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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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We describe the clinical course of a patient with disseminated strongyloidiasis who was treated for two weeks with oral albendazole and a veterinary formulation of subcutaneous ivermectin. To assess the pharmacokinetics and potential for toxicity, ivermectin levels in the serum and cerebrospinal fluid (CSF) were determined.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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Four days after admission, the lymph node biopsy showed S. stercoralis larvae. Treatment with albendazole (400 mg twice a day) and ivermectin (15 mg [200 µg/kg] once a day) was initiated and administered via a nasogastric tube. Abundant, motile larvae were subsequently observed in nasogastric aspirate fluid and sputa. On the sixth day after admission, 48 hours after starting antihelmintic therapy, the patient became drowsy, hypoxic, hypotensive, and febrile, which necessitated intubation, mechanical ventilation, and vasopressor support. During the next 24 hours, the gastric output was extremely high (the nasogastric tube could not be clamped even for 15 minutes) and the effectiveness of administering albendazole and ivermectin by nasogastric tube was questioned. A veterinary formulation of subcutaneous ivermectin (Ivomec, Merial Canada Inc., Victoriaville, Quebec, Canada) was therefore obtained and administered on the seventh day after admission (Table 1
). Albendazole was administered for 13 days though a nasogastric tube and ivermectin (15 mg [200 µg/kg]) was administered undiluted (1.5 mL of a 10 mg/mL solution) subcutaneously.
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), the patient remained in an unexplained coma (Glasgow coma score = 5). No cause was identified despite extensive investigations: normal results were obtained with two computed tomographic scans of the head, one un-infused magnetic resonance image of the head, three cerebrospinal fluid (CSF) examinations (normal protein, glucose, and cell counts and the absence of larvae), and an electroencephalogram that showed nonspecific encephalopathic changes but no seizure activity. After 10 days of subcutaneous ivermectin, the patient began to hypersalivate, remained comatose, but had a normal pupil size (~ 4 mm). Because of concerns of potential ivermectin central nervous system (CNS) toxicity that manifests in humans with mydriasis, ataxia, tremors, emesis, lethargy and coma,6,7 subcutaneous ivermectin was discontinued after 14 days. Over the following week and a half, the patient was weaned from the ventilator and the salivation decreased. The patient remained comatose and died of an aspiration pneumonia 35 days after coming to the hospital. Consent for postmortem examination was denied.
Serum ivermectin concentration.
The primary site of ivermectin toxicity in humans and animals is the CNS.6,7 We investigated the potential role of ivermectin toxicity in the persistent coma and excessive salivation of the patient by determination of ivermectin concentration in serum and CSF using high-performance liquid chromatography (HPLC). The analysis used an analytical method similar to that described for moxidectin,8 a related avermectin drug. Briefly, OasisTM HLB 30-mg cartridges (Waters, Milford, MA) were used for solid-phase extraction of plasma, serum, and CSF. Extracted samples were derivatized with 100 µL of N-methylimidazole in acetonitrile (1:1 v/v) and 150 µL of trifluoroaceticanhydride in acetonitrile (1:2 v/v). Derivatized samples were transferred to autoinjector vials and placed on a 717 plus autosampler with a 501 pump (Waters). Twenty microliters was injected into an Ultrasphere® C18 5 µm 4.6 x 250 mm column (Alltech, Deerfield, IL). The mobile phase was tetrahydrofuran-acetonitrile-water (40:38:22, v/v/v) with a flow rate of 1.0 mL/minute. An RF10AxL detector (Shimadzu, Kyoto, Japan) was used for fluorescence detection with excitation at 365 nm and emission at 475 nm. Moxidectin was the internal standard in the analysis and the assay had a detection limit of 0.2 ng/mL. The results of ivermectin analysis are shown in Table 1.
Plasma levels of ivermectin were very low (0.8 ng/mL) three hours after the third daily dose of ivermectin administered by nasogastric tube. However, within 12 hours of having received one subcutaneous dose of ivermectin, serum levels were several-fold higher (5.8 ng/mL). Over the next 14 days, subcutaneous ivermectin (15 mg [200 µg/kg]) a day produced serum ivermectin levels between 11.4 and 17.2 ng/mL with no significant accumulation. The ivermectin level was still 14.8 ng/mL 48 hours after the last dose of subcutaneous ivermectin because the peak absorption is slow after a subcutaneous dose of ivermectin (in animals ranges = 1–4 days).9–14 Ivermectin and its metabolites were not detected in CSF after five subcutaneous doses.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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The pharmacokinetics of orally administered ivermectin in humans is well known. Fifty to sixty percent of ivermectin administered as a tablet or capsule is absorbed.7 Ivermectin is detectable in plasma within one hour15 and reaches peak levels ranging from 20 to 54.4 ng/mL 4–5 hours after a single dose of 200 µg/kg.7,15,16 Ivermectin is metabolized in the liver and its metabolites are excreted primarily in the bile. In some patients, an enterohepatic cycle produces a secondary plasma peak between 6 and 12 hours after dosing.7,15 The half-life of the parent drug is 12–56 hours6,7,15,17 and the half-life of its metabolites is up to three days.7 The therapeutic plasma ivermectin range for intestinal strongyloides is not known, but at a dose of 200 µg/kg/day for 1–2 days, parasitologic cure rates range from 83% to 97%.18–20
Unfortunately, parenterally administered antihelminthics have not been approved for use in humans, and the experience with alternatives to oral administration is limited to one report of rectal thiabendazole,4 one report of rectal ivermectin,3 and one report of subcutaneous ivermectin.5 There are no pharmacokinetic data on subcutaneous ivermectin in humans but the kinetics have been studied extensively in large animals. The time to maximum concentration (Cmax) in large animals ranges from 1.2 to 4 days.9–14 Assuming an absorption half-life in humans of approximately one day (extrapolated from animal data)9–14 and a relatively short elimination half-life of 12–56 hours, steady state should be reached within one week of multiple dosing. In this patient (Table 1), the mean steady-state serum ivermectin concentration was approximately 13.6 ng/mL with an estimated clearance of 46.0 L/hour (calculated by dividing the dose rate [15 mg/24 hours] by the steady-state concentration). The estimated ivermectin clearance is higher than expected for a healthy male subject (31.8 L/hour) (Vanapalli S and others, unpublished data) and may explain why the steady-state serum ivermectin levels were lower than those observed after oral dosing (mean Cmax = 87 ng/mL after 7 days of 30 mg given orally every 72 hours in healthy fasting volunteers).6
The elevated clearance of ivermectin in this patient may have been the result of his extremely low albumin level 7 g/L [reference range = 35–51 g/L] shortly after admission, which increased slowly to only 22 g/L over the course of the next three weeks. Hypoalbuminemia is common in disseminated strongyloidiasis and was found in 67% of patients in one series from the Dominican Republic.21 Ivermectin is highly bound to human serum albumin22 and the percentage of free drug therefore increases with decreasing albumin level.23 The extent of protein binding in the plasma or tissues also affects the volume of distribution of ivermectin. Individuals with low plasma protein binding will have a greater volume of distribution and lower steady-state concentrations.
