JAC Advance Access originally published online on January 31, 2006
Journal of Antimicrobial Chemotherapy 2006 57(3):384-410; doi:10.1093/jac/dki473
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Review |
Fluconazole for the management of invasive candidiasis: where do we stand after 15 years?
1 Université Paris V, Service des Maladies Infectieuses et Tropicales, Hôpital Necker Enfants Malades, Paris, France; 2 Unité de Mycologie Moléculaire, CNR Mycologie et Antifongiques, CNRS FRE 2849, Institut Pasteur, Paris, France; 3 Department of Infectious and Tropical Diseases, North Manchester General Hospital, Dlaunays Road, Manchester M8 9LR, UK; 4 Service d'Hématologie-Greffe de Moelle, Hôpital Saint-Louis, Paris, France; 5 The University of Manchester, Education and Research Centre, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK
* Correspondence address. Université Paris V, Infectious Diseases Department, Necker Enfants Malades University Hospital, 149 rue de Sèvres, 75015 Paris, France. Tel: +33-1-42-19-26-63; Fax: +33-1-42-19-26-22; E-mail: olivier.lortholary{at}nck.aphp.fr
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Abstract |
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Candida spp. are responsible for most of the fungal infections in humans. Available since 1990, fluconazole is well established as a leading drug in the setting of prevention and treatment of mucosal and invasive candidiasis. Fluconazole displays predictable pharmacokinetics and an excellent tolerance profile in all groups, including the elderly and children. Fluconazole is a fungistatic drug against yeasts and lacks activity against moulds. Candida krusei is intrinsically resistant to fluconazole, and other species, notably Candida glabrata, often manifest reduced susceptibility. Emergence of azole-resistant strains as well as discovery of new antifungal drugs (new triazoles and echinocandins) have raised important questions about its use as a first line drug. The aim of this review is to summarize the main available data on the position of fluconazole in the prophylaxis or curative treatment of invasive Candida spp. infections. Fluconazole is still a major drug for antifungal prophylaxis in the setting of transplantation (solid organ and bone marrow), intensive care unit, and in neutropenic patients. Prophylactic fluconazole still has a place in HIV-positive patients in viro-immunological failure with recurrent mucosal candidiasis. Fluconazole can be used in adult neutropenic patients with systemic candidiasis, as long as the species identified is a priori susceptible. Among non-neutropenic patients with candidaemia fluconazole is one of the first line drugs for susceptible species. Cases reports and uncontrolled studies have also reported its efficacy in the setting of osteoarthritis, endophthalmitis, meningitis, endocarditis and peritonitis caused by Candida spp. among immunocompetent adults. In paediatrics, fluconazole is a well tolerated and major prophylactic drug for high-risk neonates, as well as an alternative treatment for neonatal candidiasis. Importantly 15 years after its introduction in the antifungal armamentarium, fluconazole is still a first line treatment option in several cases of invasive candidiasis. Its prophylactic use should however be limited to selected high-risk patients to limit the risk of emergence of azole-resistant strains.
Keywords: Candida spp. , neutropenia , intensive care unit , bone marrow transplantation , solid organ transplantation , systemic candidiasis
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Introduction |
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Fluconazole was discovered by Richardson et al.1,2 working at Pfizer in Sandwich, UK in a programme initiated in 1978. The original patent covering its structure had been filed by Riley and colleagues at ICI Pharmaceuticals, who discontinued antifungal research prior to fluconazole's launch. Fluconazole was identified because of its in vivo activity, and only many years later were in vitro systems found to measure in vitro activity. Phase 2 studies commenced in 1988 and were focused on Candida, cryptococcal and coccidioidal infections, initially using doses of 50 mg daily.3–6 Prophylaxis studies in neutropenia followed. The increasing need for orally active azoles because of the AIDS epidemic, and respectable efficacy despite low doses of the drug, led to rapid Foods and Drugs Administration and European licensures in 1990 (http://www.fda.gov/bbs/topics/ANSWERS/ANS00051.html; 21 September 2005, date last accessed). Fears of severe idiosyncratic liver failure akin to ketoconazole effects did not materialize, and larger doses of fluconazole were explored for more seriously ill patients, especially for those with cryptococcal and coccidioidal meningitis and invasive candidiasis. The last is the focus of this review.
The aim of this article is to review the current prophylactic or curative use of fluconazole in the management of invasive candidiasis 15 years after its introduction in the anti-infective armamentarium. Probably in excess of 100 million patients have received fluconazole worldwide between 1990 and 2005.
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Pharmacokinetics and pharmacodynamics |
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Mechanism of action
Fluconazole is a semi-synthetic azole designated an imidazole due to the presence of three nitrogen atoms on the azole ring, which is active against numerous yeasts, but not filamentous fungi. It acts by the inhibition of C-14 
demethylase which is required for ergosterol synthesis, an essential building block of fungal cell membrane. C-14 demethylase is part of the fungal cytochrome P450 complex and as such can also have an effect on the human cytochrome P450 complex leading to potential drug interactions and side effects. Fluconazole is a fungistatic drug against Candida spp.7
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Pharmacokinetics |
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Fluconazole is well absorbed with a bioavailability of over 80%. Peak levels are reached in 1–2 h in healthy fasting adults and gastrointestinal absorption is not influenced by the gastric pH. Its volume of distribution is reported to be 0.7–1.0 L/kg, and 11% is protein bound.8 The majority is excreted via the kidneys (60–75%) with a further 8–10% being recoverable from the faeces. It is also removed by haemodialysis. The half-life is 27–34 h in adult population, allowing for once-a-day administration.
The pharmacokinetics of fluconazole vary with age. Neonates have a 2- to 3-fold higher volume of distribution than adults (
2 L/kg) that falls to 1 L/kg by 3 months of age.9 The mean volume of distribution is greater and more variable in premature neonates. It is therefore necessary to double the fluconazole dose for neonates in order to achieve comparable plasma levels. Because of reduced glomerular filtration and reduced activity of hepatic enzymes, the half-life is increased in neonates compared with adults (55–90 h). It is thus recommended to administer the drug every 72 h in neonates during the first 2 weeks of life, and then every 48 h in weeks 2–4 of life. Following this period, daily dosing would be appropriate.10,11
The diffusion in tissues and body fluids is excellent, with CSF concentrations reaching at least 70% of blood levels even in the absence of inflamed meninges (see Table 1).8
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A small study of four patients looking at the penetration of fluconazole into brain tissue found that brain levels closely paralleled plasma levels with a daily dose of 400 mg suggesting that this dose may be appropriate for those with brain abscesses caused by susceptible yeasts.12 A case report of acute cholecystitis due to Candida albicans found higher biliary concentration of fluconazole with oral dosing compared with intravenous dosing.13 Fluconazole penetrates well into joint fluids for the treatment of septic arthritis. Fluconazole can also be administered intraperitoneally for candidal peritonitis in patients on continuous ambulatory peritoneal dialysis with good bioavailability (87%) and plasma levels.14 The ocular penetration is also good.15 Indeed, aqueous humour concentrations are reported to reach over 80% of the serum concentration within the day following administration of a single oral dose of 200 mg fluconazole.16
Formulations
Different formulations are available for the treatment or prophylaxis of systemic candidiasis: tablets, capsules, oral solution and intravenous formulation. The intravenous formulation is a simple solution in water.
Dosing
In adults (prophylaxis or treatment). A dose of 200–400 mg/day is recommended in prophylactic setting. For the treatment of systemic candidiasis, a loading dose of 800 mg/day is recommended on the first day, followed by a 400 mg/day dose.
In children. A wide range of doses has been used in children. Recommended doses are of 3 mg/kg/day after the age of 1 year. Neonates with invasive candidiasis should receive 3–6 mg/kg every 72 h during the first 2 weeks of life, every 48 h during 2–4 weeks of life and then once a day at the same dose.11,17
In pregnancy. Owing to good bioavailability and volume of distribution, fluconazole is found in breast milk. Fetal abnormalities have been reported after long-term usage among pregnant women.18 Manufacturers recommend that fluconazole is to be avoided if breast feeding, and that it should be used in pregnancy only if the potential benefit justifies the possible risk to the fetus.
In renal failure. As fluconazole is mainly renally excreted some dose alterations are recommended for those with a decreased creatinine clearance: see Table 2.
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In other settings. In a small review of 14 surgical patients hospitalized in the intensive care unit (ICU) with fluconazole-susceptible deep mycoses, enteral fluconazole was found to give similar levels in urine and exudates from the site of infection as did parenteral fluconazole. Levels in patients with thermal burns vary considerably from normal to shorter half-lives possibly due to the greater volume of distribution.19 Patients on fluconazole prophylaxis during bone marrow transplantation (BMT) who develop haemorrhagic cystitis secondary to chemotherapy excrete more fluconazole in their urine than those who do not.20
Drug interactions
Owing to fluconazole's metabolism via the liver and the CYP450 family of enzymes, the potential exists for many drug interactions. Table 3 lists some of the more important drug interactions.
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Case reports also include an individual with raised carbamazepine levels during concomitant fluconazole use presumed to be due to cytochrome P450 inhibition.21 However decreased fluconazole and other azole levels have also been reported in four patients receiving concomitant antiepileptic therapy leading to antifungal failure.22,23 As a weak inhibitor of cytochrome P450-3A, fluconazole at the standard dose does not inhibit clearance of the H-1 antagonist terfenadine. Higher doses (>200 mg/day) are contraindicated with terfenadine, because of the risk of impairment of the clearance of the drug, and exposing the patients to severe side effects, including QTc-interval prolongation.24 (http://www.pfizer.com/pfizer/download/uspi_diflucan.pdf; 29 September 2005, date last accessed).
Side effects
Fluconazole displays an excellent profile of tolerance in the range of doses recommended in invasive candidiasis. Side effects do occur especially with doses >400 mg/day. They have been reported to occur more often in those with the human immunodeficiency virus (HIV).25 Common side effects include headache, nausea and abdominal pain. Raised transaminase serum levels may occur in some cases: from 1% of cases in preventive use for BMT to 10% in preventive use for patients with acute leukaemia and even 20% in the setting of ICU.26–28 Although generally mild, elevation of liver transaminases can eventually lead to the stopping of fluconazole. Patients with AIDS might be at higher risk for hepatotoxicity with fluconazole.29 Rare cases of fulminant hepatitis have been reported.30 Hair loss, which is reversible on stopping the drug, and anorexia have also been reported.31,32
Neurotoxicity can occur with very high doses above 1200 mg/day.33 Very unusually anaphylaxis and Stevens Johnson syndrome have been reported.34
Safety and tolerability have been also clearly assessed in the paediatric population, mirroring the excellent profile of tolerance observed in adult population.35 In 1999, Novelli and Holzel reviewed data from 562 children treated with fluconazole: 10.3% presented with treatment-related side effects including 7.7% involving gastrointestinal tract disturbances and 1.2% involving the skin.35
Monitoring of levels
There are no routine indications for measuring fluconazole levels. Patients with short bowel who require long-term therapy may require confirmation of absorption. Drug monitoring should be performed among neonates (especially premature infants) with invasive candidiasis to ensure therapeutic plasma concentrations of fluconazole within a range between 4 and 20 mg/L. Salivary concentrations are proportional to plasma levels after 1 week and could potentially be used to monitor compliance.36
Pharmacodynamics
Dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome in experimental systemic candidiasis was the AUC/MIC ratio.37 However, clinical response is also related to the immune status of the patient and presence of foreign materials or vegetations.38
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Activity of fluconazole against Candida species |
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 TopAbstractIntroductionPharmacokinetics and...Pharmacokinetics Activity of fluconazole against... Fluconazole for prophylaxis of...Fluconazole in children/infantsConclusionsTransparency declarationsReferences |
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It should be noted that breakpoints have been defined for the susceptibility of Candida species to fluconazole using the M27 NCCLS method.39 Candida isolates are qualified as susceptible if MIC values are
8 mg/L, S-DD (susceptible dependent upon dose) if at 16 or 32 mg/L and resistant if 
64 mg/L. When considering the relevance of these breakpoints, they have been well validated for the management of mucosal candidiasis in HIV-infected patients, but much less for the treatment of systemic candidiasis.
Generally, first isolates of Candida spp. are susceptible to fluconazole when they are first isolated from a patient who has not been treated with an azole, with the exception of all Candida krusei and occasional isolates of other species. When examining the susceptibility of Candida species currently isolated from blood cultures, it indeed appears that 95% of C. albicans isolates remain susceptible to fluconazole. This is also the case for Candida tropicalis and Candida parapsilosis (refs 40, 41; Observatoire des levures and F. Dromer, unpublished data). The worldwide per- centage of Candida glabrata susceptible to fluconazole according to geography ranges between 62.1% in Latin America and 80.9% in the Asia-Pacific region.42
The susceptibility data are much different in the populations receiving long-term fluconazole prophylaxis. These data will be presented later in the article.
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Fluconazole for prophylaxis of systemic candidiasis in transplanted patients |
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Solid organ transplants
Liver transplants.
