilarial densities. In the context of mass ivermectin distribution for onchocerciasis control in Africa, it is crucial to define precisely the geographical distribution of Loa loa in relation to that of Onchocerca volvulus and predict the prevalence of heavy infections. To that end, the distribution of Loa loa microfilarial densities were determined in 4183 individuals living in 36 villages in the Lekie Division in central Cameroon, to predict prevalences of Loa loa -related post-ivermectin adverse events [ ]. The value of k , an estimate of the degree of microfilarial overdispersion in Loa loa , varied around 0.3 independently of microfilarial intensity, host age, village, and endemicity. Based on these results a semi-empirical model was developed to predict the prevalence of heavy Loa loa microfilarial loads in a community, which could be useful in identifying areas and populations at risk of severe adverse events after ivermectin.

In a 3-year double-blind trial [ ] in Cameroon the effect of ivermectin, given at 3-monthly intervals and/or in high doses (800 micrograms/kg) on adult Onchocerca volvulus was determined in 643 individuals and compared with the standard annual dose of 150 micrograms/kg. No patient developed a serious adverse reaction, none required hospitalization, and none withdrew because of an adverse reaction. Mild adverse reactions began soon after the start of treatment. Of 1129 consultations for adverse reactions, 367 took place in the a few hours after treatment (day 0); 449, 195, and 118 consultations took place on days 1, 2, and 3 respectively. The incidence of adverse reactions fell steadily over the course of the trial. After the first dose, 3-monthly treatment was associated with a reduced risk of reactions, especially edematous swelling, pruritus, and back pain. Edematous swelling and subjective ocular problems were associated with high doses of ivermectin.

Sarcoptes scabiei

The treatment of scabies has been reviewed [ ]. Topical treatments are poorly tolerated by some patients. An alternative approach is to use oral ivermectin, which has been used extensively for several parasitic infections, including onchocerciasis, lymphatic filariasis, and other nematode-related infestations. Ivermectin is thought to interrupt glutamate-induced and γ-aminobutyric acid-induced neurotransmission in parasites, leading to nematode paralysis and death. In humans ivermectin does not cross the intact blood–brain barrier. The efficacy and effectiveness of oral ivermectin is equivalent to, or better than, that of topical lindane, benzylbenzoate, and permethrin. Cure rates are 70–74% with a single dose of ivermectin and 95% when a second dose is taken 2 weeks later. The poorer efficacy of a single dose may reflect the fact that ivermectin is not ovicidal.

Two cases of scabies treated with oral ivermectin (200 micrograms/kg) have been reported [ ].

• A 72-year-old man developed crusted scabies, having used an oral glucocorticoid, owing to a presumed misdiagnosis by an earlier physician. He was successfully treated with two oral doses of ivermectin 7 days apart with topical crotamiton 10% and a keratolytic ointment (5% salicylic acid in petrolatum). However, the nail scabies failed to respond. Live mites were detected from all his toenails 2 weeks after the second dose of ivermectin. Complete cure was achieved by occlusive dressings with lindane for 1 month. Follow-up observations did not reveal any adverse effects of ivermectin or signs of relapse.

• A 52-year-old woman, who had taken oral glucocorticoids for mesangial nephritis, developed common scabies, but a topical scabicide, crotamiton, was not effective, and 2 weeks after treatment with a single dose of oral ivermectin eggs were still detected from a burrow on her trunk. Her treatment was completed after a further two doses of oral ivermectin at 7 day intervals.

In both cases, oral ivermectin did not cause any clinical or laboratory adverse effects. Oral ivermectin is effective for crusted scabies, but not effective for nail scabies. A repeat treatment with ivermectin appears to result in the highest rate of cure.

In an uncontrolled open study 101 patients with scabies were treated with a single oral dose of ivermectin 200 micrograms/kg and then followed at 3 days and at 2 and 4 weeks [ ]. Two weeks after the start of treatment 89 patients were completely free of scabies, while another three had only mild lesions and pruritus with negative skin scrapings. The other nine patients had persistent pruritus and new lesions and were treated with a second dose, with a complete cure in all cases after 4 weeks. Twelve patients reported minor adverse effects, consisting of drowsiness (n = 4), arthralgia and bone aches (n = 2), dyspnea (n = 3), headache (n = 1), nausea (n = 1), and blurred vision (n = 1). The adverse effects were mostly reported at the first follow-up and were easily tolerated. Ivermectin appears to be a safe and effective treatment for scabies in a dose of 200 micrograms/kg, although a second dose is necessary for complete cure in a few patients.

• An 11-year-old girl developed severe crusted Norwegian scabies [ ]. Gamma-benzene hexachloride lotion and topical keratolytics had no significant effect. She was given a single oral dose of ivermectin 6 mg/kg with dramatic effect. The pruritus subsided in 4 hours and the lesions started to clear 2 days later. A second dose of 6 mg was given after 3 weeks when no skin lesions were found anymore. The only adverse effect was some edema of the skin after the first dose, which did not occur after the second dose, suggesting that the reaction was more related to the intensity of the infection then to the effect of the drug itself.

