Use Of Fluconazole Prophylaxis Research Articles

Safety of fluconazole in kidney transplant recipients for prevention of coccidioidomycosis.

Coccidioides is an endemic fungus that causes infections ranging from mild respiratory illness to life-threatening disease, and immunocompromised hosts such as solid organ transplant recipients are at higher risk for disseminated infection and mortality. Our center administers fluconazole prophylaxis to kidney transplant recipients residing in geographic areas with higher incidences of coccidioidomycosis. However, because drug-drug interactions occur between triazoles and immunosuppressants used in transplant medicine, we undertook a study to ascertain whether fluconazole prophylaxis was associated with any important safety outcomes in kidney transplant recipients. This retrospective study evaluated patients who had undergone kidney transplantation between 2016 and 2019. Data on patient demographics, transplant-related clinical information, use of fluconazole prophylaxis (200 mg daily for 6-12 months post-transplant), and patient outcomes were obtained. The primary outcome was mean estimated glomerular filtration rate (eGFR) at 12 months, comparing those who received fluconazole prophylaxis to those who did not. Secondary outcomes included mean eGFR at 3 months, 6 months, and 9 months post-transplant, patient survival, biopsy-proven graft rejection, graft loss, or a new requirement for post-transplant dialysis, all within 12 months post-transplant. The mean eGFR at 12 months was similar between both groups, with 66.4 ml/min/1.73 m² in the fluconazole prophylaxis group vs. 64.3 ml/min/1.73 m² in the non-fluconazole prophylaxis group (P=0.55). Secondary outcomes were similar across both groups. Multivariable linear regression found no significant association between fluconazole use and graft function. Fluconazole prophylaxis for prevention of coccidioidomycosis was not associated with adverse graft outcomes in kidney transplant recipients.

2446. Effect of the Implementation of a Fluconazole Prophylaxis Protocol on the Incidence of Invasive Fungal Infection in High-Risk Neonates

Abstract Background Invasive fungal infection (IFI) is one of the most important causes of morbidity and mortality in the neonatal intensive care unit. International societies have supported the use of fluconazole prophylaxis for neonates weighing < 1000 grams, but administration to other high-risk patients remains controversial. An institutional fluconazole prophylaxis guideline was implemented in December 2020 to include two other groups of neonates. Methods One hundred thirty infants who were admitted at the NICU from January 2020 to January 2022 and fulfilled one of the following criteria: weight of < 1000 grams (Group A), weight of ≤1500 grams and on broad-spectrum antibiotics (Group B), or weight of >1500 grams and on prolonged nil per os (NPO) (Group C) were included in the study. They were divided into two groups: those who were born prior to the implementation of the protocol (January to December 2020) and not given fluconazole prophylaxis, and those born after (January 2021 to January 2022) and given prophylaxis. The primary outcome was the development of IFI. Results A total of 130 infants were included in this study with 21 (5 control, 16 prophylaxis), 69 (28 control, 41 prophylaxis), and 40 (16 control, 24 prophylaxis) patients in Groups A, B, and C, respectively. There were no significant differences in the development of IFI among the groups (Group A: control - 40%, prophylaxis - 62%; Group B: control - 21.4%, prophylaxis - 22%; Group C: control - 29.2%, prophylaxis 31.5%) with a p-value of > 0.05. The presence of a central vascular access line, endotracheal tube, placement on NPO, histamine H2-blockers, and necrotizing enterocolitis were associated with the development of IFI. Candida parapsilosis comprised 60% of isolates. All isolates had 100% susceptibility to fluconazole. Jaundice developed in 3.7% of patients given fluconazole, with elevations in AST, ALT, and TB. Incidence of fungal infection in high-risk neonates There were no significant differences in the development of IFI among the three high-risk groups, with p-value of > 0.05. Conclusion Invasive fungal infection remains a heavy burden to high-risk neonates. The protocol at present does not significantly prevent the occurrence of IFI. There is a need to revise the protocol to include the presence of a combination of multiple risk factors (central line, endotracheal tube, prolonged NPO, H2-blockers, and necrotizing enterocolitis) before initiating fluconazole prophylaxis. Disclosures All Authors: No reported disclosures

