Oral miltefosine for refractory Acanthamoeba keratitis

Hirabayashi, Kristin E.; Lin, Charles C.; Ta, Christopher N.

doi:10.1016/j.ajoc.2019.100555

Cited by 19 publications

(13 citation statements)

References 16 publications

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“…This causes Acanthamoeba to persist long enough as the vulnerable trophozoites 22,23 and to allow a second cytotoxic agent to exert its effect 24 . The combination of different administration routes has also provided positive outcomes, for example topical and systemic administration using topical chlorhexidine 0.06% and propamidine isetionate 0.1% and the zwitterionic alkylphosphocholine (APC) called miltefosine 25,26 . APCs are also effective against kinetoplastids (Trypanosoma and Leishmania), anaerobic parasites (Trichomonas and Entamoeba) and other amoebae (Naegleria, as well as Acanthamoeba) trophozoites and cysts, but can induce encystation in Acanthamoeba [27][28][29][30][31][32] .…”

mentioning

confidence: 99%

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

Mooney

Masala

Martial

et al. 2020

Sci Rep

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the opportunistic pathogen, Acanthamoeba castellanii is the causative agent for the sight threatening infection Acanthamoeba keratitis (AK). it is commonly associated with contact lens wearers, and prevalence is increasing at an alarming rate due to an inadequate preventive strategy to protect the lens from this protist. This problem is compounded by the lack of an effective acanthamoebocide, particularly with cysticidal activity in the contact lens solutions. We have used cytotoxicity assays and a variety of biophysical approaches to show that two molecules with tails made of alkyl carbon, alkylphosphocholines (APCs) and quaternary ammonium compounds (QACs) had significant chain-length dependent efficacy against A. castellanii trophozoites, the latter producing death via permeabilization, and DNA complexing. QACs were more effective than APCs and had activity against cysts. Conversely, the QAC with 12 alkyl carbon chain, was non toxic, its presence increased A. castellanii trophozoites biomass and delayed encystation by 96 h. Interestingly, it was unable to induce excystation and increased trophozoite sensitivity to APC16. These results present a mono-and multi-inhibitor management strategy effective against trophozoites and cysts that may be useful for formulating into contact lense cleaning solutions and reducing AK incidence. Acanthamoeba are free-living protists, existing as active trophozoites and non-replicative cysts characterised by double cellulose cell walls 1. They have opportunistic tendencies and can cause the diseases, Acanthamoeba keratitis (AK), cutaneous acanthamoebiasis (CA) and granulomatous amoebic encephalitis (GAE) 2,3. Whilst CA and GAE are lethal but rare and affect the skin and CNS, respectively, the non-lethal AK causes severe infection in the cornea, threatening sight loss and causing emotional and psychological trauma, described as life-changing in patients 4. Trophozoites to cysts interconversion and vice versa (encystation and excystation) is induced by external environmental cues 5,6 and poses significant challenges for curative treatment particularly causing AK resurgences and relapses 7. AK cases are increasing and prevalence is high amongst contact lens users 8,9. Cases of AK within the UK have risen drastically within the last 20 years and continue to do so 10. The reason for this upsurge in incidence rates does not appear to be as a result of increased lens wearers but is as of yet unknown, likely the result of multiple factors 10. Spatial geographic differences are common with 15 times more cases reported in the UK than the USA 11,12 , and 8 times more in Scotland than England 13. These differences are strongly linked with water supply, quality and usage 12. Indeed, the incidence of AK in contact lens users is believed to be due to rinsing of contact lenses with domestic tap water 14. Further, the lack of anti-acanthamoebocides in cleaning solutions is another issue. Despite the presence of preservative compounds such as polyhexamethylene biguanide used in existing solutions,...

