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Background: The aim of this study is to assess the factors influencing the early mortality (7-day after index blood culture) in haematological malignancy patients with Gram negative bacilli (GNB) bacteraemia., Methods: Infection control committee records were reviewed to identify the cases between March 2006 and June 2011. Only one bacteraemic episode per patient was included in the study., Results: A total of 154 patients with GNB bacteraemia were identified. The early mortality rate was 19.5% (30 out of 154). Blood cultures revealed Enterobacteriacea in 120 patients (Escherichia coli; 86, Klebsiella spp.; 28, Enterobacter cloacea; 6) and glucose non-fermenting GNB in 34 patients (Pseudomonas aeruginosa; 15, Acinetobacter baumannii; 11, Stenotrophomonas maltophilia; 7, Burkholderia cepacia; 1). Forty (33.3%) out of 120 Enterobacteriaceae were extended spectrum beta-lactamase (ESBL) producers and 18 (52.9%) out of 34 glucose non-fermenting GNB were multidrug resistant. Carbapenems were administered as first line therapy in 139 out of 154 patients. In univariate analysis Pitt's bacteraemia score, presence of aplastic anaemia, bacteraemia caused by glucose non-fermentating GNB, inappropriate empirical antibacterial treatment, presence of severe sepsis or septic shock, unable to achieve microbiological cure, and intensive care unit (ICU) acquired bacteraemia were associated with mortality. Multivariate analysis showed ICU acquired bacteraemia (OR, 12.55; 95% CI, 2.34-67.38, p=0.003) as an independent factor associated with early mortality., Conclusion: Haematological malignancy patients who require ICU care are at high risk for early mortality related to GNB bacteraemia. Based on the local findings pointing out high rate of multidrug resistance, carbapenems combined with colistin seems to be a reasonable approach as empirical treatment of these patients. However, increasing carbapenem resistance rate is of concern., (Copyright © 2013 Elsevier Editora Ltda. All rights reserved.)

Objective: To describe characteristics of Clostridium difficile infection (CDI) and markers of severe CDI among patients with hematologic malignancies., Design: Case-control study., Setting: Tertiary care teaching hospital., Patients and Methods: Inpatients with hematologic malignancies and CDI were age and time matched with 2 control inpatients without hematologic malignancies. Chart reviews were performed, and C. difficile isolates were strain typed., Results: Case patients (n = 41) and control patients (n = 82) patients were different in respect to receipt of immunosuppressive agents within 2 months (92.7% vs 25.6%; P < .0001); neutropenia within 2 months (75.6% vs 3.7%; P < .0001) and mean (± standard deviation) white blood cell (WBC) count at diagnosis (vs 4.9 ± 14.1 vs 11.8 ± 6.8 x 10(3) cells/mL; P <.0001); baseline mean creatinine level (0.89 ± 0.1 vs 1.6 ± 2.4 mg/dL; P = .003), mean creatinine level at diagnosis (0.83 ± 0.4 vs 1.85 ± 1.9 mg/dL; P = .004), and creatinine increases of 1.5 times over baseline (2.4% vs 15.1%; P = .02). Immunosuppressive agents and creatinine level remained significant in multivariable analysis (P = .03 for both variables). Severity correlated with mortality when measured by alternate severity criteria but not when measured by the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America criteria, which are based solely on WBC count and creatinine elevation. The prevalence of the epidemic BI/NAP1/027 strain was similar in both groups., Conclusions: Patients with hematologic malignancies had lower creatinine levels at the time of CDI diagnosis compared with control patients. WBC counts also tended to be lower in case patients. CDI severity criteria based on WBC count and creatinine level may not be applicable to patients with hematologic malignancies.

Background: Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised children. We investigated the usefulness of an Aspergillus galactomannan (GM) antigen assay as a diagnostic tool for IA in pediatric cancer patients and hematopoietic cell transplantation (HCT) recipients., Procedure: The GM antigen assay results were analyzed in 749 blood samples from 99 patients. A GM index (GMI) greater than or equal to 0.5 on at least two separate occasions was considered positive. A review of the clinical data was performed for subjects with proven or probable IA., Results: Twenty-one of 23 patients with proven or probable IA had positive GM antigen test results (91.3% sensitivity, 95% CI 71.9-98.9; 81.7% specificity, 95% CI 69.6-90.5; P < 0.0001). The false-positive rate was 18.3%. Being younger than 3 years of age, having a solid tumor, and receiving HCT within 4 weeks of the test were statistically significant factors for causing false-positive results (P < 0.05). Among the 23 patients with IA (six proven, 17 probable), 16 (69.6%) had hematological malignancies, five (22.7%) had solid tumors, and two (8.7%) had primary immunodeficiency. Nineteen patients (82.6%) received HCT. The most common clinical site of IA was the lungs (91.3%), and consolidation was the most frequent finding in chest CT scans (36.8%). The mortality at 12 weeks was 43.5%., Conclusions: Having a positive GM assay at least twice is useful in diagnosing IA in pediatric patients with cancer and HCT recipients., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The pharmacokinetic variability of hydroxy-itraconazole (OH-ITZ), an active metabolite of itraconazole (ITZ), is not fully known., Methods: Oral solution of ITZ was administered in 46 immunocompromised patients as a single 200 mg dose for at least 12 days. The plasma concentrations of ITZ, active OH-ITZ, and keto-itraconazole (keto-ITZ), an inactive metabolite, 12 h after administration were determined by LC-UV or LC-MS/MS., Results: The mean±SD of plasma concentrations of ITZ, OH-ITZ, and keto-ITZ were 833±468, 798±454, and 3.94±2.68 μg/l, respectively. A greater correlation coefficient was observed between plasma concentrations of ITZ and OH-ITZ (r=0.90, P<0.01) than between OH-ITZ and keto-ITZ (r=0.44, P<0.01). Plasma concentration of OH-ITZ was inversely correlated with concentration ratio of keto-ITZ to OH-ITZ (r=-0.52, P<0.01). Plasma concentrations of ITZ and OH-ITZ were correlated with serum concentration of albumin (r=0.36, P=0.01 and r=0.37, P=0.01) and estimated glomerular filtration rate (r=-0.27, P=0.08 and r=-0.35, P=0.02)., Conclusions: The pharmacokinetic variability of OH-ITZ was associated with saturated metabolism to keto-ITZ, serum concentration of albumin, and renal function in immunocompromised patients. The plasma concentration of OH-ITZ was strongly correlated with that of ITZ. Prevention of fungal infections can be improved by determining the plasma concentration of ITZ or OH-ITZ., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The diagnosis of latent Mycobacterium tuberculosis infection (LTBI) is recommended in hematological malignancy patients and before hematopoietic stem cell transplantation (Guidelines for the prevention and management of infectious complications of solid organ transplantation, 2004). Compared to traditional methods such as tuberculin skin test (TST), T-SPOT.TB has been shown to be more specific. In the present study we enrolled 536 patients for whom T-SPOT.TB was performed, among which 295 patients also received the TST test. The agreement (79%) between T-SPOT.TB and TST was poor (?=0.274, P<0.001). The patients with positive T-SPOT.TB results numbered 62 (11.6%), in which only 20 (48.8%) of the 41 receiving the TST test had positive results. A majority of the patients with T-SPOT.TB positive results had some other evidence ofTB, such as TB history, clinical symptoms and an abnormal chest CT scan. Active TB was found in 9 patients, in which 2 had negative TST results. We followed up the patients and no one developed active TB. Our study suggested that the T-SPOT.TB may be more useful for screening LTBI and active TB in hematological malignancy patients and hematopoietic stem cell transplant recipients than the TST test.