S8.2a Trends in epidemiology of pediatric Candida infections

S8.2 What is new in pediatric mycology?, September 23, 2022, 3:00 PM - 4:30 PM Invasive Candida infections are a cause of increased morbidity and excessive mortality in immunocompromised and critically ill patients including premature neonates. In the pediatric setting, they are more frequent in the neonatal intensive care unit (ICU), in the pediatric ICU, and in the pediatric oncology/hematology departments. Its frequency in other pediatric departments, such as gastroenterology, surgery, and nephrology is less of a problem. Candida albicans remains the most frequent Candida species, whereas other non-albicans Candida spp. are less frequent. Candida parapsilosis is second in frequency, but in certain pediatric settings and countries, it may be first. While C. albicans is almost entirely susceptible to azoles, C. parapsilosis has started to manifest increasing resistance to fluconazole and this is of concern. However, due to improved infection control and prevention measures and to use of fluconazole prophylaxis in a number of neonatal ICUs, its incidence has been shown to decrease in a multi-state study conducted by the Centers of Disease Control and Prevention in the United States. Another large multinational study that was conducted in many European countries showed no changes in epidemiology over a number of years, and more non-albicans Candida, particularly C. parapsilosis, in South Europe. The epidemiology of Candida in pediatric ICU has been less studied. Similar epidemiology and risk factors exist in PICU as in neonates. Abdominal surgery and multi-site colonization with Candida of patients are risk factors for developing invasive Candida infections, mainly candidemia. In the patients with hematological malignancies, antifungal prophylaxis for mold infections is also active against Candida, therefore, the incidence of invasive candidiasis is relatively low. However, non-Candida albicans species with reduced susceptibility to azoles, such as C. glabrata, are found more frequently. In pediatric patients with solid organ transplantation, invasive candidiasis is the most frequent fungal infection, mainly in those with liver transplantation. Candida causes infection in the first weeks after transplantation earlier than other fungal infections.

A Quality Improvement Project Aimed at Standardizing the Prescribing of Fluconazole Prophylaxis in a Level IV Neonatal Intensive Care Unit.

Invasive candidiasis has a high morbidity and mortality among premature neonates. Antifungal prophylaxis with fluconazole significantly lowers the risk of invasive fungal infection in this population. We noted the use of fluconazole prophylaxis in our level IV neonatal intensive care unit (NICU) was variable and sought to standardize prescribing of prophylactic fluconazole. We formed a multidisciplinary team to develop an evidence-based protocol using literature and expert consensus to guide appropriate use of fluconazole prophylaxis in our level IV NICU. After determining baseline fluconazole prophylaxis prescribing before protocol implementation, we used plan-do-study-act (PDSA) cycles to introduce protocolized prescribing and incorporate it into daily practice. A 6-month intervention phase was followed by a 2-year control phase, in which monthly audits were performed to evaluate protocol adherence. Results were displayed in a statistical process control chart. Before protocol implementation, fluconazole prophylaxis prescribing adhered to the protocol in 81% of patients. During the first PDSA cycle, adherence increased significantly to 94.5% (86/91 patients), which further increased to 98.7% (74/75 patients) during the second PDSA cycle and remained at 96% (120/125 patients) during the control phase (P < 0.0001). A multidisciplinary group-designed protocol was successful in standardizing fluconazole prophylaxis prescribing for infants in the level IV NICU. Adherence to protocol was high following implementation and was sustained for the duration of the project. There were no cases of invasive candidiasis noted.

Epidemiology of visceral mycoses in patients with acute leukemia and myelodysplastic syndrome: Analyzing the national autopsy database in Japan

Visceral mycoses (VM) are a deadly common infection in patients with acute leukemia and myelodysplastic syndrome (MDS). We retrospectively analyzed the data from the centralized "Annual Report of Autopsy Cases in Japan" that archives the national autopsy cases since 1989. Among the total of 175,615 archived autopsy cases, 7183 cases (4.1%) were acute leukemia and MDS patients. While VM was only found in 7756 cases (4.4% in total cases), we found VM had a disproportionally high prevalence among acute leukemia and MDS patients: 1562 VM cases (21.7%) and nearly sixfold higher in prevalence. Aspergillus spp. was the most predominant causative agent (45.0%), and Candida spp. was the second (22.7%) among confirmed single pathogen involved cases. The prevalence of Candida spp. infection decreased about 50% due to the widely use of fluconazole prophylaxis, which may skew toward doubling of the Mucormycetes incidence compared to 30 years ago. Complicated fungal infection (> one pathogen) was 11.0% in acute leukemia and MDS in 2015. It was 14.7 times higher than in other populations. Among 937 patients who received allogeneic hematopoietic cell transplantation (HCT), the prevalence of VM was 28.3% and 23.3% with GVHD. Aspergillus spp. was less prevalent, but Candida spp. was more associated with GVHD. Its prevalence remains stable. Although Aspergillus spp. was the primary causative agent, non-albicans Candida spp. was increasing as a breakthrough infection especially in GVHD cases. Complicated pathogen cases were more common in acute leukemia and MDS.

