Necesidad de una disponibilidad real de fármacos oculares tópicos antifúngicos y antiamebianos en el Sistema Sanitario Español / Need for real availability of topical anti-fungal and anti-amoeba eye drugs in the Spanish Health System

No disponible

Clinical mycology in Latin America and the Caribbean: A snapshot of diagnostic and therapeutic capabilities.

Despite the existence of endemic mycoses in Latin America and the Caribbean, in addition to a large population of patients at risk for invasive mycoses, the capability of medical centres to perform a proper diagnosis in mycology has not been studied in the region. Moreover, availability of antifungal drugs in the region is unknown. Here, we report the results of a survey involving 129 centres in 24 countries. Only 9% of centres would have the potential to apply for the minimum standards in mycology, as determined by the European Confederation of Medical Mycology. There is an urgent need to improve diagnostic conditions in Latin America and the Caribbean, as well as providing access to safer and more efficacious antifungal drugs.

Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries.

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.

A qualitative evaluation of an implementation study for cryptococcal antigen screening and treatment in Uganda.

Cryptococcal meningiti s causes 15% of AIDS-related deaths globally. Screening and preemptive treatment for cryptococcal antigen (CrAg) in the blood of persons with advanced HIV/AIDS reduces mortality. National and international HIV guidelines recommend CrAg screening; however, implementation studies and evaluations of how to integrate CrAg screening programs into existing HIV care infrastructure are lacking.During a CrAg screening program in Kampala, Uganda, we interviewed 15 health care workers (2 coordinating research nurses and 13 clinic personnel) from 6 HIV clinics between March and April 2017, to identify barriers to implementation as well as facilitating factors for program success. The interviews were coded and themes compiled.We found key factors for successful implementation of a CrAg screening program were: adequate supplies of fluconazole and CrAg lateral flow assay (LFA) point-of-care tests, timely patient follow-up, and quick turnaround time of laboratory results. Although both CrAg LFA kits and fluconazole are on the national formulary, stockouts are common, affecting patient care. The CrAg screening recommendation by national HIV guidelines remains integral to the success of the program, as overburdened clinics are otherwise reluctant to adopt additional screening. Collaboration with Ministries of Health for support with enforcing national guidelines, and procuring supplies is paramount to a successful CrAg screening program.Development of a CrAg screening and treatment program within the HIV clinic infrastructure has a number of barriers. Education and training of clinic staff, along with partnership with the Ministry of Health to ensure adequate supplies, facilitated the program.

