hyperinfection syndrome is recognized as an emerging global infectious disease with high mortality rates,16
timely diagnosis remains a problem17
and systematic preventive therapy is not used routinely.18
For example, in the US, treatment errors occurred more often among providers unfamiliar with immigrant health. When presented with a hypothetical case scenario, physicians-in-training in the United States had poor recognition (9%) of the need for parasite screening and frequently advocated empiric corticosteroids (23%).19
Delayed treatment leads to increased likelihood of dissemination and severe disease. However, treatment options for severe disease are limited, and are adapted from recommendations for chronic, uncomplicated strongyloidiasis, for which ivermectin has been identified as optimal treatment.20
The experience in our ivermectin-treated patients illustrates four main points. First, the mortality rate of disseminated strongyloidiasis remains high. Second, in critically ill patients, absorption of oral ivermectin is likely to be suboptimal. Third, access to parenteral ivermectin remains restricted such that timely drug procurement is difficult under the best of circumstances. Fourth, in disseminated strongyloidiasis, the pharmacokinetics, pharmacodynamics, and overall efficacy of ivermectin are poorly understood.
For our patients, conventional oral ivermectin therapy failed, as judged by persistent parasite burden. Treatment failure has been associated previously with HTLV-1 infection and steroid use.18,21
In our cases, failure was associated with HTLV-1 infection of only one patient. Ivermectin failure in the other three cases was likely related to corticosteroid use, which may impair host immune responses or alter parasite population kinetics.22
In all four of these cases, failure of oral ivermectin therapy appeared to be related to poor drug absorption caused by some combination of vomiting, diarrhea, and/or ileus. Each patient was critically ill with pulmonary dissemination, all required intensive care and mechanical ventilation, and two patients died. These cases underscore the severity of disseminated strongyloidiasis and the difficulty of providing treatment in the likely presence of poor gastrointestinal absorption.
In our cases, ivermectin was ultimately delivered by one or more non-approved methods, either by the rectal and/or subcutaneous route. This treatment appeared to eradicate infection in three of four patients, although our results may be limited by the use of routine stool examination. Fresh stool examinations by the Baermann sedimentation technique or stool culture on agar media would have had greater sensitivity and are now recommended.23
Rectal dosing of ivermectin required no special procedure, but provision of subcutaneous ivermectin required labor-intensive coordination among the primary caregivers, the IRB, the FDA officer assigned to compassionate IND reviews, a pharmacist, the Animal Medical Center and the infectious diseases service. Physical proximity of our medical center, five blocks from the Animal Medical Center, facilitated access to veterinary ivermectin. In addition, we have now developed a clinical team to facilitate ivermectin access and have created form documents for approval and consent for compassionate use of ivermectin, all of which expedited the access process for our later cases. The maximum number of emergency, compassionate use IRB approvals allowed for a single drug at our institution is three, which necessitated formal submission of a research protocol to continue to offer parenteral ivermectin therapy, anticipating that we will continue to encounter disseminated strongyloidiasis.
This case series and similar case reports6–14
raise the question of whether and when subcutaneous ivermectin will become more accessible. The number of cases for which this therapy is indicated but not sought or obtained is unknown. More centralized data collection related to disseminated strongyloidiasis may provide incentive for industry to market this drug for humans.
The pharmacokinetics, pharmacodynamics, and efficacy of ivermectin in disseminated strongyloidiasis remain poorly understood. Subcutaneous ivermectin is absorbed slowly and the kinetics of rectal absorption are unknown. Because of high mortality and potential delays in diagnosis and gaining access to subcutaneous ivermectin, there is a desire to achieve systemic levels of ivermectin without delay. The optimal mode of ivermectin administration, therapeutic level, and dose and duration of treatment have yet to be established. Use of rectal and subcutaneous routes and splitting the site of subcutaneous injections are strategies to enhance the absorption of ivermectin, but there is little or no pharmacokinetic data to support this practice. It is also worth noting that some patients have failed to respond to subcutaneous ivermectin, including patient 4 in this report.11,13
Thus, the delivery and efficacy of parenteral ivermectin in extraintestinal Strongyloides
infection merits further evaluation. Early studies of ivermectin for intestinal versus non-intestinal infection were performed in canines by using oral formulation ivermectin only.24,25
One study showed efficacy against extraintestinal Strongyloides
whereas a second study found that oral ivermectin was ineffective against tissue dwelling, third-stage larvae.25
Published human data on the use of subcutaneous ivermectin for treatment of disseminated strongyloidiasis are limited to the case reports mentioned above, and include both successes and failures. In our experience, gastrointestinal clearance can occur despite ongoing pulmonary infection (cases 2–4). This observation raises the question of whether there is a failure of drug delivery or failure of efficacy at a major site of involvement, the respiratory tract.
This report is the first to document that subcutaneous ivermectin can reach measurable concentrations in respiratory secretions (case 4, and ). In this patient, plasma ivermectin concentrations also reached 99.8 ng/mL, which is in the range of well-tolerated levels in healthy subjects (50–100 ng/mL).26,27
However, because this patient was sedated and paralyzed for mechanical ventilation, physical examination was of limited use in assessing for possible ivermectin-associated neurotoxicity.6
In case 4, the sharp increase in concentrations after the final ivermectin dose likely indicates a depot effect from subcutaneous administration, as described.6
The concentrations in plasma and respiratory secretions in case 4 are well above the reported value sufficient to paralyze 50% of S. ratti
and S. venezuelensis in vitro
(2.4 ng/mL), although the therapeutic concentration required in humans against S. stercoralis
Despite seemingly adequate concentrations, pulmonary infection persisted in case 4. Possible explanations include ivermectin-resistant Strongyloides
, limited ivermectin efficacy against non-intestinal stages of Strongyloides
, or inadequate concentration of free ivermectin (despite detectable total ivermectin concentrations). In each of our cases, ivermectin was used off-label because there are no approved non-oral medications available for disseminated disease. Of note, the package insert for oral ivermectin states that “ivermectin activity against Strongyloides stercoralis
is limited to the intestinal stages.” As judged by previous reports of successful parasite eradication by using parenteral ivermectin6–10,12,14
and our cases 2 and 3, parenteral therapy may become the standard approach for disseminated strongyloidiasis by default during periods of likely poor absorption, but with sparse data to guide its use.