Could Fungicides Lead to Azole Drug Resistance in a Cross-Resistance Manner among Environmental Cryptococcus Strains?

Acquired resistance among fungal strains is a growing concern. The reasons for the emergence of this phenomenon, with great clinical implications, are only partially explained and related to the frequent use of fluconazole prophylaxis or therapeutic regimens in medical practice, and evidence of environmental origin of resistance is warranted. Soil exposed to azole fungicides may select acquired resistant fungal strains and improve the proliferation and maintenance of phenotypes in this environment. So far, the greatest focus on cross-resistance in relation to azoles is with genus Aspergillus. In view of fungicides and drugs present similar triazole chemical structure and mechanisms of action, our results showed that fungicides in agricultural areas may decrease fungal sensibility to azole drugs, becoming a potential source of resistance for invasive human mycoses agents. The abusive usage of fungicide in agriculture could play a role in the therapeutic failure of cryptococcosis.

Prevention of Invasive Candidiasis in Premature Neonates: Administering Fluconazole or Not?

Fluconazole prophylaxis (FP) for invasive candidiasis (IC) in preterm newborns is still a debated topic. In this review, we describe the most important papers on the topic, and we discuss pros and cons of the use FP in newborns according to these paper’s findings. Since 2001, several studies have been published on the use of FP to prevent IC. While most of them agree on the effectiveness of FP in reducing IC, especially in NICUs with high IC rates, the lack of evidence of decrease in overall mortality, and the risks associated with fluconazole administration both concerning neurodevelopmental impairment and the increase in Candida resistances still pose great concern against the universal implementation of FP. A local risk-based selection strategy could represent the best choice to optimize the benefits of FP and minimize the potential long-term toxicity and the development of resistant pathogens.

Efficacy and safety of fluconazole prophylaxis in extremely low birth weight infants: multicenter pre-post cohort study.

BackgroundThere have been many studies supporting fluconazole prophylaxis in preterm infants for prevention of invasive fungal infections (IFIs). However, the routine use of fluconazole prophylaxis in neonatal intensive care units (NICUs) raises concerns with respect to resistance development, including the selection of resistant Candida species. We aimed to evaluate the efficacy and safety of fluconazole prophylaxis in extremely low birth weight (ELBW) infants.MethodsAn interventional pre-post cohort study at two tertiary NICUs was conducted. Data from two 5-year periods with and without fluconazole prophylaxis (Mar 2008–Feb 2013 and Mar 2003–Feb 2008) was compared. Prophylactic fluconazole was administered starting on the 3rd day at a dose of 3 mg/kg twice a week for 4 weeks during the prophylaxis period.ResultsThe fluconazole prophylaxis group consisted of 264 infants, and the non-prophylaxis group consisted of 159 infants. IFI occurred in a total of 19 neonates (4.7 %) during the 10-year study period. Fluconazole prophylaxis lower the fungal colonization rate significantly (59.1 % vs. 33.9 %, P <0.001). However, the incidence of IFIs in ELBW infants was not reduced after fluconazole prophylaxis (4.4 % vs. 5.5 %, P = 0.80). Rather, although the increase did not reach statistical significance, fluconazole prophylaxis tended to increase the incidence of invasive infections involving fluconazole-resistant C. parapsilosis (0 % vs. 41.7 %, P = 0.11).ConclusionsFluconazole prophylaxis was not efficacious in decreasing IFIs in ELBW infants. There is a need for targeting prophylaxis to greatest risk population and prospective studies to measure the long-term effect of fluconazole prophylaxis on the emergence of organisms with antifungal resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12887-016-0605-y) contains supplementary material, which is available to authorized users.

