Post-engraftment Bloodstream Infections After Allogeneic Hematopoietic Cell Transplantation: Risk Factors and Association with Mortality.

BACKGROUND: Bloodstream infections (BSIs) are major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to analyze the incidence, etiology, risk factors and outcomes of post-engraftment BSI in allo-HCT recipients. MATERIALS AND METHODS: The retrospective study included 261 patients with documented engraftment after first allo-HCT performed from January 2018 till September 2021. RESULTS: Of 261 patients 29 (11.1%) developed at least one post-engraftment BSIs episode with a median time to post-engraftment BSI of 49 days (range, 1 - 158 days from the engraftment). A total of 45 pathogens were isolated from blood - 64.4% (n = 29) were represented by Gram-negative bacteria, and 35.6% (n = 16) - by Gram-positive bacteria. Secondary graft failure (hazard ratio [HR]: 39.93; 95% confidence interval [CI]: 7.64-208.74; P <0.001), secondary poor graft function (HR: 18.07; 95% CI: 3.53 - 92.44; P <0.001), and acute gut graft-versus-host-disease (GvHD) grade II-IV (HR: 29.86; 95% CI: 10.53 - 84.68; P <0.001) were associated with the higher risk of Gram-negative post-engraftment BSIs. Overall 30-day survival after post-engraftment BSIs was 71.4%. By multivariate analysis post-engraftment BSIs (HR: 3.09; 95% CI: 1.29 - 7.38; P = 0.011), and acute gut GvHD grade II-IV (HR: 6.60; 95% CI: 2.78 - 15.68; P <0.001) were associated with the higher 180-day non-relapse mortality risk. CONCLUSION: Gram-negative bacteria prevailed in the etiology of post-engraftment BSIs with secondary graft failure. secondary poor graft function. and acute gut GvHD being the main predisposing factors for their development. Post-engraftment BSIs were associated with the higher risk of non-relapse mortality after allo-HCT.

Impact of fluoroquinolone administration and gut mucosal colonization on the risk of pre-engraftment bloodstream infections after allogeneic hematopoietic cell transplantation.

Fluoroquinolones (FQ) has been used after allogeneic hematopoietic stem cell transplantation (allo-HCT) for decades. This study on 284 allo-HCT recipients aimed to analyze the impact of FQ on pre-engraftment BSI. A total of 154 patients were colonized with resistant gram-negative bacteria, and 130 patients were not. Colonized patients did not receive FQ (n = 147) except 7 who received FQ as sequential therapy; 98 non-colonized patients received FQ, whereas 32 did not. Gram-negative (p < 0.0001), and ESBL-E BSI (p < 0.0001) were higher in colonized patients receiving FQ. No difference was found in gram-positive BSI (p = 0.452). In multivariate analysis colonized patients with (p < 0.0001) or without FQ (p = 0.007), omission of FQ in non-colonized patients (p = 0.038), and active disease (p = 0.042) were associated with gram-negative BSI, whereas mismatched unrelated donor transplantations - with gram-positive BSI (p = 0.009). Colonized patients with FQ have a higher risk of gram-negative BSI. In non-colonized patients, FQ prophylaxis is effective approach significantly reducing gram-negative BSI risk.

The Use and Effectiveness of Ceftazidime-Avibactam in Real-World Clinical Practice: EZTEAM Study.