Treatment for HIV-associated cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis is a severe fungal infection that occurs primarily in the setting of advanced immunodeficiency and remains a major cause of HIV-related deaths worldwide. The best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis is unclear, particularly in resource-limited settings where management of drug-related toxicities associated with more potent antifungal drugs is a challenge. OBJECTIVES: To evaluate the best induction therapy to reduce mortality from HIV-associated cryptococcal meningitis; to compare side effect profiles of different therapies. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE (PubMed), Embase (Ovid), LILACS (BIREME), African Index Medicus, and Index Medicus for the South-East Asia Region (IMSEAR) from 1 January 1980 to 9 July 2018. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the ISRCTN registry; and abstracts of select conferences published between 1 July 2014 and 9 July 2018. SELECTION CRITERIA: We included randomized controlled trials that compared antifungal induction therapies used for the first episode of HIV-associated cryptococcal meningitis. Comparisons could include different individual or combination therapies, or the same antifungal therapies with differing durations of induction (less than two weeks or two or more weeks, the latter being the current standard of care). We included data regardless of age, geographical region, or drug dosage. We specified no language restriction. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardized forms. The main outcomes included mortality at 2 weeks, 10 weeks, and 6 months; mean rate of cerebrospinal fluid fungal clearance in the first two weeks of treatment; and Division of AIDS (DAIDS) grade three or four laboratory events. Using random-effects models we determined pooled risk ratio (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean differences (MD) and 95% CI for continuous outcomes. For the direct comparison of 10-week mortality, we assessed the certainty of the evidence using the GRADE approach. We performed a network meta-analysis using multivariate meta-regression. We modelled treatment differences (RR and 95% CI) and determined treatment rankings for two-week and 10-week mortality outcomes using surface under the cumulative ranking curve (SUCRA). We assessed transitivity by comparing distribution of effect modifiers between studies, local inconsistency through a node-splitting approach, and global inconsistency using design-by-treatment interaction modelling. For the network meta-analysis, we applied a modified GRADE approach for assessing the certainty of the evidence for 10-week mortality. MAIN RESULTS: We included 13 eligible studies that enrolled 2426 participants and compared 21 interventions. All studies were carried out in adults, and all but two studies were conducted in resource-limited settings, including 11 of 12 studies with 10-week mortality data.In the direct pairwise comparisons evaluating 10-week mortality, one study from four sub-Saharan African countries contributed data to several key comparisons. At 10 weeks these data showed that those on the regimen of one-week amphotericin B deoxycholate (AmBd) and flucytosine (5FC) followed by fluconazole (FLU) on days 8 to 14 had lower mortality when compared to (i) two weeks of AmBd and 5FC (RR 0.62, 95% CI 0.42 to 0.93; 228 participants, 1 study), (ii) two weeks of AmBd and FLU (RR 0.58, 95% CI 0.39 to 0.86; 227 participants, 1 study), (iii) one week of AmBd with two weeks of FLU (RR 0.49, 95% CI 0.34 to 0.72; 224 participants, 1 study), and (iv) two weeks of 5FC and FLU (RR 0.68, 95% CI 0.47 to 0.99; 338 participants, 1 study). The evidence for each of these comparisons was of moderate certainty. For other outcomes, this shortened one-week AmBd and 5FC regimen had similar fungal clearance (MD 0.05 log10 CFU/mL/day, 95% CI -0.02 to 0.12; 186 participants, 1 study) as well as lower risk of grade three or four anaemia (RR 0.31, 95% CI 0.16 to 0.60; 228 participants, 1 study) compared to the two-week regimen of AmBd and 5FC.For 10-week mortality, the comparison of two weeks of 5FC and FLU with two weeks of AmBd and 5FC (RR 0.92, 95% CI 0.69 to 1.23; 340 participants, 1 study) or two weeks of AmBd and FLU (RR 0.85, 95% CI 0.64 to 1.13; 339 participants, 1 study) did not show a difference in mortality, with moderate-certainty evidence for both comparisons.When two weeks of combination AmBd and 5FC was compared with AmBd alone, pooled data showed lower mortality at 10 weeks (RR 0.66, 95% CI 0.46 to 0.95; 231 participants, 2 studies, moderate-certainty evidence).When two weeks of AmBd and FLU was compared to AmBd alone, there was no difference in 10-week mortality in pooled data (RR 0.94, 95% CI 0.55 to 1.62; 371 participants, 3 studies, low-certainty evidence).One week of AmBd and 5FC followed by FLU on days 8 to 14 was the best induction therapy regimen after comparison with 11 other regimens for 10-week mortality in the network meta-analysis, with an overall SUCRA ranking of 88%. AUTHORS' CONCLUSIONS: In resource-limited settings, one-week AmBd- and 5FC-based therapy is probably superior to other regimens for treatment of HIV-associated cryptococcal meningitis. An all-oral regimen of two weeks 5FC and FLU may be an alternative in settings where AmBd is unavailable or intravenous therapy cannot be safely administered. We found no mortality benefit of combination two weeks AmBd and FLU compared to AmBd alone. Given the absence of data from studies in children, and limited data from high-income countries, our findings provide limited guidance for treatment in these patients and settings.

Anti-Candida albicans natural products, sources of new antifungal drugs: A review.