Prophylactic fluconazole in very low birth weight infants admitted to neonatal intensive care unit: randomized controlled trial

Objective: To evaluate the effect of fluconazole prophylaxis on invasive fungal infection (IFI) in very low birth weight (VLBW) infants in the Neonatal Intensive Care Unit (NICU). Methods: VLBW infants receiving antibiotics for more than 3 days were randomized to receive either fluconazole (6 mg/kg) or placebo, every other day for 7 days followed by everyday till day 28 or discharge whichever was earlier. The primary outcome was IFI, and secondary outcome was fungal attributable mortality and all-cause mortality. Results: The incidence of IFI was significantly lower (21%) in the fluconazole group compared to the control group (43.2%, 95%CI 0.09–0.37, p < 0.05). The ARR (absolute risk reduction) was 22.2% and the NNT (number needed to treat) was 5. Fungal attributable mortality was also lower in the fluconazole group (2.6% versus 18.9%, 95%CI 0.003–0.52, p < 0.05). Conclusion: In VLBW neonates on the NICU, use of fluconazole prophylaxis decreases IFI and fungal attributable mortality.

Antifungal susceptibility testing of Candida in the Clinical Laboratory: how to do it, when to do it, and how to interpret it

Significant changes in the management of fungaemia have occurred in the last decade with increased use of fluconazole prophylaxis, of empirical treatment and of echinocandins as first-line agents for documented disease. The emergence of drug resistance in fungal pathogens has a profound impact on human health given limited number of antifungal drugs. Antifungal resistance in Candida may be either intrinsic or acquired and may be encountered in the antifungal drug exposed but also the antifungal drug naive patient The variation in resistance rates between centers emphasizes that it is essential to have knowledge of the local Candida species distribution and antifungal resistance rates to guide initial therapy for Candida BSI. Moreover, all Candida isolates from blood and normally sterile sites should be identified to the species level. The Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing have developed breakpoints and epidemiological cutoff values that are now established for Candida spp. Clinical microbiology laboratories will be employed commercial susceptibility assays, rather than reference broth microdilution methods and comparative studies are particularly important. Vitek 2®, Etest® and Sensititre YeastOne® provided a high degree of essential agreement and comparable sensitivity and specificity to BMD-RPMI for identifying resistance to azole and echinocandins in Candida spp.

Initial fluconazole prophylaxis may not be required in adults with acute leukemia or myelodysplastic/myeloproliferative disorders after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation.

In the myeloablative transplant setting, the early use of fluconazole prophylaxis provides a benefit in overall survival. Recent changes in transplantation practices, including the use of peripheral blood stem cells (PBSC) and/or reduced intensity conditioning (RIC) regimen may have favorably impacted the epidemiology of invasive fungal infections (IFI) after allogeneic stem cell transplantation (allo-SCT). Yet, the impact of removing fluconazole prophylaxis after RIC PBSC allotransplant is ill known. Here, a retrospective analysis was performed comparing patients who received fluconazole as antifungal prophylaxis (n = 53) or not (n = 56) after allo-SCT for acute leukemia or myelodysplastic/myeloproliferative syndrome. Sixteen IFI were documented (14 %) at a median time of 103 days after transplantation, including eight before day +100, at a similar rate, whether the patients received fluconazole prophylaxis (13 %) or not (16 %). IFI were due mainly to Aspergillus species (87 %), and only two Candida-related IFI (13 %) were documented in the non-fluconazole group before day +100. The incidences of IFI (overall, before or after day +100) as well as 3-year overall and disease-free survival, non-relapse mortality, or acute and chronic graft-versus-host disease (GVHD) were similar between both groups. In conclusion, this study suggests that fluconazole may not be required at the initial phase of RIC allo-SCT using PBSC. This result has to be confirmed prospectively while Aspergillus prophylaxis should be discussed in this particular setting.

Relationship of fluconazole prophylaxis with fungal microbiology in hospitalized intra-abdominal surgery patients: a descriptive cohort study.

