Steffen Engelhart

Itraconazole Prevents Invasive Fungal Infections in Neutropenic Patients Treated for Hematologic Malignancies: Evidence From a Meta-Analysis of 3,597 Patients

PURPOSE Efficacy of antifungal prophylaxis has not yet been convincingly proven in numerous trials of various antifungals. New evidence and the anti-Aspergillus efficacy of itraconazole prompted a new look at the data for the prevention of invasive fungal infections. PATIENTS AND METHODS Randomized, controlled studies with itraconazole for antifungal prophylaxis in neutropenic patients with hematologic malignancies were identified from electronic databases and hand searching. RESULTS Thirteen randomized trials included 3,597 patients who were assessable for invasive fungal infections. Itraconazole reduced the incidence of invasive fungal infection (mean relative risk reduction, 40% +/- 13%; P =.002), the incidence of invasive yeast infections (mean, 53% +/- 19%; P =.004) and the mortality from invasive fungal infections (mean, 35% +/- 17%; P =.04) significantly. The incidence of invasive Aspergillus infections was only reduced in trials using the itraconazole cyclodextrine solution (mean, 48% +/- 21%; P =.02) and not itraconazole capsules (mean, 75% +/- 73% increase; P =.3). The overall mortality was not changed. Adverse effects were rare, hypokalemia was noted in three studies, and a higher rate of drug discontinuation was found in trials that compared itraconazole cyclodextrine solution to a control without cyclodextrine. The effect of prophylaxis was clearly associated with a higher bioavailable dose of itraconazole. CONCLUSION Antifungal prophylaxis with itraconazole effectively prevents proven invasive fungal infections and-shown for the first time for antifungal prophylaxis-reduces mortality from these infections and the rate of invasive Aspergillus infections in neutropenic patients with hematologic malignancies. Adequate doses of the oral cyclodextrine solution (at least 400 mg/d) or i.v. formulations (200 mg/d) of itraconazole are necessary for these effects.

Occurrence of Toxigenic Aspergillus versicolor Isolates and Sterigmatocystin in Carpet Dust from Damp Indoor Environments

ABSTRACT Over the past decade, there has been growing concern regarding the role of toxigenic fungi in damp indoor environments; however, there is still a lack of field investigations on exposure to mycotoxins. The goal of our pilot study was to quantify the proportion of toxigenic Aspergillus versicolor isolates in native carpet dust from damp dwellings with mold problems and to determine whether sterigmatocystin can be detected in this matrix. Carpet dust samples (n = 11) contained from <2.5 × 101 to 3.6 × 105 (median, 3.1 × 104) A. versicolor CFU/g of dust, and the median proportion of A. versicolor from total culturable fungi was 18%. Based on thin-layer chromatography detection of sterigmatocystin, 49 of 50 A. versicolor isolates (98%) were found to be toxigenic in vitro. By using high-performance liquid chromatography-electrospray ionization tandem mass spectrometry, sterigmatocystin could be detected in low concentrations (2 to 4 ng/g of dust) in 2 of 11 native carpet dust samples. From this preliminary study, we conclude that most strains of A. versicolor isolated from carpet dust are able to produce sterigmatocystin in vitro and that sterigmatocystin may occasionally occur in carpet dust from damp indoor environments. Further research and systematic field investigation are needed to confirm our results and to provide an understanding of the health implications of mycotoxins in indoor environments.

Therapeutic vaccination against metastatic renal cell carcinoma by autologous dendritic cells: preclinical results and outcome of a first clinical phase I/II trial

