Cryptococcal meningitis following umbilical cord blood transplantation, association between the occurrence of cryptococcal infection and tacrolimus discontinuation among allogeneic hematopoietic stem cell recipients.

Few cases of cryptococcal infection following umbilical cord blood transplantation (UCBT) have been reported. We report a case, where cryptococcal infection occurred soon after rapidly reducing the dose of tacrolimus in a UCBT recipient who received micafungin prophylaxis during the early phase of transplantation. The etiology of cryptococcal infection following allogeneic hematopoietic stem cell transplantation (allo-HSCT), including UCBT, might be associated with rapid dose-reduction of calcineurin inhibitors, such as tacrolimus during early phase of allo-HSCT. To our knowledge, this is the first English-language report to describe in detail a case of cryptococcal meningitis with fungemia during early phase of UCBT.

Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease.

BACKGROUND: Antifungal prophylaxis with a new oral tablet formulation of posaconazole may be beneficial to patients at high risk for invasive fungal disease. A two-part (Phase 1B/3) study evaluated posaconazole tablet pharmacokinetics (PK) and safety. METHODS: Patients with neutropenia following chemotherapy for haematological malignancy or recipients of allogeneic HSCT receiving prophylaxis or treatment for graft-versus-host disease received 300 mg posaconazole (as tablets) once daily (twice daily on day 1) for up to 28 days without regard to food intake. Weekly trough PK sampling was performed during therapy, and a subset of patients had sampling on days 1 and 8. Cmin-evaluable subjects received ≥6 days of dosing, and were compliant with specified sampling timepoints. Steady-state PK parameters, safety, clinical failure and survival to day 65 were assessed. ClinicalTrials.gov, NCT01777763; EU Clinical Trials Register, EUDRA-CT 2008-006684-36. RESULTS: Two hundred and ten patients received 300 mg posaconazole (as tablets) once daily. Among Cmin-evaluable subjects (n = 186), steady-state mean Cmin was 1720 ng/mL (range = 210-9140). Steady-state Cmin was ≥700 ng/mL in 90% of subjects with 5% (10 of 186) <500 ng/mL and 5% (10 of 186) 500-700 ng/mL. Six (3%) patients had steady-state Cmin ≥3750 ng/mL. One patient (<1%) had an invasive fungal infection. The most common treatment-related adverse events were nausea (11%) and diarrhoea (8%). There was no increase in adverse event frequency with higher posaconazole exposure. CONCLUSIONS: In patients at high risk for invasive fungal disease, 300 mg posaconazole (as tablets) once daily was well tolerated and demonstrated a safety profile similar to that reported for posaconazole oral suspension: most patients (99%) achieved steady-state pCavg exposures >500 ng/mL and only one patient (<1%) had a pCavg <500 ng/mL.

Antifungal prophylaxis with liposomal amphotericin B and caspofungin in high-risk patients after liver transplantation: impact on fungal infections and immune system.

Antifungal prophylaxis may be required in high-risk patients undergoing liver transplantation and for that reason we aimed to verify its role and its related impact on the graft. From January 2006 throughout 2012, 250 liver transplants were evaluated and 54 patients identified as being at higher risk were randomly selected to undergo the following schedule: 28 patients received liposomal amphotericin B and 26 received caspofungin. We evaluated, throughout 12 months, renal and liver function tests, bacterial and fungal infection episodes, and intensive care unit (ICU) stay, as well as the Th1 and Th2 cytokine network. Differences were analyzed according to non-parametric tests (two-tailed p values). Neither of the groups showed episodes of invasive fungal infection during the 12 months follow-up; however, patients receiving prophylaxis with liposomal amphotericin B had reduced episodes of bacterial infections coupled with an improved immune system response compared with those receiving caspofungin. Finally, a reduced stay in the ICU was also observed. In conclusion, even if the results of liposomal amphotericin B and caspofungin prophylaxis strategies did not differ in terms of invasive fungal infection rate, patients receiving prophylaxis with liposomal amphotericin B had a reduced ICU stay and an improved Th2 status, as well as a reduced number of post-transplant bacterial infections. Further studies are required to better address and evaluate these findings.

Central Venous Catheter-related Fungemia Caused by Rhodotorula glutinis.

Bloodstream infection due to Rhodotorula glutinis is extremely rare and mostly associated with underlying immunosuppression or cancer. Vascular access devices provide the necessary surfaces for biofilm formation and are currently responsible for a significant percentage of human infections. In this work, we describe a rare case of central venous catheter-related Rhodotorula glutinis fungemia in a female patient with acute myelogenous leukemia in remission. The timely removal of central venous catheter was an essential element for overcoming this CVC-related Rhodotorula fungemia.