IntroductionHistorically, Candida albicans has represented the most common cause of candidemia. However, the proportion of bloodstream infections due to non-albicans Candida species has increased. Because of the risk for candidemia in intra-abdominal surgical patients, some experts advocate the use of fluconazole prophylaxis. The impact of this practice on the distribution of Candida species isolated in breakthrough fungal infections in this population is unknown. We examined the association of fluconazole prophylaxis with the distribution of Candida species in intra-abdominal surgery patients.MethodsWe retrospectively identified cases with a positive blood culture (BCx) for Candida among hospitalized adult intra-abdominal surgery patients between July 2005 and October 2012. Distribution of Candida species isolated represented our primary endpoint. Qualifying surgical cases were determined based on a review of discharge International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Patients receiving low-dose fluconazole prior to the positive BCx with a known indication for prophylaxis including neutropenia, ICU exposure or history of organ transplantation were classified as prophylaxis. Appropriateness of fungal treatment was determined by the timing and selection of antifungal agent based on fungal isolate.ResultsAmong 10,839 intra-abdominal surgery patients, 227 had candidemia. The most common Candida species isolated was C. albicans (n = 90, 39.6%) followed by C. glabrata (n = 81, 35.7%) and C. parapsilosis (n = 38, 16.7%). Non-albicans Candida accounted for 57.7% of isolates among the 194 non-prophylaxis patients and 75.8% among the 33 prophylaxis patients (P = 0.001). C. glabrata, the most common non-C. albicans species, was more prevalent than C. albicans in persons given prophylaxis, but not in those without prophylaxis. A total of 63% of those with candidemia were treated inappropriately based on the timing and selection of antifungal administration.ConclusionsSelection pressure from fluconazole prophylaxis in at-risk surgical patients may be associated with a drift toward fluconazole-resistant species in subsequent candidemia. Tools are needed to guide appropriate treatment through the prompt recognition and characterization of candidemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0590-1) contains supplementary material, which is available to authorized users.

Changes in the incidence of candidiasis in neonatal intensive care units.

Neonatal invasive candidiasis is associated with significant morbidity and mortality. We describe the association between invasive candidiasis and changes in use of antifungal prophylaxis, empirical antifungal therapy, and broad-spectrum antibacterial antibiotics over time. We examined data from 709,325 infants at 322 NICUs managed by the Pediatrix Medical Group from 1997 to 2010. We determined the cumulative incidence of invasive candidiasis and use of antifungal prophylaxis, broad-spectrum antibacterial antibiotics, and empirical antifungal therapy by year. We identified 2063 (0.3%) infants with 2101 episodes of invasive candidiasis. Over the study period, the annual incidence of invasive candidiasis decreased from 3.6 episodes per 1000 patients to 1.4 episodes per 1000 patients among all infants, from 24.2 to 11.6 episodes per 1000 patients among infants with a birth weight of 750-999 g, and from 82.7 to 23.8 episodes per 1000 patients among infants with a birth weight <750 g. Fluconazole prophylaxis use increased among all infants with a birth weight <1000 g (or <1500 g), with the largest effect on birth weights <750 g, increasing from 3.8 per 1000 patients in 1997 to 110.6 per 1000 patients in 2010. The use of broad-spectrum antibacterial antibiotics decreased among all infants from 275.7 per 1000 patients in 1997 to 48.5 per 1000 patients in 2010. The use of empirical antifungal therapy increased over time from 4.0 per 1000 patients in 1997 to 11.5 per 1000 patients in 2010. The incidence of invasive candidiasis in the NICU decreased over the 14-year study period. Increased use of fluconazole prophylaxis and empirical antifungal therapy, along with decreased use of broad-spectrum antibacterial antibiotics, may have contributed to this observation.

Epidemiological changes with potential implication for antifungal prescription recommendations for fungaemia: data from a nationwide fungaemia surveillance programme

Significant changes in the management of fungaemia have occurred over the last decade with increased use of fluconazole prophylaxis, of empirical treatment and of echinocandins as first-line agents for documented disease. These changes may impact the epidemiology of fungaemia. We present nationwide data for Denmark from 2010 to 2011. A total of 1081 isolates from 1047 episodes were recorded in 995 patients. The numbers of patients, episodes and recovered isolates increased by 13.1%, 14.5% and 14.1%, respectively, from 2010 to 2011. The incidence rate was significantly higher in 2011 (10.05/100 000) than in 2010 (8.82/100 000), but remained constant in the age groups 0–79 years. The incidence rate was highest at the extremes of age and in males. Candida albicans accounted for 52.1% but declined during 2004–11 (p 0.0155). Candida glabrata accounted for 28% and increased during 2004–2011 (p <0.0001). Candida krusei, Candida tropicalis and Candida parapsilosis remained rare (3.3–4.2%). The species distribution changed with increasing age (fewer C. parapsilosis and more C. glabrata) and by study centre. Overall, the susceptibility rates were: amphotericin B 97.3%, anidulafungin 93.8%, fluconazole 66.7%, itraconazole 69.6%, posaconazole 64.2% and voriconazole 85.0%. Acquired echinocandin resistance was molecularly confirmed in three isolates. The use of systemic antifungals doubled over the last decade (2002–2011) (from 717 000 to 1 450 000 defined daily doses/year) of which the vast majority (96.9%) were azoles. The incidence of fungaemia continues to increase in Denmark and is associated with a decreasing proportion being susceptible to fluconazole. Changes in demography, higher incidence in the elderly and higher antifungal consumption can at least in part explain the changes.