INTRODUCTION: Ceftazidime-avibactam has proven activity against multidrug-resistant (MDR) bacteria in clinical trials and real-world studies. This study was conducted to describe the patterns of use of ceftazidime-avibactam (including indications and associated antibiotics), and the effectiveness and safety of ceftazidime-avibactam in real-world clinical practice. METHODS: This non-interventional medical chart review study was conducted in 11 countries across the European and Latin American (LATAM) regions. Consecutive patients treated in clinical practice with at least one dose of ceftazidime-avibactam for an approved indication per country label since 01 January 2018 (or launch date in the country if posterior) were enrolled. Effectiveness analyses were conducted in patients treated with ceftazidime-avibactam for at least 72 h. RESULTS: Of the 569 eligible patients enrolled, 516 (90.7%) were treated for at least 72 h (354 patients from Europe and 162 patients from LATAM); 390 patients (75.7%) had switched from another antibiotic line for Gram-negative coverage. Infection sources were intra-abdominal, urinary, respiratory, bloodstream infections, and other infections (approximately 20% each). K. pneumoniae was the most common microorganism identified in the latest microbiological evaluation before starting ceftazidime-avibactam (59.3%). Two-thirds of microorganisms tested for susceptibility were MDR, of which 89.3% were carbapenem-resistant. The common MDR mechanisms for K. pneumoniae were carbapenemase (33.9%), oxacillinase 48 (25.2%), extended-spectrum beta-lactamase (21.5%), or metallo-beta-lactamase (14.2%) production. Without prior patient exposure, 17 isolates (mostly K. pneumoniae) were resistant to ceftazidime-avibactam. Treatment success was achieved in 77.3% of patients overall (88.3% among patients with urinary infection), regardless of first or second treatment line. In-hospital mortality rate was 23.1%. Adverse events were reported for six of the 569 patients enrolled. CONCLUSION: This study provides important real-world evidence on treatment patterns, effectiveness, and safety of ceftazidime-avibactam in clinical practice through its recruitment in the European and LATAM regions. Ceftazidime-avibactam is one of the antibiotics to consider for treatment of MDR bacteria. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03923426.

Recurrent bloodstream infections after allogeneic hematopoietic cell transplantation.

BACKGROUND: Although colonization is an established risk factor for bloodstream infection (BSI) due to identical strain, prior infection with resistant bacteria should also be considered during the management of febrile neutropenia. This study aimed to analyze the rate and etiology of recurrent BSI in allogeneic hematopoietic cell transplant (allo-HCT) recipients to determine its potential impact on decision-making. MATERIALS AND METHODS: The retrospective study included 284 allo-HCT recipients. Recurrent BSI was defined as a new BSI episode occurring in a period of more than 72 hours after antibiotic withdrawal. RESULTS: Overall, 104 patients (36.6%) developed at least one BSI, and 23 of them (22.1%) experienced recurrent BSI episodes (n = 30). Median time to recurrent BSI was 41 days (range 5-526 days). Recurrent BSI was associated with second allo-HCT (p < 0.0001), primary (p = 0.021), and secondary graft failure (p = 0.024). Carbapenem-resistant gram-negative bacteria were more common during recurrent BSI episodes (23.7% vs. 6.0%; p = 0.003). In only 17.5% patients experiencing recurrent BSI episode and in only 3.9% of patients with at least one BSI episode phenotypically identical recurring pathogen was isolated. CONCLUSIONS: In view of low rate of recurrent BSI due to identical pathogen, empirical antimicrobial therapy should not be based on data on previous BSI episodes.

Distribution of virulence genes and capsule types in Klebsiella pneumoniae among bloodstream isolates from patients with hematological malignancies.

The hypervirulent Klebsiella pneumoniae (hv-K. pneumoniae) pathotype has been spreading over during the last years. We evaluated the distribution of virulence genes (iucA, rmpA or rmpA2) and capsule types in K. pneumoniae isolates. A total of 572 K. pneumoniae were evaluated; of those 114 (20%) were carbapenemase-producing K. pneumoniae (CP-K.pneumoniae); 285 (49.8%) - extended-spectrum ß-lactamase-producing K. pneumoniae (ESBL-K. pneumoniae); and 173 (30.2%) - non-CP- and non-ESBL. Among CP-K. pneumoniae the prevalent sequence type was ST395 (37.7%), followed by ST23 (16.7%). A total of 138 (24.1%) hv-K. pneumoniae were detected. The rate of hv-K. pneumoniae (55.3%) was higher among CP-K. pneumoniae compared to ESBL-K. pneumoniae (17.3%) and non-CP- and non-ESBL (15.8%).The iucA and rmpA2 genes were detected in 89.5% of ST23 and 58.1% of ST395. The K57 capsule type was detected in all ST23; K2 was found in 55.8% of ST395. The hv-K. pneumoniae were common in bloodstream isolates, with a significantly higher rate among CP-K. pneumoniae. Most of them belonged to ST23/K57 and ST395/K2.

Incidence, etiology, risk factors, and outcomes of pre-engraftment bloodstream infections after first and second allogeneic hematopoietic cell transplantation.