Among solid organ transplantation, liver transplantation has conveyed the highest risk of fungal infection, Candida species accounting for at least 60% of them.43,44 C. albicans is the most frequently involved, followed by C. glabrata and C. tropicalis. The subsequent associated mortality of these infections is high, ranging between 30 and 100%.43,45 Invasive candidiasis is strongly related to several conditions: haemodialysis or a creatinine level of 2 mg/dL, fungal colonization, ICU hospitalization, exposure to >3 antibiotics, acute hepatic failure, surgical events (urgent surgery, a long procedure >11 h, biliary digestive anastomosis and the need for substantial intra-operative transfusions) and several post-operative events. These include re-intervention, haemodialysis, early colonization (from 2 days before to 3 days after transplantation), retransplantation, biliary leaks, infarcted tissue, bacterial, and cytomegalovirus and HHV-6 infections.46–52 Enhanced immunosuppression with steroids, OKT3 monoclonal antibody treatment of rejection as well as antimicrobial prophylaxis to prevent ascites infection may also facilitate the development of invasive candidiasis. Thus, subgroups presenting a high risk of invasive candidiasis have been individualized and are the appropriate targets of fluconazole prophylaxis. The annual incidence of invasive candidiasis among liver transplant recipients has been estimated to range between 6 and 15%, but is now decreasing due to significant technical developments, surgical improvements and the wide use of fluconazole as fungal prophylaxis in this subset of high-risk patients. Indeed, Singh et al. in a retrospective study documenting the evolving trends in liver transplantation practices and their impact on fungal infections observed a significant decline in the incidence of invasive candidiasis. Candida infections occurred in 9% of the patients between 1990 and 1992, in 1.5% between 1993 and 1995, and in 1.7% of the patients from 1996 onwards.44
Three randomized double-blind studies have shown the efficacy of fluconazole in the prevention of candidiasis in this setting (see Table 4). In 1996, Lumbreras et al.53 compared the efficacy of nystatin (4 x 106 U every 6 h, n = 67) versus fluconazole (oral 100 mg/day, n = 76) administered during the first 4 weeks after transplantation. Fluconazole significantly reduced the rate of Candida sp. colonization (7% versus 17%), and proven superficial infection (10% versus 25%), with a trend towards a reduction of invasive candidiasis (2% versus 9%). At that dose, fluconazole was safe and well tolerated, without any interference with ciclosporin. In 1999, Winston et al.46 studied fluconazole (oral 400 mg/day, n = 119) compared with placebo (n = 117) given for 10 weeks after transplantation. Fluconazole significantly reduced the incidence of fungal colonization (34% versus 78%), superficial infection (4% versus 28%) and invasive infection (6% versus 23%). Of interest, fluconazole also reduced the mortality associated with invasive fungal infection (2% versus 13%) although global mortality rate was not reduced among fluconazole-treated population (11% versus 14%). However, significantly higher serum ciclosporin levels were reported in the fluconazole-treated group. In 2002, Winston et al.54 compared the efficacy of fluconazole (oral 400 mg/day, n = 108) versus itraconazole (oral 200 mg twice a day, n = 104) given for the first 10 weeks after transplantation. Both equally reduced the rate of colonization (from first to last day of treatment): from 77 to 30% for fluconazole, and from 67 to 25% for itraconazole. Rates of invasive candidiasis were similar to those described in the author's former study. Other studies have also looked to the contribution of fluconazole in the prophylaxis of invasive candidiasis in liver transplant recipients.
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Tortorano et al.55 in 1995 observed a better prevention and clearance of C. albicans colonization with fluconazole than with oral amphotericin B, although clearance of Candida spp. was not found to be different, because of fluconazole inefficiency on non-albicans species. Finally, Kung et al.56 in a historical comparison reported a higher survival rate among patients receiving fluconazole as prophylaxis (n = 45, 100 mg/day) compared with untreated patients (n = 72): 75% versus 58%. As highlighted by the recently published Infectious Diseases Society of America (IDSA) guidelines, fluconazole-based prophylaxis is therefore recommended among high-risk liver transplant recipients (with
2 previously defined risk factors), during the early post-operative period.57 This practice has been shown to be efficient in decreasing the incidence of invasive candidiasis. However, a shift towards non-albicans Candida species in colonization or invasive infections has occurred during the past 10 years with a rise from 15 to 39% after widespread use of fluconazole.49 This trend emphasizes that the use of fluconazole as prophylaxis should be strictly targeted to high-risk patients and not be generalized to all liver recipients. Kidney transplants. Given the low incidence of severe Candida sp. infections in this population and the lack of specific studies, the use of fluconazole is not recommended in this setting, in Europe and North America.58,59
Pancreas and pancreas–kidney transplants. Intra-abdominal and urinary tract infections are the most common sites of fungal infections among pancreas and pancreas–kidney transplant recipients. In a retrospective survey of 445 consecutive pancreatic and pancreas–kidney transplantations, fungal intra-abdominal infections occurred in 41/445 (9.2%) patients and were associated with three times higher risk of death.60 87% of all invasive fungal infections following pancreas transplantation are caused by Candida species.61 Enteric drainage procedures, living relative donor as well as previous or simultaneous kidney transplantation are associated with a higher incidence of fungal infection.60 Underlying diabetes mellitus is a predisposing condition. A consistent characteristic of pancreas-transplanted patients with candidiasis is colonization of the urine with Candida species.62 Benedetti et al.60 observed that patients receiving fluconazole prophylaxis (n = 108, 400 mg/day for 7 days) had lower rate of fungal infection than those who did not (n = 327): 6% versus 10%. It should be noted that randomized comparative studies of antifungal prophylaxis in pancreas transplantation are lacking. However, data from the Benedetti study suggest that fluconazole might be administered prophylactically in that setting, especially in patients who experienced high-risk procedures or those colonized by Candida spp.
Small bowel transplantation. In a retrospective study of 29 patients with small bowel transplantation, Kusne et al.63 reported 20 cases of invasive fungal infections, 16 of them due to Candida species, which was involved in 9% of all positive blood cultures. Although never evaluated, current recommendations advocate that fluconazole might be administered in that setting.57 The use of new biological immunosuppressants such as almetuzumab which is associated with severe T cell cytopenia and high risk of opportunistic infections might convey higher risk of infection and could justify the use of preventive fluconazole.64
Heart, lung and heart–lung transplantation. Aspergillus is the main fungal pathogen involved in that setting. Taken its lack of efficacy on moulds, fluconazole as any prophylaxis targeting Candida sp. is not relevant.43,60,66
Bone marrow transplantation
Invasive fungal infections are still a major cause of morbidity and mortality among recipients of bone marrow or peripheral stem cell transplantation. Allogeneic BMT recipients are at special risk.66 In the pre-engraftment phase (day 0–day 30), the two major identified risk factors for invasive fungal infections are (i) prolonged neutropenia and (ii) breaks in the mucocutaneous barrier.67 The most prevalent fungal pathogens are yeasts, especially Candida spp., and, as neutropenia continues, Aspergillus sp. Post-engraftment from day 30 to day 100 is characterized by impaired cell-mediated immunity. Susceptibility to fungal infections is then related to factors suppressing the T lymphocyte immune response: existence of graft-versus-host disease, use of corticosteroids or anti-T lymphocyte antibodies, and use of T-depleted grafts. This period is more likely associated with mould infections, especially with Aspergillus sp., and also to some extent to chronic disseminated candidiasis.68 Two main randomized double-blind studies have demonstrated the benefit of fluconazole among BMT recipients (allogeneic + autologous) as shown in the Table 5.69,70 At the dose of 400 mg/day, fluconazole was able to significantly decrease the risk of superficial and invasive candidal infections and the overall number of deaths related to fungal disease. Furthermore, fluconazole was able to reduce the fungal colonization at the endpoint of evaluation. Slavin et al. showed a significant decrease of overall mortality at day 110 post-allogeneic transplantation after a 75 day regimen of fluconazole.70 Confirmation and extension of this benefit was shown by Marr et al.71 on the same cohort with the survival benefit persisting after up to 8 years of follow-up. Indeed, administration of placebo was shown to be an independent factor for poor survival.
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Fluconazole has also been compared with other antifungal drugs in allogeneic and autologous BMT (see Table 6). It has been shown to be as efficient as intravenous amphotericin B (0.2 mg/kg/day) for lowering Candida colonization and superficial and invasive fungal infections in randomized non-blinded trials.73 Three randomized non-blinded studies have compared the efficacy of itraconazole and fluconazole in bone marrow recipients, with conflicting results.74–76 Annaloro et al.74 did not observe any difference in infection-related death, invasive candidiasis or in the need for curative doses of amphotericin B. Winston et al.75 observed statistically more invasive fungal infections in the fluconazole group than in the itraconazole one (n = 138, 25% versus 9%), all of them related to non-albicans Candida species and moulds (Aspergillus sp., Fusarium sp. and Rhizopus sp.). However, no difference in survival could be detected. Tolerance of itraconazole was lower than that of fluconazole. Marr et al.76 failed to show any superiority of itraconazole in an intention-to-treat analysis, whereas on-treatment analysis revealed a higher rate of invasive fungal infection in the fluconazole group (mostly invasive mould infections). However, only one study has shown increased incidence of infections due to Aspergillus species or other moulds in patients treated with fluconazole.79 Therefore, although with a spectrum of activity limited to yeasts, fluconazole has been widely adopted as an effective and safe therapy. Its use is now recommended from the day of haematopoietic stem cell transplantation until engraftment in guidelines for prevention of opportunistic infections among allogeneic bone marrow recipients.67 The optimal dose of fluconazole in that setting is not clearly determined. The posology of 400 mg/day is recommended by the IDSA. However, lower doses have been shown to be similarly effective in reducing the risk of invasive infections and candidal colonization.71,76 MacMillan et al.77 in a large cohort of 253 patients demonstrated similar efficiency of high and low dosages of fluconazole (200 and 400 mg/day) on the rate of fungal colonization and infection. No increase of reduced susceptibility in isolates of Candida was seen at the low doses. The adoption of fluconazole as prophylactic regimen in BMT has raised concern about a shift of colonization towards azole-resistant strains of Candida sp. Indeed, Marr et al.78 observed that out of 585 patients undergoing BMT with prophylactic fluconazole 44% were colonized with Candida sp. during the procedure, half of them with a species other than C. albicans. However, no increase in invasive candidiasis or in deaths related to non-albicans Candida infections could be observed. Very recently, van Burik et al.79 in a large randomized double-blind multicentre study on 882 patients observed superior efficacy of the echinocandin micafungin (50 mg/day) over fluconazole (400 mg/day) on the prevention of invasive fungal infection among bone marrow recipients: 80% of success versus 73%. Further cost–benefit studies are required to determine whether micafungin could be an alternative to fluconazole in that setting, particularly as fluconazole is now generic.
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Fluconazole for prophylaxis of Candida infections in neutropenic patients
Neutropenic patients with haematological malignancies are at high risk for developing invasive and superficial mycoses. However, all of them do not share the same risk of fungal infection.
Prolonged deep neutropenia as observed in intensive induction or salvage regimens for acute leukaemia, use of corticosteroids and exposure to high-dose cytosine arabinoside or to monoclonal antibodies (anti-CD52) are deeply immunosuppressing conditions facilitating the emergence of invasive fungal infections.80
Studies versus placebo. Seven studies have shown the efficacy of fluconazole in the setting of fungal prophylaxis among neutropenic patients (excluding BMT), including five randomized, double-blind placebo-controlled trials.81–87 Indeed, fluconazole has been shown to significantly reduce Candida species colonization, superficial infections, invasive proven candidal infections as well as fungal-related mortality. A broad range of doses were used in these studies ranging from 50 to 400 mg/day. However, no benefit on overall mortality has been observed (see Table 7).
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Comparative studies. Fluconazole has also been compared with other antifungal agents (see Table 8). When compared with oral polyenes, it was at least equivalent in terms of prevention of superficial infection, except in the study by Rozenberg et al. suggesting that amphotericin B (400 mg x 4/day) might more efficiently reduce superficial candidal colonization.88–98 Egger et al.88 also suggested that fluconazole might reduce the need for curative amphotericin B among neutropenic patients, but taken the absence of consensus about the use of amphotericin B in the case of persistent fever, these results are of low clinical pertinence. Fluconazole has an excellent tolerance profile in that population, with similar efficiency and fewer side effects than intravenous polyene prophylaxis.98
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Optimal dose is not clearly defined in neutropenic patients. Dosages ranging from 100 to 400 mg/day were used with apparently the same efficacy. Low doses of 50 mg/day prevent superficial candidiasis but not invasive disease. Oral administration was apparently as efficient as the intravenous one, although this point had never been extensively studied in appropriate comparative studies, especially as more recent studies allowed either route of administration.