Abstract. In this study we have presented in vitro data and results of a preliminary clinical trial using dendritic cells (DC) in patients with progressive metastatic renal cell carcinoma. DC precursor cells were obtained from peripheral blood mononuclear cells (PBMC). DC were pulsed with autologous tumor cell lysate if available. In total, 15 patients were treated with a median of 3.95×106 DC administered and ultrasound-guided into a lymph node or into adjacent tissue. Seven patients remained with progressive disease (PD), 7 patients showed stable disease (SD), and one patient displayed a partial response (PR). Most interestingly, the patient who was treated with the highest number of DC (14.4×106 DC/vaccine) displayed a PR. Delayed-type hypersensitivity (DTH) reaction using autologous tumor lysate was positive in 3 out of 13 patients, including the patient with PR. Two out of 3 patients receiving additional treatment with keyhole limpet hemocyanin (KLH) showed reactivity to KLH after vaccination. CD3+CD4+ and CD3+CD28+ cells as well as the proliferation rate of peripheral blood lymphocytes (PBL) increased significantly in the blood of patients during therapy. In conclusion, our observations confirm the capability of tumor-lysate pulsed autologous DC vaccines to stimulate an immune response in patients with metastatic renal cell carcinoma even in the presence of a large tumor burden. The lack of adverse effects together with immunologic effects support further investigation of this novel therapeutic approach. Further studies are necessary to demonstrate clinical effectiveness in cancer patients, in particular in patients with less advanced disease.

Norovirus outbreak in a pediatric oncology unit

Objective. Norovirus (NV) is an etiologic agent of outstanding importance that can cause severe epidemic gastroenteritis in day-care centers, schools, nursing homes, and hospitals. Therefore NV requires foremost attention as a pathogen responsible for epidemics of gastroenteritis in immunocompromised inpatients. In this study, a NV outbreak in a pediatric oncology unit is described and the consequences for this high-risk population are discussed. Material and methods. Stool and vomitus samples from 11 patients were tested for NV and other relevant viruses during the outbreak by reverse transcriptase-polymerase chain reaction (RT-PCR) and/or enzyme-linked immunosorbent assay (ELISA) (whenever an appropriate ELISA was available). Norwalk virus PCR amplifications were sequenced and phylogenetic analysis was performed.Results. The index patient and the chain of infection were identified. Follow-up investigation surprisingly demonstrated viral shedding for a maximum of 140 days (median 23 days). Three patients experienced severe or life-threatening symptoms, probably related to NV infection.Conclusions. In the event of an outbreak of gastroenteritis (involving two or more symptomatic patients) in a pediatric oncology unit, the search for NV in stool or vomitus specimens should be initiated in good time. As long as the data are limited regarding whether a detectable viral antigen or RNA in stools represents an infectious virus, patients have to be isolated as long as the diagnostic assays remain positive. During the acute phase of the illness, health-care workers should wear masks in addition to practicing meticulous hand hygiene with a disinfectant of proven activity against NV. Pediatric oncology patients must be closely monitored during follow-up investigations as they may shed the virus for months. There is some evidence from the outbreak described here that those patients face a greater risk of severe NV-related complications.

Surveillance for Nosocomial and Central Line-Related Infections Among Pediatric Hematology-Oncology Patients

OBJECTIVE To determine the incidence of all nosocomial infections (NIs) in pediatric hematology-oncology patients, as well as central venous access device (CVAD)-associated infections acquired during home care. DESIGN Prospective surveillance study. SETTING The Pediatric Hematology and Oncology Department at the University Hospital Bonn. PATIENTS All patients admitted from January through October 1998 (surveillance period). METHODS Standardized surveillance system based on the Centers for Disease Control and Preventions National Nosocomial Infections Surveillance System. RESULTS A total of 143 patients were hospitalized for 3,701 days (776 admissions) during the surveillance period. Of the 40 NIs detected, 26 were CVAD-related, with 21 bloodstream infections (BSIs) and 5 local infections. Four were Clostridium difficile-associated diarrheal illnesses, 3 were pneumonias, and 7 were other infections. The incidence of NIs was 10.8 per 1,000 patient-days (5.2 NIs/100 admissions). The overall CVAD-related BSI rate was 7.4 per 1,000 utilization days, without a significant difference between implanted infusion ports and tunneled catheters. In addition, 7 CVAD-related infections occurred during home care. All 8 BSIs associated with tunneled catheters and 13 (76%) of the 17 BSIs associated with ports were acquired nosocomially. For inpatients and outpatients combined, the exit sites of tunneled catheters were more likely to become locally infected than were the needle entry sites of ports (relative risk, 8.0; P=.007). In 30 (75%) of the 40 NIs, the affected patients had severe neutropenia (<500/mm3) at the time of infection. CONCLUSIONS Most NIs in the pediatric hematology-oncology patients were associated with CVAD devices. Although many infections in this high-risk population may not be preventable through infection control measures, the careful evaluation of specific infection rates permits the identification of risk factors that may be targeted by infection control programs. Prospective surveillance for NIs on pediatric oncology units is an indispensable tool for this internal quality control.