INTRODUCTION: Candida albicans is the most prevalent fungal pathogen in humans. Due to the development of drug resistance, there is today a need for new antifungal agents for the efficient management of C. albicans infections. Therefore, we reviewed antifungal activity, mechanisms of action, possible synergism with antifungal drugs of all natural substances experimented to be efficient against C. albicans for future. METHODS: An extensive and systematic review of the literature was undertaken and all relevant abstracts and full-text articles analyzed and included in the review. REVIEW: A total of 111 documents were published and highlighted 142 anti-C. albicans natural products. These products are mostly are reported in Asia (44.37%) and America (28.17%). According to in vitro model criteria, from the 142 natural substances, antifungal activity can be considered as important for 40 (28.20%) and moderate for 24 (16.90%). Sixteen products have their antifungal activity confirmed by in vivo gold standard experimentation. Microbial natural products, source of antifungals, have their antifungal mechanism well described in the literature: interaction with ergosterol (polyenes), inhibition 1,3-ß-d-glucan synthase (Echinocandins), inhibition of the synthesis of cell wall components (chitin and mannoproteins), inhibition of sphingolipid synthesis (serine palmitoyltransferase, ceramide synthase, inositol phosphoceramide synthase) and inhibition of protein synthesis (sordarins). Natural products from plants mostly exert their antifungal effects by membrane-active mechanism. Some substances from arthropods are also explored to act on the fungal membrane. Interestingly, synergistic effects were found between different classes of natural products as well as between natural products and azoles. CONCLUSION: Search for anti-C. albicans new drugs is promising since the list of natural substances, which disclose activity against this yeast is today long. Investigations must be pursued not only to found more new anti-Candida compounds from plants and organisms but also to carried out details on molecules from already known anti-Candida compounds and to more elucidate mechanisms of action.

Antifungal drug development: challenges, unmet clinical needs, and new approaches.

Invasive, life-threatening fungal infections are an important cause of morbidity and mortality, particularly for patients with compromised immune function. The number of therapeutic options for the treatment of invasive fungal infections is quite limited when compared with those available to treat bacterial infections. Indeed, only three classes of molecules are currently used in clinical practice and only one new class of antifungal drugs has been developed in the last 30 years. Here we summarize the unmet clinical needs of current antifungal therapy, discuss challenges inherent to antifungal drug discovery and development, and review recent developments aimed at addressing some of these challenges.

Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal.

Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.

A critical comparison between the World Health Organization list of essential medicines for children and the Brazilian list of essential medicines (Rename).

OBJECTIVE: To perform a critical comparison between the Brazilian national essential medicines list (Rename, 2012) with the list of essential medicines for children (LEMC, 2011) of the World Health Organization (WHO), regarding the differences among drugs and formulations listed for children. METHODS: The LEMC drugs were classified into four categories: 1) absent in Rename; 2) included in Rename but without any formulation suitable for children; 3) listed in Rename only in some formulations; 4) present in Rename in all formulations. The missing formulations were analyzed by therapeutic group. Alternatives present in Rename were searched. RESULTS: From the 261 drugs of interest on the LEMC, 30.3% are absent from Rename, 11.1% are in Rename but without any pediatric formulation, and 32.2% are present in some but not all formulations listed in LEMC. Considering all formulations items listed in the LEMC (n = 577), 349 are missing from Rename, of these 19.6% due to their strength, and 18.5% due to the the dosage form. Useful formulations specific for neonatal care, respiratory tract, central nervous system, and anti-infectives, among other groups, are missing. CONCLUSION: The lack of age-appropriate formulations of essential medicines for children in Brazil includes important therapeutic groups and indispensable drugs for severe clinical conditions. Some of these products exist in the Brazilian pharmaceutical market, but not in public facilities; others could be produced by national laboratories with commercial interest or stimulated by a specific governmental policy, as in other countries.