Recently two meta-analyses reviewed the data extracted from all major studies on fluconazole prophylaxis in neutropenic patients with or without BMT.99,100 Comparators were fungal-related deaths, superficial and invasive candidal infections, use of parenteral antifungal therapy, and infection and colonization with fluconazole-resistant species. In 2000, Kanda et al. reviewed 16 controlled studies involving 3734 patients.99 Superficial infections were clearly reduced by the use of fluconazole (combined OR 0.23; 95% CI 0.17–0.31). In trials involving neutropenic patients without BMT, the benefit of fluconazole on invasive infections appeared only in studies in which the incidence of fungal infection was >15%: with a combined OR at 0.23 (95%CI 0.15–0.36). There was also no difference in the incidence rate of invasive aspergillosis between control and study groups. Colonization by C. krusei was more frequent in fluconazole-treated patients (OR 2.01; 95% CI 1.3–3.12). Colonization by C. glabrata was more frequent among patients with low-dose (50–200 mg/day) regimen (OR 2.04; 95% CI 1.18–3.53). However, there was also no difference between test and control groups in the incidence rate of invasive proven infections with C. krusei, C. glabrata or Aspergillus sp. Fungal-related mortality was not reduced in fluconazole-treated patients. In 2002, Bow et al.100 similarly reviewed 38 trials, including 14 involving fluconazole (4062 patients with malignant disease and severe neutropenia). Fluconazole regimen was associated with benefit on superficial and invasive fungal infections and also on fungal infection-related mortality (weighted OR 0.53; 95% CI 0.34–0.83). Overall mortality was not reduced, and no excess of invasive aspergillosis could be evidenced. One negative issue was subsequently identified in a retrospective study including 3002 patients, Viscoli et al. found that absorbable antifungal prophyl axis in neutropenic patients was associated with an increased rate of bacteraemia, with an estimated OR of 1.42 (95% CI 1.07–1.88).101
There is no clear international recommendation about the use of fluconazole or other antifungal drugs in the non-BMT profoundly neutropenic setting. The IDSA 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer indicate that ‘routine use of fluconazole or itraconazole for all cases of neutropenia is not recommended. However, in certain circumstances in which the frequency of systemic infection due to C. albicans is high and the frequency of systemic infection due to other Candida species and Aspergillus species is low, some physicians may elect to administer antifungal prophylaxis (D-II).102 In German guidelines, fluconazole prophylaxis (400 mg/day) among patients undergoing conventional chemotherapy is a grade C-I recommendation (poor evidence).103 French guidelines on the care of invasive candidiasis in adults were recently updated. The use of fluconazole prophylaxis (400 mg/day) is a high grade recommendation (A-I) among allogeneic bone marrow recipients, but not in the setting of autologous BMT or acute leukaemia (http://www.srlf.org/Data/Documents/HTML/O2_refenticls_OA-recommendations/20040513.asp date last accessed 26 December 2005). Thus, in the light of the previously described meta-analysis, fluconazole might be appropriate in neutropenic patients with a high risk of fungal infection, i.e. those with long duration of neutropenia, prolonged corticosteroid therapy, but probably other drugs will be better choices.
Fluconazole as prophylaxis for systemic candidiasis in ICU adults
The extent of the problem. There is an increasing incidence of both bacterial and fungal sepsis occurring in ICU patients. A US study found that the absolute number of deaths due to invasive mycoses rose from 1557 in 1980 to 6534 in 1997.104 Although much of this increase was associated with fungal infections related to HIV, there were also marked increases in deaths due to candidiasis, aspergillosis and other mycoses in the non-HIV population. A UK study looking at the outcome of candidaemia infections reported 18.7 episodes of candidaemia per 100000 finished consultant episodes. Of them, 45.4% occurred in an ICU setting, and C. albicans was isolated in 65% of cases.105 A Swiss study found that two-thirds of episodes of candidaemia occurred in ICU or on surgical wards, with invasive candidiasis occurring 5–10 times more frequently in an ICU setting than on other wards.106 Strikingly, in spite of all therapeutic innovations in the field of antifungal therapy, the crude and attributable mortality of nosocomial fungaemias have not decreased over the past 15 years (38%).107
How are patients at risk of invasive candidiasis identified?. The diagnosis of invasive candidiasis may be difficult due to the high frequency of colonization, especially in patients who are on broad spectrum antibiotics. A prospective study of non-neutropenic patients in whom Candida species were isolated found that digestive and respiratory samples and the isolation of non-albicans species were risk factors for invasive candidiasis.108 Additionally the most significant risk factors for invasive candidaemia identified in a surgical ICU in those who had undergone surgery were prior surgery, acute renal failure, receipt of total parenteral nutrition and the presence of a central venous catheter.109 This study also found that administration of an antifungal agent was associated with decreased risk for invasive candidal infection. For critically ill surgical patients, Pittet et al.110 proposed a Candida colonization index based on the ratio between the number of colonized sites and the number of sites tested. Although its use in hospital practice is complex, expensive and time-consuming, this index was highly predictive of invasive candidiasis: indeed a threshold of 0.5 or more correctly identified the infected patients an average of 6 days before the documented candidiasis. An alternative approach has been considered using both anti-Candida antibody and antigen titres.111 A high concordance between the two has been observed for patients with invasive candidal disease compared with patients who were only colonized with Candida. Sensitivity and specificity reached 100 and 83.3% respectively when the two tests were combined.112
Studies that have been done. A recent paper has highlighted the importance of appropriate trial design of antifungal prophylaxis and the need for appropriate assessment of risk factors to identify those patients who are at higher risk.113 Fluconazole has previously been assessed as a prophylactic agent in ITU settings with contradictory results.
Concerns over a shift in Candida isolates that are less susceptible or resistant to fluconazole may be balanced against the justification of using it in appropriately identified high-risk patients.114
For. Three prospective randomized placebo-controlled trials have emphasized the efficacy of fluconazole in that setting (see Table 9). In one study, 260 critically ill surgical patients staying in ICU for >3 days, mainly pre-hepatic transplantation patients, were randomly assigned to either placebo or 400 mg of fluconazole per day. The risk of fungal infection was reduced by 55% in the fluconazole group, compared with the control group who experienced 15% of invasive infections.115 In a small study of 43 surgical patients with recurrent gastrointestinal leaks or perforations, the use of fluconazole prophylaxis resulted in decreased isolation of Candida in surveillance cultures and in a decrease in candidal peritonitis: 4% versus 35%, with a decrease in global invasive candidiasis (9% versus 35%).116 A slightly different approach was used in a study of 204 critically ill patients in surgical and medical ICU where fluconazole was used as part of a selective digestive decontamination regimen.28 These patients appear to more closely represent a typical group of ICU patients. Invasive Candida infections occurred less frequently: in 8% of the fluconazole group compared with 20% of the placebo group, and no shift towards non-albicans species was observed.
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Several reviews of historical cohorts have provided similar results. A recent retrospective review in a surgical ICU comparing the use of fluconazole prophylaxis versus a historical cohort found that prophylaxis decreased the incidence of candidaemia and did not find an increase in non-albicans species.117 No reduction of mortality with fluconazole was observed. Secondary Candida infections in high-risk patients with trauma occurred in 9/62 (14.5%) patients who did not receive fluconazole prophylaxis compared with 3/145 (2%) of a historical cohort who did.118
In another randomized prospective study of bacterial septic shock, fluconazole had a measurable positive impact on survival, although no fungal infection was diagnosed. This unclear beneficial effect might be related to fluconazole's observed ability to enhance the bactericidal activity of neutrophils, or to prevent Candida spp. infection which was not diagnosed by standard blood cultures which are known to be relatively insensitive.119,120
Against. One group of patients at increased risk of invasive candidiasis includes those who have undergone recent liver transplantation. In a previously cited prospective study of 35 post-liver-transplantation patients, patients with C. albicans infections were less likely to have received antifungal prophylaxis than those with non-albicans Candida infections (13.6% versus 50%, P = 0.04). Non-albicans Candida infections and prior antifungal prophylaxis correlated with poorer outcome.49 A further study looked at 125 critically ill patients who received either fluconazole prophylaxis or placebo during their entire stay in ICU.121 There were no significant differences in the incidence of candidal infections nor any difference in the mortality or length of stay on ICU. In the study performed by Pelz et al.115 among pre-liver-transplantation patients, no benefit of fluconazole on survival could be noticed, although a clear reduction of fungal infection was observed.
There are however concerns that the use of prophylactic fluconazole in critical care patients favours the emergence of non-albicans species, some of which are less susceptible or resistant to fluconazole. One review paper in 2002 suggested that there was no evidence of therapeutic benefit with prophylactic fluconazole used in this manner.122 In a small retrospective review of critically ill patients on ITU who did or did not receive fluconazole, the mortality was higher in the fluconazole group and this group also demonstrated increased bacterial resistance. There was a trend towards increasing Candida resistance to fluconazole over the period of the study.123
Tortorano et al.124 recently reported a 20 year study on the evolving trends of candidiasis in an Italian ICU. When comparing the data from 2000 and the data from the 1980s, the rate of Candida spp. invasive infections and colonization appeared stable. However, the authors reported an increased number of mixed colonization (39% versus 6%), with a reduction of colonization by C. albicans (78% versus 93%) and a flare up of C. glabrata involvement (35%). Two cases of acquired resistance to fluconazole in C. glabrata strains were documented. MICs to other azoles were also elevated in both cases, with one case resistant to itraconazole and less susceptible to voriconazole.
In summary, fluconazole prophylaxis in the ICU has been shown to reduce the incidence of invasive candidal infections in some high-risk patients, such as those with a perforated viscus, major trauma and possible pancreatitis. The role of acquired resistance to fluconazole in this setting is however unclear, and prophylaxis has not been shown to reduce mortality. Even if the epidemiology of Candida sp. infections in ITU does not display the shift towards azole less-susceptible strains observed in the AIDS population, the regular use of fluconazole prophylaxis may lead to selection of resistant organisms. Larger trials with appropriate selection of patients are needed. This view has been reported in detail previously.125,126
Fluconazole for prophylaxis of oesophagitis in HIV-infected patients
Mucosal candidiasis had markedly contributed to the morbidity of HIV-infected patients worldwide, until the era of highly active antiretroviral therapy (HAART), which led to a drastic reduction of both colonization and infection by Candida spp.127 However, Candida is still one of the most common fungal pathogens observed in the HIV-infected population who do not have access to HAART, and candidiasis is still a concern in Europe and in United States among patients with poor adherence to antiviral treatment or viro-immunological failure.
Primary prophylaxis. Mucosal infections are not targeted for primary prophylaxis, because of the effectiveness of curative antifungal therapy in that setting, the low mortality associated with mucosal candidiasis and potential for resistant Candida spp. to develop as well as of the possibility of drug interactions.
However, in the pre-HAART era, Powderly et al.128 demonstrated in 1995, in a randomized multicentre unblinded trial, that oral fluconazole (200 mg/day), compared with clotrimazole troches, was associated with fewer episodes of oesophageal and oropharyngeal candidiasis.
Secondary prophylaxis. When recurrences are frequent or severe, long-term oral azole use may be considered to improve quality of life. Seven randomized placebo-controlled studies performed during the pre-HAART era have clearly demonstrated the efficacy of fluconazole in that setting, with doses ranging from 50, 100 or 200 mg/day to 150 and 400 mg/week.129–135 Three of them included more than 20 patients per arm132,133,135 (see Table 10). Fluconazole decreased the rate of mucosal infections caused by Candida (vaginal, oropharyngeal and oesophageal). Daily regimens of fluconazole probably convey better protection against new superficial infection events. Indeed, Havlir et al.134 observed significantly higher rates of thrush among weekly treated population than among daily treated (19.9% versus 12.3%), with shorter time to onset of the initial episode. The tolerance of fluconazole was good. Such long-term strategies raise the concern about emergence of fluconazole-resistant C. albicans and non-albicans strains.
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Pagani et al.135 identified in vitro fluconazole resistance in 12 patients within their cohort of 135 patients. Of them, eight were receiving the fluconazole regimen and four were placebo-treated and five presented with clinical failure at the endpoint of study (four receiving fluconazole and one placebo-treated). The incidence of resistant candidiasis was not found significantly different in these two small groups. However, microbiological resistance was significantly associated with the cumulative dose of fluconazole before entry in a multiple regression analysis, and patients with clinical failure had received larger cumulative doses of fluconazole before study entry (mean value 8.7 g versus 2.9 g). In a similar approach, Vazquez et al.136 observed that 17% of the fluconazole-treated patients had fluconazole-resistant Candida sp. isolated in the mouth, versus only 8% in the placebo group. However this difference was not significant.