Outbreaks of Serratia marcescens in neonatal and pediatric intensive care units: clinical aspects, risk factors and management.

The following recommendations are derived from a systematic analysis of 34 Serratia marcescens outbreaks described in 27 publications from neonatal and pediatric intensive care units (NICU, PICU), in which genotyping methods were used to confirm or exclude clonality. The clinical observation of two or more temporally related cases of nosocomial S. marcescens infection should raise the suspicion of an outbreak, particularly in the NICU or PICU setting. Since colonized or infected patients represent the most important reservoir for cross transmission, hygienic barrier precautions (contact isolation/cohortation, the use of gloves and gowns in addition to strictly performed hand disinfection, enhanced environmental disinfection) should immediately be implemented and staff education given. Well-planned sampling of potential environmental sources should only be performed when these supervised barrier precautions do not result in containment of the outbreak. The current strategy of empiric antibiotic treatment should be reevaluated by a medical microbiologist or an infectious disease specialist. Empiric treatment of colonized children should use combination therapy informed by in vitro susceptibility data; in this context the high propensity of S. marcescens to cause meningitis and intracerebral abscess formation should be considered. In vitro susceptibility patterns do not reliably prove or exclude the clonality of the outbreak isolate. Genotyping of the isolates by pulse-field gel electrophoresis or PCR-based methods should be performed, but any interventions to interrupt further nosocomial spread should be carried out without waiting for the results.

Rotavirus infections in paediatric oncology patients: A matched-pairs analysis

Objective. To conduct a systematic investigation of the clinical relevance of rotavirus infection in the setting of paediatric cancer patients receiving intensive chemotherapy. Material and methods. Twenty-eight paediatric cancer patients with positive rotavirus antigen tests were eligible for a retrospective case-control study (January 1995–December 2004). Rota-positive patients were compared with 28 rota-negative patients matched for age, underlying disease and chemotherapy. The National Cancer Institute Common Toxicity Criteria were used to determine clinical severity. Results. Median duration of rota-related symptoms (diarrhoea, fever and vomiting) was 7 days (range 4–34 days; 75th percentile 9 days). Median duration of viral shedding was 17 days (4–73 days; 75th percentile 39.5 days). The rota infection was nosocomially acquired in 19 patients (68%). The proportions of patients with diarrhoea ≥NCI II, fever >39°C, clinically relevant dehydration, metabolic acidosis, mucositis and neutropenia were significantly higher in rota-positive patients. Rota-positive patients tended to have a prolonged period of hospitalization (median 8 versus 4 days; p=0.008). A higher proportion of rota-positive patients had to receive parenteral nutrition and tube feeding (p<0.001). Conclusions. Rotavirus is a clinically relevant but preventable pathogen in paediatric cancer patients, since many cases seem to be nosocomial in origin. Rapid microbiological testing and contact precautions should be strictly applied to any symptomatic patient and to their immediate contacts. Prolonged viral shedding in immunocompromised paediatric patients necessitates repeated testing in order to determine the duration of isolation.

Surveillance for nosocomial infections and fever of unknown origin among adult hematology-oncology patients.