The major side effect of ivermectin is neurotoxicity that usually manifests in animals and humans as mydriasis, ataxia, tremors, and emesis, followed by lethargy, coma, and death.6,7,24–26 Humans can tolerate relatively high doses of ivermectin. In healthy, human volunteers, single doses of up to 2,000 µg/kg, and doses up to 1,091 µg/kg administered three times at 72-hour intervals produced no evidence of toxicity.6 A child who accidentally ingested 6,600–8,600 µg/kg had emesis, mydriasis, and sedation, but eventually recovered.7
The patient in this report had possible clinical signs of ivermectin toxicity (coma and hypersalivation). However, the plasma ivermectin concentrations in this patient were almost 20-fold lower than those that were well tolerated in human safety studies.6 Furthermore, ivermectin was undetectable in the CSF after five doses of subcutaneous ivermectin when the serum level was 12.1 ng/mL. Although ivermectin is well tolerated in healthy adults, approximately 10% of ivermectin-treated (150 µg/kg) patients with onchocerciasis showed adverse reactions that required additional medical treatment.27 In addition, in onchocerciasis patients in Sierra Leone, serum ivermectin levels did not correlate with adverse reactions.17 We therefore cannot rule out the possibility that the coma was due to either ivermectin or its metabolites (whose pharmacodynamic properties are unknown). Two metabolite peaks were noted on all chromatograms analyzed from post-admission days 16–23 in serum specimens, but not in CSF specimens. They were present in significant amounts with peak area ratios of 0.54–0.85 and 0.24–0.38 ng/mL relative to an ivermectin of 1 area ratio.
Disseminated strongyloidiasis is a challenging disease with a high mortality rate despite available effective therapy. This case highlights the need for the availability of alternative routes of administration of ivermectin given its poor oral bio-availability in the presence of an ileus. The severe hypoalbuminemia in this patient, which occurs commonly in disseminated strongyloidiasis, also raises the concern that increased clearance of ivermectin will further decrease the ability to achieve adequate levels after oral dosing. It was not completely excluded that this patient had serious CNS toxicity due to parenteral ivermectin. It would therefore be prudent for other clinicians considering using subcutaneous ivermectin in a patient with disseminated strongyloidiasis to carefully monitor signs and symptoms consistent with ivermectin CNS toxicity and to measure ivermectin levels.
Received April 1, 2005. Accepted for publication June 14, 2005.
* Address correspondence to Christina Greenaway, Department of Microbiology, Division of Infectious Diseases, Room G-143, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Côte St., Catherine Road, Montreal, Quebec, Canada, H3T 1E2. E-mail: ca.greenaway{at}mcgill.ca 
Authors’ addresses: Stephen A. Turner and Christina Greenaway, Department of Microbiology, Division of Infectious Diseases, Room G-143, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Côte St., Catherine Road, Montreal, Quebec, Canada, H3T 1E2, E-mails: trnrstephen{at}aol.com and ca.greenaway{at}mcgill.ca. J. Dick MacLean, McGill University for Tropical Diseases, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec, Canada, H3G 1A4, E-mail: dick.maclean{at}mcgill.ca. Lawrence Fleckenstein, University of Iowa College of Pharmacy, S-427-Phar, 115 South Grand Ave, Iowa City, IA 52242, E-mail: l-fleckenstein{at}uiowa.edu.
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This article has been cited by other articles:
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  V. Leung, G. N. Al-Rawahi, J. Grant, L. Fleckenstein, and W. Bowie Failure of Subcutaneous Ivermectin in Treating Strongyloides Hyperinfection Am J Trop Med Hyg, December 1, 2008; 79(6): 853 - 855. [Abstract] [Full Text] [PDF]
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 M. Segarra-Newnham Manifestations, Diagnosis, and Treatment of Strongyloides stercoralis Infection Ann. Pharmacother., December 1, 2007; 41(12): 1992 - 2001. [Abstract] [Full Text] [PDF]
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