An update on pediatric invasive aspergillosis.

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised adults and children, the number of which has been continuously increasing in the last decades. The purpose of our review was to provide epidemiological, clinical, and biological data and antifungal treatment options in the pediatric population. Several biological assays (galactomannan enzyme immunoassay, ß-D-glucan, detection of Aspergillus spp. DNA) have proven useful adjuncts for the diagnosis of IA in adult studies. However, data on these assays in children is limited by small sample sizes and sometimes conflicting results concerning their sensitivity/specificity. Pediatric treatment recommendations are mainly extrapolated from results of clinical trials performed in adults. It is thus necessary to develop new antifungal formulations specifically adapted to the pediatric population and to evaluate their pharmacokinetic/pharmacodynamic profile, their safety, and their effectiveness in infants and children.

Posaconazole: promising but problematic in practice in pediatric patients.

Posaconazole is a broad-spectrum antifungal agent used for the prevention and treatment of invasive fungal infections. It is currently only licensed for use in children greater than 12 years of age. Absorption of the oral formulation is unpredictable and affected by mucositis and concomitant medications. We reviewed studies of posaconazole use in children younger than 12 years in relation to attainment of target serum concentrations.

Serum posaconazole levels during acute myeloid leukaemia induction therapy: correlations with breakthrough invasive fungal infections.

The usefulness of posaconazole therapeutic drug monitoring (TDM) is still a matter of debate. A correlation between posaconazole serum levels and breakthrough invasive fungal infections (IFI) has not been clearly demonstrated so far. We analysed posaconazole serum levels in patients with acute myeloid leukaemia (AML) during induction therapy and correlated them with the incidence of breakthrough IFI and the need of systemic antifungal therapy. Overall, 77 AML patients receiving posaconazole were evaluated for serum levels; breakthrough IFI were observed in five with at least one posaconazole TDM (6.5%). Median serum level was 534 ng ml(-1) (IQ range: 298.5-750.5 ng ml(-1) ) and did not change significantly over time. Four of the 40 patients with median posaconazole levels <500 ng ml(-1) developed IFI, as compared with only 1 of the 37 patients with median levels ≥500 (10% vs. 2.7%, P = 0.19). Median posaconazole levels on day 7 were 384.5 ng ml(-1) (IQ range: 207-659 ng ml(-1) ) and 560.5 ng ml(-1) (IQ range: 395-756 ng ml(-1) ) in patients requiring or not systemic antifungal treatment respectively (P = 0.067). These results seem to confirm that higher median serum levels of posaconazole correlate with higher prophylactic efficacy against proven/probable IFI and with lesser need of systemic antifungal therapy.

Validation of sterility testing of cord blood: challenges and results.

BACKGROUND: Sterility testing for cord blood (CB) products is mandatory to prevent transplantation-transmitted microbial infections. Here, the automated BacT/ALERT (bioMérieux) culture system was validated to detect microbial contamination in CB units processed at the Canadian National Public Cord Blood Bank. STUDY DESIGN AND METHODS: A three-phase validation was developed. CB units were prepared with pentastarch (Phases 1 and 2) or hetastarch (Phase 3). In Phase 1, CB was spiked with approximately 100 colony-forming units/mL of Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Bacteroides fragilis, and Candida albicans. Plasma (8 mL) and buffy coat (BC; 0.5 and 8 mL) were inoculated into culture bottles. In Phases 2 and 3, a mix of red blood cells (RBCs) and plasma (4 mL each) was used as the inoculant. In Phase 3, Aspergillus brasiliensis was added as a test organism and microbial concentrations in the by-product RBCs and plasma were determined. The BC fractions were cryopreserved and tested 3 months later. RESULTS: In Phase 1, bacteria failed to grow in CB units containing antibiotics. Thus, antibiotic-free units were used for the other phases. C. albicans was not always captured in plasma, but using a mix of RBCs and plasma, all organisms were detected. The use of pentastarch or hetastarch did not affect microbial recovery. C. albicans and A. brasiliensis were preferentially recovered in RBCs and BC. Cryopreservation did not affect microbial survival during CB processing. CONCLUSIONS: A mix of plasma and RBCs is appropriate for CB sterility testing. Interestingly, fungi preferentially segregate to cellular fractions. The clinical significance of the bactericidal /or bacteriostatic effect of antibiotics in CB merits further investigation.

The burden of mucosal barrier injury laboratory-confirmed bloodstream infection among hematology, oncology, and stem cell transplant patients.