Invasive fungal infections are important causes of morbidity and attributable mortality in neutropenic patients with hematological malignancies, myelodysplasia, and aplastic anemia. Successful risk-based strategies can be implemented for prophylaxis, empirical therapy, and preemptive therapy for the prevention and early treatment of invasive fungal infections in neutropenic hosts. The use of echinocandins for invasive candidiasis and voriconazole for invasive aspergillosis has significantly improved outcome. Recent studies demonstrate, however, that resistant fungal pathogens may emerge during the course of these antifungal interventions. Although triazole-resistant Candida spp. have been well described as causes of breakthrough candidemia, other organisms now pose a similar threat. Such organisms include echinocandin-resistant Candida glabrata and Candida parapsilosis species complex. The Mucorales, Fusarium spp., and Scedosporium spp. may emerge in the setting of voriconazole prophylaxis. The challenges of these emerging pathogens underscore the need for the development of new antifungal agents and strategies.

Background: Our unit adopted the single administration of cefepime as the initial treatment for febrile episodes in neutropenic patients with hematological malignancies. However, recently, cefepime-resistant gram-negative bacteremia, including those with extended-spectrum β-lactamase (ESBL)-producers, was frequently observed in these patients. Therefore, we instituted a rotation of primary antibiotics for febrile neutropenic patients in an attempt to control antibiotic resistance., Methods: This prospective trial was performed from August 2008 through March 2011 at our unit. After a pre-intervention period, in which cefepime was used as the initial agent for febrile neutropenia, 4 primary antibiotics, namely, piperacillin-tazobactam, ciprofloxacin, meropenem, and cefepime, were rotated at 1-month intervals over 20 months. Blood and surveillance cultures were conducted for febrile episodes, in order to assess the etiology, the resistance pattern (particularly to cefepime), and the prognosis., Results: In this trial, 219 patients were registered. A 65.9% reduction in the use of cefepime occurred after the antibiotic rotation. In the surveillance stool cultures, the detection rate of cefepime-resistant gram-negative isolates, of which ESBL-producers were predominant, declined significantly after the intervention (8.5 vs 0.9 episodes per 1000 patient days before and after intervention respectively, P<0.01). Interestingly, ESBL-related bacteremia was not detected after the initiation of the trial (1.7 vs 0.0 episodes per 1000 patient days before and after intervention respectively, P<0.01). Infection-related mortality was comparable between the 2 periods., Conclusions: We implemented a monthly rotation of primary antibiotics for febrile neutropenic patients. An antibiotic heterogeneity strategy, mainly performed as a cycling regimen, would be useful for controlling antimicrobial resistance among patients treated for febrile neutropenia.

We investigated the source of fungi in the lungs of patients with hematological malignancies who had invasive pulmonary fungal infections (IPFI). We also conducted a prospective study to evaluate the efficacy of different mouthwash solutions in preventing IPFI in patients with hematologic malignancies. In order to determine the source of fungi in the lungs of 30 patients with hematologic malignancies who had IPFI, we collected samples from sites with suspected fungal infection and used PCR and sequencing for pathogen identification. For the prospective study, we enrolled 158 patients with hematological malignancies who had IPFI and randomly assigned them to one of three mouthwash groups: 1% nystatin, 2.5% sodium bicarbonate, or normal saline. Fungal staining and incidence of IPFI, oral fungal infection, and intestinal fungal infection were evaluated. We showed that 96.7% of the fungi isolated from the throats and the lungs were identical; 76.9% of the fungi from the lungs and digestive tracts were identical and, 84.6 % of the fungi from the throats and digestive tract were identical. Patients using 1% nystatin had lower incidence of IPFI (1.6%) and fungal enteritis (1.6%) than those using sodium bicarbonate (16.3% and 14.3%) or normal saline (27.7% and 12.8%). All treatments had low incidences of oral fungal infections (0 to 4.3%). Our data showed that fungi originating from mouth and throat cause IPFI. We also showed that use of a prophylactic mouthwash containing 1% nystatin was effective in preventing IPFI in patients with hematological malignancies.

Infectious pathogens have been linked to the genesis of malignancy in a variety of different settings. Initial studies in virology led to the important discovery of key genetic alterations underlying common malignancies, and further, lent support to the notion that malignancy can be promoted by the process of viral infection and cellular transformation. In this review, we summarize a series of hematologic malignancies with derivations from and associations with infectious organisms. Among these are a variety of lymphomas, including Hodgkin's lymphoma (Hodgkin's disease), Burkitt lymphoma, and a host of other non-Hodgkin's lymphomas. Through innovative and ground-breaking studies, some of these malignancies have been directly linked to viral infection, such as the Epstein-Barr virus (EBV), while others have been merely associated with infection through epidemiologic studies and case-reports. Some malignancies have been demonstrated to be caused by viral infection, such as adult T-cell leukemia and lymphoma (ATLL), which is caused by the human T cell lymphotropic virus type I (HTLV-I), in certain endemic area. In the future, additional malignant states may be found to be associated with infectious etiology, which could allow for novel approaches to prevention and treatment.

Invasive fungal disease is associated with increased morbidity and mortality in hematologic malignancy patients and hematopoietic stem cell transplant recipients. Timely recognition and treatment of invasive fungal diseases in these patients are essential and decrease mortality. However, conventional definitive diagnostic methods are difficult and time consuming. While conventional microbiological and histopathological methods are still needed for a definitive diagnosis of invasive fungal disease, new noninvasive diagnostic methods including serologic and molecular biomarkers are now available. These new diagnostic methods facilitate an early diagnosis of invasive fungal disease and allow for utilization of a pre-emptive treatment approach, which may ultimately lead to improved treatment outcomes and reduced toxicity.

Background: Bacterial infections are a major threat to pediatric oncology patients with fever and neutropenia. Current management consists of empiric broad-spectrum antibiotics and prompt medical evaluation. Local bacterial susceptibility rates were published in 2005, and the local protocol (piperacillin and amikacin) was established as an adequate empiric treatment with -100% efficiency against the common pathogens in our pediatric hemato-oncology ward., Aim: To characterize the spectrum of bacteria isolated from blood cultures at the pediatric hemato-oncology ward between 2008- 2010, and to evaluate the current protocol., Methods: A prospective study, conducted in the pediatric hemato-oncologic ward among hospitalized children (2 months - 18 years) with fever and neutropenia. Blood cultures from peripheral blood and central lines were obtained from all patients at admission. Bacterial resistance to various antimicrobial agents was determined., Results: During 2008-2010, 195 admissions (105 children) due to fever and neutropenia were recorded. Approximately 30% of all blood cultures were positive for a pathogen with -50% Gram positive bacteria mostly CONS. The most prevalent Gram negative bacteria were acinetobacter and klebsiella spp. Candida species were isolated from 7% of positive cultures. Susceptibility rates for the current empiric antimicrobial regimen were about 90%. CONS bacteremia rate increased from 4% in 2000-2002 to 29% in 2008-2010 (p < 0.01)., Conclusions: The currently applied empiric antimicrobial protocol is an optimal first line regimen, considering the susceptibility of the most common pathogens. Judicious use of carbapenems for gram negative bacteria and glycopeptides or other novel antimicrobial agents in cases of CONS bacteremia is required.