The best prophylaxis for mucosal candidiasis relies on HAART. For patients with immuno-virological failure, fluconazole appears to be an effective prophylactic drug. Noting the probable long-term emergence of resistant strains, its use should be limited to the setting of severe frequent recurrences, as suggested in the recently updated French guidelines for HIV care.137
Fluconazole in adult neutropenic patients with systemic candidiasis
Fluconazole is an alternative treatment to amphotericin B in neutropenic patients if the infecting strain is susceptible to it. This conclusion is based on three already dated main studies, of which only one was randomized and consisted of a small number of affected patients.138–140 De Pauw et al.138 showed that fluconazole at a dose of 400 mg/day cured six out of nine patients, namely four of the six patients with candidaemia, one of the two patients suffering from generalized candidiasis and the fourth patient suffering from Candida-induced meningitis. The other two studies showed that fluconazole at a dose of 400 mg/day (in adults) was just as effective and better tolerated than deoxycholate amphotericin at a dose of 0.6–0.7 mg/kg/day. Fluconazole in neutropenic patients is often used successfully at higher doses such as 800 mg/day (even 1200 mg/day), but this is not supported by published data. The combination of fluconazole (800 mg/day) and amphotericin B (0.7 mg/kg/day) has not been studied in neutropenic patients. The IDSA is cautious not to recommend the use of fluconazole as a first line treatment if the patient's condition is not stable and/or if the strain has not been identified.57 In practice, this limits the indication of fluconazole as initial treatment. In theory at least, only patients colonized by a strain that is usually susceptible to fluconazole (C. albicans, C. tropicalis, C. parapsilosis) and who have not received azole prophylaxis can be treated by first line fluconazole.141 As long as the yeast is identified as fluconazole susceptible and the patient is stable, fluconazole is indicated in neutropenic patients.
Chronic disseminated candidiasis is mostly observed in neutropenic patients with haematological malignancies. Its incidence ranges from 3 to 7% and is decreasing following the common practice of fluconazole as a prophylactic regimen in haematology patients.26,142 The efficacy of fluconazole in that setting was evaluated only in observational or retrospective studies.143,144 Anaissie et al.143 reported an 88% rate of cure in a series of 20 patients either resistant or intolerant to amphotericin B after prescription of fluconazole (100–400 mg/day, median 30 weeks). Kauffman et al.144 similarly reported 100% success in six patients resistant to amphotericin B (200–400 mg/day for 2–14 months). Several authors believe that the daily dosage should be raised to 600–800 mg/day.145 In conclusion, fluconazole cannot be used as first line treatment in the setting of systemic candidiasis among neutropenic patients. It is recommended when switching initial amphotericin B therapy to oral maintenance regimen, if the patient was not previously on fluconazole prophylaxis and was not known to be colonized/infected with a less-susceptible or resistant strain. Treatment should be maintained for months, until disappearance of calcification of the lesions, especially if further antineoplastic drugs courses have to be administered.
Fluconazole in adult non-neutropenic patients with candidaemia
Fluconazole has often been used for treatment of fungal infections in non-neutropenic patients (see Table 11). Early trials using fluconazole looked at different doses. A paper from the early 1990s compared doses of 5 mg/kg versus 10 mg/kg to treat candidiasis in ICU patients. The clinical response rate was better in the 10 mg/kg group and deaths were reduced in this group (24% versus 3%) with fluconazole being well tolerated at both doses.146 Six studies compared the efficacy of fluconazole and amphotericin B in non-neutropenic patients with invasive candidiasis.139,140,147–150 Of them three were randomized, double-blind multicentre studies.140,147,148 All confirmed the similar efficacy of both drugs with better tolerance of the fluconazole regimen. In 1994, Rex et al.148 compared in a randomized prospective multicentre study fluconazole (400 mg/day) and amphotericin B (0.5–0.6 mg/kg/day) among 237 patients. Both displayed the same clinical and microbiological efficacy and the same mortality rate at 2 weeks. In 1996, Anaissie et al.140 performed in the same year a prospective, randomized, multicentre study of 164 patients (including 104 non-neutropenic patients) with more consistency in the fluconazole and amphotericin B doses (fluconazole 400 mg/day, amphotericin B 25–50 mg/day). Although clinical response rates were similar, there was significantly less toxicity in the fluconazole group. Philips et al.147 in 1997, in a prospective randomized study confirmed the pattern of efficacy (resolution of fungaemia and death at day 14) of fluconazole (400 mg/day) and amphotericin B (0.6 mg/kg/day). Other kinds of studies were also performed. Nguyen et al.150 in 1995 failed to find any difference of mortality between the fluconazole-treated (100–800 mg/day) and amphotericin B-treated groups in an open, prospective multicentre trial. In 1996 Abele-Horn et al.149 compared patients hospitalized in ICU treated either with fluconazole (400 mg/day on day 1 then 200 mg/day) or amphotericin B (1–1.5 mg/kg/day) plus flucytosine in a randomized prospective trial: no difference in clinical/microbiological response or death could be found. In 1996 Anaissie et al.139 compared the same drugs in cancer patients with candidiasis and enrolled 90 patients. Doses of both fluconazole and amphotericin were highly variable (fluconazole 200–600 mg/day, amphotericin B 0.3–1.2 mg/kg/day). The two cohorts were well matched and response rates at day 5 for each cohort were similar, overall response rates were slightly better for fluconazole and there were significantly fewer toxic effects in the fluconazole group.
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A more recent comparison of fluconazole versus fluconazole plus amphotericin B in non-neutropenic subjects compared 800 mg/day of fluconazole versus the same dose plus 0.7 mg/kg/day of amphotericin B in a randomized blinded multicentre trial involving 219 patients.151 Success rates were slightly higher and there was a faster clearance rate of candidaemia in the combination group compared with fluconazole alone. This suggests that the two drugs are not antagonistic and may perhaps act synergistically.
Although fluconazole may be the preferred agent in non-neutropenic patients because of its low toxicity, the recent introduction of caspofungin challenges this place, particularly as it has a broader spectrum of action. A randomized study comparing caspofungin versus amphotericin B for the treatment of candidaemia in both neutropenic and non-neutropenic patients has been completed, but there is no direct comparison with fluconazole.152 Results of a prospective randomized controlled multicentre trial comparing anidulafungin, a new echinocandin, and fluconazole in patients with candidaemia should be available soon.
Fluconazole for the treatment of specific Candida organ infections
All randomized studies using fluconazole to date have been undertaken in oesophageal candidiasis or candidaemia, none in Candida organ infection, although some patients with invasive candidiasis have been included in the randomized studies. Therefore, the data presented here come from non-comparative open-label studies.
Osteoarticular infections due to Candida sp
Very few data are available on the efficacy of fluconazole as first line therapy in osteoarticular infections due to Candida sp. Some observations associated with spondylodiscitis have been published and have been summarized in Table 12.153–162 Fluconazole (200–400 mg/day initially, >2 months) proved to be efficacious in three cases of knee infections due to C. parapsilosis.163–165 A prosthetic joint infection and osteomyelitis of the knee due to C. albicans were cured with high doses of 800 mg/day of fluconazole for 2 months in combination with repeated surgical debridement, after a 10 day course of fluconazole 400 mg/day which seemed to be inefficient.166 Fluconazole (400–800 mg/day for 6 months) was also effective for the treatment of C. albicans post-surgical mediastinitis in two cases.167,168 Fluconazole (400 mg/day for 7 months) successfully treated an old patient with acute myeloid leukaemia who presented with C. tropicalis arthritis of the knee.169 The latest IDSA guidelines recommend surgical debridement and initial course of amphotericin B for 2–3 weeks, followed by fluconazole for a total duration of 6–12 months.57
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Endophthalmitis due to Candida sp.
A combination of partial or complete vitrectomy, intraocular amphotericin B and antifungal drugs is the usual therapeutic approach to Candida sp. eye infections. Several documented clinical cases reported the efficacy of fluconazole, alone or in combination with other treatments, in cases of endophthalmitis due to Candida spp.16,170–173 Finally, several recent series confirmed fluconazole efficacy in cases of severe ocular infections due to susceptible Candida sp. in non-neutropenic patients.174–180 Their results are summarized in Table 13. Most cases are due to C. albicans, and fluconazole-resistant species causing endophthalmitis is extremely rare. On the basis of these data, the IDSA recommends the use of fluconazole in this indication, particularly as follow-up therapy.58
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Meningitis due to Candida sp
Very few data exist on fluconazole's efficacy for the initial treatment of Candida sp. meningitis in adults, although this drug has a very good CSF penetration. Oral fluconazole (800 mg/day for 3 months then 200 mg/day) was successful for the treatment of a C. albicans meningitis in an HIV-infected patient with a CD4 cell count of 35 cells/mm3 who refused intravenous therapy.181
Endocarditis due to Candida sp
No series has documented the efficacy of fluconazole in endocarditis due to Candida sp. Only a few clinical cases have been published and most of these are summarized in Table 14.182–198 These cases illustrate the efficacy of fluconazole (sometimes with no surgical treatment) in endocarditis due to C. albicans and also in endocarditis related to some non-albicans Candida spp., especially C. parapsilosis. However, no study has demonstrated the superiority of fluconazole over amphotericin B in this indication, and there are insufficient data to recommend fluconazole as the first line treatment for endocarditis due to Candida spp.58,199 The echinocandins might have a place as primary therapy in these cases. Fluconazole (200–400 mg/day) is often employed as part of a long-term suppressive regimen, especially if valve replacement is not possible because of the high propensity for delayed relapse of candidal endocarditis.200,201
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Peritonitis due to Candida sp.
Peritonitis due to Candida sp. may develop in patients with peritoneal dialysis catheters, or in those with surgical or traumatic injury to the gut wall. In this latter situation, Candida spp. are usually part of a polymicrobial infection. Isolation of Candida by direct examination of peritoneal fluid is an independent factor for a severe outcome,202 and recent small studies suggest that prompt, effective, adequate and safe antifungal therapy should be given in all cases of Candida sp. peritonitis in order to lower the mortality rate and shorten the hospital stay.113,116 In a recent study of 23 cases secondary to peptic ulcer perforation, the mortality rate in patients receiving fluconazole (200 mg intravenously, twice daily for 2–4 weeks) was high (five of eight cases), probably related to inadequate or too late initiation of antifungal therapy.203 Some cases showing fluconazole efficacy have been reported in patients with continuous ambulatory peritoneal dialysis, either alone or in combination with flucytosine.204–207 Catheter removal is crucial in these cases.
Urinary infections due to Candida spp.
Candida is by far the most frequent agent of urinary fungal infections. The line between colonization and real infection is generally blurred. Candiduria usually present as nosocomial infections, favoured by indwelling urinary catheters, immunosuppressive drugs or antibiotic prescriptions, diabetes mellitus and extreme ages. C. albicans is involved in half of the cases, followed by C. glabrata in 15% of the cases. In 10% of cases, infection involves more than one species.208 Fluconazole achieves a 10 times higher concentration in urine than in blood with powerful effect even on C. glabrata infections. Therefore, it represents a first line treatment of any Candida urinary tract infection.
In a randomized placebo-controlled multicentre study among patients with asymptomatic candiduria, Sobel et al.209 found that fluconazole (200 mg/day) hastened the time to negative results of urine cultures. However, the rate of negative urine cultures 2 weeks after the end of therapy was similar in the fluconazole- and placebo-treated groups, showing the minimal utility of treatment in that setting. Indeed, asymptomatic candiduria should be treated only in high-risk situations, namely patients with neutropenia, infants with low birth weight, patients with renal allografts, and patients who will undergo urologic manipulations (recommendation of grade B-III from the IDSA). The optimal regimen in that setting is not known. Short courses regimen are not recommended and therapy for 1–2 weeks should be efficient.
Ascending pyelonephritis treatment should also include adequate urinary drainage and removal of obstructive fungus balls.210 Urinary tract devices should be optimally removed or at least replaced.
Haematogenous renal involvement should be treated with high-dose parenteral fluconazole (6 mg/kg/day) in accordance with the recently published IDSA guidelines.57
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Fluconazole in children/infants |
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No specific approval of fluconazole has been obtained in young children before the age of 6 months, but a few studies have evaluated its use in several settings.
Prophylaxis of systemic candidiasis in neonates
Few studies have focused on the use of fluconazole as a prophylactic agent against invasive candidiasis in neonates. Kaufman et al.211 demonstrated in 2001 the efficacy and safety of fluconazole (3 mg/kg every 3 days during the first 2 weeks, then every 2 days during the following 2 weeks and then every day until the sixth week of life) in extremely low birth weight and high-risk infants (<1000 g) in preventing both colonization and invasive fungal infection. High risk was defined as the presence of a central vascular catheter or endotracheal tube. Indeed, among the 50 infants randomly assigned to fluconazole, the rate of colonization (22%) was significantly lower than in the 50 placebo-treated ones (60%); no invasive fungal infection developed in the fluconazole group compared with a 20% rate of infection in the placebo group. No adverse effect of fluconazole was documented.