INTRODUCTION: With an increasing number of allogeneic hematopoietic cell transplantations (allo-HCT) bloodstream infections (BSI) are still among the most common and serious complications. This study aimed to analyze the incidence, etiology, risk factors, and outcomes of pre-engraftment BSI after the first and the second allo-HCT. MATERIALS AND METHODS: This is a retrospective study of 284 patients who underwent the first allo-HCT and 37 patients after the second allo-HCT at the National Research Center for Hematology in Moscow, Russia, from January 2018 till September 2021. RESULTS: Cumulative incidence of pre-engraftment BSI was 29.9% after the first allo-HCT and 35.1% after the second (p = .805). The median time to the first BSI was 9 days (range 0-61 days) after the first and 16 days (range 1-28 days) after the second allo-HCT (p = .014). A total of 113 pathogens were isolated during 94 BSI episodes after the first allo-HCT (gram-negative bacteria 52.2%; gram-positive bacteria 47.7%). Fourteen pathogens were isolated during 14 BSI episodes after the second allo-HCT (gram-negative bacteria 50.0%; gram-positive bacteria 50.0%). The only significant difference was found in the rate of carbapenem-resistant gram-negative bacteria, which was higher after the second allo-HCT compared to the first (57.1% vs. 13.6%; p = .048). Mismatched unrelated donor (hazards ratio [HR] 3.01; 95% confidence interval [CI]: 1.62-5.60; p < .0001) and haploidentical donor transplantations (HR 1.84; 95% CI: 1.02-3.33; p = .042) were the only independent risk factors associated with the higher risk of pre-engraftment BSI. Overall 30-day survival after all BSI episodes was 94.4%. Survival was lower after BSI during the second allo-HCT compared to the first (71.4% vs. 97.9%; p < .0001), particularly after BSI was caused by carbapenem-resistant gram-negative bacteria (25.0% vs. 100.0%; p = .0023). The non-relapse mortality rate at day +60 was 4.0%, and the risk was highly associated with primary graft failure (HR 9.62; 95% CI: 1.33-71.43), second allo-HCT (HR 6.80; 95% CI: 1.36-34.48), and pre-engraftment BSI caused by carbapenem-resistant gram-negative bacteria (HR 32.11; 95% CI: 4.91-210.15). CONCLUSIONS: Pre-engraftment BSI is still a common complication after allo-HCT, particularly after mismatched unrelated and haploidentical donor transplantations. BSI incidence was slightly higher after the second allo-HCT with a significantly higher rate of carbapenem-resistant BSI. Although pre-engraftment BSI would generally follow a benign clinical course, survival was dramatically lower during the second allo-HCT, especially after carbapenem-resistant BSI.

In vitro activity of anidulafungin, caspofungin, fluconazole and amphotericin B against biofilms and planktonic forms of Candida species isolated from blood culture in patients with hematological malignancies.

OBJECTIVE: The aim of the present study was to evaluate the in vitro susceptibility of anidulafungin, caspofungin, fluconazole and conventional amphotericin B against biofilms and planktonic forms of Candida species isolated from blood culture in patients with hematological malignancies. MATERIALS AND METHODS: Antifungal susceptibility for planktonic forms and biofilms of Candida was determined by broth microdilution method as described by Clinical and Laboratory Standards Institute M27 methodology and metabolic XTT-based [2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] reduction assay, respectively. RESULTS: A total of 75 Candida isolates were evaluated between 2006-2018 yy at the National Research Center for Hematology, Russia, Moscow. Biofilm production was detected in 34 (45.3%) Candida species. Antifungal susceptibility was tested for 27 common species of Candida forming biofilms (8 C.krusei, 7 C.tropicalis, 7 C.albicans, 5 C.parapsilosis). MICs below the susceptibility breakpoints were found for 100% of planktonic forms of Candida species for anidulafungin, 85.2% for caspofungin, and 66.7% for fluconazole. Amphotericin B MIC90 for Candida species were less than or equal to 1 µg/ml. Candida biofilms were susceptible in vitro for both tested echinocandins, but MIC80 of anidulafungin were lower compared to caspofungin. The highest MIC80 against Candida biofilms was found for fluconazole (>1,024 µg/ml for all tested isolates) and for conventional amphotericin B (range 4-16 µg/ml). CONCLUSION: The majority of Candida isolates grown as planktonic forms were susceptible to anidulafungin, caspofungin, conventional amphotericin B and fluconazole. Anidulafungin displayed higher activity against Candida biofilms than caspofungin. All Candida biofilms were resistant to fluconazole and conventional amphotericin B.