Potentiation of Vincristine Toxicity with Concomitant Fluconazole Prophylaxis in Children with Acute Lymphoblastic Leukemia

Use of azole antifungals as prophylaxis is becoming an increasingly common practice in acute lymphoblastic leukemia (ALL). Limited literature in adults heightened the awareness of possible increased vincristine (VCR) toxicity in patients receiving concomitant azole therapy. This is due to inhibition of cytochrome P450 3A4, which may increase overall exposure to VCR, resulting in dose reductions or omissions. The primary objective of this study was to determine whether the use of fluconazole prophylaxis increases vincristine toxicity in children with ALL. The authors retrospectively evaluated children with ALL between January 2004 and December 2009. Patients were subdivided into 2 groups based on whether or not they received fluconazole prophylaxis during induction therapy. Data were collected for up to 3 months following the completion of induction therapy. Thirty-one patients were included for analysis. There was no significant difference in gender, race, steroid use, gastrointestinal (GI) toxicity, VCR dose modification, and the rate of fungal or bacterial infections between these 2 groups. Only advanced age is an independent predictor of neuropathy. Patients receiving fluconazole were 4.5 times more likely to experience neuropathy than those not receiving azole; however, this was not statistically significant. The authors report an increased incidence of VCR toxicity in patients with ALL receiving concomitant fluconazole prophylaxis. Judicious use of azole anitfungals is warranted in children with ALL.

European survey on the use of prophylactic fluconazole in neonatal intensive care units

Neonatal fungal infections are associated with substantial mortality and morbidity. Although prophylactic use of several antifungals has been proposed, this practice remains controversial. In order to evaluate the use of fluconazole prophylaxis in European NICUs, we conducted a cross-sectional survey by means of a structured questionnaire that was sent to European level II and III neonatal intensive care units, over a 9-month period, as part of a neonatal research FP7 European project. A total of 193 questionnaires from 28 countries were analysed. Use of antifungal prophylaxis was reported by 55% of the responders, and the most frequently used antifungal agent was fluconazole (92%). Main indications for prophylaxis were low gestational age (<28 weeks) and birth weight (<1,000 g). A dose of 3 mg/kg was used in 66% of NICUs using fluconazole, with an administration interval of 72 h in 52% of them. All responders acknowledged the need for additional trials on the efficacy of prophylactic fluconazole. Non-users of fluconazole prophylaxis were more likely to be influenced by the local incidence of candidiasis, the risk of increasing antifungal resistance and the absence of specific recommendations by paediatric societies. Conclusions: Major concerns about the use of fluconazole prophylaxis include its efficacy, the risk of emergence of resistant species and the absence of clear consensus to support routine use. Future studies that address these issues will contribute to a more rational use of fluconazole prophylaxis.

Fluconazole Prophylaxis in High-Risk Neonates

To evaluate the literature regarding the use of fluconazole prophylaxis in high-risk neonates. Literature was accessed through MEDLINE (February 2001-August 2009) using the search terms fluconazole and prophylaxis, with limits for age group (ie, birth-18 y). Reference citations from identified articles were also reviewed. DATA SELECTION AND DATA EXTRACTION: All prospective and retrospective studies in English identified from MEDLINE were evaluated. Critically ill neonates possess a number of risk factors that predispose them to fungal colonization with Candida spp. In many cases, colonization may progress to invasive systemic infections despite efforts aimed at early diagnosis and treatment. Because of its success among immunocompromised patients, fluconazole prophylaxis has been suggested as a possible approach for reducing the rates of both colonization and invasive fungal infections among at-risk neonates. To date, 4 prospective randomized controlled trials and 8 retrospective cohort studies have examined fluconazole prophylaxis in neonates. Although fluconazole prophylaxis appears to reduce the rates of colonization and invasive fungal infections, no trial in this review was able to demonstrate a significant difference in long-term morbidity or mortality. Concerns also remain regarding the adverse effects associated with prolonged exposure to fluconazole therapy. Lack of standardized study designs and treatment regimens also limit widespread recommendation for the use of fluconazole prophylaxis in clinical practice. While it may be beneficial for critically ill neonates with certain predisposing risk factors (eg, central venous access, sustained exposure to broad-spectrum antibiotics, or units with significantly high incidence of invasive fungal infections), existing research does not support the use of fluconazole prophylaxis based on birth weight or gestational age alone. Multifactor analysis evaluating the effect of fluconazole prophylaxis is necessary to establish which neonates would benefit from this practice.

