Repurposing antifungals: population pharmacokinetics of itraconazole and hydroxy-itraconazole following administration of a nanocrystal formulation.

OBJECTIVES: To describe itraconazole and hydroxy-itraconazole pharmacokinetics following intravenous (IV) administration of a previously developed nanocrystal formulation (NCF) in haematopoietic cell transplant (HCT) recipients for prophylaxis of invasive fungal disease. METHODS: In a prospective Phase II study, 10 HCT recipients received itraconazole NCF administered in 2-hour infusions of 200 mg twice daily for 2 days, followed by 200 mg once daily until Day 14. Full pharmacokinetic curves were obtained on Days 7 and 14. Additional samples were collected pre- and post-infusion until Day 6, pre-infusion on Days 10 and 12, and during washout on Days 16, 17, 18, 19 and 28. Itraconazole and hydroxy-itraconazole pharmacokinetics were analysed by non-linear mixed-effects population pharmacokinetic modelling. RESULTS: Four-hundred and seventy-one itraconazole and 471 paired hydroxy-itraconazole concentrations from 10 patients were included for analysis. Data were best described by a semi-mechanistic model with central and peripheral itraconazole compartments and a hydroxy-itraconazole compartment with dissolution of itraconazole drug particles from nanocrystals and first-order distribution and elimination. The final model included interindividual variability on itraconazole clearance and hydroxy-itraconazole clearance. CONCLUSIONS: This study provides information on the pharmacokinetic properties of the itraconazole NCF useful for development of this formulation. Our results suggest that itraconazole NCF is a suitable formulation and may warrant renewal in the setting of repurposing. Our findings may be useful for the reformulation of other highly lipophilic compounds as well.

The impact of anti-mould prophylaxis on Aspergillus PCR blood testing for the diagnosis of invasive aspergillosis.

BACKGROUND: The performance of the galactomannan enzyme immunoassay (GM-EIA) is impaired in patients receiving mould-active antifungal therapy. The impact of mould-active antifungal therapy on Aspergillus PCR testing needs to be determined. OBJECTIVES: To determine the influence of anti-mould prophylaxis (AMP) on the performance of PCR blood testing to aid the diagnosis of proven/probable invasive aspergillosis (IA). METHODS: As part of the systematic review and meta-analysis of 22 cohort studies investigating Aspergillus PCR blood testing in 2912 patients at risk of IA, subgroup analysis was performed to determine the impact of AMP on the accuracy of Aspergillus PCR. The incidence of IA was calculated in patients receiving and not receiving AMP. The impact of two different positivity thresholds (requiring either a single PCR positive test result or ≥2 consecutive PCR positive test results) on accuracy was evaluated. Meta-analytical pooling of sensitivity and specificity was performed by logistic mixed-model regression. RESULTS: In total, 1661 (57%) patients received prophylaxis. The incidence of IA was 14.2%, significantly lower in the prophylaxis group (11%-12%) compared with the non-prophylaxis group (18%-19%) (P < 0.001). The use of AMP did not affect sensitivity, but significantly decreased specificity [single PCR positive result threshold: 26% reduction (P = 0.005); ≥2 consecutive PCR positive results threshold: 12% reduction (P = 0.019)]. CONCLUSIONS: Contrary to its influence on GM-EIA, AMP significantly decreases Aspergillus PCR specificity, without affecting sensitivity, possibly as a consequence of AMP limiting the clinical progression of IA and/or leading to false-negative GM-EIA results, preventing the classification of probable IA using the EORTC/MSGERC definitions.

Interlaboratory evaluation of Mucorales PCR assays for testing serum specimens: A study by the fungal PCR Initiative and the Modimucor study group.