Kicklighter et al.212 similarly observed the safety of fluconazole at 6 mg/kg (for 6 weeks) and its efficacy among neonates with low birth weight (<1500 g) in the prevention of rectal colonization (however, occurrence of invasive candidiasis was similar in both groups). A Cochrane review of fluconazole prophylaxis in preterm infants demonstrated a reduced risk of invasive infection (related risk 0.20) and mortality (related risk 0.44) in fluconazole-treated patients compared with placebo-treated patients.213 Although concerns about resistance to azoles have been raised, the vast majority of Candida spp. strains have remained susceptible to fluconazole over the past decade in this population.40
Fluconazole in systemic candidiasis in children/infants
Neonatal candidaemia. Candidaemia is a major cause of sepsis in neonatal ICU, representing up to 16% of all sepsis cases. The related mortality rate is high, often nearly 50%.214 Most cases are related to C. albicans and C. parapsilosis, with a recent rise in cases related to C. tropicalis. The main risk factors for invasive candidiasis among neonates are low birth weight, intravascular catheters, intratracheal intubation, total parenteral nutrition and administration of intralipid solution and recent administration of broad-spectrum antibiotics and corticosteroids.10
Treatment with amphotericin B and 5-flucytosine has been the gold standard for years. However amphotericin B has some serious side effects, which makes it mandatory to consider its use in that setting. With good profile of tolerance, good diffusion in all tissues and body fluids, and reliable oral absorption, fluconazole has been studied as an alternative (see Table 15). In 1994, Fasano et al.215 reported the compassionate use of fluconazole among 40 newborns, including 11 who presented with Candida sp. meningitis. They were treated with a mean daily dosage of 5 mg/kg/day for a mean duration of 26 days. Of the 32 patients with evaluable outcome, 31 experienced clearance of infection. Other studies have confirmed these results in the recent years.11,216–220 In a multicentre prospective randomized study, Driessen et al.220 compared the efficacy and safety of either amphotericin B ± 5-flucytosine or fluconazole (oral or intravenous dose of 10 mg/kg as initial dose, and then 5 mg/kg/day) in neonates with candidaemia. In the fluconazole group 8/12 (67%) survived versus 6/11 (55%) in the other group.220 Among the four patients who died in the fluconazole group, two had treatment failure versus one in the amphotericin B group. Cytolytic hepatitis was less frequent in the fluconazole-treated group. Two isolated case reports also suggest that the association of fluconazole and flucytosine might be synergistic in the treatment of neonatal candidaemia.222,223
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Very recently, Mondal et al.229 compared the efficacy and safety of oral itraconazole versus oral fluconazole (both doses of 10 mg/kg/day) in newborns and paediatric patients with candidaemia. Similar cure rate (81 and 82%), mortality rate (9.5 and 13.5%) and number of side effects were observed.224 Fluconazole thus appears as a safe and effective systemic antifungal agent in the setting of neonatal candidiasis.
Children with systemic candidiasis. Excluding the setting of neonatal candidiasis, very few studies have however focused on the paediatric population when studying the efficiency of fluconazole for the treatment of invasive candidiasis.
In 1991 Viscoli et al. reported the outcome of 24 immunocompromised children treated with fluconazole (6 mg/kg/day) for 34 episodes of proven invasive candidiasis. A total of 30/34 clinical and microbiological cures were achieved. Two patients with fungaemia due to C. parapsilosis required an increase in dosage of up to 12 mg/kg. Transient drug-related increases of liver transaminases occurred in two cases (6%).225 In 1994 Fasano et al. reported the outcome of 63 children with AIDS, cancer or transplantation prospectively receiving fluconazole as compassionate treatment (dose regimen ranging from 0.16 to 11 mg/kg/day, mean 3.4 mg/kg/day).215 Half of them had fungaemia, while the others had respiratory, urinary tract or superficial oropharyngeal infections. Clinical cure or improvement was achieved in 52/63 (83%) and pathogen eradication was achieved in 43/59 (73%).17 Huttova et al.218 reported in 1998 the outcome of 10 children with nosocomial fungal meningitis, including 8 cases of candidal meningitis treated using fluconazole. Five of them survived with clinical and microbiological cure.
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Conclusions |
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Almost 15 years after its launch, fluconazole remains a cornerstone of antifungal prophylaxis and therapy of invasive candidiasis. It has an excellent pharmacokinetic and safety profile even in debilitated patients, with good tissue penetration and a lack of major drug interactions particularly with immunosuppressive agents. It can be prescribed in patients with renal failure if daily dosages are adapted to the creatinine serum level. Its spectrum of antimicrobial efficacy is reasonable and it remains active against most intrinsically susceptible Candida spp. encountered in systemic disease, with <5% of C. albicans resistant to fluconazole in that setting. Although C. krusei is intrinsically resistant to fluconazole, it is rarely reported as a cause of systemic infection outside neutropenic patients. Thus C. glabrata is the only species which might now limit the use of fluconazole for the first line therapy of yeast fungaemia when the species is not identified. Similarly, patients who recently received fluconazole as antifungal prophylaxis should not be treated with fluconazole for the curative treatment of a presumed or proven episode of systemic candidiasis. The fungistatic effect of fluconazole against Candida spp. does not appear to influence the outcome of candidaemic episodes at least in comparison with amphotericin B, which is apparently fungicidal against Candida spp. Finally, when summarizing its valuable properties, the strong demonstration of its efficacy in large randomized controlled trials and selected clinical series, its availability in various commercial presentations and its current low cost, fluconazole still remains a leading antifungal drug against susceptible Candida species.
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Transparency declarations |
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C. C., E. H., A. L., P. R. and F. D. have no conflicts to declare. D. W. D.: In the past 5 years, D. W. D. has received grant support from Astellas, Merck, Pfizer, F2G, OrthoBiotech, Indevus, Basilea, the Fungal Research Trust, the Wellcome Trust, the National Institute of Allergy and Infectious Diseases and the European Union. He has been an advisor/consultant to Merck, Basilea, Vicuron (now Pfizer), Schering Plough, Indevus, F2G, Nektar, Daiichi, Sigma Tau, Astellas, PPL Therapeutics and Uriach. He has been paid for talks on behalf of Astellas, Merck and Pfizer. He holds founder shares in F2G Ltd and GBE Diagnostics Ltd. and talks on behalf of Astellas, Merck and Gilead Sciences. O. L.: Speakers bureau for Pfizer.
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References |
|---|
1. Richardson K. The discovery and profile of fluconazole. J Chemother 1990; 2: 51–4.[Web of Science][Medline]
2.
Richardson K, Brammer KW, Marriott MS et al. Activity of UK-49,858, a bis-triazole derivative, against experimental infections with Candida albicans and Trichophyton mentagrophytes. Antimicrob Agents Chemother 1985; 27: 832–5.
3.
Van't Wout JW, Mattie H, van Furth R. A prospective study of the efficacy of fluconazole (UK-49,858) against deep-seated fungal infections. J Antimicrob Chemother 1988; 21: 665–72.
4. Van’t Wout JW, de Graeff-Meeder ER, Paul LC et al. Treatment of two cases of cryptococcal meningitis with fluconazole. Scand J Infect Dis 1988; 20: 193–8.[Web of Science][Medline]
5.
Tucker RM, Williams PL, Arathoon EG et al. Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemother 1988; 32: 369–73.
6.
Byrne WR, Wajszczuk CP. Cryptococcal meningitis in the acquired immunodeficiency syndrome (AIDS): successful treatment with fluconazole after failure of amphotericin B. Ann Intern Med 1988; 108: 384–5.
7.
Hughes CE, Beggs WH. Action of fluconazole (UK-49,858) in relation to other systemic antifungal azoles. J Antimicrob Chemother 1987; 19: 171–4.
8. Debruyne D. Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses. Clin Pharmacokinet 1997; 33: 52–77.[Web of Science][Medline]
9. Brammer KW, Coates PE. Pharmacokinetics of fluconazole in pediatric patients. Eur J Clin Microbiol Infect Dis 1994; 13: 325–9.[CrossRef][Web of Science][Medline]
10. Schwarze R, Penk A, Pittrow L. Administration of fluconazole in children below 1 year of age. Mycoses 1999; 42: 3–16.[CrossRef][Web of Science][Medline]
11. Schwarze R, Penk A, Pittrow L. Treatment of candidal infections with fluconazole in neonates and infants. Eur J Med Res 2000; 5: 203–8.[Medline]
12. Thaler F, Bernard B, Tod M et al. Fluconazole penetration in cerebral parenchyma in humans at steady state. Antimicrob Agents Chemother 1995; 5: 1154–6.
13. Bozzette SA, Gordon RL, Yen A et al. Biliary concentrations of fluconazole in a patient with candidal cholecystitis: case report. Clin Infect Dis 1992; 4: 701–3.
14. Debruyne D, Ryckelynck JP, Moulin M et al. Pharmacokinetics of fluconazole in patients undergoing continuous ambulatory peritoneal dialysis. Clin Pharmacokinet 1990; 18: 491–8.[Web of Science][Medline]
15. Tod M, Lortholary O, Padoin C et al. Intravenous penetration of fluconazole during endophthalmitis. Clin Microbiol Infect 1997; 3: 143–4.[Medline]
16. Urbak SF, Degn T. Fluconazole in the management of fungal ocular infections. Ophthalmologica 1994; 3: 147–56.
17. Fasano C, O'Keefe J, Gibbs D. Fluconazole treatment of children with severe fungal infections not treatable with conventional agents. Eur J Clin Microbiol Infect Dis 1994; 13: 344–7.[CrossRef][Web of Science][Medline]
18. Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet 1997; 72: 253–6.[CrossRef][Web of Science][Medline]
19. Buijk SL, Gyssens IC, Mouton JW et al. Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastro-intestinal function. Intensive Care Med 2001; 27: 115–21.[CrossRef][Web of Science][Medline]
20. El-Yazigi A, Ellis M, Ernst P et al. Pharmacokinetics of oral fluconazole when used for prophylaxis in bone marrow transplant recipients. Antimicrob Agents Chemother 1997; 41: 914–17.[Abstract]
21. Finch CK, Green CA, Self TH. Fluconazole-carbamazepine interaction. South Med J 2002; 95: 1099–100.[Web of Science][Medline]
22. Tucker RM, Denning DW, Hanson RH et al. Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations. Clin Infect Dis 1992; 14: 165–74.[Web of Science][Medline]
23. Stockley IH. Stockley's Drug Interactions: A Source Book of Interactions, Their Mechanisms, Clinical Importance and Management, 6th edn. London, UK: Pharmaceutical Press, 2002.
24. von Moltke LL, Greenblatt DJ, Duan SX et al. Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo. J Clin Psychopharmacol 1996; 16: 104–12.[CrossRef][Web of Science][Medline]
25. Brockmeyer NH, Tillmann I, Mertins L et al. Pharmacokinetic interaction of fluconazole and zidovudine in HIV-positive patients. Eur J Med Res 1997; 2: 377–83.[Medline]
26. van Burik JA, Leisenring W, Myerson D et al. The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis. An autopsy study of 355 patients. Medicine 1998; 77: 246–54.[CrossRef][Medline]
27. Wingard JR. Antifungal chemoprophylaxis after blood and marrow transplantation. Clin Infect Dis 2002; 34: 1386–90.[CrossRef][Web of Science][Medline]
28. Garbino J, Lew DP, Romand JA et al. Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill patients: a randomized, double-blind, placebo-controlled trial in patients treated by selective digestive decontamination. Intensive Care Med 2002; 28: 1708–17.[CrossRef][Web of Science][Medline]
29. Gearhart MO. Worsening of liver function with fluconazole and review of azole antifungal hepatotoxicity. Ann Pharmacother 1994; 28: 1177–81.[Abstract]
30. Crerar-Gilbert A, Boots R, Fraenkel D et al. Survival following fulminant hepatic failure from fluconazole induced hepatitis. Anaesth Intensive Care 1999; 27: 650–2.[Web of Science][Medline]
31.
Pappas PG, Kauffman CA, Perfect J et al. Alopecia associated with fluconazole therapy. Ann Intern Med 1995; 123: 354–7.
32. Stevens DA, Diaz M, Negroni R et al. Safety evaluation of chronic fluconazole therapy. Fluconazole Pan-American Study Group. Chemotherapy 1997; 5: 371–7.
33. Anaissie EJ, Kontoyiannis DP, Huls C et al. Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections. J Infect Dis 1995; 172: 599–602.[Web of Science][Medline]
34. Gussenhoven MJ, Haak A, Peereboom-Wynia JD et al. Stevens-Johnson syndrome after fluconazole. Lancet 1991; 338: 120.[Medline]
35.
Novelli V, Holzel H. Safety and tolerability of fluconazole in children. Antimicrob Agents Chemother 1999; 43: 1955–60.
36. Koks CH, Crommentuyn KM, Hoetelmans RM et al. Can fluconazole concentrations in saliva be used for therapeutic drug monitoring? Ther Drug Monit 2001; 4: 449–53.[CrossRef]
37.
Louie A, Drusano GL, Banerjee P et al. Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother 1998; 42: 1105–9.
38. Pittrow L, Penk A. Plasma and tissue concentrations of fluconazole and their correlation to breakpoints. Mycoses 1997; 40: 25–32.[Web of Science][Medline]
39. Rex JH, Pfaller MA, Galgiani JN et al. Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. Clin Infect Dis 1997; 24: 235–47.[Web of Science][Medline]
40. Pfaller MA, Diekema DJ. Twelve years of fluconazole in clinical practice: global trends in species distribution and fluconazole susceptibility of bloodstream isolates of Candida. International Fungal Surveillance Participant Group. Clin Microbiol Infect 2004; 10 Suppl 1: 11–23.[CrossRef][Web of Science][Medline]
41.
Tortorano AM, Rigoni AL, Biraghi E et al. The European Confederation of Medical Mycology (ECMM) survey of candidaemia in Italy: antifungal susceptibility patterns of 261 non-albicans Candida isolates from blood. J Antimicrob Chemother 2003; 52: 679–82.