Hepatic Candida infection (HCI; known as chronic disseminated candidosis or CDC) is a distinct form of disseminated Candida infection with predominant involvement of the liver. Diagnosis of HCI is usually made on clinical suspicion together with multiple lesions in liver on ultrasound (US), CT and/or MRI scan. Fungal elements may not always be visible in liver tissue and mycological culture is frequently negative, making the evidence for proven fungal disease difficult. We studied a novel commercially available low-cost and density-array (LCD) chip technique for a molecular diagnosis of HCI. This is a two-step procedure with PCR amplification after DNA extraction followed by hybridization on a small chip provided by the manufacturer (Fungi 2.1, Chipron GmbH). The analysis of DNA from 45 fungal control strains showed an excellent specificity and sensitivity. The DNA from 11 liver biopsies of patients with haematological malignancies suffering from CDC was analysed on the LCD chip and overall 11 fungal pathogens could be detected in eight liver biopsies, supporting the clinical diagnosis of HCI/CDC. Analysis of liver biopsies from controls was negative for fungal DNA in all samples studied. In conclusion, the novel LCD chip technique examined in our study was able to detect fungal pathogens in liver biopsies from patients with haematological malignancies and suspected HCI/CDC but was negative in control biopsies., (© 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.)

Taurolidine has demonstrated inhibition of biofilm formation in vitro. The aim of this study was to compare the effect of catheter locking with taurolidine vs heparin in biofilm formation in central venous catheters. Forty-eight children with cancer were randomized to catheter locking by heparin (n = 22) or taurolidine (n = 26), respectively. After removal, catheters were examined by standardized scanning electron microscopy to assess quantitative biofilm formation. Biofilm was present if morphologically typical structures and bacterial cells were identified. Quantitative and semi-quantitative cultures were also performed. Biofilm was identified in 23 of 26 catheters from the taurolidine group and 21 of 22 catheters from the heparin group. A positive culture was made of six of the catheters locked with taurolidine and heparin, respectively (p = 0.78). The rate of catheter-related bloodstream infections (CRBSI) was 0.1 per 1000 catheter-days using taurolidine and 0.9 per 1000 catheter-days using heparin (p = 0.03). This randomized trial confirmed that the use of taurolidine as catheter-lock compared with heparin reduced the rate of CRBSIs; this reduction was not related to a reduction in the intraluminal biofilm formation and the rate of bacterial colonization detected by scanning electron microscopy in the two groups., (© 2012 The Authors APMIS © 2012 APMIS.)

The European Organization for Research and Treatment of Cancer and the Mycosis Study Group (EORTC-MSG) radiological definitions of invasive pulmonary aspergillosis (IPA) may lack diagnostic sensitivity. We evaluated applying less restrictive radiological criteria, when supported by specific microbiological findings, to define IPA in acute myeloid leukaemia (AML), lymphoproliferative diseases (LD) and allogeneic stem cell transplant (allo-SCT) patients. Overall, 109 consecutive episodes of proven/probable IPA in 56 AML, 31 LD and 22 allo-SCT patients diagnosed from February 2006 through to January 2011 were considered. IPA was diagnosed with EORTC-MSG criteria (control group, 76 patients) or without prespecified radiological criteria (study group, 33 patients). The latter differed from the former by the inclusion of patients with pulmonary infiltrates not fulfilling the three EORTC-MSG IPA specific findings of dense, well-circumscribed lesions with or without halo sign, air crescent sign or cavity. All the analysed clinical and mycological characteristics, 3-month response to antifungal therapy and 1- and 3-month cumulative survival were comparable in the control and study groups in AML, LD and allo-SCT patients. Seventeen of 33 (51.5%) patients of the study group fulfilled EORTC-MSG radiological criteria at subsequent imaging performed a median of 15 days (range, 6-40 days) after documentation of the pulmonary infection. Our study seems to confirm the possibility of revising the EORTC-MSG criteria by extending the radiological suspicion of IPA to less specific chest computerized tomography scan findings when supported by microbiological evidence of Aspergillus infection in high-risk haematological patients., (© 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.)

This study was aimed to establish the approach of quantitative PCR (q-PCR) for diagnosis of invasive fungal infections (IFI) in patients with hematologic malignancies. Specimens from 40 patients with hematologic malignancies were chosen for q-PCR and galactomannan (GM) test. The 28S rRNA, a real high consensus sequence of fungi, was selected as target gene to design primer and probe. The DNA of fungal species was extracted from serum specimens. The results showed that q-PCR sensitivity, specificity, positive and negative predictive values were 0.89, 0.85, 0.89, 0.85 respectively; GM test sensitivity, specificity, positive and negative predictive values were 0.83, 0.80, 0.88, 0.73 respectively; as combined q-PCR with GM test, these values were 0.94, 0.85, 0.89, 0.92 respectively. It is concluded that the q-PCR assay can be used for early diagnosis for IFI in patients with hematologic malignancies, q-PCR combined with GM test can enhance the diagnosis sensitivity for IFI.

We here investigate the occurrence of fluoride intake-associated alterations in patients with hematologic disease on triazol antifungal medication. Clinical, laboratory, and radiology data of overall 43 patients with hematologic malignancies taking voriconazole (n = 20), posaconazole (n = 8), and itraconazole (n = 4), and a hematologic patient control group (n = 11) are described. Bone pain and radiologic evidence of periostitis were exclusively observed in patients receiving long-term voriconazole. Cessation of treatment led to clinical improvement in all cases. In line with clinical evidence, fluoride serum concentration was elevated in patients receiving voriconazole (median, 156.5 μg/L; interquartile range, 96.8 μg/L; normal < 30 μg/L) but not in the other treatment groups (P < .001 for all comparisons vs voriconazole). We conclude that serum fluoride levels were elevated on average 5-fold above normal levels in hematologic patients receiving voriconazole. Clinically relevant skeletal disease was associated with renal insufficiency and above 10-fold elevated fluoride levels, and was reversible on termination of voriconazole treatment.

For many years Pneumocystis pneumonia was thought to be caused by the reactivation of a latent infection, but several studies have demonstrated that Pneumocystis jirovecii infection can be acquired de novo. On the basis of our results obtained from a patient with recurrent pneumocystosis, we support the hypothesis that recurrent episodes are caused by reinfection.