Interlaboratory evaluations of Mucorales qPCR assays were developed to assess the reproducibility and performance of methods currently used. The participants comprised 12 laboratories from French university hospitals (nine of them participating in the Modimucor study) and 11 laboratories participating in the Fungal PCR Initiative. For panel 1, three sera were each spiked with DNA from three different species (Rhizomucor pusillus, Lichtheimia corymbifera, Rhizopus oryzae). For panel 2, six sera with three concentrations of R. pusillus and L. corymbifera (1, 10, and 100 genomes/ml) were prepared. Each panel included a blind negative-control serum. A form was distributed with each panel to collect results and required technical information, including DNA extraction method, sample volume used, DNA elution volume, qPCR method, qPCR template input volume, qPCR total reaction volume, qPCR platform, and qPCR reagents used. For panel 1, assessing 18 different protocols, qualitative results (positive or negative) were correct in 97% of cases (70/72). A very low interlaboratory variability in Cq values (SD = 1.89 cycles) were observed. For panel 2 assessing 26 different protocols, the detection rates were high (77-100%) for 5/6 of spiked serum. There was a significant association between the qPCR platform and performance. However, certain technical steps and optimal combinations of factors may also impact performance. The good reproducibility and performance demonstrated in this study support the use of Mucorales qPCR as part of the diagnostic strategy for mucormycosis.

Using routine blood parameters to anticipate clinical outcomes in invasive aspergillosis.

OBJECTIVE: In invasive aspergillosis (IA), monitoring response to antifungal treatment is challenging. We aimed to explore if routine blood parameters help to anticipate outcomes following IA. METHODS: Post hoc secondary analysis of two multicenter randomized trials was performed. The Global Comparative Aspergillosis Study (GCA, n = 123) and the Combination Antifungal Study (CAS, n = 251) constituted the discovery and validation cohorts respectively. The outcome measures were response to treatment and survival to 12 weeks. Interval platelet, galactomannan index (GMI) and C-reactive protein (CRP) levels prior and during antifungal treatment were analysed using logistic regression, Kaplan-Meier survival and receiver operating characteristic (ROC) analyses. RESULTS: The 12-week survival was 70.7% and 63.7% for the GCA and CAS cohorts respectively. In the GCA cohort, every 10 × 109/L platelet count increase at week 2 and 4 improved 12-week survival odds by 6-18% (odds ratio (OR) 1.06-1.18, 95% confidence interval (CI) 1.02-1.33). Survival odds also improved 13% with every 10 mg/dL CRP drop at week 1 and 2 (OR 0.87, 95% CI 0.78-0.97). In the CAS cohort, week 2 platelet count was also associated with 12-week survival with 10% improved odds for every 10 × 109/L platelet increase (OR, 1.10, 95% CI 1.04-1.15). A GMI drop of 0.1 unit was additionally found to increase the odds of treatment response by 3% at the baseline of week 0 (OR 0.97, 95% CI 0.95-0.99). Week 2 platelet and CRP levels performed better than GMI on ROC analyses for survival (area under ROC curve 0.76, 0.87 and 0.67 respectively). A baseline platelet count higher than 30 × 109/L clearly identified patients with >75% survival probability. CONCLUSIONS: Higher serial platelets were associated with overall survival while GMI trends were linked to IA treatment response. Routine and simple laboratory indices may aid follow-up of response in IA patients.

Epidemiology of invasive aspergillosis and triazole-resistant Aspergillus fumigatus in patients with haematological malignancies: a single-centre retrospective cohort study.

Objectives: To investigate the epidemiology and clinical relevance of triazole resistance among patients undergoing treatment for haematological malignancies who are at risk of invasive aspergillosis (IA). Methods: This was a retrospective cohort study for which the records of consecutive patients given chemotherapy for AML or myelodysplastic syndrome (MDS) or who had received an allogeneic HSCT from 2006 to 2012 were reviewed for IA. Triazole resistance was detected by the VIPcheck™ screening method and confirmed by determining the MIC by EUCAST methodology. Results: A total of 432 patients were included, comprising 182 (42.1%) patients who had undergone chemotherapy for AML or MDS, and 250 (57.9%) patients who had undergone an allogeneic HSCT. Probable or proven IA was diagnosed in 36 cases (8.3%, 95% CI 6.0%-11.4%). Of these, 12 (33.3%) were based on recovery of Aspergillus fumigatus from sputum, bronchoalveolar lavage or biopsy, and triazole resistance was found in 2 instances. A. fumigatus was also recovered from one or more specimens from 13 patients without probable or proven IA. Triazole resistance was documented for three patients. The survival rate of patients with IA caused by voriconazole-resistant isolates could not be assessed. Conclusions: The overall frequency of voriconazole-resistant IA among patients at high risk was low. However, the rate of triazole resistance may have been underestimated by the low detection rate based on recovery of A. fumigatus. Alternative diagnostic tests, such as PCR-based assays, may prove better at detecting IA due to triazole-resistant A. fumigatus.