The outcome of Ph-negative acute lymphoblastic leukemia presenting during pregnancy and treated on the Russian prospective multicenter trial RALL-2009.

We report the data on 15 women who presented with Ph-negative acute lymphoblastic leukemia (ALL) between Jan 2009 until Dec 2016 and who were treated on the prospective multicenter RALL-2009 clinical trial. A comparison of their outcome was made with 129 non-pregnant females who entered the study and were treated by the same schedule. 10-years OS for pregnant and non-pregnant women was 58.6 % (29.6 %-85.0 %) and 43.3 % (32.1 %-58.8 %), DFS was 46 % (15.2 %-78.8 %) and 51 % (39.7 %-64.6 %); probability of relapse was 49 % (16.6 %-83.3 %) and 40.3 % (27.3 %-53.4 %), respectively. Twelve born during the study children are well and alive with a median age 5 years 2 months (2 years - 9 years). Though small, our study has shown some specific features of ALL diagnosed during pregnancy (more T-cell ALL, higher initial WBC, later responses) and has shown that the long-term outcome of women with ALL treated while pregnant is equivalent to female control patients treated on the same protocol.

Intercontinental study on pre-engraftment and post-engraftment Gram-negative rods bacteremia in hematopoietic stem cell transplantation patients: Risk factors and association with mortality.

OBJECTIVES: We present here data on Gram-negative rods bacteremia (GNRB) rates, risk factors and associated mortality. METHODS: Data on GNRB episodes were prospectively collected in 65 allo-/67 auto-HSCT centers in 24 countries (Europe, Asia, Australia). In patients with and without GNRB, we compared: demography, underlying disease, HSCT-related data, center` fluoroquinolone prophylaxis (FQP) policy and accreditation status, and involvement of infection control team (ICT). RESULTS: The GNRB cumulative incidence among 2818 allo-HSCT was: pre-engraftment (pre-eng-allo-HSCT), 8.4 (95% CI 7-9%), post-engraftment (post-eng-allo-HSCT), 5.8% (95%CI: 5-7%); among 3152 auto-HSCT, pre-eng-auto-HSCT, 6.6% (95%CI: 6-7%), post-eng-auto-HSCT, 0.7% (95%CI: 0.4-1.1%). GNRB, especially MDR, was associated with increased mortality. Multivariate analysis revealed the following GNRB risk factors: (a) pre-eng-allo-HSCT: south-eastern Europe center location, underlying diseases not at complete remission, and cord blood source; (b) post-eng-allo-HSCT: center location not in northwestern Europe; underlying non-malignant disease, not providing FQP and never accredited. (c) pre-eng-auto-HSCT: older age, autoimmune and malignant (vs. plasma cell) disease, and ICT absence. CONCLUSIONS: Benefit of FQP should be explored in prospective studies. Increased GNRB risk in auto-HSCT patients transplanted for autoimmune diseases is worrying. Infection control and being accredited are possibly protective against bacteremia. GNRB are associated with increased mortality.

Needles in a haystack: Extremely rare invasive fungal infections reported in FungiScopeⓇ-Global Registry for Emerging Fungal Infections.

OBJECTIVES: Emerging invasive fungal infections (IFI) have become a notable challenge. Apart from the more frequently described fusariosis, lomentosporiosis, mucormycosis, scedosporiosis, and certain dematiaceae or yeasts, little is known about extremely rare IFI. METHODS: Extremely rare IFI collected in the FungiScopeⓇ registry were grouped as Dematiaceae, Hypocreales, Saccharomycetales, Eurotiales, Dermatomycetes, Agaricales, and Mucorales. RESULTS: Between 2003 and June 2019, 186 extremely rare IFI were documented in FungiScopeⓇ. Dematiaceae (35.5%), Hypocreales (23.1%), Mucorales (11.8%), and Saccharomycetales (11.3%) caused most IFI. Most patients had an underlying malignancy (38.7%) with acute leukemia accounting for 50% of cancers. Dissemination was observed in 26.9% of the patients. Complete or partial clinical response rate was 68.3%, being highest in Eurotiales (82.4%) and in Agaricales (80.0%). Overall mortality rate was 29.3%, ranging from 11.8% in Eurotiales to 50.0% in Mucorales. CONCLUSIONS: Physicians are confronted with a complex variety of fungal pathogens, for which treatment recommendations are lacking and successful outcome might be incidental. Through an international consortium of physicians and scientists, these cases of extremely rare IFI can be collected to further investigate their epidemiology and eventually identify effective treatment regimens.