Uma comparação crítica entre a Lista de Medicamentos Essenciais para Crianças da Organização Mundial de Saúde e a Relação Nacional de Medicamentos Essenciais (Rename) / A critical comparison between the World Health Organization list of essential medicines for children and the Brazilian list of essential medicines (Rename)

OBJECTIVE: To perform a critical comparison between the Brazilian national essential medicines list (Rename, 2012) with the list of essential medicines for children (LEMC, 2011) of the World Health Organization (WHO), regarding the differences among drugs and formulations listed for children. METHODS: The LEMC drugs were classified into four categories: 1) absent in Rename; 2) included in Rename but without any formulation suitable for children; 3) listed in Rename only in some formulations; 4) present in Rename in all formulations. The missing formulations were analyzed by therapeutic group. Alternatives present in Rename were searched. RESULTS: From the 261 drugs of interest on the LEMC, 30.3% are absent from Rename, 11.1% are in Rename but without any pediatric formulation, and 32.2% are present in some but not all formulations listed in LEMC. Considering all formulations items listed in the LEMC (n = 577), 349 are missing from Rename, of these 19.6% due to their strength, and 18.5% due to the the dosage form. Useful formulations specific for neonatal care, respiratory tract, central nervous system, and anti-infectives, among other groups, are missing. CONCLUSIONS: The lack of age-appropriate formulations of essential medicines for children in Brazil includes important therapeutic groups and indispensable drugs for severe clinical conditions. Some of these products exist in the Brazilian pharmaceutical market, but not in public facilities; others could be produced by national laboratories with commercial interest or stimulated by a specific governmental policy, as in other countries.

OBJETIVO: Realizar uma comparação crítica entre a Relação Nacional de Medicamentos Essenciais (Rename, 2012) e a Lista de Medicamentos Essenciais para Crianças (LMEC, 2011) da Organização Mundial de Saúde (OMS), com relação às diferenças entre os medicamentos e as formulações listadas para crianças. MÉTODOS: Os medicamentos da LMEC foram classificados em quatro grupos: 1) não constam na Rename; 2) constam na Rename, porém sem qualquer formulação adequada para crianças; 3) listados na Rename apenas com algumas formulações; 4) constam na Rename em todas as formulações. As formulações que faltam foram analisadas por grupos terapêuticos. As alternativas presentes na Rename foram pesquisadas. RESULTADOS: Dos 261 medicamentos de interesse listados na LMEC, 30,3% não estão presentes na Rename, 11,1% estão na Rename, mas sem qualquer formulação pediátrica, e 32,3% estão presentes em algumas, mas não todas as formulações listadas na LMEC. Considerando todos os itens de formulações listados na LMEC (n = 577), 349 não constam na Rename, desses, 19,6% devido à intensidade de dosagem, e 18,5% devido à forma farmacêutica. Faltam formulações úteis específicas para cuidado neonatal, trato respiratório e sistema nervoso central, anti-infecciosos, entre outros grupos. CONCLUSÃO: A ausência de formulações adequadas à idade de medicamentos essenciais para crianças no Brasil inclui importantes grupos terapêuticos e medicamentos indispensáveis para quadros clínicos graves. Alguns desses produtos são encontrados no mercado farmacêutico brasileiro, porém não existem em unidades públicas; outros poderiam ser produzidos por laboratórios nacionais com interesse comercial ou estimulados por uma política governamental específica, como é feito em outros países.

Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings.