Self-reported vs state-recorded motor vehicle collisions among older community dwelling individuals.

INTRODUCTION: Motor vehicle collisions (MVCs) continue to place an increased burden on both individuals and health care systems. Self-reported and state-recorded police reports are the most common methods for MVC evaluation in epidemiologic studies, with varying degrees of agreement of information when compared in previous studies. The objective of the current study is to address the differences in MVC reporting and provide a more robust measure of the agreement between self-reported and state-recorded MVCs in a community dwelling population of older adults. METHODS: A three-year prospective study was conducted in a population-based sample of 2000 licensed drivers aged 70 and older. At annual visits, participants were asked to self-report information on any MVC that occurred over the prior year where police were called to the scene. Information on police-reported MVCs was also ascertained from Alabama official state-recorded databases. The kappa coefficient was calculated to determine overall agreement between any self-reported and state-recorded crashes, as well as the raw number of crashes reported. In addition, agreement was stratified by demographics, health status, medication use, functional status (i.e. vision, cognition), and driving habits. RESULTS: 1747 participants who completed three years of follow up were involved in 225 state-recorded MVCs and 208 self-reported MVCs yielding overall substantial agreement between any self-report and state-recorded MVC (kappa=0.64). Cumulative number of self-reported and state-recorded MVCs was also compared, with agreement slightly reduced (kappa=0.55). The clinical characteristic resulting in the greatest variation in agreement with drivers was impaired contrast sensitivity showing better agreement between self-reported and state-recorded MVCs (kappa=0.9) than those with non-impaired contrast sensitivity (kappa=0.6). CONCLUSION: Study results showed substantial agreement between self-reported and state-recorded MVCs for any MVC involvement among the study population. When examining the reporting of the total number of MVCs over the three year period, agreement was reduced to a moderate level. There was consistency in agreement across MVC risk factors except among individuals with contrast sensitivity. These findings have implications for the design and analytic planning of epidemiologic and clinical research focused on MVCs.

Hospital-onset Clostridium difficile infection among solid organ transplant recipients.

Clostridium difficile infection (CDI) is a considerable health issue in the United States and represents the most common healthcare-associated infection. Solid organ transplant recipients are at increased risk of CDI, which can affect both graft and patient survival. However, little is known about the impact of CDI on health services utilization posttransplantation. We examined hospital-onset CDI from 2012 to 2014 among transplant recipients in the University HealthSystem Consortium, which includes academic medical center-affiliated hospitals in the United States. Infection was five times more common among transplant recipients than among general medicine inpatients (209 vs 40 per 10 000 discharges), and factors associated with CDI among transplant recipients included transplant type, risk of mortality, comorbidities, and inpatient complications. Institutional risk-standardized CDI varied more than 3-fold across high-volume hospitals (infection ratio 0.54-1.82, median 1.04, interquartile range 0.78-1.28). CDI was associated with increased 30-day readmission, transplant organ complications, cytomegalovirus infection, inpatient costs, and lengths of stay. Total observed inpatient days and direct costs for those with CDI were substantially higher than risk-standardized expected values (40 094 vs 22 843 days, costs $198 728 368 vs $154 020 528). Further efforts to detect, prevent, and manage CDI among solid organ transplant recipients are warranted.

A rationale for reduced-frequency dosing of anidulafungin for antifungal prophylaxis in immunocompromised patients.

OBJECTIVES: Reduced-frequency dosing strategies of anidulafungin may offer a more convenient way of providing adequate antifungal prophylaxis to patients at high risk of invasive fungal diseases. We aimed to provide the pharmacological rationale for the applicability of reduced-frequency dosing regimens. METHODS: We defined two groups of 10 patients that were to receive anidulafungin at 200 mg every 48 h or 300 mg every 72 h. Blood samples were drawn daily and two pharmacokinetic curves were constructed after 1 and 2 weeks of treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. ClinicalTrials.gov identifier: NCT01249820. RESULTS: The AUC over a 6 day period (IQR) for a typical patient on 200 mg every 48 h or 300 mg every 72 h resulted in 348 mg ·â€Šh/L (310.6-386.7) and 359 mg ·â€Šh/L (319.1-400.9), respectively, comparable to the licensed regimen [397.0 mg ·â€Šh/L (352.4-440.5)]. In the final model, the volume of distribution proved to be dependent on the lean body mass and CL of cyclosporine A. All three regimens resulted in comparable dose-normalized exposure over time. CONCLUSIONS: We now have sufficient evidence to start using less frequent dosing regimens and demonstrate their value in clinical practice. These less frequently applied infusions enable more personalized care in an outpatient setting with reduced costs.

