JAC Advance Access originally published online on July 23, 2007
Journal of Antimicrobial Chemotherapy 2007 60(3):459-460; doi:10.1093/jac/dkm260
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Leading articles |
Invasive Candida species infection: the importance of adequate empirical antifungal therapy
Department of Molecular Microbiology and Infection, Flowers Building, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
* Tel: +44-207-589-5111; E-mail: d.armstrong{at}imperial.ac.uk
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Candida species are a common cause of bloodstream and invasive infection in critically ill and immunosuppressed patients. Furthermore, invasive Candida infection carries a poor prognosis and may initially be mistaken for bacterial infection. An article in this issue of the Journal investigates the relationship between adequacy of initial empirical therapy and outcome from invasive Candida infection. This study shows that adequate empirical therapy is received by only a quarter of patients, and that inappropriate therapy is associated with increased mortality. These findings highlight the importance of appropriate empirical therapy in invasive Candida infection.
Keywords: antifungal therapy , candidiasis , clinical mycology
Candidaemia and invasive candidiasis are a major cause of nosocomial infection, linked to a number of risk factors such as immunosuppressive therapy, intravenous catheters and critical illness.1 A particular problem with this group of patients is that they are difficult to distinguish clinically from patients with bacterial sepsis, at least early in infection. This often leads to an initial delay in instituting antifungal therapy, and furthermore the choice of initial empirical therapy may be inappropriate. In this issue of the Journal, Parkins et al.2 investigate the relationship between the adequacy of initial empirical antifungal therapy and outcome from bloodstream and invasive Candida infections. Only one-third of patients received empirical antifungal therapy, and furthermore the therapy was only deemed appropriate in 26% of patients. Crucially the authors were able to demonstrate that adequate empirical therapy was associated with a significant reduction in mortality from 46% to 27%. Notably, in this study around half of the infections were demonstrated to be due to non-albicans species, with 22% due to Candida glabrata alone.
These findings raise a number of issues with respect to management of patients with invasive Candida infections. Clearly, the early identification of patients likely to have invasive Candida infection needs to be improved.3 Known risk factors for invasive candidiasis and candidaemia include prior antimicrobial therapy, venous and urinary catheters, intensive care unit admission, parenteral nutrition, major surgery and immunosuppressive therapies.4 However, many of these risk factors also predispose patients to bacterial infection. It is therefore often difficult to distinguish these groups, although patients with Candida colonization at multiple sites are more likely to develop invasive disease.5 The development of rapid identification tests to identify invasive Candida infection early would solve this problem, and in this context both antigen testing for (1,3)-ß-D-glucan and PCR-based assays may be useful.6,7
The choice of initial antifungal agent for the empirical treatment of suspected invasive Candida infection is also difficult. The use of fluconazole prophylaxis over the last two decades is believed to have led to an increase in non-albicans species with reduced fluconazole susceptibility.8 Furthermore, the development of a number of new azole and echinocandin antifungals has greatly increased the available treatment options.9,10 Parkins et al.2 demonstrated in their study that overall 69% of isolates were fluconazole-susceptible. In contrast, 99% of isolates were susceptible to amphotericin B or caspofungin, and 98% susceptible to voriconazole. Notably, empirical fluconazole therapy was more likely to be deemed inadequate and inadequate therapy was associated with a greater risk of death, although no direct link to fluconazole was demonstrated. Current Infectious Diseases Society of America (IDSA) guidelines for the empirical treatment of suspected candidaemia or invasive Candida infection recommend that fluconazole may be used in clinically stable patients, and that caspofungin is an excellent alternative due to its wide spectrum of activity and low rate of adverse effects.11 For clinically unstable patients however, amphotericin B is preferred due to its greater spectrum of activity although there is increasing evidence that echinocandins and voriconazole are as effective.12,13 Once Candida infection is confirmed, species level identification is in most cases an effective method for prediction of antifungal susceptibility.14 However for deep-seated infections, MIC testing is crucial. The findings of Parkins et al.2 suggest that accurate and timely MIC testing may be more important than has been previously recognized.
The rising cost of novel antifungals, in conjunction with a rapid increase in available therapies, increasing fluconazole resistance, local variation in prevalent Candida species, the availability of alternatives to culture-based tests, and the growing evidence that inappropriate and delayed therapy increases mortality, has resulted in a growing need for local mycology diagnostic laboratories and clinical mycology expertise.3 Sadly, the UK has witnessed a decline in diagnostic mycology services over the last two decades, with just four laboratories in England and Wales now providing specialized services, and no dedicated surveillance programme for fungal infections.15,16 Currently, most Candida isolates are handled by local microbiology laboratories. Germ tube-positive bloodstream isolates are assumed to be C. albicans. Germ tube-negative Candida bloodstream isolates are sent to regional mycology laboratories for speciation and MIC testing. However this process may be protracted, leading to a delay in the institution of appropriate antifungal therapy. Furthermore, there is a current lack of UK-based clinicians with specialist expertise in fungal infection, and no defined career path for training in Clinical Mycology. These issues are currently being addressed through the establishment of a UK Clinical Mycology Network and a Diploma in Medical Mycology (www.bsmm.org/files/dipmedmyc.pdf). Similar concerns have been raised in the United States with respect to training in medical mycology.17
The publication of this study further underscores the increasing complexities of managing invasive fungal infections in the 21st century. Rapid advances in modern immunosuppressive therapies, diagnostic mycological tests and new antifungal therapies have transformed medical mycology into a fast-moving field, in which an increasing population of patients is at risk from invasive fungal infection. The time has come to provide improved training and diagnostic services in this area.
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None to declare.
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1 Viudes A, Peman J, Canton E, et al. Candidemia at a tertiary-care hospital: epidemiology, treatment, clinical outcome and risk factors for death. Eur J Clin Microbiol Infect Dis (2002) 21:767–74.[CrossRef][Web of Science][Medline]
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Parkins MS, Sabuda DM, Elsayed S, et al. Adequacy of empirical antifungal therapy and effect on outcome among patients with invasive Candida species infections. J Antimicrob Chemother (2007) 60:613–18.
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7 Odabasi Z, Mattiuzzi G, Estey E, et al. ß-D-Glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis (2004) 39:199–205.[CrossRef][Web of Science][Medline]
8 Perfect JR. Antifungal resistance: the clinical front. Oncology (Williston Park) (2004) 18:15–22.
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11 Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis (2004) 38:161–89.[CrossRef][Web of Science][Medline]
12 Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet (2007) 369:1519–27.[CrossRef][Web of Science][Medline]
13 Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet (2005) 366:1435–42.[CrossRef][Web of Science][Medline]
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Fleck R, Dietz A, Hof H. In vitro susceptibility of Candida species to five antifungal agents in a German university hospital assessed by the reference broth microdilution method and Etest. J Antimicrob Chemother (2007) 59:767–71.
15 Gardiner G, Lamagni T. Longitudinal trends in candidaemia in England and Wales. Clin Microbiol Infect (2007) 13(Suppl_1):S351.[CrossRef]
16 Health Protection Agency. Fungal Diseases in the UK—The current provision of support for diagnosis and treatment: assessment and proposed network solution. Advisory Committee for Fungal Infection and Superficial Parasites (2006) www.hpa.org.uk/publications/2006/fungal_disease (22 June 2007, date last accessed).
17 Steinbach WJ, Mitchell TG, Schell WA, et al. Status of medical mycology education. Med Mycol (2003) 41:457–67.[CrossRef][Web of Science][Medline]
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