Outbreaks of scabies in elderly people require special management for disease control. Owing to the frequent failure of repeated non-synchronized therapeutic efforts with conventional external antiscabies treatments, special eradication programs are required. The management of outbreaks of scabies with allethrin, permethrin, and ivermectin has been evaluated [ ]. Healthy infested people (n = 240) were treated once simultaneously with an external scabicide, such as allethrin or permethrin; this was effective in 99%. Those with crusted scabies (n = 12) were hospitalized and treated with systemic ivermectin or ivermectin plus permethrin; seven patients received ivermectin twice after an interval of 8 days and one received permethrin three times. Unfortunately, no details of adverse effects were given.

Strongyloidiasis

The efficacy and adverse effects of ivermectin 200 micrograms/kg, repeated 2 weeks later, have been studied in 50 patients with chronic strongyloidiasis, aged 30–79 years [ ]. The eradication rate was 96% at 2 weeks after the first dose and 98% after the second dose. There was no recurrence after follow-up of 4 months. One patient had nausea and vomiting 3 hours after the first dose and again after the second dose, but they were transient and required no therapy. In four patients there were mild laboratory abnormalities (slight increases in liver function tests in two, microscopic hematuria in one, and mild leukopenia and lymphocytosis in one). Of the 50 patients 12 were positive for human T lymphotropic virus type-I.

In a randomised, open study, a 7-day course of oral albendazole 800 mg/day was compared with a single oral dose of the parenteral veterinary formulation of ivermectin 200 micrograms/kg in 42 Thai patients with chronic strongyloidiasis [ ]. The primary end-points were relief of symptoms (if present) and clearance of Strongyloides larvae from the feces immediately after treatment and at follow-up 16 weeks later. Cure rates in the albendazole and ivermectin groups were 38% and 76% respectively in the intention-to-treat analysis, and 50% and 89% respectively in the per-protocol analysis. One patient had acute generalized exanthematous pustulosis (AGEP) 1 day after receiving ivermectin. Five patients who took albendazole and one patient who took ivermectin had transient changes in transaminases, a well-recognized and reversible effect.

Wuchereria bancrofti

Early-stage elephantiasis caused by bancroftian filariasis in a 27-year-old traveller was treated with a single-dose oral combination of ivermectin 24 mg plus albendazole 400 mg, followed by albendazole 800 mg for 21 days [ ]. To avoid a severe Mazzotti-like reaction, he was given oral glucocorticoids and antihistamines for 3 days. He had a transient rash, pruritus, and mild hypotension on the days after the initial treatment, but otherwise remained well and the swelling subsided. Within 1 month he was free of symptoms. At the last follow-up examination, 3 years after treatment, there was no clinical or laboratory evidence of relapse. The authors thought that this type of treatment should be evaluated on a wider scale, given the minimal adverse events and apparent therapeutic efficacy.

The efficacy of annual mass chemotherapy with a combination of diethylcarbamazine and ivermectin on bancroftian filariasis in rural southern India has been studied, as has the supplementary role of controlling the vector mosquito Culex quinquefasciatus [ ]. Nine villages, topographically and ecologically similar but reasonably isolated from each other, were selected and split into three comparable groups of three villages each. Group A received chemotherapy with diethylcarbamazine at about 6 mg/kg and ivermectin at 400 micrograms/kg. Group B received chemotherapy and vector control. The most important vector-breeding sites were soakage pits, which were treated with expanded polystyrene beads. Minor vector-breeding sources, such as domestic or irrigation wells, were treated by adding larvae-eating Talapia fish or a commercial insecticide based on Bacillus sphaericus . Group C received no intervention. After the first round of treatment, combination chemotherapy alone caused a 60% drop in the annual filarial transmission potential, whereas the combined strategy reduced the transmission potential by 96%. After two rounds of treatment, the reduction in transmission potential was similar with the two strategies (about 91–96% reduction), whereas the prevalence of microfilaremia was reduced by 88–92%. Adverse events after combination therapy were reported in 20% of those who had taken diethylcarbamazine and ivermectin for the first time. The patients with adverse events had increased microfilarial counts. The most common adverse reactions were headache (72% of adverse events), giddiness (67%), fever, and weakness. The incidence of adverse events among those taking combination therapy for a second time was relatively low (5.5%). The adverse events were also less severe in the second round than in the first. When antifilarial treatment was withdrawn in the third and final year of the study, transmission was resumed in the absence of vector control, whereas no infective female mosquitoes were detected in villages with vector control. Vector control, although obviously not cost-effective in the short term, could therefore play an important supplementary role in an integrated program, by preventing re-establishment of transmission after chemotherapy has been completed.