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confidence: 99%

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

Mooney

Masala

Martial

et al. 2020

Sci Rep

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“…Because cellular and organelle membranes are a ubiquitous target, this medication is not without risk for significant off-target toxicity, including teratogenicity, nausea, vomiting, fever, headache, and nephrotoxicity. Less frequently, it can have severe outcomes, such as Stevens-Johnson syndrome and profound thrombocytopenia [ 13 ]. Laboratory and animal studies have yielded promising results; however, large-scale studies of efficacy in humans are lacking due in part to the rarity of the condition.…”

Section: Discussionmentioning

confidence: 99%

Acanthamoeba Keratitis: A Single-Institution Series of Four Cases With Literature Review

Smith¹,

Ashraf²,

Haghnegahdar³

et al. 2022

Cureus

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Acanthamoeba species are free-living protozoa found pervasively in water and soil, which can cause infections of the central nervous system, skin, and eye. Amoebic keratitis (AK) is a vision-threatening, often chronic infection that is associated with the use of soft contact lenses due to corneal microtrauma and improper cleaning and storage. Although AK infections are rare, they cause significant morbidity including vision loss due to the diagnostic and therapeutic challenges they pose.The clinical course is determined by the organism's inherent pathogenicity, delay of diagnosis, and the paucity of data on effective therapeutic regimens. The case series and review of literature that follows examine current latest best practices in AK diagnosis including in vivo confocal microscopy (IVCM) and therapeutic interventions including miltefosine.

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“…Miltefosine is an alkylphosphocholine effective against protozoal infections such as visceral leishmaniasis, trypanosoma cruzi, and Entamoeba histolytica. 5 In vitro and in vivo studies have demonstrated the amoebicidal activity of Miltefosine without a negative effect on cell viability. 6 , 7 , 8 In 2016, oral miltefosine received orphan drug designation from the United States (U.S.) Food and Drug Administration for treatment of Acanthamoeba keratitis.…”

Section: Discussionmentioning

confidence: 99%

“…Use of miltefosine is typically reserved for recalcitrant cases of AK in which patients have failed to improve after 4–6 weeks of treatment with other anti-amoebic therapies including oral voriconazole. 5 The recommended dosage is 50 mg bid for 30–44 kg body weight and 50 mg TID for ≥45 kg body weight, and serial liver function testing should be performed to monitor for hepatotoxicity. 5 Case series have shown miltefosine may be a viable adjunctive therapy for recalcitrant AK but its use may be associated with a severe inflammatory reaction in the cornea that is typically seen after 2 weeks of treatment.…”

Section: Discussionmentioning

confidence: 99%

“… 5 The recommended dosage is 50 mg bid for 30–44 kg body weight and 50 mg TID for ≥45 kg body weight, and serial liver function testing should be performed to monitor for hepatotoxicity. 5 Case series have shown miltefosine may be a viable adjunctive therapy for recalcitrant AK but its use may be associated with a severe inflammatory reaction in the cornea that is typically seen after 2 weeks of treatment. 9 …”

Section: Discussionmentioning

confidence: 99%

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Treatment of recalcitrant Acanthamoeba Keratitis with Photoactivated Chromophore for Infectious Keratitis Corneal Collagen Cross-Linking (PACK-CXL)

Watson

Shekhawat

Daoud

2022

American Journal of Ophthalmology Case Reports

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Purpose To describe a case of recalcitrant Acanthamoeba Keratitis (AK) complicated by medical non-compliance and medication intolerance that was successfully treated with photoactivated chromophore for infectious keratitis corneal collagen cross-linking (PACK-CXL). Observations A 31-year-old male presented with right eye pain and redness in the setting of fresh water exposure and scleral contact lens wear. He had lack of a response to treatment with antiviral therapy for 3 months by an outside provider. Cultures were found to be positive for Acanthamoeba and the patient was treated with an extended course of various anti-amoebic therapies with poor compliance due to pain and toxicity. He was eventually treated with intrastromal voriconazole and Miltefosine without improvement and eventually had PACK-CXL with resolution of his infection and pain. Conclusion PACK-CXL was associated with a dramatic improvement in a case of recalcitrant Acanthamoeba keratitis unresponsive to both traditional and novel therapies and may be a viable alternative or adjunctive therapy for Acanthamoeba keratitis.

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Oral miltefosine for refractory Acanthamoeba keratitis

Cited by 19 publications

References 16 publications

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

Acanthamoeba Keratitis: A Single-Institution Series of Four Cases With Literature Review

Treatment of recalcitrant Acanthamoeba Keratitis with Photoactivated Chromophore for Infectious Keratitis Corneal Collagen Cross-Linking (PACK-CXL)

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