Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries

Loyse, Angela; Thangaraj, Harry; Easterbrook, Philippa; Ford, Nathan; Roy, Monika; Chiller, Tom; Govender, Nelesh P.; Harrison, Thomas S.; Bicanic, Tihana

doi:10.1016/s1473-3099(13)70078-1

Cited by 163 publications

(149 citation statements)

References 58 publications

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“…However, several liposomal drugs are either approved for clinical use or in clinical trial studies (Table 1). [48][49][50][51][52][53][54][55][56][57][58][59] Optimizing the ideal liposome for crossing the BBB has important implications for the treatment of neurological diseases. Different liposomal formulations and strategies have been developed for enhancing drug delivery across the BBB.…”

Section: Introductionmentioning

confidence: 99%

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

Vieira

Gamarra

2016

IJN

356

238

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This review summarizes articles that have been reported in literature on liposome-based strategies for effective drug delivery across the blood–brain barrier. Due to their unique physicochemical characteristics, liposomes have been widely investigated for their application in drug delivery and in vivo bioimaging for the treatment and/or diagnosis of neurological diseases, such as Alzheimer’s, Parkinson’s, stroke, and glioma. Several strategies have been used to deliver drug and/or imaging agents to the brain. Covalent ligation of such macromolecules as peptides, antibodies, and RNA aptamers is an effective method for receptor-targeting liposomes, which allows their blood–brain barrier penetration and/or the delivery of their therapeutic molecule specifically to the disease site. Additionally, methods have been employed for the development of liposomes that can respond to external stimuli. It can be concluded that the development of liposomes for brain delivery is still in its infancy, although these systems have the potential to revolutionize the ways in which medicine is administered.

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Section: Introductionmentioning

confidence: 99%

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

Vieira

Gamarra

2016

IJN

356

238

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“…Sub-Saharan Africa, with the highest HIV burden, is the most affected region, accounting for 80% of all CM-associated mortality, despite access to antiretroviral therapy (ART) (2,3).…”

Section: Introductionmentioning

confidence: 99%

Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis

Sabiiti¹,

Robertson²,

Beale³

et al. 2014

J. Clin. Invest.

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134

173

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Background. Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis.Methods. Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis.Results. High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003).Conclusion. These findings underscore the contribution of cryptococcal-phagocyte interactions and laccasedependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM.

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“…Fluconazole monotherapy relies on the assumption that the organism is not resistant to fluconazole, yet drug susceptibility testing is uncommon in sub-Saharan Africa. Additionally, low-dose preemptive therapy over multiple weeks could lead to the selection of resistant organisms, with limited alternative treatment options available (14). Recently, it has been shown that the antidepressant sertraline (Zoloft; Pfizer, New York) may exhibit antifungal properties against C. neoformans by inhibiting protein translation (15).…”

mentioning

confidence: 99%

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

Smith

Achan

Hullsiek

et al. 2015

Antimicrob Agents Chemother

167

132

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iCryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/l, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC 50 of 4 g/ml and an MIC 90 of 8 g/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC 50 to 8 g/ml and an MIC 90 value of 32 g/ml, with 31% of isolates with a fluconazole MIC of >16 g/ml. We observed an amphotericin B MIC 50 of 0.5 g/ml and an MIC 90 of 1 g/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzed Cryptococcus susceptibility to sertraline, with an MIC 50 of 4 g/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P ‫؍‬ 0.52).

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Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries

Cited by 163 publications

References 58 publications

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

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Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries

Cited by 163 publications

References 58 publications

Getting into the brain: liposome-based strategies for effective drug delivery across the blood&ndash;brain barrier

Getting into the brain: liposome-based strategies for effective drug delivery across the blood&ndash;brain barrier

Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

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Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier