- Management of amphotericin-induced phlebitis among HIV patients with cryptococcal meningitis in a resource-limited setting: a prospective cohort study. [Journal Article]
- BIBMC Infect Dis 2019 Jun 26; 19(1):558
- CONCLUSIONS: Amphotericin-induced phlebitis is common with amphotericin, yet phlebitis is a preventable complication even in resource-limited settings.
- Absence of cutaneous involvement in disseminated Talaromyces marneffei infection in an AIDS patient: a case report and literature review. [Case Reports]
- IDInfect Drug Resist 2019; 12:1493-1499
- CONCLUSIONS: Talaromycosis is a fairly common opportunistic infection among AIDS patients in Thailand, despite a rise in CD4 count which may reflect a change in immune status. To a lesser extent, a systemic disease without skin involvement can be expected in real clinical practice.
- Preclinical Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antifungal Activity of Liposomal Amphotericin B. [Journal Article]
- CIClin Infect Dis 2019 May 02; 68(Supplement_4):S244-S259
- The improved safety profile and antifungal efficacy of liposomal amphotericin B (LAmB) compared to conventional amphotericin B deoxycholate (DAmB) is due to several factors including, its chemical co…
The improved safety profile and antifungal efficacy of liposomal amphotericin B (LAmB) compared to conventional amphotericin B deoxycholate (DAmB) is due to several factors including, its chemical composition, rigorous manufacturing standards, and ability to target and transit through the fungal cell wall. Numerous preclinical studies have shown that LAmB administered intravenously distributes to tissues frequently infected by fungi at levels above the minimum inhibitory concentration (MIC) for many fungi. These concentrations can be maintained from one day to a few weeks, depending upon the tissue. Tissue accumulation is dose-dependent with drug clearance occurring most rapidly from the brain and slowest from the liver and spleen. LAmB localizes in lung epithelial lining fluid, within liver and splenic macrophages and in kidney distal tubules. LAmB has been used successfully in therapeutic and prophylactic animal models to treat many different fungal pathogens, significantly increasing survival and reducing tissue fungal burden.
- Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis. [Journal Article]
- MBIOMBio 2019 May 28; 10(3)
- Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivalin…
Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivaling the impact of tuberculosis and malaria. However, the most effective antifungal agent, amphotericin B, requires intravenous delivery and has significant renal and hematopoietic toxicity, making it difficult to utilize, especially in resource-limited settings. The present studies describe a new nanoparticle crystal encapsulated formulation of amphotericin B known as encochleated amphotericin B (CAmB) that seeks to provide an oral formulation that is low in toxicity and cost. Using a 3-day delayed model of murine cryptococcal meningoencephalitis and a large inoculum of a highly virulent strain of serotype A C. neoformans, CAmB, in combination with flucytosine, was found to have efficacy equivalent to parental amphotericin B deoxycholate with flucytosine and superior to oral fluconazole without untoward toxicity. Transport of fluorescent CAmB particles to brain as well as significant brain levels of amphotericin drug was demonstrated in treated mice, and immunological profiles were similar to those of mice treated with conventional amphotericin B. Additional toxicity studies using a standardized rat model showed negligible toxicity after a 28-day treatment schedule. These studies thus offer the potential for an efficacious oral formulation of a known fungicidal drug against intrathecal cryptococcal disease.IMPORTANCE Cryptococcus neoformans is a significant global fungal pathogen that kills an estimated quarter of a million HIV-infected individuals yearly and has poor outcomes despite therapy. The most effective therapy, amphotericin B, is highly effective in killing the fungus but is available only in highly toxic, intravenous formulations that are unavailable in most of the developing world, where cryptococcal disease in most prevalent. For example, in Ethiopia, reliance on the orally available antifungal fluconazole results in high mortality, even when initiated as preemptive therapy at the time of HIV diagnosis. Thus, alternative agents could result in significant saving of lives. Toward this end, the present work describes the development of a new formulation of amphotericin B (CAmB) that encapsulates the drug as a crystal lipid nanoparticle that facilitates oral absorption and prevents toxicity. Successful oral absorption of the drug was demonstrated in a mouse model that, in combination with the antifungal flucytosine, provided efficacy equal to a parental preparation of amphotericin B plus flucytosine. These studies demonstrate the potential for CAmB in combination with flucytosine to provide an effective oral formulation of a well-known, potent fungicidal drug combination.