Background: Immunocompromised patients with hematological malignancies and/or recipients of hematopoietic stem cell transplants are constantly exposed to several fungal, bacterial, and viral respiratory pathogens., Methods: We retrospectively evaluated all patients with invasive pulmonary aspergillosis (IPA) and underlying hematological malignancies for the presence of concurrent, microbiologically documented pulmonary infections during a 5-year period (2005-2010)., Results: We found 126 such patients that frequently had coinfections (49%) with respiratory pathogens other than Aspergillus species, with a higher rate in patients with probable IPA (53%) than in those with proven IPA (29%; P=0.038)., Conclusions: As the majority of patients with IPA in daily practice have probable IPA, often according to only the combination of positivity for serological biomarkers and radiological findings, our data may raise skepticism about both the certainty of IPA diagnosis and the evaluation of response to antifungals in a subset of these patients., (Copyright © 2012. Published by Elsevier Ltd.)

Objectives: Diagnosing invasive pulmonary aspergillosis (IPA) remains a challenge in patients with hematological malignancies. The clinical significance of testing bronchoalveolar lavage (BAL) samples both with polymerase chain reaction (PCR) and Aspergillus galactomannan ELISA (GM) is unclear, and the BAL cutoff for GM has not been clearly evaluated yet., Methods: Using a validated nested PCR assay and a GM ELISA, we prospectively examined BAL samples from 87 hematological patients at high risk of IPA. Of 76 (87%) evaluable patients, 29 patients had proven or probable disease., Results: The receiver operating characteristic (ROC) analysis of GM optical density (OD) cutoff levels yielded a BAL OD of 0.5 to be optimal. We identified 29 probable or proven cases based on this OD. Sensitivity and specificity for BAL GM were 0.79 (95% CI, 0.62-0.9) and 0.96 (95% CI, 0.86-0.99), respectively. For BAL PCR, sensitivity and specificity were 0.59 (95% CI, 0.41-0.75) and 0.87 (95% CI, 0.75-0.94), respectively. Combining BAL GM and PCR for diagnosis showed a sensitivity and specificity rate of 0.55 (95% CI, 0.38-0.72) and 1.0 (95% CI, 0.93-1.0), respectively, if positivity was defined by positive results for both tests. If either positive BAL GM or positive BAL PCR results defined test positivity, the sensitivity was 0.83 (95% CI, 0.65-0.92), and the specificity was 0.83 (95% CI, 0.70-0.91), Conclusions: In terms of optimal sensitivity and specificity, a GM OD cutoff of 0.5 was determined for BAL samples. Positivity for both GM and Aspergillus PCR in BAL makes a pulmonary aspergillosis highly likely., (© 2012 John Wiley & Sons A/S.)

Objective: To study the prevalence and drug resistance of extended-spectrum-β-lactamases (ESBLs)-producing bacteria in blood culture isolated from children with hematological malignancy after chemotherapy., Methods: Blood samples taken from 3264 children with hematological malignancy and severe infection following chemotherapy between 2002 and 2008 were cultured using the Bact/ALTER 3D blood culture system. VITEK 60 automicroscan was used to identify viral species and to conduct drug resistance tests. The results were indentified according to National Committee for Clinical Laboratory Standard guidelines., Results: Fifty-eight strains of Escherichia coli and fifty-one strains of Klebsiella pneumoniae were isolated. Thirty-eight strains of Escherichia coli and nineteen strains of Klebsiella pneumoniae were ESBLs-producing and these ESBLs-producing strains were less susceptible than those that were non-ESBLs-producing to most antibiotics. Both ESBL- and non-ESBL-producing strains were susceptible to imipenem, piperacillin/tazobactam and amikacin., Conclusions: The prevalence of ESBLs-producing bacteria is high in childrn with hematological malignancy and infection following chemotherapy. ESBLs-producing bacteria are resistant to common antibiotics, suggesting that antibiotic treatment based on the result of antimicrobial susceptibility test is necessary in these children.

Acinetobacter infections are fast emerging as a major nosocomial threat across the globe. With a predilection for blood stream infections in critically ill, immunocompromised patients, their presence is now being felt in febrile neutropenics with underlying malignancies and marrow failure. We aimed through this study to ascertain the current circulating pathogens and levels of antimicrobial resistance in blood stream infections in febrile neutropenia patients, with specific emphasis on elucidating acinetobacter and pseudomonas infections. Clinical and laboratory records of all consecutive neutropenic patients with underlying haematological malignancies and marrow failure, admitted to our AIIMS, New Delhi from April 2009 to March 2010 were analysed for blood stream infections, pathogen profiles and antimicrobial resistance. All clinical and microbiological variables were statistically analysed to elucidate potential risk factors, infection patterns and drug resistance trends. Of the 1,165 blood cultures investigated, 105 episodes of blood stream infections were microbiologically confirmed in febrile neutropenia patients. Gram-negative infections (n = 78, 72.9%) dominated with acinetobacter spp (n = 20, 18.7%) emerging as the most common pathogen. Acinetobacter and pseudomonas together were responsible for 42.9% of all blood stream infections. Both acinetobacter and pseudomonas displayed very high resistance to all five major classes of antibiotics, including multidrug resistance (90.0% and 76.9%) and ESBL production (90.0% and 84.6%), respectively. Comparison of infection patterns and resistance levels with reports over the past decade from this centre and other centres across the globe, revealed a striking increase in multidrug resistant acinetobacter blood stream infections in these patients. Multidrug resistant acinetobacter Infections are a fast emerging threat in febrile neutropenia patients and at this centre in general. Similar early trends from some Indian centres and neighbouring developing countries suggest grave concern. These emerging circulating pathogens and drug resistance patterns demand to systematically evaluate antibiotic and hospital infection policies and to sensitise all clinicians to curb this pathogen capable of rapid nosocomial spread.

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in haematopoietic stem cell transplant (HCT) recipients and patients with haematological malignancies. Early treatment initiation is vital for improving survival, but is hampered by difficulties in timely diagnosis. Prophylaxis with a broad-spectrum antifungal, such as voriconazole, has the potential to decrease the incidence of IFI in haematology patients. Based on a growing body of data, voriconazole appears to be effective for the primary and secondary prevention of IFIs in HCT recipients, with generally good tolerability., (© 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

The aim of this study was to investigate the clinical situation of invasive fungal infections in patients with hematological malignancies, and discuss the susceptible factors and precautions. 541 patients with hematological malignancies from 2008 Jan to 2011 Dec in hospital 307 of Chinese PLA were statistically retrospectively analyzed in term of clinical manifestation, image examination, culture results of secretions, therapy and so on. The results showed that 63 out of 541 patients got invasive fungal infections. The respiratory tract and intestinal tract were the most common infection sites (62.34 and 19.48, respectively); Candida albicans (66.67) and Candida glabrata (12.82) were the most common pathogens. It is concluded that the main risk factors are as follows: primary diseases, chemotherapy, glucocorticoid, leukopenia after chemotherapy, applications of broad-spectrum antibiotics and aging. It is suggested that a stratification of risk factors is helpful in preventing and treating invasive fungal infections.