Recent advances in molecular and non-PCR-based platforms for the rapid diagnosis of invasive candidasis in the ICU

Invasive candidasis (IC) accounts for 15?30% of all nosocomial intensive care unit (ICU) infections. Two-thirds of infections are due to candidemia, a rate 5?10 times higher compared with that in the general hospital population. Crude mortality rates and associated health costs remain high, despite advances in antifungal therapy. Candida albicans remains the most frequently isolated species (45%) although there has been a slow but definite shift towards non-C. albicans species (especially Candida glabrata) infections, which has been attributed to the increased use of fluconazole prophylaxis in some centres. Early antifungal therapy significantly reduces IC-related mortality but is often delayed because ?gold standard? diagnosis by culture and/or histology is insensitive (for example, 50% candidemia cases not detected by blood culture) and slow (at least 48?96 hours required for species detection and identification). This article highlights a number of recent advances in molecular and non-PCR-based technologies that have enabled more rapid diagnosis of IC in the ICU (a recent review provides a comprehensive summary of molecular and serological methods in diagnostic mycology).

Clinical Aspects of Invasive Candidiasis in the Surgical Patient

Improvements in post-surgical care have led to decreased mortality, but to an increased number of critically ill surgical patients at high risk of fungal colonization and invasive disease. Use of catheters, enteral nutrition, antibacterials and haemodialysis add to the risk. Although Candida albicans remains the most common species causing invasive candidiasis in the post-surgical setting, there has been an increase in the prevalence of non-albicans species associated with the increased use of fluconazole prophylaxis in surgical intensive care units. The prompt diagnosis of candidiasis is complicated by a lack of specific clinical symptoms and difficulties in laboratory diagnosis; therefore, it is vital to recognize at-risk patients and initiate therapy promptly in these individuals. While Candida scoring systems to identify at-risk patients have been developed, these need to be validated in prospective interventional trials. Newer azole and echinocandin antifungal agents have expanded the range of available treatments, and prophylactic antifungal therapy in at-risk, critically ill surgical patients has been shown to be effective.

Fluconazole Prophylaxis Decreases the Combined Outcome of Invasive Candida Infections or Mortality in Preterm Infants: In Reply

We thank Dr Kaufman for his comments regarding the safety and efficacy of fluconazole prophylaxis in preventing invasive Candida infections in infants weighing <1000 g at birth. We concur that the evidence from published, randomized, controlled trials (both single and multicenter) strongly supports this approach as a means to prevent Candida-associated death or neurodevelopmental impairment that occurs in almost three quarters of Candida-infected preterm infants.1 In addition, while being cognizant of the limitation of their retrospective study design, 7 single-center cohort studies with retrospective controls have all demonstrated a reduction in Candida infections and associated deaths through the use of fluconazole prophylaxis. No randomized, controlled trial or retrospective cohort study has reported any fluconazole-attributable adverse events that persisted past hospital discharge. In addition, although justifiable concern for the emergence of fluconazole-resistant Candida species in the NICU has been voiced, this has not been demonstrated to date.2–4The majority of infants given fluconazole prophylaxis in all studies reported to date used birth weights of <1000 g as an inclusion criterion.2 We agree that rates of invasive Candida infections are considerably higher in infants weighing <750 g and that these infants also are at highest risk of poor outcome. However, the risks of invasive Candida infections in infants with birth weights between 750 and 1000 g are not trivial, and these infants also are likely to have ongoing risk factors that enhance their risk of acquiring infection beyond several weeks of life.1Undoubtedly, there are unanswered questions regarding which preterm infants will benefit most from fluconazole prophylaxis. There are approaches that deserve further study, such as targeting infants with different birth weights and gestation, confining prophylaxis to time periods of highest risk, or, conversely, prolonging prophylaxis for infants with ongoing risk factors. Although we agree that such studies are needed, we believe that there are sufficiently strong data to consider fluconazole prophylaxis for infants weighing <1000 g in NICUs in which incidence exceeds 5% and adherence to infection control measures is high.