- Fluconazole plus flucytosine is a good alternative therapy for non-HIV and non-transplant-associated cryptococcal meningitis: A retrospective cohort study. [Journal Article]
- MMycoses 2019; 62(8):686-691
- Cryptococcal meningitis (CM) carries a high risk of mortality with increasing incidences in immune competent hosts. Current treatments are not well tolerated, and evaluation of other treatments is ne…
Cryptococcal meningitis (CM) carries a high risk of mortality with increasing incidences in immune competent hosts. Current treatments are not well tolerated, and evaluation of other treatments is needed. Fluconazole and 5-flucytosine in treating immune competent hosts have not been characterised. To evaluate the efficacy of fluconazole and 5-flucytosine in treating non-HIV- and non-transplant-associated CM. We performed a retrospective cohort study of the outcomes in immune competent patients with CM treated with fluconazole and 5-flucytosine or deoxycholate-amphotericin B and 5-flucytosine. The primary outcome was treatment response evaluated at the 12th week after initiation of antifungal therapy. A total of 43 and 47 patients received amphotericin B deoxycholate and 5-flucytosine or fluconazole and 5-flucytosine, respectively. A total of 38 (88.4%) patients cannot tolerate recommended doses of amphotericin B deoxycholate and 5-flucytosine (patients needed dose reduction during the treatment). Patients given fluconazole and 5-flucytosine had higher baseline cryptococcal burdens (median 3632 versus 900 cryptococci/mL, P = 0.008). No significant differences were seen in cryptococcus clearance (74.4% vs 70.2%, P = 0.814), treatment time (39 days, 20-69 days vs 21 days, 7-63 days, P = 0.107) and successful response (including complete and partial responses) rates (69.7% vs 72.3%, P = 0.820). Fluconazole and 5-flucytosine treatment had lower total adverse events (19.1% vs 90.7%, P < 0.001). Fluconazole and 5-flucytosine had relatively high efficacy with few adverse events in treating CM. Fluconazole and 5-flucytosine therapy is promising in patients that do not tolerate or are not suited for amphotericin B deoxycholate treatment.
- Lipsosomal amphotericin B: a review of its properties, function, and use for treatment of cutaneous leishmaniasis. [Journal Article]
- RRRes Rep Trop Med 2019; 10:11-18
- The genus Leishmania includes a number of protozoan parasites that cause a wide range of infections named leishmaniasis. Leishmaniasis may be appear in three clinical forms - cutaneous (CL), visceral…
The genus Leishmania includes a number of protozoan parasites that cause a wide range of infections named leishmaniasis. Leishmaniasis may be appear in three clinical forms - cutaneous (CL), visceral, and mucocutaneous (MCL) - with variation in their presentation and severity: diffuse CL and post-kala-azar dermal leishmaniasis). The prevalent signs of CL are nonhealing ulcers on exposed skin, but infected patients may have other dermatologic symptoms. In the 1960s, amphotericin B deoxycholate was introduced as a second-line therapy for CL and MCL. However, widespread administration of the agent was prevented, due to its renal and systemic toxicity, high price, and obstacles to intravenous use in leishmaniasis-endemic regions. Amphotericin B binds to ergosterol in the photogenic cell membranes and causes changes in membrane permeability, leakage of ions, and finally cell death. Compared to amphotericin B deoxycholate, a higher dose of liposomal amphotericin B should be administered to show the treatment effect. A high percentage of liposomal amphotericin B is "fastened" in the liposome and not biologically effective. Amphotericin B deoxycholate has some toxic effects, and liposomal amphotericin B is meaningfully less toxic compared to it. Treatment options for CL are limited, due to variation in species causing CL and pharmacokinetic issues. Amphotericin B is effective against some particular forms of CL.
- Nitroglycerin-Citrate-Ethanol Catheter Lock Solution Is Highly Effective for In Vitro Eradication of Candida auris Biofilm. [Journal Article]
- AAAntimicrob Agents Chemother 2019; 63(7)
- Candida auris poses emerging risks for causing severe central line-associated bloodstream infections. We tested in vitro the ability of antifungal lock solutions to rapidly eradicate C. auris biofilm…
Candida auris poses emerging risks for causing severe central line-associated bloodstream infections. We tested in vitro the ability of antifungal lock solutions to rapidly eradicate C. auris biofilms. Liposomal amphotericin B, amphotericin B deoxycholate, fluconazole, voriconazole, micafungin, caspofungin, and anidulafungin failed to completely eradicate all 10 tested C. auris biofilms. Conversely, nitroglycerin-citrate-ethanol (NiCE) catheter lock solution completely eradicated all replicates for all of C. auris biofilms tested.
