A 30-year-old Bangladeshi gentleman presented with history of sand entering his left eye and was diagnosed as having fungal keratitis by private ophthalmologist. He was treated with three doses of conventional subconjunctival amphotericin B injections (1.5 mg of amphotericin B and 1.2 mg of deoxycholate) over the inferior bulbar conjunctiva and topical antibiotics. Subsequently, he developed conjunctival necrosis over the site of injections and there was no clinical improvement of the keratitis. He was then treated with intensive antifungal and antibiotics eye drops. Debridement of epithelial plug was done and he was given intracameral amphotericin B injection. There was gradual improvement observed then with conjunctival epithelialization. The conjunctival tissue was completely healed after three months along with the corneal ulcer. Subconjunctival injection of Amphotericin B (AMB) may be considered as an adjunct therapy in severe fungal keratitis to address the issue of compliance. Close monitoring is needed due to its known complication of scleritis, scleral thinning and conjunctival necrosis. Liposomal AMB which is known to cause less toxicity given via subconjunctival injection in human subjects needs to be further studied.
Brain-eating amoebae including Acanthamoeba spp., Naegleria fowleri, and Balamuthia mandrillaris cause rare infections of the central nervous system that almost always result in death. The high mortality rate, lack of interest for drug development from pharmaceutical industries, and no available effective drugs present an alarming challenge. The current drugs employed in the management and therapy of these devastating diseases are amphotericin B, miltefosine, chlorhexidine, pentamidine, and voriconazole which are generally used in combination. However, clinical evidence shows that these drugs have limited efficacy and high host cell cytotoxicity. Repurposing of drugs is a practical approach to utilize commercially available, U.S. Food and Drug Administration approved drugs for one disease against rare diseases caused by brain-eating amoebae. In this Perspective, we highlight some of the success stories of drugs repositioned against neglected parasitic diseases and identify future potential for effective and sustainable drug development against brain-eating amoebae infections.
The pathogenic free-living amoeba, Acanthamoeba castellanii, is responsible for a rare but deadly central nervous system infection, granulomatous amoebic encephalitis and a blinding eye disease called Acanthamoeba keratitis. Currently, a combination of biguanides, amidine, azoles and antibiotics are used to manage these infections; however, the host cell cytotoxicity of these drugs remains a challenge. Furthermore, Acanthamoeba species are capable of transforming to the cyst form to resist chemotherapy. Herein, we have developed a nano drug delivery system based on iron oxide nanoparticles conjugated with isoniazid, which were further loaded with amphotericin B (ISO-NPs-AMP) to cause potent antiamoebic effects against Acanthamoeba castellanii. The IC50 of isoniazid conjugated with magnetic nanoparticles and loaded with amphotericin B was found to be 45 μg/mL against Acanthamoeba castellanii trophozoites and 50 μg/mL against cysts. The results obtained in this study have promising implications in drug discovery as these nanomaterials exhibited high trophicidal and cysticidal effects, as well as limited cytotoxicity against rat and human cells.
Talaromycosis typically occurs as an opportunistic infection among immunocompromised individuals. Infection caused by species other than T. marneffei is uncommon. While most reported cases describe infection in the lungs, we report an extremely rare intracranial Talaromyces species infection. This 61-year-old with end-stage renal disease who was unwell for the previous two months, presented with fever and worsening confusion lasting for three days. Lumbar puncture was suggestive of meningitis. Cerebrospinal fluid (CSF) culture was later confirmed to be Penicillium chrysogenum. The patient was co-infected with Group B Streptococcus sepsis. He improved with amphotericin B and ceftriaxone and was discharged with oral itraconazole for four weeks. However, he died of unknown causes two weeks later at home. Talaromyces species infection in the central nervous system is uncommon. This case highlighted a rare but life-threatening fungal meningitis. Among the four reported cases worldwide, none of the patients survived.
Invasive aspergillosis predominantly occurs in immunocompromised patients and is often resistant to different therapeutically strategies. However, mortality significantly increases if the central nervous system is affected. In this report we describe two cases of invasive aspergilosis, one with kidney involvement with a successful treatment while the other with pulmonary and cerebral involvement with a grave outcome.
Matched MeSH terms: Amphotericin B/therapeutic use
Parasitic infections have remained a significant burden on human and animal health. In part, this is due to lack of clinically-approved, novel antimicrobials and a lack of interest by the pharmaceutical industry. An alternative approach is to modify existing clinically-approved drugs for efficient delivery formulations to ensure minimum inhibitory concentration is achieved at the target site. Nanotechnology offers the potential to enhance the therapeutic efficacy of drugs through modification of nanoparticles with ligands. Amphotericin B, nystatin, and fluconazole are clinically available drugs in the treatment of amoebal and fungal infections. These drugs were conjugated with gold nanoparticles. To characterize these gold-conjugated drug, atomic force microscopy, ultraviolet-visible spectrophotometry and Fourier transform infrared spectroscopy were performed. These drugs and their gold nanoconjugates were examined for antimicrobial activity against the protist pathogen, Acanthamoeba castellanii of the T4 genotype. Moreover, host cell cytotoxicity assays were accomplished. Cytotoxicity of these drugs and drug-conjugated gold nanoparticles was also determined by lactate dehydrogenase assay. Gold nanoparticles conjugation resulted in enhanced bioactivity of all three drugs with amphotericin B producing the most significant effects against Acanthamoeba castellanii (p ＜ 0.05). In contrast, bare gold nanoparticles did not exhibit antimicrobial potency. Furthermore, amoebae treated with drugs-conjugated gold nanoparticles showed reduced cytotoxicity against HeLa cells. In this report, we demonstrated the use of nanotechnology to modify existing clinically-approved drugs and enhance their efficacy against pathogenic amoebae. Given the lack of development of novel drugs, this is a viable approach in the treatment of neglected diseases.