Breakthrough candidaemias during empirical therapy with fluconazole in non-cancer and non-HIV adults caused by in vitro-susceptible Candida spp.: report of 33 cases.

The objective of this study was to assess risk factors and the outcome of breakthrough fungaemias (BFs) occurring during fluconazole (FLU) therapy in non-cancer and non-HIV individuals. Thirty-three fungaemias occurring during therapy with FLU among a total of 310 fungaemias observed within a 10-y national survey were analysed. The agar disk diffusion method was used for antifungal susceptibility testing and the Vitek system for species identification. Univariate and multivariate analysis was performed to determine risk factors for BF. All BFs were due to species known to be susceptible to FLU: Candida albicans (25/33), C. parapsilosis (6/33) and C. guillermondii (2/33). The mean number of positive blood cultures per episode was 2.4. The MIC of Candida spp. to FLU was 0.5-8 mg/ml (all strains were susceptible in vitro). Neonatal age (< 4 weeks), very low birth weight, prior surgery, central venous catheter placement, artificial ventilation, total parenteral nutrition and C. parapsilosis were significantly related to BF in univariate analysis, but only central venous catheter placement was significantly related in multivariate analysis. However, the outcome of BFs and non-BFs was similar. All BFs occurred in non-HIV patients who were not previously treated with azoles, and were caused by in vitro FLU-susceptible species (C. albicans and C. tropicalis). Thus factors other than in vitro susceptibility play a role in BFs.

Breakthrough fungaemia in neonates and infants caused by Candida albicans and Candida parapsilosis susceptible to fluconazole in vitro.

Breakthrough fungaemias due to Candida albicans and Candida parapsilosis appearing during fluconazole therapy in neonates and infants were assessed for risk factors and outcome. Forty fungaemias occurred during therapy with fluconazole within a 12 year national survey and were compared with 161 cases of non-breakthrough paediatric fungaemias. The agar disc diffusion test method was used for antifungal susceptibility testing and the Vitek system for species identification. Univariate and multivariate analysis for risk factors for breakthrough fungaemia were carried out. All the fungaemias were a result of strains susceptible to fluconazole at 0.25-4 mg/L in vitro [C. albicans (85%) and C. parapsilosis (15%)]. The mean number of positive blood cultures per episode was 2.2. Sixteen children had 'early' breakthrough fungaemias (within 4-5 days) and 24 fungaemias appeared on day 6 and later. Mean fluconazole MICs in the 'early' group were 1.2, and 2.8 mg/L in the 'late' group (P < 0.03, t-test). However, no difference was observed in the average dose of fluconazole used in the two groups. Neonatal age, total parenteral nutrition, very low birth weight, before surgery, central or umbilical venous catheterization and artificial ventilation were all significantly related to breakthrough fungaemia in univariate analysis but only central or umbilical venous catheterization were significant in multivariate analysis. The outcome of breakthrough fungaemia was better overall and attributable mortalities in non-breakthrough fungaemia was significantly higher in comparison with breakthrough fungaemia.

Persistent fungemia--risk factors and outcome in 40 episodes.

The aim of this multicenter survey was to assess risk factors and mortality in patients with persistent fungemia (PF). Cases of persistent fungemia, defined as positive blood culture for at least 3 causative days of antifungal therapy were selected. Forty cases of persistent fungemia (lasting more than 3 days) were compared with 270 non-persistent fungemias appearing within the same period, and analyzed by univariate and multivariate analysis for risk factors and outcome. The median number of days of positive culture was 4.4 (3 - 20): 22 episodes were due to Candida albicans, 1 due to non-albicans Candida spp., 6 episodes due to non-Candida spp. Yeasts: 15 were catheter related, 16 patients had yeast-infected surgical wounds, 12 were neutropenic, 4 cases were caused by species resistant in vitro, 2 to amphotericin B (Trichosporon spp.) and 2 to fluconazole (C. laurentii, C. glabrata). Fifteen patients (37.5%) died, 7 of whom due to fungemia. Nineteen cases had one known risk factor (10 had infected wound, 4 infected vascular catheter, 3 were neutropenic and 2 had inappropriate therapy). Fourteen cases had two known risk factors (4 had wound and infected catheter, 4 neutropenia and infected catheter, 2 neutropenia and resistant organism, 4 other combinations. Two cases had 3 known risk factors and one had 4 risk factors for persistent fungemia. Artificial ventilation, C. glabrata etiology, non-Candida spp. yeasts such as Trichosporon spp. and Cryptococcus spp. and prior surgery were significantly associated with persistent fungemia in univariate, whereas only C. glabrata etiology in multivariate analysis. Breakthrough fungemia during empiric therapy with fluconazole was also observed more frequently in patients with persistent fungemia. However, there was no difference in both attributable and overall mortality between both groups.