Invasive pulmonary aspergillosis (IPA) is a leading cause of morbidity and mortality in haematological malignancy patients and hematopoietic stem cell transplant recipients(1). Detection of IPA represents a formidable diagnostic challenge and, in the absence of a 'gold standard', relies on a combination of clinical data and microbiology and histopathology where feasible. Diagnosis of IPA must conform to the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycology Study Group (EORTC/MSG) consensus defining "proven", "probable", and "possible" invasive fungal diseases(2). Currently, no nucleic acid-based tests have been externally validated for IPA detection and so polymerase chain reaction (PCR) is not included in current EORTC/MSG diagnostic criteria. Identification of Aspergillus in histological sections is problematic because of similarities in hyphal morphologies with other invasive fungal pathogens(3), and proven identification requires isolation of the etiologic agent in pure culture. Culture-based approaches rely on the availability of biopsy samples, but these are not always accessible in sick patients, and do not always yield viable propagules for culture when obtained. An important feature in the pathogenesis of Aspergillus is angio-invasion, a trait that provides opportunities to track the fungus immunologically using tests that detect characteristic antigenic signatures molecules in serum and bronchoalveolar lavage (BAL) fluids. This has led to the development of the Platelia enzyme immunoassay (GM-EIA) that detects Aspergillus galactomannan and a 'pan-fungal' assay (Fungitell test) that detects the conserved fungal cell wall component (1 →3)-β-D-glucan, but not in the mucorales that lack this component in their cell walls(1,4). Issues surrounding the accuracy of these tests(1,4-6) has led to the recent development of next-generation monoclonal antibody (MAb)-based assays that detect surrogate markers of infection(1,5). Thornton(5) recently described the generation of an Aspergillus-specific MAb (JF5) using hybridoma technology and its use to develop an immuno-chromatographic lateral-flow device (LFD) for the point-of-care (POC) diagnosis of IPA. A major advantage of the LFD is its ability to detect activity since MAb JF5 binds to an extracellular glycoprotein antigen that is secreted during active growth of the fungus only(5). This is an important consideration when using fluids such as lung BAL for diagnosing IPA since Aspergillus spores are a common component of inhaled air. The utility of the device in diagnosing IPA has been demonstrated using an animal model of infection, where the LFD displayed improved sensitivity and specificity compared to the Platelia GM and Fungitell (1 → 3)-β-D-glucan assays(7). Here, we present a simple LFD procedure to detect Aspergillus antigen in human serum and BAL fluids. Its speed and accuracy provides a novel adjunct point-of-care test for diagnosis of IPA in haematological malignancy patients.

Objective: To evaluate the clinical efficacy and safety of intravenous panipenem-betamipron in the treatment of hematological malignancies infections., Methods: From October 2009 to December 2010, a total of 286 hematological malignancy infection patients were recruited into this open-label, perspective and multicenter clinical trial to receive an intravenous daily dose panipenem-betamipron of 0.5 g every 6 or 8 hours for 7 - 14 days. All clinical change and adverse reactions were recorded., Results: The total effective rate of panipenem-betamipron in the treatment of hematological malignancy infections was 86.6% (206/238). The effective rates of septicemia, pulmonary infections, urinary tract infections, digestive canal infections, oral infections and other infections were 68.2% (15/22), 89.3% (100/112), 77.8% (14/18), 100% (22/22), 83.3% (10/12) and 86.5% (45/52) respectively. The overall bacterial eradication rate was 85.07% (57/67) and the rate of adverse reactions 5.9% (17/286)., Conclusion: Panipenem-betamipron is both safe and effective in the treatment of hematological malignancy infections.

Background: Mucormycosis is a deadly invasive fungal infection whose characteristics are only partially understood., Methods: Data on mucormycosis obtained in France between 2005 and 2007 from 2 notification systems were merged. The 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group definition criteria were applied and risk factors for death were analyzed by hazard ratios (HRs) calculated from the Cox proportional hazards regression model., Results: A total of 101 cases (60 proven, 41 probable), mostly in men (58%) >50 years (mean age, 50.7 ± 19.9) were recorded. Hematological malignancies represented 50% (median time for occurrence, 8.8 months after disease onset), diabetes 23%, and trauma 18% of cases. Sites of infection were lungs (28%; 79% in hematology patients), rhinocerebral (25%; 64% in diabetic patients), skin (20%), and disseminated (18%). Median time between first symptoms and diagnosis was 2 weeks. The main fungal species were Rhizopus oryzae (32%) and Lichtheimia species (29%). In cases where the causative species was identified, R. oryzae was present in 85% of rhinocerebral forms compared with only 17% of nonrhinocerebral forms (P < .001). Treatment consisted of surgery in 59% and antifungals in 87% of cases (liposomal amphotericin B in 61%). Ninety-day survival was 56%; it was reduced in cases of dissemination compared with rhinocerebral (HR, 5.38 [2.0-14.1]; P < .001), pulmonary (HR, 2.2 [1.0-4.7]; P = .04), or skin localization (HR, 5.73 [1.9-17.5]; P = .002); survival was reduced in cases of hematological malignancies compared with diabetes mellitus (HR, 2.3 [1.0-5.2]; P < .05) or trauma (HR, 6.9 [1.6-28.6], P = .008) and if ≥2 underlying conditions (HR, 5.9 [1.8-19.0]; P = .004). Mucormycosis localization remained the only independent factor associated with survival., Conclusions: This 3-year study performed in one country shows the diverse clinical presentation of mucormycosis with a high prevalence of primary skin infection following trauma and a prognosis significantly influenced by localization.

Mucormycosis is an emerging angioinvasive infection caused by the ubiquitous filamentous fungi of the Mucorales order of the class of Zygomycetes. Mucormycosis has emerged as the third most common invasive mycosis in order of importance after candidiasis and aspergillosis in patients with hematological and allogeneic stem cell transplantation. Mucormycosis also remains a threat in patients with diabetes mellitus in the Western world. Furthermore, this disease is increasingly recognized in recently developed countries, such as India, mainly in patients with uncontrolled diabetes or trauma. Epidemiological data on this type of mycosis are scant. Therefore, our ability to determine the burden of disease is limited. Based on anatomic localization, mucormycosis can be classified as one of 6 forms: (1) rhinocerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, (5) disseminated, and (6) uncommon presentations. The underlying conditions can influence clinical presentation and outcome. This review describes the emerging epidemiology and the clinical manifestations of mucormycosis.

This study was performed to evaluate the impact of extended-spectrum β-lactamase (ESBL)-producing bacteremia on outcome in patients with hematologic malignancy. We collected and analyzed data on 156 hematologic malignancy patients with Escherichia coli or Klebsiella pneumoniae bacteremia from the database of nationwide surveillance studies for bacteremia. Thirty-seven of the 156 patients (23.7%) harbored ESBL-producing bacteremia. No significant differences in underlying diseases were found in either group. The multivariate analysis showed that significant factors associated with ESBL-producing bacteremia were ICU care (OR = 7.03, 95% CI = 1.79-27.6) and nosocomial acquisition (OR = 5.66, 95% CI = 1.60-20.23). There was an association between prior receipt of cephalosporins and ESBL-producing bacteremia, although this association was not statistically significant (OR = 2.27, 95% CI = 0.99-5.23). The overall 30-day mortality rate of the study population was 20.4% (29/142), and the 30-day mortality rate for the ESBL group was significantly higher than that for the non-ESBL group (44.8% vs. 14.2%, P < 0.001). Multivariate analysis showed that ESBL-producing bacteremia was the most important risk factor associated with 30-day mortality (OR, 5.64; 95% CI, 1.91-16.67), along with ICU care (OR = 4.35, 95% CI = 1.16-16.26) and higher Pitt bacteremia score (per 1-point increment) (OR = 1.50, 95% CI = 1.18-1.92). In conclusion, ESBL-producing bacteremia was the most important risk factor associated with 30-day mortality in patients with hematologic malignancy, along with ICU care and higher Pitt bacteremia score. Our data suggest that determining the optimal empiric antimicrobial therapy in patients with hematologic malignancy is now becoming a challenge for clinicians in the era of multidrug-resistant Gram-negative bacilli.