42.
Pfaller MA, Messer SA, Boyken L et al. Geographic variation in the susceptibilities of invasive isolates of Candida glabrata to seven systemically active antifungal agents: a global assessment from the ARTEMIS Antifungal Surveillance Program conducted in 2001 and 2002. J Clin Microbiol 2004; 42: 3142–6.
43. Paya CV. Fungal infections in solid-organ transplantation. Clin Infect Dis 1993; 16: 677–88.[Web of Science][Medline]
44. Singh N, Wagener MM, Marino IR et al. Trends in invasive fungal infections in liver transplant recipients: correlation with evolution in transplantation practices. Transplantation 2002; 73: 63–7.[CrossRef][Web of Science][Medline]
45. Fung JJ. Fungal infection in liver transplantation. Transplant Infect Dis 2002; 4: 18–23.[Medline]
46.
Winston DJ, Pakrasi A, Busuttil RW. Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1999; 131: 729–37.
47. Gladdy RA, Richardson SE, Davies HD et al. Candida infection in pediatric liver transplant recipients. Liver Transpl Surg 1999; 5: 16–24.[CrossRef][Web of Science]
48.
Castaldo P, Stratta RJ, Wood RP et al. Clinical spectrum of fungal infections after orthotopic liver transplantation. Arch Surg 1991; 126: 149–56.
49. Husain S, Tollemar J, Dominguez EA et al. Changes in the spectrum and risk factors for invasive candidiasis in liver transplant recipients: prospective, multicenter, case-controlled study. Transplantation 2003; 75: 2023–9.[CrossRef][Web of Science][Medline]
50. George MJ, Snydman DR, Werner BG et al. The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG-Study Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland. Am J Med 1997; 103: 106–13.[CrossRef][Web of Science][Medline]
51. Dockrell DH, Mendez JC, Jones M et al. Human herpesvirus 6 seronegativity before transplantation predicts the occurrence of fungal infection in liver transplant recipients. Transplantation 1999; 67: 399–403.[CrossRef][Web of Science][Medline]
52. Tollemar J, Ericzon BG, Barkholt L et al. Risk factors for deep Candida infections in liver transplant recipients. Transplant Proc 1990; 22: 1826–7.[Web of Science][Medline]
53. Lumbreras C, Cuervas-Mons V, Jara P et al. Randomized trial of fluconazole versus nystatin for the prophylaxis of Candida infection following liver transplantation. J Infect Dis 1996; 174: 583–8.[Web of Science][Medline]
54. Winston DJ, Busuttil RW. Randomized controlled trial of oral itraconazole solution versus intravenous/oral fluconazole for prevention of fungal infections in liver transplant recipients. Transplantation 2002; 74: 688–95.[CrossRef][Web of Science][Medline]
55. Tortorano AM, Viviani MA, Pagano A et al. Candida colonization in orthotopic liver tranplantation: fuconazole versus oral amphoericin B. J Mycol Med 1995; 5: 21–4.
56. Kung N, Fisher N, Gunson B et al. Fluconazole prophylaxis for high-risk liver transplant recipients. Lancet 1995; 345: 1234–5.[Medline]
57. 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]
58. Paya CV. Prevention of fungal infection in transplantation. Transpl Infect Dis 2002; 4: S46–51.[CrossRef]
59. Lortholary O, Dupont B. Antifungal prophylaxis during neutropenia and immunodeficiency. Clin Microbiol Rev 1997; 10: 477–504.[Abstract]
60. Benedetti E, Gruessner AC, Troppmann C et al. Intra-abdominal fungal infections after pancreatic transplantation: incidence, treatment, and outcome. J Am Coll Surg 1996; 183: 307–16.[Web of Science][Medline]
61. Lumbreras C, Fernandez I, Velosa J et al. Infectious complications following pancreatic transplantation: incidence, microbiological and clinical characteristics, and outcome. Clin Infect Dis 1995; 20: 514–20.[Web of Science][Medline]
62. Patterson JE. Epidemiology of fungal infections in solid organ transplant patients. Transpl Infect Dis 1999; 1: 229–36.[CrossRef][Medline]
63. Kusne S, Furukawa H, Abu-Elmagd K et al. Infectious complications after small bowel transplantation in adults: an update. Transplant Proc 1996; 28: 2761–2.[Web of Science][Medline]
64. Paterson DL, Ndirangu M, Kwak EJ et al. Opportunistic infections in solid-organ transplant recipients pre-treated with alumetuzumab. In: Abstracts of the Forty-Fourth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2004. Abstract K-1427, p. 357. American Society for Microbiology, Washington, DC, USA.
65.
Kramer MR, Marshall SE, Starnes VA et al. Infectious complications in heart-lung transplantation. Analysis of 200 episodes. Arch Intern Med 1993; 153: 2010–6.
66. Goodrich JM, Reed EC, Mori M et al. Clinical features and analysis of risk factors for invasive candidal infection after marrow transplantation. J Infect Dis 1991; 164: 731–40.[Web of Science][Medline]
67. Dykewicz CA, Centers for Disease Control and Prevention (U.S.); Infectious Diseases Society of America; American Society of Blood and Marrow Transplantation. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Clin Infect Dis 2001; 33: 139–44.[CrossRef][Web of Science][Medline]
68. Sable CA, Donowitz GR. Infections in bone marrow transplant recipients. Clin Infect Dis 1994; 18: 273–81.[Web of Science][Medline]
69. Goodman JL, Winston DJ, Greenfield RA et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326: 845–51.[Abstract]
70. Slavin MA, Osborne B, Adams R et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation—a prospective, randomized, double-blind study. J Infect Dis 1995; 171: 1545–52.[Web of Science][Medline]
71.
Marr KA, Seidel K, Slavin MA et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood 2000; 96: 2055–61.
72. Alangaden G, Chandrasekar PH, Bailey E et al. Antifungal prophylaxis with low-dose fluconazole during bone marrow transplantation. The Bone Marrow Transplantation Team. Bone Marrow Transplant 1994; 14: 919–24.[Web of Science][Medline]
73. Wolff SN, Fay J, Stevens D et al. Fluconazole versus low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group. Bone Marrow Transplant 2000; 25: 853–9.[CrossRef][Web of Science][Medline]
74.
Annaloro C, Oriana A, Tagliaferri E et al. Efficacy of different prophylactic antifungal regimens in bone marrow transplantation. Haematologica 1995; 80: 512–17.
75.
Winston DJ, Maziarz RT, Chandrasekar PH et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med 2003; 138: 705–13.
76.
Marr KA, Crippa F, Leisenring W et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103: 1527–33.
77. MacMillan ML, Goodman JL, DeFor TE et al. Fluconazole to prevent yeast infections in bone marrow transplantation patients: a randomized trial of high versus reduced dose, and determination of the value of maintenance therapy. Am J Med 2002; 112: 369–79.[CrossRef][Web of Science][Medline]
78. Marr KA, Seidel K, White TC et al. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Infect Dis 2000; 181: 309–16.[CrossRef][Web of Science][Medline]
79. van Burik JA, Ratanatharathorn V, Stepan DE et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004; 39: 1407–16.[CrossRef][Web of Science][Medline]
80. Prentice HG, Kibbler CC, Prentice AG. Towards a targeted, risk-based, antifungal strategy in neutropenic patients. Br J Haematol 2000; 110: 273–84.[CrossRef][Web of Science][Medline]
81. Laverdiere M, Rotstein C, Bow EJ et al. Impact of fluconazole prophylaxis on fungal colonizatin and infection rates in neutropenic patients. The Canadian Fluconazole Study. J. Animicrob Chemother 2000; 46: 1001–8.
82.
Winston DJ, Chandrasekar PH, Lazarus HM et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia. Results of a randomized placebo-controlled, double-blind, multicenter trial. Ann Intern Med 1993; 118: 495–503.
83. Chandrasekar PH, Gatny CM. Effect of fluconazole prophylaxis on fever and use of amphotericin in neutropenic cancer patients. Bone Marrow Transplantation Team. Chemotherapy 1994; 40: 136–43.[Web of Science][Medline]
84. Rotstein C, Bow EJ, Laverdiere M et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group. Clin Infect Dis 1999; 28: 331–40.[Web of Science][Medline]
85. Yamac K, Senol E, Haznedar R. Prophylactic use of fluconazole in neutropenic cancer patients. Postgrad Med J 1997; 71: 284–6.
86. Kern W, Behre G, Rudolf T et al. Failure of fluconazole prophylaxis to reduce mortality or the requirement of systemic amphotericin B therapy during treatment for refractory acute myeloid leukemia: results of a prospective randomized phase III study. German AML Cooperative Group. Cancer 1998; 83: 291–301.[CrossRef][Web of Science][Medline]
87. Schaffner A, Schaffner M. Effect of prophylactic fluconazole on the frequency of fungal infections, amphotericin B use, and health care costs in patients undergoing intensive chemotherapy for hematologic neoplasias. J Infect Dis 1995; 172: 1035–41.[Web of Science][Medline]
88. Egger T, Gratwohl A, Tichelli A et al. Comparison of fluconazole with oral polyenes in the prevention of fungal infections in neutropenic patients. A prospective, randomized, single-center study. Support Care Cancer 1995; 3: 139–46.[CrossRef][Web of Science][Medline]
89. Morgenstern GR, Prentice AG, Prentice H et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. U.K. Multicentre Antifungal Prophylaxis Study Group. Br J Haematol 1999; 105: 901–11.[CrossRef][Web of Science][Medline]
90. Ellis ME, Clink H, Ernst P et al. Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients. Eur J Clin Microbiol Infect Dis 1994; 13: 3–11.[CrossRef][Web of Science][Medline]
91.
Philpott-Howard JN, Wade JJ, Mufti GJ et al. Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. Multicentre Study Group. J Antimicrob Chemother 1993; 31: 973–84.
92. Ninane J. A multicentre study of fluconazole versus oral polyenes in the prevention of fungal infection in children with hematological or oncological malignancies. Multicentre Study Group. Eur J Clin Microbiol Infect Dis 1994; 13: 330–7.[CrossRef][Web of Science][Medline]
93.
Menichetti F, Del Favero A, Martino P et al. Preventing fungal infection in neutropenic patients with acute leukemia: fluconazole compared with oral amphotericin B. The GIMEMA Infection Program. Ann Intern Med 1994; 120: 913–18.
94. Akiyama H, Mori S, Tanikawa S et al. Fluconazole versus oral amphotericin B in preventing fungal infection in chemotherapy-induced neutropenic patients with haematological malignancies. Mycoses 1996; 36: 373–8.
95. Meunier F, Aoun M, Janssens M et al. Chemoprophylaxis of fungal infections in granulocytopenic patients using fluconazole versus oral amphotericin B. Drug Invest 1991; 3: 258–65.
96.
Rozenberg-Arska M, Dekker AW, Branger J et al. A randomized study to compare oral fluconazole to amphotericin B in the prevention of fungal infections in patients with acute leukaemia. J Antimicrob Chemother 1991; 27: 369–76.
97. Brammer KW. Management of fungal infection in neutropenic patients with fluconazole. Haematol Blood Transfus 1990; 33: 546–50.[Medline]
98. Bodey GP, Anaissie EJ, Elting LS et al. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B. Cancer 1994; 73: 2099–106.[CrossRef][Web of Science][Medline]
99. Kanda Y, Yamamoto R, Chizuka A et al. Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta-analysis of 16 randomized, controlled trials. Cancer 2000; 89: 1611–25.[CrossRef][Web of Science][Medline]
100. Bow EJ, Laverdiere M, Lussier N et al. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials. Cancer 2002; 94: 3230–46.[CrossRef][Web of Science][Medline]
101. Viscoli C, Paesmans M, Sanz M et al. Association between antifungal prophylaxis and rate of documented bacteremia in febrile neutropenic cancer patients. Clin Infect Dis 2001; 32: 1532–7.[CrossRef][Web of Science][Medline]
102. Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34: 730–51.[CrossRef][Web of Science][Medline]
103. Cornely OA, Bohme A, Buchheidt D et al. Prophylaxis of invasive fungal infections in patients with hematological malignancies and solid tumors—guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003; 82 Suppl 2: 186–200.[CrossRef][Web of Science][Medline]
104. McNeil MM, Nash SL, Hajjeh RA et al. Trends in mortality due to invasive mycotic diseases in the United States, 1980–1997. Clin Infect Dis 2001; 33: 641–7.[CrossRef][Web of Science][Medline]
105. Kibbler CC, Seaton S, Barnes RA et al. Management and outcome of bloodstream infections due to Candida species in England and Wales. J Hosp Infect 2003; 54: 18–24.[CrossRef][Web of Science][Medline]
106. Marchetti O, Bille J, Fluckiger U et al. Fungal Infection Network of Switzerland. Epidemiology of candidemia in Swiss tertiary care hospitals: secular trends, 1991-2000. Clin Infect Dis 2004; 38: 311–20.[CrossRef][Web of Science][Medline]
107. Gudlaugsson O, Gillespie S, Lee K et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 2003; 37: 1172–7.[CrossRef][Web of Science][Medline]
108. Ibanez-Nolla J, Nolla-Salas M, Leon MA et al. Early diagnosis of candidiasis in nonneutropenic critically ill patients. J Infect 2004; 48: 181–92.[CrossRef][Web of Science][Medline]
109. Blumberg HM, Jarvis WR, Soucie JM et al. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis 2001; 33: 177–86.[CrossRef][Web of Science][Medline]
110. Pittet D, Monod M, Suter PM et al. Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg 1994; 220: 751–8.[Web of Science][Medline]
111.