OBJECTIVE: To evaluate the impact and burden of the new National Healthcare Safety Network surveillance definition, mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI), in hematology, oncology, and stem cell transplant populations. DESIGN: Retrospective cohort study. SETTING: Two hematology, oncology, and stem cell transplant units at a large academic medical center. METHODS: Central line-associated bloodstream infections (CLABSIs) identified during a 14-month period were reviewed and classified as MBI-LCBI or non-MBI-LCBI (MBI-LCBI criteria not met). During this period, interventions to improve central line maintenance were implemented. Characteristics of patients with MBI-LCBI and non-MBI-LCBI were compared. Total CLABSI, MBI-LCBI, and non-MBI-LCBI rates were compared between baseline and postintervention phases of the study period. RESULTS: Among 66 total CLABSI cases, 47 (71%) met MBI-LCBI criteria. Patients with MBI-LCBI and non-MBI-LCBI were similar in regard to most clinical and demographic characteristics. Between the baseline and postintervention study periods, the overall CLABSI rate decreased from 3.37 to 3.21 infections per 1,000 line-days (incidence rate ratio, 0.95; 4.7% reduction, P=.84), the MBI-LCBI rate increased from 2.08 to 2.61 infections per 1,000 line-days (incidence rate ratio, 1.25; 25.3% increase, P=.44), and the non-MBI-LCBI rate decreased from 1.29 to 0.60 infections per 1,000 line-days (incidence rate ratio, 0.47; 53.3% reduction, P=.12). CONCLUSIONS: Most CLABSIs identified among hematology, oncology, and stem cell transplant patients met MBI-LCBI criteria, and CLABSI prevention efforts did not reduce these infections. Further review of the MBI-LCBI definition and impact is necessary to direct future definition changes and reporting mandates.

Micafungin twice weekly as antifungal prophylaxis in paediatric patients at high risk for invasive fungal disease.

BACKGROUND: Current guidelines recommend antifungal prophylaxis for children at high risk for invasive fungal disease (IFD), but the use of polyenes and triazoles may not be feasible in some patients due to toxicities and drug-drug interactions. Micafungin is well tolerated, with intravenous daily dosing being the current standard. Recent reports indicate safety and efficacy of intermittent dosing of micafungin. METHODS: We analysed safety, efficacy and micafungin serum concentrations of children at high risk for IFD receiving prophylactic micafungin between 3 and 4 mg/kg twice weekly. All children were intolerant or had contraindications to polyenes and triazoles. RESULTS: A total of 21 children (median age = 9 years) at high risk for IFD were included in the analysis. No significant clinical adverse event occurred, and end of treatment values of parameters of renal and hepatic function in serum were not different from baseline. Proven or probable breakthrough IFD did not occur in any of the patients. In 9 out of 11 patients in whom plasma micafungin concentrations were assessed, the first trough concentration exceeded 150 ng/mL, a concentration proposed to be effective for prophylaxis. CONCLUSIONS: Our data indicate that micafungin administered twice weekly at a dosage of 3-4 mg/kg of bodyweight could be a convenient, safe and efficient alternative for antifungal prophylaxis in children at high risk for IFD.

[Invasive mould disease in haematological patients]. / Enfermedad fúngica invasora por hongos filamentosos en pacientes hematológicos.

Invasive mould infections (IMI) are a persistent problem with high morbidity and mortality rates among patients receiving chemotherapy for hematological malignancies and hematopoietic stem cell transplant recipients. Management of IMI in this setting has become increasingly complex with the advent of new antifungal agents and diagnostic tests, which have resulted in different therapeutic strategies (prophylactic, empirical, pre-emptive, and directed). A proper assessment of the individual risk for IMI appears to be critical in order to use the best prophylactic and therapeutic approach and increase the survival rates. Among the available antifungal drugs, the most frequently used in the hematologic patient are fluconazole, mould-active azoles (itraconazole, posaconazole and voriconazole), candins (anidulafungin, caspofungin and micafungin), and lipid formulations of amphotericin B. Specific recommendations for their use, and criteria for selecting the antifungal agents are discussed in this paper.

[Results of the implementation of the Bacteremia Zero project in Catalonia, Spain]. / Resultados de la aplicación del proyecto Bacteriemia Zero en Catalunya.