Mucositis not neutropenia determines bacteremia among hematopoietic stem cell transplant recipients.

BACKGROUND: In the 1960s, it was reported that infectious complications were the main cause of fever during neutropenia that followed hematopoietic stem cell transplant (HSCT). More recently, mucositis has become recognized as an important determinant of the inflammatory response and infectious complications. METHODS: The objective of this prospective study was to determine the impact of intestinal mucositis, as measured by plasma citrulline, and neutropenia on the systemic inflammatory response (C-reactive protein) and the occurrence of bacteremia among 2 cohorts of HSCT recipients: 1 composed of 18 patients who had been treated with a myeloablative (MA) regimen (high-dose melphalan) and the other involving 19 patients who had received the non-myeloablative (NMA) regimen (fludarabine and cyclophosphamide). Blood cultures were obtained for surveillance from admission onwards as well as at the onset of fever. RESULTS: The MA regimen induced severe intestinal mucositis manifest by citrullinemia <10 µmol/L, which was accompanied by an inflammatory response, and bacteremia affected 8 (44%) of 18 patients and coincided with the nadir of citrullinemia. By contrast, those who had been treated with the NMA regimen did not develop severe intestinal mucositis, had a moderate inflammatory response, and only 2 (11%) of the 19 patients developed bacteremia. However, both groups experienced profound neutropenia and its duration was significantly longer for those receiving the NMA regimen. CONCLUSION: This study suggests that severe intestinal mucositis, i.e., citrullinemia <10 µmol/L, defines the period of risk of bacteremia better than does neutropenia, and that measuring plasma citrulline may prove useful in deciding who needs empirical antimicrobial therapy and when.

Trends in the outcomes of Dutch haematological patients receiving intensive care support.

BACKGROUND: Because of the assumed dismal prognosis there is still reluctance to admit haematological patients to the intensive care unit (ICU). This study was conducted to determine trends in outcome of allogeneic haematopoietic stem cell transplant (HSCT) recipients transferred to the intensive care unit in a Dutch tertiary care hospital. METHODS: All patients who received allogeneic HSCT between 2004-2010 were included in the analyses. Baseline and outcome characteristics were compared and risk factors for ICU admission and survival were identified. Changes in outcome over time of three cohorts of HSCT recipients were investigated. RESULTS: Of 319 consecutive HSCT recipients, 49 (15%) were transferred to the ICU for a median (IQR) of 10 (6-45) days following their transplantation, of whom 43% were severely neutropenic and 90% had received systemic immunosuppressive therapy for graft-versus-host disease prophylaxis. Univariate logistic regression showed that transplantation from an unrelated donor and myeloablative conditioning were significant risk factors for ICU admission. Prolonged use of vasopressors, invasive mechanical ventilation and male gender were significant predictors for ICU mortality, while neutropenia and graft-versus-host disease were not. Over the years, APACHE-II severity of illness scores remained unchanged (21.0±7.1, 20.1±5.6, 21.2±6.6), while 100-day post-transplant mortality of patients who had been transferred to the ICU decreased significantly from 78% (2004÷2005) to 57% (2006÷2007), and 35% (2008÷2009). CONCLUSIONS: While for allogeneic HSCT patients the severity of illness on admission to the ICU did not change, the 100-day post-transplant survival improved. These data indicate that reluctance to submit haematological patients to the ICU is not warranted.

Incidence of and risk factors for persistent gram-positive bacteraemia and catheter-related thrombosis in haematopoietic stem cell transplantation.