Sendid B, Poirot JL, Tabouret M et al. Combined detection of mannanaemia and antimannan antibodies as a strategy for the diagnosis of systemic infection caused by pathogenic Candida species. J Med Microbiol 2002; 51: 433–42.
112. Bar W, Hecker H. Diagnosis of systemic Candida infections in patients of the intensive care unit. Significance of serum antigens and antibodies. Mycoses 2002; 45: 22–8.[Medline]
113. Calandra T, Marchetti O. Clinical trials of antifungal prophylaxis among patients undergoing surgery. Clin Infect Dis 2004; 39: S185–92.[Medline]
114. Sypula WT, Kale-Pradhan PB. Therapeutic dilemma of fluconazole prophylaxis in intensive care. Ann Pharmacother 2002; 36: 155–9.[Abstract]
115. Pelz RK, Hendrix CW, Swoboda SM et al. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg 2001; 233: 542–8.[CrossRef][Web of Science][Medline]
116. Eggimann P, Francioli P, Bille J et al. Fluconazole prophylaxis prevents intraabdominal candidiasis in high-risk surgical patients. Crit Care Med 1997; 27: 1066–72.
117. Swoboda SM, Merz WG, Lipsetta PA. Candidemia: the impact of antifungal prophylaxis in a surgical intensive care unit. Surg Infect 2003; 4: 345–54.[CrossRef]
118. Todd JC, O'Neal VG, Grady KP et al. Reduction of secondary mycotic infections in the trauma intensivie care unit with fluconazole. J Trauma 1991; 31: 1722–27.
119. Jacobs S, Price Evans DA, Tariq M et al. Fluconazole improves survival in septic shock: a randomized double-blind prospective study. Crit Care Med 2003; 31: 1938–46.[CrossRef][Web of Science][Medline]
120. Zervos EE, Fink GW, Norman JG et al. Fluconazole increases bactericidal activity of neutrophils through non-cytokine-mediated pathway. J Trauma 1996; 41: 465–70.[Web of Science][Medline]
121. Ables AZ, Blumer NA, Valainis GT et al. Fluconazole prophylaxis of severe Candida infection in trauma and postsurgical patients: a prospective, double-blind, randomised placebo-controlled trial. Infect Dis Clin Pract 2000; 9: 169–75.[CrossRef]
122.
Kam LW, Lin JD. Management of systemic candidal infections in the intensive care unit. Am J Health Syst Pharm 2002; 59: 33–41.
123.
Rocco TR, Reinert SE, Simms HH. Effects of fluconazole administration in critically ill patients: analysis of bacterial and fungal resistance. Arch Surg 2000; 135: 160–5.
124. Tortorano AM, Caspani L, Rigoni AL et al. Candidosis in the intensive care unit: a 20-year survey. J Hosp Infect 2004; 57: 8–13.[CrossRef][Web of Science][Medline]
125. Eggimann P, Garbino J, Pittet D. Management of Candida species infections in critically ill patients. Lancet Infect Dis 2003; 3: 772–85.[CrossRef][Web of Science][Medline]
126. Eggimann P, Garbino J, Pittet D. Epidemiology of Candida species infections in critically ill non-immunosuppressed patients. Lancet Infect Dis 2003; 3: 685–702.[CrossRef][Web of Science][Medline]
127. Martins MD, Lozano-Chiu M, Rex JH. Declining rates of oropharyngeal candidiasis and carriage of Candida albicans associated with trends toward reduced rates of carriage of fluconazole-resistant C. albicans in human immunodeficiency virus-infected patients. Clin Infect Dis 1998; 27: 1291–4.[Web of Science][Medline]
128.
Powderly WG, Finkelstein D, Feinberg J et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med 1995; 332: 700–5.
129. Leen CL, Dunbar EM, Ellis ME et al. Once-weekly fluconazole to prevent recurrence of oropharyngeal candidiasis in patients with AIDS and AIDS-related complex: a double-blind placebo-controlled study. J Infect 1990; 21: 55–60.[CrossRef][Web of Science][Medline]
130.
Stevens DA, Greene SI, Lang OS. Thrush can be prevented in patients with acquired immunodeficiency syndrome and the acquired immunodeficiency syndrome-related complex. Randomized, double-blind, placebo-controlled study of 100-mg oral fluconazole daily. Arch Intern Med 1991; 151: 2458–64.
131. Just-Nubling G, Gentschew G, Meissner K. Fluconazole prophylaxis of recurrent oral candidiasis in HIV-positive patients. Eur J Clin Microbiol Infect Dis 1991; 10: 917–21.[CrossRef][Web of Science][Medline]
132. Marriott DJ, Jones PD, Hoy JF et al. Fluconazole once a week as secondary prophylaxis against oropharyngeal candidiasis in HIV-infected patients. A double-blind placebo-controlled study. Med J Aust 1993; 158: 312–16.[Web of Science][Medline]
133.
Schuman P, Capps L, Peng G et al. Weekly fluconazole for the prevention of mucosal candidiasis in women with HIV infection. A randomized, double-blind, placebo-controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. Ann Intern Med 1997; 126: 689–96.
134. Havlir DV, Dube MP, McCutchan JA et al. Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS. Clin Infect Dis 1998; 27: 1369–75.[Web of Science][Medline]
135.
Pagani JL, Chave JP, Casjka C et al. Efficacy, tolerability and development of resistance in HIV-positive patients treated with fluconazole for secondary prevention of oropharyngeal candidiasis: a randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother 2002; 50: 231–40.
136. Vazquez JA, Peng G, Sobel JD et al. Evolution of antifungal susceptibility among Candida species isolates recovered from human immunodeficiency virus-infected women receiving fluconazole prophylaxis. Clin Infect Dis 2001; 33: 1069–75.[CrossRef][Web of Science][Medline]
137. Delfraissy JF. Prise en charge thérapeutique des patients infectés pas le VIH. Rapport Delfraissy. Paris: Flammarion, 2004.
138. De Pauw BE, Raemaekers JM, Donnelly JP et al. An open study on the safety and efficacy of fluconazole in the treatment of disseminated Candida infections in patients treated for hematological malignancy. Ann Hematol 1995; 70: 83–7.[Web of Science][Medline]
139. Anaissie EJ, Vartivarian SE, Abi-Said D et al. Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched cohort study. Am J Med 1996; 101: 170–6.[CrossRef][Web of Science][Medline]
140. Anaissie EJ, Darouiche RO, Abi-Said D et al. Management of invasive candidal infections: results of a prospective, randomized, multicenter study of fluconazole versus amphotericin B and review of the literature. Clin Infect Dis 1996; 23: 964–72.[Web of Science][Medline]
141. Myoken Y, Kyo T, Kohara T et al. Breakthrough fungemia caused by azole-resistant Candida albicans in neutropenic patients with acute leukemia. Clin Infect Dis 2003; 36: 1496–7.[CrossRef][Web of Science][Medline]
142. Anttila VJ, Farkkila M, Jansson SE et al. Diagnostic laparoscopy in patients with acute leukemia and suspected hepatic candidiasis. Eur J Clin Microbiol Infect Dis 1997; 16: 637–43.[CrossRef][Web of Science][Medline]
143. Anaissie E, Bodey GP, Kantarjian H et al. Fluconazole therapy for chronic disseminated candidiasis in patients with leukemia and prior amphotericin B therapy. Am J Med 1991; 91: 142–50.[CrossRef][Web of Science][Medline]
144. Kauffman CA, Bradley SF, Ross SC et al. Hepatosplenic candidiasis: successful treatment with fluconazole. Am J Med 1991; 91: 137–41.[CrossRef][Web of Science][Medline]
145. Kontoyiannis DP, Luna MA, Samuels BI et al. Hepatosplenic candidiasis. A manifestation of chronic disseminated candidiasis. Infect Dis Clin North Am 2000; 14: 721–39.[CrossRef][Web of Science][Medline]
146. Graninger W, Presteril E, Schneeweiss B et al. Treatment of Candida albicans fungaemia with fluconazole. J Infect 1993; 26: 133–46.[CrossRef][Web of Science][Medline]
147. Phillips P, Shafran S, Garber G et al. Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients. Canadian Candidemia Study Group. Eur J Clin Microbiol Infect Dis 1997; 16: 337–45.[CrossRef][Web of Science][Medline]
148.
Rex JH, Bennett JE, Sugar AM et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 1994; 331: 1325–30.
149. Abele-Horn M, Kopp A, Sternberg U et al. A randomized study comparing fluconazole with amphotericin B/5-flucytosine for the treatment of systemic Candida infections in intensive care patients. Infection 1996; 24: 426–32.[CrossRef][Web of Science][Medline]
150.
Nguyen MH, Peacock JE Jr, Tanner DC et al. Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study. Arch Intern Med 1995; 155: 2429–35.
151. Rex JH, Pappas PG, Karchmer AW et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in non-neutropenic subjects. Clin Infect Dis 2003; 36: 1221–8.[CrossRef][Web of Science][Medline]
152.
Mora-Duarte J, Betts R, Rotstein C et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002; 347: 2020–9.
153. Sugar AM, Saunders C, Diamond RD et al. Successful treatment of Candida osteomyelitis with fluconazole. A noncomparative study of two patients. Diagn Microbiol Infect Dis 1990; 13: 517–20.[CrossRef][Web of Science][Medline]
154. Tang C. Successful treatment of Candida albicans osteomyelitis with fluconazole. J Infect 1993; 26: 89–92.[CrossRef][Web of Science][Medline]
155. Lafont A, Olive A, Gelman M et al. Candida albicans spondylodiscitis and vertebral osteomyelitis in patients with intravenous heroin drug addiction. Report of 3 new cases. J Rheumatol 1994; 21: 953–6.[Web of Science][Medline]
156. Hennequin C, Bouree P, Hiesse C et al. Spondylodiskitis due to Candida albicans: report of two patients who were successfully treated with fluconazole and review of the literature. Clin Infect Dis 1996; 23: 176–8.[Web of Science][Medline]
157. Jonnalagadda S, Veerabagu MP, Rakela J et al. Candida albicans osteomyelitis in a liver transplant recipient: a case report and review of the literature. Transplantation 1996; 62: 1182–4.[CrossRef][Web of Science][Medline]
158. Rossel P, Schonheyder HC, Nielsen H. Fluconazole therapy in Candida albicans spondylodiscitis. Scand J Infect Dis 1998; 30: 527–30.[CrossRef][Web of Science][Medline]
159. Turner DL, Johnson SA, Rule SA. Successful treatment of candidal osteomyelitis with fluconazole following failure with liposomal amphotericin B. J Infect 1999; 38: 51–3.[CrossRef][Web of Science][Medline]
160. El-Zaatari MM, Hulten K, Fares Y et al. Successful treatment of Candida albicans osteomyelitis of the spine with fluconazole and surgical debridement: case report. J Chemother 2002; 14: 627–30.[Web of Science][Medline]
161. Seravalli L, Van Linthoudt D, Bernet C et al. Candida glabrata spinal osteomyelitis involving two contiguous lumbar vertebrae: a case report and review of the literature. Diagn Microbiol Infect Dis 2003; 45: 137–41.[CrossRef][Web of Science][Medline]
162. Garbino J, Schnyder I, Lew DP et al. An unusual cause of vertebral osteomyelitis: Candida species. Scand J Infect Dis 2003; 35: 288–91.[CrossRef][Web of Science][Medline]
163. Tunkel AR, Thomas CY, Wispelwey B. Candida prosthetic arthritis: report of a case treated with fluconazole and review of the literature. Am J Med 1993; 94: 100–3.[CrossRef][Web of Science][Medline]
164. Cushing RD, Fulgenzi WR. Synovial fluid levels of fluconazole in a patient with Candida parapsilosis prosthetic joint infection who had an excellent clinical response. J Arthroplasty 1997; 12: 950.[CrossRef][Web of Science][Medline]
165. Fukasawa N, Shirakura K. Candida arthritis after total knee arthroplasty—a case of successful treatment without prosthesis removal. Acta Orthop Scand 1997; 68: 306–7.[Web of Science][Medline]
166. Lerch K, Kalteis T, Schubert T et al. Prosthetic joint infections with osteomyelitis due to Candida albicans. Mycoses 2003; 46: 462–6.[CrossRef][Web of Science][Medline]
167. Clancy CJ, Nguyen MH, Morris AJ. Candidal mediastinitis: an emerging clinical entity. Clin Infect Dis 1997; 25: 608–13.[Web of Science][Medline]
168. Petrikkos G, Skiada A, Sabatakou H et al. Case report. Successful treatment of two cases of post-surgical sternal osteomyelitis, due to Candida krusei and Candida albicans, respectively, with high doses of triazoles (fluconazole, itraconazole). Mycoses 2001; 44: 422–5.[Web of Science][Medline]
169. Weers-Pothoff G, Havermans JF, Kamphuis J et al. Candida tropicalis arthritis in a patient with acute myeloid leukemia successfully treated with fluconazole: case report and review of the literature. Infection 1997; 25: 109–11.[CrossRef][Web of Science][Medline]
170. Laatikainen L, Tuominen M, von Dickhoff K. Treatment of endogenous fungal endophthalmitis with systemic fluconazole with or without vitrectomy. Am J Ophthalmol 1992; 113: 205–7.[Web of Science][Medline]
171.
