Ketoconazole withdrawn by FDA, for almost all indications
July 30 2013
Ketoconazole withdrawn by FDA, for almost all indications
Ketoconazole, the world’s first oral azole antifungal, is being retired by the FDA. First launched by Janssen Pharmaceutica (Belgium) in 1985, it transformed the treatment of oral and oesophageal candidiasis and some endemic mycoses such as coccidioidomycosis. This week, the FDA restricted its use to the occasional patient with endemic mycoses, as a last resort.
The FDA cites “severe liver injuries and adrenal gland problems, and advising that it can lead to harmful drug interactions with other medications”, as the reason for it shift in position. Early after launch, ketoconazole was extensively used for skin fungal infections, and was very effective for many and convenient. Unfortunately about 1 in 10,000-15,000 developed severe hepatic reactions, which were either fatal, or more recently required transplantation. Adrenal dysfunction is also a significant issue.
The European Medicines Agency’s (EMA's) Committee on Medicinal Products for Human Use has also recommended that the marketing authorisations of oral ketoconazole-containing medicines should be suspended throughout the European Union (EU). The CHMP concluded that the risk of liver injury is greater than the benefits in treating fungal infections. (EMA report). The EMA recommends that patients currently taking oral ketoconazole for fungal infections should make a non-urgent appointment with their doctor to discuss suitable alternative treatments.
Ketoconazole tablets are used throughout the world, as it is less expensive than other antifungals, but its use should be curtailed for all but the shortest courses. Fluconazole is a much safer alternative. Ketoconazole (Nizoral) shampoo carries no risk.
What are the point of care tests for fungal infections
July 22 2013
Over recent decades the application of modern technologies has transformed the diagnosis of infectious diseases. A recent article in the New England Journal of Medicine (link) re-emphasises the difficulties and challenges of performing complex analytical procedures in resource limited and urban areas. Microscopic examination of sputum for tuberculosis is a good example. To overcome this and many other problems there has been an unrelenting drive to develop point of care tests (POCs) that do not require a sophisticated laboratory. Very few of these approaches have been applied to fungal infections.
The first generation of POC tests were designed to detect biomarkers such as antigens, antibodies and simple biochemical reactions. Such biomarkers are increasingly used in POCs for a wide range of infectious diseases, for example, syphilis, hepatitis, measles, schistosomiasis and trichomoniasis. Although not exactly POCs, latex agglutination tests for cryptococcal antigen and numerous ELISA platforms for Aspergillus circulating antigens have been in use since the 1970s. More recently, lateral flow devices of various hues have been developed and validated for cryptococcal antigen and an exoantigen of Aspergillus fumigatus.
The NEJM article tantalises us with second and third generation POCs appearing on the horizon, made possible with recent industry and donor investment. Second generation tests detect more complex and less accessible biomarkers such as nucleic acids and cell surface markers, and take advantage of advances in microfluidics, microelectronics, optical systems, and laboratory-on-a-chip nucleic acid test (NAT)-based amplification and detection techniques. NAT-based technologies have been applied to tuberculosis and drug-resistance screening, and testing of HIV viral load. We are told that additional applications are in the pipeline for other blood-borne and respiratory infections. Will pulmonary fungal infections be included?
African conference on fungal infections in AIDS
July 08 2013
Cape Town, South Africa. An EMBO sponsored workshop integrating clinical, public health and fundamental science aspects of fungal infections in AIDS was held July 3rd to 5th, 2013. Attendees from all over Africa, Asia, and the Americas discussed the changing status of fungal infections in AIDS, with a particular focus on cryptococcal meningitis. The HIV burden in South Africa was a dominant theme, with over 2 million patients on antiretroviral therapy, but an estimated additional 4 million HIV infected people still needing treatment. A remarkable 30% of pregnant women test positive for HIV, placing enormous numbers of people at risk of deadly fungal complications.
Other fungal infections were also highlighted, notably oral thrush, penicilliosis in SE Asia, paracoccidioidomycosis in Brazil, histoplasmosis in central America and aspergillosis complicating TB and HIV in Uganda.
The meeting was chaired by Professor Gordon Brown from Aberdeen and Cape Town universities. He said of the meeting: “The challenge of fungal infections in AIDS remains a ‘Clear and present danger’ to so many HIV-infected people. This high level workshop was designed to share international experiences and push forward the research agenda across many fronts.”
No access to life-saving drugs for cryptococcal meningitis in sub-Saharan Africa
June 10 2013
Cryptococcal meningitis kills everyone affected unless treated and this is not possible in several of the most needy African countries because the drugs are not available. In 2010 the Infectious Disease Society of America recommended combination amphotericin B and flucytosine. Despite this and the extraordinary 25 year international response to HIV, numerous sub-Saharan countries remain without either drug, and all without flucytosine. The alternative fluconazole is only 50% effective at best. Yet both amphotericin B and flucytosine have been available across the world-for over 50 years.
Dr Angela Loyse and colleagues most from St George’s Hospital, London have reviewed this access to treatment problem in a paper published this week in Lancet Infectious Diseases. They make a number of recommendations including:
• Improve estimates of cryptococcal meningitis disease burden
• Ensure wider dissemination of best clinical practice
• Include all cryptococcal meningitis drugs on WHO core Essential Medicines List
• Register antifungals in low-income and middle-income countries
• Pooled procurement of antifungals
• Increase competition through generation of generics
• Ensure preferential pricing for low-income and middle-income countries by pharmaceutical companies
• Ensure socially responsible licensing of intellectual property for new antifungals or formulations developed by research organisations
• Optimise existing antifungal strategies in clinical trials in low-income and middle-income countries
• Stimulate research and development of novel antifungals by designation of cryptococcal meningitis as a neglected disease
Other institutions involved included the HIV Department, World Health Organisation; Medicines Sans Frontieres, Cape Town; Mycotic Disease Branch, Centres for Disease Control, Atlanta; and the National Institute for
Communicable Diseases, Johannesburg.
Bioconference -Opportunities for better outcomes for systemic fungal disease: not relying on culture
May 28 2013
Online Bioconference LIVE on May 29 -31st, 2013. Featured Speaker Professor David Denning. Topic: "Opportunities for better outcomes for systemic fungal disease by not relying on culture". This Bioconference is free.
Synopsis: Early diagnosis of life-threatening fungal infection is critical to good outcomes. Numerous studies attest to the poor yield from fungal culture and the much better yield of antigen, real-time PCR and antibody tests. The new cryptococcal antigen lateral flow device is a simple point of care test, that is highly sensitive on serum, plasma, urine and CSF to detect occult antigenemia prior to meningitis or for diagnosing cryptococcal meningitis. Only about 50% of Candida bloodstream infections are detected by blood culture, which is further compromised by fluconazole use. Blood cultures take 24-72 hours to be positive in most instances and an additional 24 hours for identification. Real-time PCR is much faster and more sensitive, but no test is yet FDA approved or CE-marked.
Beta-D-glucan testing on blood is useful for Candida infections although does not distinguish genera or species, and so is best used as a rule out test. Blood cultures for Aspergillus are uniformly negative, whereas antigen and real-time PCR on both blood and respiratory fluids has a 80-95% sensitivity.