A cohort of 439 haematopoietic SCT recipients was analysed to determine the incidence of Gram-positive coccal bacteraemia and thromboembolic events associated with the use of central venous catheters (CVCs) and to determine risk factors for these complications. The incidences of persistent coagulase-negative staphylococcal (CoNS) bacteraemia, symptomatic thrombosis and thrombophlebitis were 25%, 9.6% and 6.6%, respectively. Duration of neutropenia (in days, odds ratio (OR) 1.02; P=0.04) and left-sided placement of the CVCs (OR 1.73; P=0.03) were independent risk factors for the occurrence of persistent CoNS bacteraemia, whereas the use of less mucotoxic conditioning regimens was associated with a lower risk (high-dose melphalan (HDM)/BEAM vs other regimens, OR 0.24; P<0.001). Use of TBI, persistent CoNS bacteraemia and tip colonisation were all significantly associated with an increased risk of symptomatic thrombosis (OR 6.03, 3.36 and 2.80, respectively; P0.02). The risk factors found in this cohort of SCT recipients differed from those found in the general cancer population, showing an important role for persisting bacteraemia in the pathogenesis of CVC-associated thrombosis. Therefore, we constructed a new algorithm in order to improve catheter management and prevent these CVC-related complications.

Impact of palifermin on intestinal mucositis of HSCT recipients after BEAM.

The matched-control study failed to show a clinical relevant impact of palifermin on intestinal mucositis, although there was a reduced inflammatory response and less febrile neutropenia among patients who had no bacteraemia.

Reduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab.

The mortality associated with post-transplant lymphoproliferative disorder (PTLD) induced by EBV infection can be reduced by monitoring EBV by polymerase-chain-reaction and rituximab given pre-emptively. We performed a retrospective analysis of the risk factors for the occurrence of EBV infection/disease and EBV-related mortality among 273 consecutive recipients of a T-cell-depleted allo-SCT during two periods: (a) before the implementation of a comprehensive protocol (2006-2008) and (b) afterwards (2009-2011). EBV infection was detected in 61 (22%) cases, and 28 cases were considered to have had EBV disease. Treatment with antithymocyte globulin was the most important risk factor (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.3-4.2, P=0.001). After implementation of the protocol, in patients experiencing EBV infection, pre-emptive therapy was started more often and sooner (median 3 vs 6 days, P=0.002). Moreover, there were fewer cases of monomorphic PTLD (4/33 (12%) vs 11/28 (39%), P=0.01), and the EBV-related mortality was lower for patients experiencing EBV infection (2/33 (6%) vs 8/28 (29%), OR 0.2; 95% CI 0.05-0.9, P=0.03). The EBV protocol proved feasible and resulted in faster initiation of pre-emptive therapy, the diagnosis in an earlier stage of EBV disease, and decreased EBV-related mortality.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures.

As the mortality associated with invasive Candida infections remains high, it is important to make optimal use of available diagnostic tools to initiate antifungal therapy as early as possible and to select the most appropriate antifungal drug. A panel of experts of the European Fungal Infection Study Group (EFISG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) undertook a data review and compiled guidelines for the clinical utility and accuracy of different diagnostic tests and procedures for detection of Candida infections. Recommendations about the microbiological investigation and detection of candidaemia, invasive candidiasis, chronic disseminated candidiasis, and oropharyngeal, oesophageal, and vaginal candidiasis were included. In addition, remarks about antifungal susceptibility testing and therapeutic drug monitoring were made.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients.

This part of the EFISG guidelines focuses on non-neutropenic adult patients. Only a few of the numerous recommendations can be summarized in the abstract. Prophylactic usage of fluconazole is supported in patients with recent abdominal surgery and recurrent gastrointestinal perforations or anastomotic leakages. Candida isolation from respiratory secretions alone should never prompt treatment. For the targeted initial treatment of candidaemia, echinocandins are strongly recommended while liposomal amphotericin B and voriconazole are supported with moderate, and fluconazole with marginal strength. Treatment duration for candidaemia should be a minimum of 14 days after the end of candidaemia, which can be determined by one blood culture per day until negativity. Switching to oral treatment after 10 days of intravenous therapy has been safe in stable patients with susceptible Candida species. In candidaemia, removal of indwelling catheters is strongly recommended. If catheters cannot be removed, lipid-based amphotericin B or echinocandins should be preferred over azoles. Transoesophageal echocardiography and fundoscopy should be performed to detect organ involvement. Native valve endocarditis requires surgery within a week, while in prosthetic valve endocarditis, earlier surgery may be beneficial. The antifungal regimen of choice is liposomal amphotericin B +/- flucytosine. In ocular candidiasis, liposomal amphotericin B +/- flucytosine is recommended when the susceptibility of the isolate is unknown, and in susceptible isolates, fluconazole and voriconazole are alternatives. Amphotericin B deoxycholate is not recommended for any indication due to severe side effects.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp.