Matched-paired analysis of patients treated for invasive mucormycosis: standard treatment versus posaconazole new formulations (MoveOn).

BACKGROUND: First-line antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B. Salvage treatment options are limited and often based on posaconazole oral suspension. With the approval of posaconazole new formulations, patients could benefit from improved pharmacokinetics, safety and tolerability. OBJECTIVES: Our aim was to assess the effectiveness of posaconazole new formulations for IM treatment. METHODS: We performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. First-line posaconazole new formulations (1st-POSnew) and first-line amphotericin B plus posaconazole new formulations (1st-AMB+POSnew) cases were matched with first-line amphotericin B-based (1st-AMB) treatment controls. Salvage posaconazole new formulations (SAL-POSnew) cases were matched with salvage posaconazole oral suspension (SAL-POSsusp) controls. Each case was matched with up to three controls (based on severity, haematological/oncological malignancy, surgery and/or renal dysfunction). RESULTS: Five patients receiving 1st-POSnew, 18 receiving 1st-AMB+POSnew and 22 receiving SAL-POSnew were identified. By day 42, a favourable response was reported for 80.0% (n = 4/5) of patients receiving 1st-POSnew, for 27.8% (n = 5/18) receiving 1st-AMB+POSnew and for 50.0% (n = 11/22) receiving SAL-POSnew. Day 42 all-cause mortality of patients receiving posaconazole new formulations was lower compared with controls [20.0% (n = 1/5) in 1st-POSnew versus 53.3% (n = 8/15) in 1st-AMB; 33.3% (n = 6/18) in 1st-AMB+POSnew versus 52.0% (n = 26/50) in 1st-AMB; and 0.0% (n = 0/22) in SAL-POSnew versus 4.4% (n = 2/45) in SAL-POSsusp]. CONCLUSIONS: Posaconazole new formulations were effective in terms of treatment response and associated mortality of IM. While posaconazole new formulations may be an alternative for treatment of IM, the limited sample size of our study calls for a cautious interpretation of these observations.

Prevalence of Clostridium Difficile-Associated Diarrhoea in Hospitalised Patients (Results of a Russian Prospective Multicentre Study).

INTRODUCTION: The objective of the study was to evaluate the prevalence of Clostridium difficile-associated diarrhoea (CDAD) among hospitalised patients with antibiotic-associated diarrhoea (AAD) in general and by specific types of medical care and hospital units. METHODS: A prospective, cross-sectional, non-interventional, multicentre study. The main inclusion criteria were: patient age ≥ 18 years, hospital stay of at least 48 h, current antibiotic therapy or antibiotic therapy within the previous 30 days, loose stools (Bristol stool types 5-7 and stool frequency ≥ 3 within ≤ 24 consecutive hours or exceeding normal for the patient) and signed informed consent form. The stool sample was taken to the local (study site) microbiology laboratory for detection of glutamate dehydrogenase (GDH) and toxins A/B using enzyme immunoassay (EIA) stool test. RESULTS: From April 2016 to April 2017, a total of 1245 patients from 12 large hospitals were enrolled in the study. Data on 81 patients were excluded from the analysis for different reasons. Data on 1164 patients (45.2% males and 54.8% females) with a mean age of 54.9 years (range 18-95 years) were analysed. Length of hospitalisation was 2-188 days (median, 8 days). The EIA stool test showed CDAD-positive results in 21.7% (253/1164) patients. The patients were from surgery units (546/1164), internal medicine units (510/1164) and intensive care units (108/1164). The prevalence of CDAD among patients from surgery, internal medicine and intensive care units was 26.2, 17.8 and 17.6%, respectively. Oncology, gastroenterology, septic surgery, oncohaematology and general medical hospital units accounted for more than 75% of all patients included; the prevalence of CDAD by those hospital units was 11.3, 15.0, 39.2, 17.6, and 27.2%, respectively. The proportion of GDH-positive and toxin A/B-negative patients by the rapid stool test result was 16.8% (196/1164). The prevalence of CDAD varied widely between the hospitals (from 0 to 44.3%). CONCLUSIONS: The prevalence of CDAD among hospitalised patients with AAD in this study was 21.7% (95% confidence interval: 14.8 and 28.7%). The percentage of CDAD varied widely between hospitals and by specific types of medical care and hospital units.