OBJECTIVE To determine the incidence of nosocomial infections (NIs) and fever of unknown origin among adult hematology-oncology patients. DESIGN Prospective surveillance study. SETTING The 18-bed hematology-oncology unit at the University Hospital Bonn, Bonn, Germany. PATIENTS All hematology-oncology patients admitted during a total of 8 months in 1998 and 1999. METHODS Standardized surveillance system based on the Centers for Disease Control and Preventions National Nosocomial Infections Surveillance system. Rates of NI and fever of unknown origin were calculated for patient-days and patient-days at risk (ie, days with neutropenia of < 500/mm3 or leukopenia of < 1,000/mm3). RESULTS Of 116 patients hospitalized for a total of 4,002 days (172 admissions; mean length of stay, 25.2 days), 32 (27.6%) had a total of 44 documented NIs (19 bloodstream infections, 15 pneumonias, 7 urinary tract infections, and 3 others). In addition, 33 fevers of unknown origin were documented in 28 patients. No patient had thrush while receiving antifungal prophylaxis. The overall rates for NI and fever of unknown origin were 11.0 and 8.2 per 1,000 patient-days (25.3 and 15.4 per 1,000 patient-days at risk), respectively. The risks for NI and fever of unknown origin were significantly higher during neutropenic days, with 34 (77.3%) of the 44 NIs and 22 (66.7%) of the 33 fevers of unknown origin occurring during 1,345 patient-days at risk. CONCLUSIONS Prospective surveillance for NIs on hematology-oncology units should include fever of unknown origin as the single most common and clinically important entity. For a meaningful comparison of surveillance data for hematology-oncology patients, the reported infection rates should include rates based on days with neutropenia, for which days with leukopenia could serve as a surrogate marker under routine conditions.

Successful management of an MRSA outbreak in a neonatal intensive care unit

We report an MRSA outbreak in our 25-bed tertiary neonatal intensive care unit (NICU), which was successfully contained. Methods include a retrospective review of patient files, microbiology records and meeting protocols. During the seven months of outbreak, 27 patients and seven health care workers (HCWs) had positive cultures for MRSA. The outbreak was caused by the epidemic Rhine-Hessen strain; cultured isolates were monoclonal. After a sharp increase of the number of new MRSA-cases the installation of an outbreak management team (OMT) and implementation of comprehensive measures (extensive screening and decolonization strategy including orally applied vancomycin, isolation wards, intensive disinfection regimen) successfully terminated the outbreak within one month. Ten (53%) of 19 patients with completed follow-up and all of the HCWs were decolonized successfully. Gastrointestinal colonization was present in 15 of 27 (56%) neonates, and was associated with poor decolonization success (30% vs. 78% in absence of gastrointestinal colonization). A comprehensive outbreak management can terminate an outbreak in a NICU setting within a short time. Thorough screening of nares, throat and especially stool is necessary for correct cohorting. Gastrointestinal decolonization in neonates seems difficult.

Impact of portable air filtration units on exposure of haematology–oncology patients to airborne Aspergillus fumigatus spores under field conditions

We undertook a one-year study to investigate the impact of the NSA model 7100A/B portable air filtration unit on exposure of haematology-oncology patients to airborne Aspergillus fumigatus spores under field conditions. Weekly measurements for airborne A. fumigatus were conducted in indoor and outdoor air, and surveillance for invasive aspergillosis was based on a combination of ward liaison, targeted chart review and consultation with the medical staff. The mean indoor A. fumigatus counts (8.1 cfu/m3; range, <0.8 to 42 cfu/m3) reflected the fungal load of outdoor air (9.4 cfu/m3; range, <0.8 to 50 cfu/m3), and were reduced by only about one third in rooms with portable air filtration units (5.3 cfu/m3; range, <0.8 to 41 cfu/m3). During the study period, a total of five cases (incidence density, 0.8 per 1000 patient-days) of invasive aspergillosis (one proven case, four suspected cases; case fatality rate 40%) were recorded. None of these five patients was allocated to a room with portable air filtration unit, however, the difference between incidence densities in rooms with and without portable air filtration units was non-significant (Fishers exact test, P=0.33). Due to the noise level and thermal discomfort, patient compliance with the air filtration units was poor. We conclude that under field conditions this air filtration unit cannot be recommended for prevention of invasive aspergillosis in neutropenic haematology-oncology patients.