Background: Invasive fungal infection (IFI) is a common and fatal complication in neutropenic patients with hematological malignancy. Empirical antifungal therapy is widely used in practice due to the difficulty of pathogens determination and illness of the hosts. The aim of this study was to evaluate the efficacy and safety of itraconazole as empirical antifungal therapy for persistent fever in neutropenic patients with hematologic malignancies., Methods: Two hundred and seventy-four patients with hematologic malignancies who had suspected fungal infections were enrolled in 18 centers across China between April 2008 and April 2009. Empirical antifungal therapy with intravenous itraconazole 200 mg twice daily was given for the first two days, followed by 200 mg once daily for the next 12 days. Oral itraconazole solution was sequential for follow-up therapy if necessary. Five composite end points were evaluated for the response, which was more restrictive and adopted for the first time in such study in China., Results: The intent-to-treat analysis included data from 274 patients (full analysis set, FAS), of whom 248 were included as the per-protocol population (PPS). As the composite end point of five indices was concerned, the overall response rate was 43.4%. Seperately, defervescence was achieved in 90% of patients in which 55.5% occured during neutropenia. The mean time to defervescence was 2.71 days. Absence of breakthrough IFI during drug administration or within the first 7 days after study completion was observed in 71.5% of patients. Fifty-five point five percent patients with IFI at baseline was successfully treated. Ninety point five percent patients survived for at least 7 days after completing the study. PPS analysis revealed that the duration of neutropenia ≥ 10 days was a statistically significant negative predictor for the response. The withdrawal rate due to drug-related toxicity or lack of efficacy was 11.0%. The incidence of adverse events was 22.6%, in which 11.6% was study drug related. The most frequent adverse events were mild to moderate liver toxicity., Conclusion: Itraconazole shows desirable efficacy and safety as empirical antifungal therapy for febrile neutropenic patients with hematologic malignancies.

Background: The study objectives were: 1) to report on invasive aspergillosis patients in a hematology department; and 2) to estimate its incidence according to the hematologic diagnosis., Design and Methods: A prospective survey of invasive aspergillosis cases was undertaken between January 2004 and December 2009 in the hematology department of a university hospital. Meetings with clinicians, mycologists and infection control practitioners were organized monthly to confirm suspected aspergillosis cases. Demographic characteristics, clinical and complementary examination results were recorded prospectively. Information on hospitalization was extracted from administrative databases. Invasive aspergillosis diagnosis followed the European Organization for Research and Treatment of Cancer criteria, and proven and probable IA cases were retained. A descriptive analysis was conducted with temporal trends of invasive aspergillosis incidence assessed by adjusted Poisson regression., Results: Overall, 4,073 hospitalized patients (78,360 patient-days) were included in the study. In total, 127 (3.1%) patients presented invasive aspergillosis. The overall incidence was 1.6 per 1,000 patient-days (95% confidence interval: 1.4, 1.9) with a decrease of 16% per year (-1%, -28%). The incidence was 1.9 per 1,000 patient-days (1.5, 2.3) in acute myeloid leukemia patients with a decrease of 20% per year (-6%, -36%). Serum Aspergillus antigen was detected in 89 (71%) patients; 29 (23%) had positive cultures, and 118 (93%), abnormal lung CT scans. One-month mortality was 13%; 3-month mortality was 42%. Mortality tended to decrease between 2004 and 2009., Conclusions: Invasive aspergillosis incidence and mortality declined between 2004 and 2009. Knowledge of invasive aspergillosis characteristics and its clinical course should help to improve the management of these patients with severe disease.

Infections due to caspofungin-resistant Candida isolates in patients exposed to caspofungin therapy are increasing. We report here a nested case-control study which aimed at identifying factors associated with bloodstream infections caused by Candida spp. having reduced susceptibility to caspofungin (CRSC) in adults suffering from hematological malignancies. In univariate and multivariate analyses, infections with CRSC were associated with caspofungin exposure in the previous 30 days (odds ratio [OR] = 5.25; 95% confidence interval [95% CI], 1.68-16.35) and with an age of ≤ 65 years (OR = 3.27; 95% CI, 1.26-8.50).

Mortality due to mucormycosis is high. We assessed clinical characteristics and mortality among stem cell transplant and hematologic malignancy patients diagnosed with mucormycosis from 2001 to 2009. Thirty patients were diagnosed with probable or proven mucormycosis during the study. Twenty-six were diagnosed premortem, and most were treated with liposomal amphotericin B single-agent antifungal therapy initially. While the initial antifungal and surgical treatment approach remained stable throughout the study period, 6-week mortality significantly declined over time (67% in 2001 to 2003 versus 45% in 2004 to 2006 versus 20% in 2007 to 2009 [P = 0.04]), as did 12-week mortality (78% in 2001 to 2003 versus 55% in 2004 to 2006 versus 20% in 2007 to 2009 [P = 0.01]).

This study was aimed to analyze the clinical features, anti-fungal therapeutic efficacy and safety in hematological malignancy patients with invasive aspergillosis (IA) after hematopoietic stem cell transplantation (HSCT) or chemotherapy. The patients with hematological malignancies received chemotherapy or HSCT were analyzed retrospectively, then the clinical characteristics and diagnosis were analyzed according to the diagnostic criteria for IA. The efficacy and safety of anti- Aspergillus therapy, and the factors influencing therapeutic response were evaluated. The results showed that out of 30 cases with IA, 2 were proven, 19 were probable, 9 were possible, and 19 were diagnosed after HSCT, most in the late period after-HSCT (> 40 d). 8 cases received fluconazol only, 6 received caspofungin only, 7 received combined therapy. The efficacy and time interval from the first day of treatment to successful response (TTR) were 87.5%, 50% and 85.7% and 38, 20 and 36 days, respectively. Combined therapy is better than single drug treatment (p < 0.05) while the TTR was not significantly different between them. The factors influencing the therapeutic efficacy were as follows: age, HSCT, GVHD and CMV, previous IFI and so on (p < 0.05). All the anti- Aspergillus medicines resulted in some injury of hepatic and renal function. However, there were no significant difference between the drugs or between combination and single drug therapy (p > 0.05). It is concluded that IA is also the major and severe complication in the patients with hematological malignancies or received HSCT. Combined therapy for anti- aspergillus is better than single drug in efficacy and safety, without increasing the adverse drug reactions for hepatic and renal function. The efficacy of anti- aspergillus may be related to age, HSCT, GVHD and CMV, previous IFI and so on.