Antimicrobial Resistance in Gram-Negative Rods Causing Bacteremia in Hematopoietic Stem Cell Transplant Recipients: Intercontinental Prospective Study of the Infectious Diseases Working Party of the European Bone Marrow Transplantation Group.

BACKGROUND: This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). METHODS: GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas ß-lactams (noncarbapenems), carbapenems, and multidrug resistance. RESULTS: Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and ß-lactam/ß-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on ß-lactam/ß-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria. CONCLUSIONS: Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial. CLINICAL TRIALS REGISTRATION: NCT02257931.

Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.

BACKGROUND: Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. METHODS: In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. FINDINGS: Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). INTERPRETATION: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. FUNDING: Astellas Pharma Global Development, Basilea Pharmaceutica International.

European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia.

Owing to increasing resistance and the limited arsenal of new antibiotics, especially against Gram-negative pathogens, carefully designed antibiotic regimens are obligatory for febrile neutropenic patients, along with effective infection control. The Expert Group of the 4(th) European Conference on Infections in Leukemia has developed guidelines for initial empirical therapy in febrile neutropenic patients, based on: i) the local resistance epidemiology; and ii) the patient's risk factors for resistant bacteria and for a complicated clinical course. An 'escalation' approach, avoiding empirical carbapenems and combinations, should be employed in patients without particular risk factors. A 'de-escalation' approach, with initial broad-spectrum antibiotics or combinations, should be used only in those patients with: i) known prior colonization or infection with resistant pathogens; or ii) complicated presentation; or iii) in centers where resistant pathogens are prevalent at the onset of febrile neutropenia. In the latter case, infection control and antibiotic stewardship also need urgent review. Modification of the initial regimen at 72-96 h should be based on the patient's clinical course and the microbiological results. Discontinuation of antibiotics after 72 h or later should be considered in neutropenic patients with fever of unknown origin who are hemodynamically stable since presentation and afebrile for at least 48 h, irrespective of neutrophil count and expected duration of neutropenia. This strategy aims to minimize the collateral damage associated with antibiotic overuse, and the further selection of resistance.

Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guidelines of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011).

The detection of multi-resistant bacterial pathogens, particularly those to carbapenemases, in leukemic and stem cell transplant patients forces the use of old or non-conventional agents as the only remaining treatment options. These include colistin/polymyxin B, tigecycline, fosfomycin and various anti-gram-positive agents. Data on the use of these agents in leukemic patients are scanty, with only linezolid subjected to formal trials. The Expert Group of the 4(th) European Conference on Infections in Leukemia has developed guidelines for their use in these patient populations. Targeted therapy should be based on (i) in vitro susceptibility data, (ii) knowledge of the best treatment option against the particular species or phenotype of bacteria, (iii) pharmacokinetic/pharmacodynamic data, and (iv) careful assessment of the risk-benefit balance. For infections due to resistant Gram-negative bacteria, these agents should be preferably used in combination with other agents that remain active in vitro, because of suboptimal efficacy (e.g., tigecycline) and the risk of emergent resistance (e.g., fosfomycin). The paucity of new antibacterial drugs in the near future should lead us to limit the use of these drugs to situations where no alternative exists.

A multidisciplinary team approach to the management of patients with suspected or diagnosed invasive fungal disease.

Implementation of evidence-based guidelines for the treatment of invasive fungal disease (IFD) requires collaboration among numerous clinical and laboratory services, as partners in patient care. The multidisciplinary team (MDT) approach has emerged as a way of providing comprehensive medical care by bringing together professionals from a wide range of disciplines in a coordinated and effective manner. Here, we propose an MDT model for IFD management aimed at facilitating communication among consultants, adherence to clinical pathways and optimized use of resources available at each centre.