- Apparent interference with extracorporeal membrane oxygenation by liposomal amphotericin B in a patient with disseminated blastomycosis receiving continuous renal replacement therapy. [Journal Article]
- AJAm J Health Syst Pharm 2019 Apr 17
- CONCLUSIONS: A 50-year-old African American man presented for dyspnea and cough and was noted to have blastomycosis on bronchoscopy. He developed respiratory failure and acute kidney injury, requiring mechanical ventilation, ECMO, and CRRT. After 4 days of liposomal amphotericin, the transmembrane pressure gradient on the membrane oxygenator increased dramatically without visualization of a clot, requiring a circuit exchange. A trough amphotericin B level taken the day before the exchange was undetectable for amphotericin B. After the circuit exchange, the patient was switched to amphotericin B deoxycholate. A subsequent trough level was 3.8 μg/mL. The patient improved and was able to be decannulated. However, he did require tracheostomy and long-term hemodialysis.In our case we believe that liposomal amphotericin B was significantly removed by ECMO and was responsible for the failure of the ECMO circuit. We would suggest amphotericin B deoxycholate be used in such patients preferentially and that serum levels of the drug be assessed when possible.
- A Rhinofacial Conidiobolus coronatus Fungal Infection Presenting as an Intranasal Tumour. [Case Reports]
- SQSultan Qaboos Univ Med J 2018; 18(4):e549-e552
- Conidiobolomycosis is a rare fungal infection that affects adults in tropical regions. We report a 42-year-old male patient who was referred to the Sulaiman Al Habib Hospital, Dubai, United Arab Emir…
Conidiobolomycosis is a rare fungal infection that affects adults in tropical regions. We report a 42-year-old male patient who was referred to the Sulaiman Al Habib Hospital, Dubai, United Arab Emirates (UAE), in 2013 with excessive nasal bleeding and a suspected nasal tumour. He reported having briefly visited central India nine months previously. Computed tomography and magnetic resonance imaging showed a highly vascularised mass in the nasal cavity. However, after surgical excision, initial treatment with amphotericin B deoxycholate was unsuccessful and the disease progressed, leading to external and internal nasal deformation and necessitating further excision and facial reconstruction. Histopathological analysis of the second biopsy revealed Splendore-Hoeppli changes consistent with a fungal infection. Microbiological findings subsequently confirmed Conidiobolus coronatus. Subsequently, the patient was successfully treated with a combination of itraconazole and fluconazole. To the best of the authors' knowledge, this is the first report of a case of rhinofacial conidiobolomycosis from the UAE.
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- Trending serial CSF samples to guide treatment of refractory coccidioidal meningitis with intrathecal liposomal amphotericin. [Journal Article]
- CNClin Neurol Neurosurg 2019; 181:41-43
- Intrathecal amphotericin B deoxycholate (AmB-d) can be prescribed as an adjunct to systemic therapy for severe or recalcitrant cases coccidioidal meningitis. Recently intravenous (IV) Liposomal ampho…
Intrathecal amphotericin B deoxycholate (AmB-d) can be prescribed as an adjunct to systemic therapy for severe or recalcitrant cases coccidioidal meningitis. Recently intravenous (IV) Liposomal amphotericin B (L-AmB) has been recommended as monotherapy therapy for refractory coccidioidal meningitis based on its advantages over (AmB-d), however, its intrathecal use has not been reported. Moreover, there is nothing in the literature quantifying clinical improvement with objective laboratory data in human patients. Consequently, there are no guidelines on how to monitor regularly for improvement of coccidioidal meningitis with treatment of intrathecal L-AmB. The present case addresses both of these. We report intrathecal use of L-AmB for refractory coccidioidal meningitis. Our data demonstrate that there is a correlation between clinical improvement and a decrease in cerebrospinal fluid (CSF) white blood cells (WBC's), protein, and coccidioidal titers with treatment of intrathecal L-AmB with serial collection of CSF studies at the same site, in our case via collection through an external ventricular drain (EVD). As a result, one may postulate that serial CSF collection can be used to monitor the treatment of coccidioidal meningitis; however this case also addresses the risk of developing ventriculitis with sustained EVD placement.