Invasive fungal diseases continue to be an important cause of morbidity and mortality in immunosuppressed patients. This is of particular interest, since the progress we made in the treatment of underlying malignancies has led to an increase of the number of persons 'at high risk'. During the last few years, several changes in clinical practice in hematology (new immunosuppressants, hematopoietic stem cell transplants) have influenced the epidemiology of invasive fungal diseases; in particular, cases due to some uncommon etiologic agents are being increasingly reported, making it even more urgent to reconsider differential diagnoses in high-risk patients. A better understanding of epidemiology, risk factors and prognosis appears to be crucial to analyze prevention and diagnostic strategies, as well as to guarantee an early and adequate treatment.

Pseudomonas is a clinically significant and opportunist pathogen, usually associated in causing high mortality nosocomial infections. The aim of this study was to determine the risk factors associated with septic shock in patients diagnosed with hematologic malignancies and Pseudomonas infections. A total of 80 Pseudomonas isolates (77 Pseudomonas aeruginosa) were collected from 66 patients aged 2-64 years: 52 with acute leukemia (79%), 7 with lymphoma (10.5%), and 7 with other hematologic disorders (10.5%), between 2001 and 2009. The median age of the patients was 30 years. Isolates were collected mostly from bloodstreams (45%) and skin lesions (31.5%). The median time for microbiologic documentation was 8 days (range 0-35 days) from onset of neutropenia. At least 11 patients (16.6%) had recurrent (≥2) infections. The clinical symptoms observed were skin lesions (34%), diarrhea (20%), isolated fever (18%), and respiratory symptoms (14%). The isolates tested were found resistant to piperacillin/tazobactam (43%), ceftazidime (31%), imipenem-cilastatin (26%), ciprofloxacin (25%), and amikacin (26%). Septic shock occurred in 16.2% of episodes (13/80). Crude mortality due to septic shock occurred in 19.6% of patients (13/66). The median time for response to antibiotic therapy in the remaining 80.4% of patients (53/66) was 2.5 days. Univariate analysis revealed that factors associated with septic shock were: fever for ≥3 days in patients on antibiotic therapy (P = 0.019), serum lactate >5 mmol (P = 0.05), hemoglobin level <50 g/l (P = 0.042), hypoproteinemia <50 g/l (P = 0.01), procalcitonin >10 ng/ml (P = 0.031), and hypophosphatemia (P = 0.001). Multivariate analysis revealed that hypophosphatemia (P = 0.018), hypoproteinemia (P = 0.028), and high serum lactate (P = 0.012) are significant factors, independently associated with increased risk of septic shock in patients with hematologic malignancies and Pseudomonas infections.

We present two patients with acute myelogenous leukemia who developed palatal mucormycosis, as well as a review of 15 well described reported cases of the same condition in patients who had hematologic malignancy and had undergone hematopoietic stem cell transplantation. Early diagnosis of palatal mucormycosis requires high suspicion of the disease along with a thorough oral examination. Mucormycosis is a devastating disease with a high mortality rate, thereby stressing the importance for early appropriate antifungal therapy in immunocompromised patients with palatal lesions while awaiting the results of histopathology and cultures.

The purpose of this study was to assess the risk factors for, and the clinical relevance of, faecal carriage by extended-spectrum β-lactamase producing Escherichia coli (ESBL-EC) in neutropenic cancer patients (NCP). An observational prospective multicentre cohort study was conducted over 2 years at two teaching hospitals. Patients with acute leukaemia or undergoing stem cell transplantation were included during neutropenia episodes. Rectal swabs were obtained at hospital admission and weekly thereafter until discharge or death. ESBL-EC colonized episodes were compared with non-colonized episodes. ESBL-EC strains were studied by PCR and isoelectric focusing, and molecular typing was performed by pulsed field gel electrophoresis (PFGE). Among 217 episodes of neutropenia, the prevalence of ESBL-EC faecal carriage was 29% (14% at hospital admission). Multivariate analysis identified previous antibiotics as the only independent risk factor for ESBL-EC faecal colonization (OR 5.38; 95% CI 2.79-10.39). Analysis of ESBL-EC isolates revealed a polyclonal distribution with CTX-M predominance (81.3%). E. coli bacteraemia was mainly caused by non-ESBL producing strains and its rate was similar in both groups (13% vs. 11%). We found no association between ESBL-EC carriage and an increased risk of ESBL-EC bacteremia or a negative influence on other clinical outcomes, including length of hospitalisation, early and overall mortality rates. ESBL-EC faecal colonization is frequent in NCP but difficult to identify by epidemiological or clinical features on presentation. Prior antibiotic therapy is the major associated risk factor. In this setting colonization does not appear to have a significant clinical relevance. Thus, routine testing for ESBL-EC faecal carriage does not seem to be beneficial.

Invasive fungal infections are a major cause of morbidity and mortality in the expanding immunocompromised population. Among these infections, the incidence of invasive aspergillosis (IA) and its financial burden have increased significantly in recent years with the parallel increase in the number of immunocompromised pediatric patients. IA is almost exclusively seen in critically ill patients who are severely immunocompromised, with underlying illness or undergoing aggressive treatment regimens. Patients with hematological malignancies and/or transplant recipients have the highest risk for developing IA infection. Diagnosis of IA is often delayed owing to a lack of noninvasive gold-standard diagnostic techniques that can be readily performed. Early treatment before the invasion and dissemination of aspergillosis to adjacent tissues and/or organs offers a higher survival chance for the patient. This article focuses on recent findings of IA epidemiology, diagnosis and treatment in pediatric patients.

Invasive aspergillosis (IA) is a major cause of mortality in patients with hematological malignancies, due largely to the inability of traditional culture and biopsy methods to make an early or accurate diagnosis. Diagnostic accuracy studies suggest that Aspergillus galactomannan (GM) enzyme immunoassay (ELISA) and Aspergillus PCR-based methods may overcome these limitations, but their impact on patient outcomes should be evaluated in a diagnostic randomized controlled trial (D-RCT). This article describes the methodology of a D-RCT which compares a new pre-emptive strategy (GM-ELISA- and Aspergillus PCR-driven antifungal therapy) with the standard fever-driven empiric antifungal treatment strategy. Issues including primary end-point and patient selection, duration of screening, choice of tests for the pre-emptive strategy, antifungal prophylaxis and bias control, which were considered in the design of the trial, are discussed. We suggest that the template presented herein is considered by researchers when evaluating the utility of new diagnostic tests (ClinicalTrials.gov number, NCT00163722).

Background: The aim of our study was to analyze the spectrum and characteristic of invasive candidiasis in selected haematological departments in the Czech and Slovak Republics, and to compare minimum inhibitory concentrations (MIC) of some antifungal agents for isolates obtained., Material and Methods: Between 1 March 2009 and 31 October 2010, Candida strains from clinically important material obtained from patients with haematological malignancies were collected. Each isolate was biochemically identified and tested for in vitro susceptibility to three known echinocandins and amphotericin B and selected azoles using the E-test. Relevant clinical data were collected., Results: The study included 63 isolates from 61 patients. The most frequently isolated species were C. albicans and C. glabrata (28 % and 19 %, respectively). However, after exclusion of isolates from bronchoalveolar lavage fluid, the percentage changed in favour of C. albicans and C. parapsilosis (25 % and 17 respectively). The MIC data showed a high susceptibility of yeasts to echinocandins and amphotericin B. Ten (16 %) strains were cross-resistant to azoles (mostly C. glabrata)., Conclusion: Invasive candidiasis is not frequent infection complication in patients with haematological malignancies in the Czech Republic and Slovakia. Moreover, the spectrum of pathogens was similar to that described in recent international studies. However, identification of susceptible and resistant strains according to MIC could be beneficial for choice of antifungal treatment.