The nationwide Bacteremia Zero (BZ) Project consists in the simultaneous implementation of measures to prevent central venous catheter-related bacteremia (CVC-B) in critically ill patients and in the development of an integral safety plan. The objective is to present the results obtained after the implementation of the BZ project in the ICUs of the Autonomous Community of Catalonia, Spain. All patients admitted to ICUs in Catalonia participating in the ENVIN-HELICS registry between January 2009 and June 2010 were included. Information was provided by 36 (92.3%) of the total possible 39 ICUs. A total of 281 episodes of CVC-B were diagnosed (overall rate of 2.53 episodes per 1000 days of CVC). The rates have varied significantly between ICUs that participated in the project for more or less than 12 months (2.17 vs. 4.27 episodes per 1000 days of CVC, respectively; p<.0001). The implementation of the BZ Project in Catalonia has been associated with a decrease greater than 40% in the CVC-B rates in the ICUs of this community, which is much higher than the initial objective of 4 episodes per 1000 days of CVC).

A novel scoring system to predict the incidence of invasive fungal disease in salvage chemotherapies for malignant lymphoma.

The requirement of antifungal prophylaxis has not been established in the chemotherapies for malignant lymphoma. This study was conducted to explore the incidence of invasive fungal diseases (IFD) and their risk factors in patients receiving salvage therapies for malignant lymphoma. We retrospectively analyzed 177 consecutive patients who received these therapies (705 courses in total) at our institute. IFD were observed in 16 courses and the incidence was 2.3 %. A multivariate analysis showed that the factors associated with IFD were primary refractoriness (adjusted odds ratio (aOR), 4.22; 95 % confidence interval (CI), 1.38-13.0; p value = 0.012), two (aOR, 10.5, 95 % CI, 1.20-91.7; p = 0.033) or more (aOR, 26.2; 95 % CI, 3.27-210; p = 0.002) previous treatment lines, and the minimum neutrophil count during the therapies equal to or less than 500/µL (aOR, 9.69; 95 % CI, 1.25-74.9; p = 0.030). Using these factors, we created the IFD scoring model by assigning one point to each of primary refractoriness, two previous treatment lines and treatment that caused neutropenia (≤500/µL minimal neutrophil count) and two points to three or more previous treatment lines. The IFD incidence of lower risk group (IFD score <3) was 0.19 % and that of higher (IFD score ≥3) was 9.0 %. In conclusion, adequate prophylaxis for IFD might be required for patients with primary refractoriness, repeated therapies, or therapies which cause neutropenia. Furthermore, the IFD scoring model of this study underscores the need to account for disease and host factors in determining administration of adequate prophylaxis in salvage treatments for malignant lymphoma.

Microbiologically documented fungal infections in pediatric patients with acute myeloid leukemia: 12.5-year experience at a single institution.

The primary objective of this study was to determine the incidence and types of microbiologically documented fungal infections in 56 children with acute myeloid leukemia admitted to Wolfson Children's Hospital. The secondary objective was to determine the factors that may affect the treatment and outcome of these infections, such as antifungal prophylaxis, absolute neutrophil count, age, and phase of therapy. Medical records were reviewed from January 1, 2000 to July 31, 2012. Over the 12.5-year study period, there were 11 patients with 25 episodes of fungal infections. Adolescents with acute myeloid leukemia (13 to 18 y old) represented 48% of the population. Children less than 3 years of age and between 3 and 12 years of age represented one quarter each. None of the patients less than 3 years of age developed fungal infections, whereas 64% of the adolescents did (P=0.01). Blood-borne infections were the most common site of infection (44%). Eighty-four percent of infections occurred in neutropenic patients. The mortality rate in the overall cohort was 28%. Patients with fungal infections had increased mortality rate of 55%. Overall candidiasis and aspergillosis were the major pathogens (28% each), although there have been no occurrences of Aspergillus sp. since 2005. On the basis of the results of our study, it would be prudent to provide antifungal coverage for both these pathogens, such as with voriconazole or echinocandins over fluconazole.

Bloodstream and central line isolates from hematopoietic stem cell transplant recipients: data from a developing country.