BACKGROUND: Despite the advent and increasingly wide availability of antiretroviral therapy, cryptococcal meningitis (CM) remains a significant cause of mortality and morbidity amongst individuals with HIV infection in resource-limited settings. The ideal management of CM remains unclear. The aim of this review is to assess the evidence for deciding on which antifungal regimen to use as well as other modalities of management to utilise especially resource poor settings in order to achieve the best possible outcome and enable an individual with CM to survive their acute illness and benefit from antiretroviral therapy. OBJECTIVES: To determine the most effective initial and consolidation treatment strategy for CM in HIV infected adults. SEARCH STRATEGY: The Cochrane HIV/AIDS group search strategy was used. Key words in the search included, meningitis, cryptococcus neoformans, treatment, trial, human immunodeficiency virus, acquired immunodeficiency syndrome, antifungal agents, amphotericin, flucytosine, fluconazole, azole, lumbar puncture, cerebrospinal fluid (CSF) pressure and acetazolamide. SELECTION CRITERIA: Randomised of HIV-infected adults with a first episode of CM diagnosed on CSF examination, by India ink staining, CSF culture or cryptococcal antigen testing. DATA COLLECTION AND ANALYSIS: Data were extracted using standardised forms and analysed using Rev Man 4.2.7 software. MAIN RESULTS: Six studies are included in the review. Five of the studies compared antifungal treatments and one study addressed lowering intracranial pressure. This study was stopped early due to excess adverse effects. The results of the other five studies as summarised as follows.Mayanja-Kizza 1998 compared fluconazole to fluconazole with 5 flucytosine. The dose of fluconazole used 200mg initially is lower than the recommended initial dose of 400mg. No survival advantage was found with the use of 5 flucytosine in addition to fluconazole.Two studies Brouwer 2004 and van der Horst 1997 compared Amphotericin (AmB) to AmB with 5 flucytosine. Both drugs were given at currently recommended doses for 2 weeks. No survival difference was found at 14 days or at 10 weeks (only recorded in Brouwer 2004). There were significantly more patients with sterile CSF cultures at 14 days in the group that received AmB with flucytosine.Brouwer 2004 compared AmB given alone to AmB given with flucytosine and fluconazole alone or in combination. This was a small study and no differences in mortality were noted between the groups.Bicanic 2008 compared high to standard dose AmB both with flucytosine. There was no difference in mortality between the two groups or adverse events.Leenders 1997 compared standard AmB to liposomal AmB. There was no difference in death rates between the two groups. But there were significantly fewer side effects in the group treated with liposomal AmB. AUTHORS' CONCLUSIONS: The main aim of this review was to determine the best treatment for cryptococcal meningitis in resource-limited settings. In these settings usually only AmB and fluconazole are available. No studies suitable for inclusion in the review were found that compared these two drugs. Therefore we are unable to recommend either treatment as superior to the other. The recommended treatment for CM is a combination of AmB and flucytosine. The optimal dosing of AmB remains unclear. Liposomal AmB is associated with less adverse events than AmB and may be useful in selected patients where resources allow.Future research into the management of cryptococcal meningitis in resource-limited settings should focus on the most effective use of medications that are available in these settings.Flucytosine in combination with AmB leads to faster and increased sterilisation of CSF compared to using AmB alone. As Flucytosine is often not available in developing countries, policy makers and national departments of heath should consider procuring this drug for HIV treatment programmes.

Caspofungin in the treatment of invasive fungal infections.

Caspofungin is a member of a new class of antifungals called Echinocandins and is the first to have marketing authorisation in the United Kingdom. This article reviews the clinical efficacy, side effect profile, dosing and administration schedule of caspofungin. The article also discusses the warnings and precautions associated with the use of this drug. Caspofungin is an effective treatment option in the management of fungal infections.

Antifungal agents in children.

Fungal pathogens are an increasingly recognized complication of organ transplantation and the ever more potent chemotherapeutic regimens for childhood malignancies. This article provides a brief overview of the current state of systemic antifungal therapy. Currently licensed drugs, including amphotericin B and its lipid derivates; 5-fluorocytosine; the azoles, including fluconazole, itraconazole, and voriconazole; and a representative of the new class of echinocandin agents, caspofungin, are discussed. Newer second-generation azoles (posaconazole and ravuconazole) and echinocandins (micafungin and anidulafungin) that are likely to be licensed in the United States in the next few years also are addressed.