Invasive aspergillosis (IA) is a major threat to the successful outcome of hematopoietic stem cell transplantation (HSCT), although individual risk varies considerably. Recent evidence has established a pivotal role for a danger sensing mechanism implicating the S100B/receptor for advanced glycation end products (RAGE) axis in antifungal immunity. The association of selected genetic variants in the S100B/RAGE axis with susceptibility to IA was investigated in 223 consecutive patients undergoing HSCT. Furthermore, studies addressing the functional consequences of these variants were performed. Susceptibility to IA was significantly associated with two distinct polymorphisms in RAGE (-374T/A) and S100B (+427C/T) genes, the relative contribution of each depended on their presence in both transplantation counterparts [patient SNP(RAGE), adjusted hazard ratio (HR), 1.97; P = 0.042 and donor SNP(RAGE), HR, 2.03; P = 0.047] or in donors (SNP(S100B), HR, 3.15; P = 7.8e-(4)) only, respectively. Functional assays demonstrated a gain-of-function phenotype of both variants, as shown by the enhanced expression of inflammatory cytokines in RAGE polymorphic cells and increased S100B secretion in vitro and in vivo in the presence of the S100B polymorphism. These findings point to a relevant role of the danger sensing signaling in human antifungal immunity and highlight a possible contribution of a genetically-determined hyperfunction of the S100B/RAGE axis to susceptibility to IA in the HSCT setting.

Background: The aim of this study was to investigate the epidemiology of oral yeast colonization and infection amongst cancer patients., Methods: Patients with solid tumor, head-neck cancer or hematological malignancy were recruited into the study. Demographic data on age, gender, type of cancer, preceding treatment with antibiotics, anti-fungal agents, chemotherapy, radiation or surgery and presence of dentures were recorded on admission. Oral examination and microbial swabs were obtained and yeast culture, identification and antifungal susceptibility performed., Results: Oral yeast colonization was prevalent in 56.8% (227/400) of all cancer patients and 18.9% (43/227) of those had clinical and microbiological evidence of infection. The incidence of oral candidiasis in yeast colonized patients was highest in head neck cancer (29.2%) followed by hematological malignancies (20.5%) and solid tumor (17%) patients. Age and dentures were identified as independent risk factors associated with yeast carriage. Candida albicans was the dominant (74%) species (497.5 per 1000 cancer admissions) followed by C. glabrata (11.5%), C. tropicalis (2.6%), C. krusei (2.6%) and C. parapsilosis (1.9%). The overall resistance to azoles was 28.2% (75/266). Resistance to specific drugs was seen for fluconazole (4.5%), itraconazole (11.7%), ketoconazole (11.3%), voriconazole (0.75%) and caspofungin (41.1%) but none to amphotericin B or nystatin., Conclusions: The highest incidence of oral candidiasis amongst cancer patients was seen in head neck cancers. The majority of infections were caused by C. albicans but almost one third of patients harbored non-C. albicans strains such as C. glabrata which were often more resistant to anti-fungal agents., (© 2010 John Wiley & Sons A/S.)

Background: Invasive aspergillosis (IA) continues to be a leading cause of morbidity and mortality in hematologic malignancy (HM) patients. We evaluated the prognostic factors for IA in HM patients., Methods: In this retrospective study, we included all HM patients diagnosed with proven or probable IA between June 1993 and June 2008., Results: A total of 449 HM patients were analyzed, the majority of which (75%) had underlying leukemia. Multivariate logistic regression analysis showed that neutropenia for more than two weeks during IA, steroid use, and intensive care admission were independently associated with failure to respond to antifungal therapy, as well as increased IA-attributable mortality (all p-values < .01). Antifungal therapy with an antimold azole-containing regimen (voriconazole or posaconazole) was also independently associated with improved response to treatment, as well as decreased IA-attributable mortality (all p-values < .0001). Survival analysis showed that primary or salvage therapy with a regimen that contained antimold azoles was significantly associated with improved survival (p < .001)., Conclusions: In HM patients, persistent neutropenia and the need for intensive care are associated with failure to respond to antifungal therapy. Use of novel antimold azoles, either as primary or salvage therapy, improves the overall outcome and IA-attributable death of HM patients with IA.

Objective: To evaluate the diagnostic value of serum galactomannan antigen (GM) and (1→3)-β-D-glucan antigen (BG) assay in invasive fungal infections (IFI) in the patients with hematologic malignancies and the role in monitoring therapeutic response., Methods: Fifty one patients with hematological malignancies met the criteria for inclusion: (1) body temperature above 38°C for 48 hours, (2) failure to respond to broad-spectrum antibiotic treatment, or (3) temperature rose again after the responded drop. Blood samples were collected twice at the first week, then once a week in at least four weeks. The double antibody sandwich enzyme-linked immunosorbent assay (ELISA) and colorimetric assay were used for detecting GM and BG. The positive GM test is defined as two consecutive tests at different time GM value > 0.5 or > 0.8 and the positive G test is defined as BG value > 80 pg/ml. The patients were assigned into four groups as proven, probable, possible, and non-fungal infection respectively, and 21 normal volunteers were as controls., Results: Two hundred and forty serum samples were collected from 51 patients including 2 of proven IFI, 26 probable IFI, 17 possible IFI and 6 non-fungal infection. The true-positive group including the proven and probable groups, and true negative group was the non-fungal infection group. GM tests were positive in 21 of 28 cases in true positive group, and only one of 6 cases in non-fungal infection. The sensitivity, specificity, positive predictive value and negative predictive value were 75%, 83.3%, 95.5% and 41.7%, respectively. G tests were positive in all 28 cases of the true positive group, and 4 in 6 non-fungal infection cases. The sensitivity, specificity, positive predictive value and negative predictive value were 100%, 33.3%, 87.5% and 100%, respectively. G test is more sensitive than GM test (P = 0.015), but there was no significant difference in specificity of the two tests (P = 0.242). In 19 of 21 patients with GM test positive, anti-fungal treatment was effective, and GM value gradually decreased to negative, two invalid patients were persistent with GM test positive. After two weeks treatment, the average GM value was significantly lower in the effective group than in the ineffective group (P < 0.05). BG values in the responded patients showed a gradual decline similar to that of GM values, but not to negative. The changes of BG value in ineffective group varied with a trend upward. The changes in BG value had no relation with treatment effectiveness., Conclusions: Serum GM and BG antigens detection provides strong evidence for early diagnosis of IFI. Combination of GM and G tests can improve the diagnostic specificity and reduce the false positive GM test seems superior to G test for monitoring GM and BG values during treatment.