Invasive candidiasis (IC) is a relatively common syndrome in neonates and children and is associated with significant morbidity and mortality. These guidelines provide recommendations for the prevention and treatment of IC in neonates and children. Appropriate agents for the prevention of IC in neonates at high risk include fluconazole (A-I), nystatin (B-II) or lactoferrin ± Lactobacillus (B-II). The treatment of IC in neonates is complicated by the high likelihood of disseminated disease, including the possibility of infection within the central nervous system. Amphotericin B deoxycholate (B-II), liposomal amphotericin B (B-II), amphotericin B lipid complex (ABLC) (C-II), fluconazole (B-II), micafungin (B-II) and caspofungin (C-II) can all be potentially used. Recommendations for the prevention of IC in children are largely extrapolated from studies performed in adults with concomitant pharmacokinetic data and models in children. For allogeneic HSCT recipients, fluconazole (A-I), voriconazole (A-I), micafungin (A-I), itraconazole (B-II) and posaconazole (B-II) can all be used. Similar recommendations are made for the prevention of IC in children in other risk groups. With several exceptions, recommendations for the treatment of IC in children are extrapolated from adult studies, with concomitant pharmacokinetic studies. Amphotericin B deoxycholate (C-I), liposomal amphotericin B (A-I), ABLC (B-II), micafungin (A-I), caspofungin (A-I), anidulafungin (B-II), fluconazole (B-I) and voriconazole (B-I) can all be used.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT).

Fungal diseases still play a major role in morbidity and mortality in patients with haematological malignancies, including those undergoing haematopoietic stem cell transplantation. Although Aspergillus and other filamentous fungal diseases remain a major concern, Candida infections are still a major cause of mortality. This part of the ESCMID guidelines focuses on this patient population and reviews pertaining to prophylaxis, empirical/pre-emptive and targeted therapy of Candida diseases. Anti-Candida prophylaxis is only recommended for patients receiving allogeneic stem cell transplantation. The authors recognize that the recommendations would have most likely been different if the purpose would have been prevention of all fungal infections (e.g. aspergillosis). In targeted treatment of candidaemia, recommendations for treatment are available for all echinocandins, that is anidulafungin (AI), caspofungin (AI) and micafungin (AI), although a warning for resistance is expressed. Liposomal amphotericin B received a BI recommendation due to higher number of reported adverse events in the trials. Amphotericin B deoxycholate should not be used (DII); and fluconazole was rated CI because of a change in epidemiology in some areas in Europe. Removal of central venous catheters is recommended during candidaemia but if catheter retention is a clinical necessity, treatment with an echinocandin is an option (CII(t) ). In chronic disseminated candidiasis therapy, recommendations are liposomal amphotericin B for 8 weeks (AIII), fluconazole for >3 months or other azoles (BIII). Granulocyte transfusions are only an option in desperate cases of patients with Candida disease and neutropenia (CIII).

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: patients with HIV infection or AIDS.

Mucosal candidiasis is frequent in immunocompromised HIV-infected highly active antiretroviral (HAART) naive patients or those who have failed therapy. Mucosal candidiasis is a marker of progressive immune deficiency. Because of the frequently marked and prompt immune reconstitution induced by HAART, there is no recommendation for primary antifungal prophylaxis of mucosal candidiasis in the HIV setting in Europe, although it has been evidenced as effective in the pre-HAART era. Fluconazole remains the first line of therapy for both oropharyngeal candidiasis and oesophageal candidiasis and should be preferred to itraconazole oral solution (or capsules when not available) due to fewer side effects. For patients who still present with fluconazole-refractory mucosal candidiasis, oral treatment with any other azole should be preferred based on precise Candida species identification and susceptibility testing results in addition to the optimization of HAART when feasible. For vaginal candidiasis, topical therapy is preferred.