Borne MJ, Elliott JH, O'Day DM. Ocular fluconazole treatment of Candida parapsilosis endophthalmitis after failed intravitreal amphotericin B. Arch Ophthalmol 1993; 111: 1326–7.
172. Zarbin MA, Becker E, Witcher J et al. Treatment of presumed fungal endophthalmitis with oral fluconazole. Ophthalmic Surg Lasers 1996; 27: 628–31.[Web of Science][Medline]
173.
Wong VK, Tasman W, Eagle RC et al. Bilateral Candida parapsilosis endophthalmitis. Arch Ophthalmol 1997; 115: 670–2.
174. Kauffman CA, Bradley SF, Vine AK. Candida endophthalmitis associated with intraocular lens implantation: efficacy of fluconazole therapy. Mycoses 1993; 36: 13–17.[Web of Science][Medline]
175. del Palacio A, Cuetara MS, Ferro M et al. Fluconazole in the management of endophthalmitis in disseminated candidosis of heroin addicts. Mycoses 1993; 36: 193–9.[Medline]
176. Luttrull JK, Wan WL, Kubak BM et al. Treatment of ocular fungal infections with oral fluconazole. Am J Ophthalmol 1995; 119: 477–81.[Web of Science][Medline]
177. Akler ME, Vellend H, McNeely DM et al. Use of fluconazole in the treatment of candidal endophthalmitis. Clin Infect Dis 1995; 20: 657–64.[Web of Science][Medline]
178. Christmas NJ, Smiddy WE. Vitrectomy and systemic fluconazole for treatment of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers 1996; 27: 1012–18.[Web of Science][Medline]
179. Essman TF, Flynn HW, Smiddy WE et al. Treatment outcomes in a 10-year study of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers 1997; 28: 185–94.[Web of Science][Medline]
180. Martinez-Vazquez C, Fernandez-Ulloa J, Bordon J et al. Candida albicans endophthalmitis in brown heroin addicts: response to early vitrectomy preceded and followed by antifungal therapy. Clin Infect Dis 1998; 27: 1130–3.[Web of Science][Medline]
181. Aleixo MJ, Caldeira L, Ferreira ML. Candida albicans meningitis: clinical case. J Infect 2000; 40: 191–2.[Web of Science][Medline]
182. Inoue Y, Yozu R, Ueda T et al. A case report of Candida parapsilosis endocarditis. J Heart Valve Dis 1998; 7: 240–2.[Web of Science][Medline]
183.
Isalska BJ, Stanbridge TN. Fluconazole in the treatment of candidal prosthetic valve endocarditis. BMJ 1988; 297: 178–9.
184.
Martino P, Meloni G, Cassone A. Candidal endocarditis and treatment with fluconazole and granulocyte-macrophage colony-stimulating factor. Ann Intern Med 1990; 112: 966–7.
185. Roupie E, Darmon JY, Brochard L et al. Fluconazole therapy of candidal native valve endocarditis. Eur J Clin Microbiol Infect Dis 1991; 10: 458–9.[CrossRef][Web of Science][Medline]
186. Hernandez JA, Gonzalez-Moreno M, Llibre JM et al. Candidal mitral endocarditis and long-term treatment with fluconazole in a patient with human immunodeficiency virus infection. Clin Infect Dis 1992; 15: 1062–3.[Web of Science][Medline]
187. Venditti M, De Bernardis F, Micozzi A, et al. Fluconazole treatment of catheter-related right-sided endocarditis caused by Candida albicans and associated with endophthalmitis and folliculitis. Clin Infect Dis 1992; 14: 422–6.[Web of Science][Medline]
188. Wallbridge DR, McCartney AC, Richardson MD. Fluconazole in the treatment of Candida prosthetic valve endocarditis. Mycoses 1993; 36: 259–61.[Web of Science][Medline]
189. Otaki M, Kitamura N. Candida prosthetic valve endocarditis. An autopsy review. Int Surg 1993; 78: 252–3.[Web of Science][Medline]
190. Czwerwiec FS, Bilsker MS, Kamerman ML et al. Long-term survival after fluconazole therapy of candidal prosthetic valve endocarditis. Am J Med 1993; 94: 545–6.[CrossRef][Web of Science][Medline]
191. Thakur RK, Skelcy KM, Kahn RN et al. Successful treatment of Candida prosthetic valve endocarditis with a combination of fluconazole and amphotericin B. Crit Care Med 1994; 22: 712–14.[Web of Science][Medline]
192. Cancelas JA, Lopez J, Cabezudo E et al. Native valve endocarditis due to Candida parapsilosis: a late complication after bone marrow transplantation-related fungemia. Bone Marrow Transplant 1994; 13: 333–4.[Web of Science][Medline]
193. Zahid MA, Klotz SA, Hinthorn DR. Medical treatment of recurrent candidemia in a patient with probable Candida parapsilosis prosthetic valve endocarditis. Chest 1994; 105: 1597–8.[CrossRef][Medline]
194. Wells CJ, Leech G, Lever AM et al. Treatment of native valve Candida endocarditis with fluconazole. J Infect 1995; 31: 233–5.[CrossRef][Web of Science][Medline]
195. Gilbert HM, Peters ED, Lang SJ et al. Successful treatment of fungal prosthetic valve endocarditis: case report and review. Clin Infect Dis 1996; 22: 348–54.[Web of Science][Medline]
196. Nguyen MH, Nguyen ML, Yu VL et al. Candida prosthetic valve endocarditis: prospective study of six cases and review of the literature. Clin Infect Dis 1996; 22: 262–7.[Web of Science][Medline]
197. Lejko-Zupanc T, Kozelj M. A case of recurrent Candida parapsilosis prosthetic valve endocarditis: cure by medical treatment alone. J Infect 1997; 35: 81–2.[CrossRef][Web of Science][Medline]
198. Joly V, Belmatoug N, Leperre A et al. Pacemaker endocarditis due to Candida albicans: case report and review. Clin Infect Dis 1997; 25: 1359–62.[Web of Science][Medline]
199. Rex JH, Walsh T, Sobel JD et al. Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America. Clin Infect Dis 2000; 30: 662–78.[CrossRef][Web of Science][Medline]
200. Baddour LM. Long-term suppressive therapy for Candida parapsilosis-induced prosthetic valve endocarditis. Mayo Clin Proc 1995; 70: 773–5.[Abstract]
201. Melgar GR, Nasser RM, Gordon SM. Fungal prosthetic valve endocarditis in 16 patients. An 11-year experience in a tertiary care hospital. Medicine 1997; 76: 94–103.[CrossRef][Medline]
202.
Dupont H, Paugam-Burtz C, Muller-Serieys C et al. Predictive factors of mortality due to polymicrobial peritonitis with Candida isolation in peritoneal fluid in critically ill patients. Arch Surg 2002; 137: 1341–6.
203. Lee SC, Fung CP, Chen HY et al. Candida peritonitis due to peptic ulcer perforation: incidence rate, risk factors, prognosis and susceptibility to fluconazole and amphotericin B. Diagn Microbiol Infect Dis 2002; 44: 23–7.[CrossRef][Web of Science][Medline]
204. Levine J, Bernard DB, Idelson BA et al. Fungal peritonitis complicating continuous ambulatory peritoneal dialysis: successful treatment with fluconazole, a new orally active antifungal agent. Am J Med 1989; 86: 825–7.[CrossRef][Web of Science][Medline]
205. Michel C, Courdavault L, al Khayat R et al. Fungal peritonitis in patients on peritoneal dialysis. Am J Nephrol 1994; 14: 113–20.[Web of Science][Medline]
206. Wang AY, Yu AW, Li PK et al. Factors predicting outcome of fungal peritonitis in peritoneal dialysis: analysis of a 9-year experience of fungal peritonitis in a single center. Am J Kidney Dis 2000; 36: 1183–92.[Web of Science][Medline]
207. Hawkins JL, Baddour LM. Candida lusitaniae infections in the era of fluconazole availability. Clin Infect Dis 2003; 36: 14–18.
208. Kauffman CA, Vazquez JA, Sobel JD et al. Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis 2000, 30: 14–18.[CrossRef][Web of Science][Medline]
209. Sobel JD, Kauffman CA, McKinsey D et al. Candiduria: a randomized, double-blind study of treatment with fluconazole and placebo. The National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis 2000; 30: 19–24.[CrossRef][Web of Science][Medline]
210. Lundstrom T, Sobel J. Nosocomial candiduria: a review. Clin Infect Dis 2001; 32: 1602–7.[CrossRef][Web of Science][Medline]
211.
Kaufman D, Boyle R, Hazen KC et al. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med 2001; 345: 1660–6.
212.
Kicklighter SD, Springer SC, Cox T et al. Fluconazole for the prophylaxis against candidal rectal colonization in the very low birth weight infant. Pediatrics 2001; 107: 293–8.
213. McGuire W, Clerihew L, Austin N. Prophylactic intravenous antifungal agents to prevent mortality and morbidity in very low birth weight infants. Cochrane Database Syst Rev 2004: CD003850.
214. Agarwal J, Bansal S, Malik GK et al. Trends in neonatal septicemia: emergence of non-albicans Candida. Indian Pediatr 2004; 41: 712–15.[Medline]
215. Fasano C, O'Keefe J, Gibbs D. Fluconazole treatment of neonates and infants with severe fungal infections not treatable with conventional agents. Eur J Clin Microbiol Infect Dis 1994; 13: 351–4.[CrossRef][Web of Science][Medline]
216. Wainer S, Cooper PA, Gouws H et al. Prospective study of fluconazole therapy in systemic neonatal fungal infection. Pediatr Infect Dis J 1997; 16: 763–7.[CrossRef][Web of Science][Medline]
217. Huang YC, Lin TY, Lien RI et al. Fluconazole therapy in neonatal candidemia. Am J Perinatol 2000; 17: 411–15.[CrossRef][Web of Science][Medline]
218. Huttova M, Hartmanova I, Kralinsky K et al. Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis. Pediatr Infect Dis J 1998; 17: 1012–15.[CrossRef][Web of Science][Medline]
219. Gurpinar AN, Balkan E, Kilic N et al. Fluconazole treatment of neonates and infants with severe fungal infections. J Int Med Res 1997; 25: 214–18.[Web of Science][Medline]
220. Driessen M, Ellis JB, Muwazi F et al. The treatment of systemic candidiasis in neonates with oral fluconazole. Ann Trop Pediatr 1997; 17: 263–71.[Web of Science][Medline]
221. Driessen M, Ellis JB, Cooper PA et al. Fluconazole vs. amphotericin B for the treatment of neonatal fungal septicemia: a prospective randomized trial. Pediatr Infect Dis J 1997; 15: 1107–12.
222. Marr B, Gross S, Cunningham C et al. Candidal sepsis and meningitis in a very-low-birth-weight infant successfully treated with fluconazole and flucytosine. Clin Infect Dis 1994; 19: 795–6.[Web of Science][Medline]
223. Oleinik EM, Della-Latta P, Rinaldi MG et al. Candida lusitaniae osteomyelitis in a premature infant. Am J Perinatol 1993; 10: 313–15.[Web of Science][Medline]
224. Mondal RK, Singhi SC, Chakrabarti A. Randomized comparison between fluconazole and itraconazole for the treatment of candidemia in a pediatric intensive care unit: a preliminary study. Pediatr Crit Care Med 2004; 5: 561–5.[CrossRef][Medline]
225.
Viscoli C, Castagnola E, Fioredda F et al. Fluconazole in the treatment of candidiasis in immunocompromised children. Antimicrob Agents Chemother 1991; 35: 365–7.
226. Decruyenaere J, Colardyn F, Vogelaers D et al. Combined use of fluconazole and selective digestive decontamination in the prevention of fungal infection after adult liver transplantation. Transplant Proc 1995; 27: 3515–16.[Web of Science][Medline]
227. Koh LP, Kurup A, Goh YT et al. Randomized trial of fluconazole versus low-dose amphotericin B in prophylaxis against fungal infections in patients undergoing hematopoietic stem cell transplantation. Am J Hematol 2002; 71: 260–7.[CrossRef][Web of Science][Medline]
228. Gluckman E, Esperou-Bourdeau H, Ribaud P et al. Comparaison entre le fluconazole et le kétoconazole pour la prophylaxie des infections fongiques chez les patients traités par greffe de moelle allogénique. Cah Oncol 1993; 2: 167–9.
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