INTRODUCTION: Bloodstream infections (BSIs) and central line infections remain among the major causes of morbidity and mortality in transplant recipients because of prolonged neutropenia and mucosal damage. The objective of this study was to determine the frequency and outcome of bacterial and fungal isolates from patients undergoing allogeneic hematopoietic stem cell transplant. MATERIALS AND METHODS: This study was conducted at the Aga Khan University and Hospital's bone marrow transplant unit. All patients who underwent an allogeneic stem cell transplant with matched sibling/parent donor were included. The study period ranged from April 2004 to December 2012. Transplantation was performed according to institutional protocols. All patients were admitted in single rooms with positive pressure and high-efficiency particulate air filters. Ciprofloxacin, fluconazole, and valaciclovir were used for standard prophylaxis, which was started at the time of conditioning. All blood cultures were obtained at clinical suspicion of systemic infection, mainly documented as fever (temperature of >38.5°C). BSIs and line infections were defined as isolation of bacterial or fungal pathogen from at least one blood/central line culture. RESULTS: In total, 101 of 108 patients developed febrile neutropenia. In the 101 patients, 245 documented febrile episodes occurred. There were 40 culture-positive episodes and 205 culture-negative episodes. Of these 40 culture-positive episodes, 22 patients had bloodstream isolates and 18 had central line isolates. The median ± standard deviation time of febrile neutropenia was day 7 ± 2 days (range: day -3 to day +13). The most common bloodstream isolate was Escherichia coli (n = 9) followed by Staphylococcus epidermidis (n = 5). One patient developed Fusarium infection. In central line infections, S. epidermidis was the most common organism (n = 8). In 2 patients with central venous catheters, Candida albicans was the isolate. Transplant-related mortality from sepsis occurred in 9.2%. CONCLUSION: E.coli was mainly responsible for BSI, while gram-positive organisms dominated catheter-related febrile episodes. Transplant-related mortality due to sepsis was 9%.

Incidence, risk factors, and outcome of bloodstream infections during the pre-engraftment phase in 521 allogeneic hematopoietic stem cell transplantations.

BACKGROUND: Bloodstream infection (BSI) after allogeneic hematopoietic stem cell transplantation (HSCT) is a well-known complication during the pre-engraftment phase. Knowledge of trends in etiology and antibiotic susceptibility of BSI is important as the time to effective antibiotic treatment is closely associated with survival in bacteremic patients with septic shock. METHODS: BSI during the pre-engraftment phase was studied retrospectively in 521 patients undergoing HSCT at our center in 2001-2008. Incidence, risk factors, outcome, and microbiology findings were investigated and compared with BSI in a cohort transplanted during 1975-1996. RESULTS: The incidence of at least 1 episode of BSI was 21%, the total attributable mortality of BSI was 3.3%, and crude mortality at day 120 after transplantation was 21%. The rate of gram-positive and gram-negative BSI was 80% and 13%, respectively. Gram-negative BSI was more frequent both in 2001-2004 and in 2005-2008 compared with 1986-1996 (P = 0.023 for 2001-2004, P = 0.001 for 2005-2008), with fluoroquinolone-resistant Escherichia coli as the predominant finding. BSI with viridans streptococci and E. coli occurred significantly earlier after HSCT than BSI with Enterococcus species, with median time of 4, 8, and 11 days, respectively (P < 0.01 both for viridians streptococci vs. Enterococcus species, and E. coli vs. Enterococcus species). Risk factors for BSI in multivariate analysis were transplantation from unrelated donor and cord blood as stem cell source, whereas peripheral blood as stem cell source was protective. CONCLUSIONS: Despite low attributable mortality of BSI, crude mortality at day 120 after transplantation was 21%, indicating an association between BSI and other risk factors for death. The risk of gram-negative BSI increased over time in parallel with an increased rate of quinolone resistance. However, the incidence and attributable mortality of gram-negative BSI remained low. Thus, prophylaxis with ciprofloxacin is still deemed appropriate, but continued assessments of the risk and benefits of fluoroquinolone prophylaxis must be performed.

Treatment of invasive fungal infections in cancer patients-updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.

Second- versus first-generation azoles for antifungal prophylaxis in hematology patients: a systematic review and meta-analysis.

Second-generation azoles may be more effective than first-generation azoles in the prevention of fungal infections in hematology patients. We performed a systematic review with meta-analysis of randomized controlled trials comparing second- with first-generation azoles in hematology patients with respect to proven or probable invasive fungal infections, invasive aspergillosis, receipt of empirical antifungal therapy, overall mortality, and withdrawal from the studies due to the development of adverse effects. We searched the Medline, Embase, and Cochrane Registry of Controlled Trials electronic databases as well as conference proceedings from 2002 to 2012 for randomized controlled trials comparing second-generation azoles (voriconazole, posaconazole) versus first-generation azoles (fluconazole, itraconazole). Treatment effect measures for all outcomes were expressed as odds ratio with 95 % confidence interval. Meta-analysis was performed using Review Manager, version 5.1. Data from four randomized clinical trials representing a large population of patients demonstrated that antifungal prophylaxis with second-generation azoles reduces proven or probable invasive fungal infections, invasive aspergillosis, and receipt of empirical antifungal therapy in high-risk hematology patients, while there were no differences between second- and first-generation azoles with regard to overall mortality and patients or withdrawal from the studies due to the development of adverse effects. In conclusion, antifungal prophylaxis with second-generation azoles can significantly reduce the incidence of invasive fungal infections and invasive aspergillosis but with no risk of an increase in adverse events.