Prospective study of fungaemia in a single cancer institution over a 10-y period: aetiology, risk factors, consumption of antifungals and outcome in 140 patients.

Over a 10-y period (1989-99) we prospectively evaluated all patients with fungaemia among 16,555 admissions (21,004 blood cultures) at a national cancer referral institution in the Slovak Republic. A prospective protocol was completed on 140 patients with fungaemia, which was then analysed in terms of aetiology, clinical characteristics, potential risk factors and outcome. The most frequently isolated organism was C. albicans, in 75 patients (52.9%), followed by non-albicans Candida spp. in 45 patients (32.1%). Non-Candida spp. yeasts represented 16 episodes in 16 patients (11.4%). Moulds caused 4 episodes in 4 patients (3.6% of all fungaemias) and all were caused by Fusarium spp. Mucositis (p = 0.025), > or = 3 positive blood cultures (p = 0.02), acute leukaemia (p = 0.00001), neutropenia (p = 0.0015), quinolone prophylaxis (p < 0.000005) and breakthrough fungaemia (p = 0.004) during prophylaxis with fluconazole (p = 0.03) and itraconazole (p = 0.005) were significantly more associated with non-Candida than C. albicans spp. Furthermore, attributable mortality was higher in the subgroup of non-Candida than C. albicans spp. (50.0 vs. 18.7%, p < 0.02). The only independent risk factor for inferior outcome was antifungal therapy of < 10 d duration (odds ratio 2.1, 95% confidence interval, p < 0.001). Aetiology, neutropenia and mucositis were not independent risk factors for higher mortality in multivariate analysis; however, they were risk factors for inferior outcome in univariate analysis (p < 0.05-0.005).

Nosocomial fungemia due to amphotericin B-resistant Candida spp. in three pediatric patients after previous neurosurgery for brain tumors.

Amphotericin B (AmB) resistance in Candida spp. is very rare. Three cases of fungemia, due to amphotericin B-resistant Candida spp. in pediatric patients after previous neurosurgery for brain tumors, are reported. The Candida strains - one C. guillermondii, one C. lusitaniae, and one C. parapsilosis - showed minimum inhibitory concentrations (MICs) to AmB of 2-4 microg/ml. Two of the three patients had been pretreated with AmB for 5-11 days. All three patients were successfully treated with intravenous fluconazole (6-10 mg/kg per day) for 16-28 days, and all survived. Despite AmB resistance in Candida spp. being very rare, C. lusitaniae, C. guillermondii, and C. parapsilosis isolates in documented infections should be tested for AmB resistance, mainly in patients not responding to therapy with AmB.

Prospective study of antibacterial susceptibility, risk factors and outcome of 157 episodes of Acinetobacter baumannii bacteremia in 1999 in Slovakia.

This study prospectively investigated all 157 cases of Acinetobacter baumannii bacteremia occurring in major university hospitals or tertiary care institutions in Slovakia during 1999 in order to determine the antimicrobial susceptibility, risk factors and outcome. Resistance to meropenem was 7.4, gentamicin 35.6, amikacin 26.5, cefepime 20.4 and ciprofloxacin 32.7%, but was only 17.3% to cefoperazone/sulbactam or ampicillin/sulbactam. Antimicrobial susceptibility of A. baumanii was lowest among isolates from cancer patients (ceftazidime 58%, piperacillin/tazobactam 52% and azthreonam 48%; p < or = 0.01-0.001). In univariate analysis, several risk factors, such as wound infection (p < or = 0.01) and ventilatory support (p < or = 0.0001), were significantly related to A. baumannii bacteremia in surgical patients. Neutropenia (p < or = 0.0001), antineoplastic chemotherapy (p < or = 0.0001) and prior antibiotic therapy (p < or = 0.0006) were significant risk factors for A. baumannii bacteremia in cancer patients. In addition, ventilatory support and surgery (p < or = 0.0001) and prior antibiotic therapy (p < or = 0.01) were significantly related to A. baumannii bacteremia in children. Colonization at other body sites (p < or = 0.05), diabetes mellitus (p < or = 0.04) and decubital ulcers/burns (p < or = 0.002) as underlying disease were significantly related to death due to A. baumannii bacteremia. In a multiple logistic regression model, decubital ulcers/burns as underlying disease (p < or = 0.0006; relative risk 5.08) and nosocomial pneumonia (p < or = 0.045; relative risk 5.08) were independent predictors of mortality. Mortality was similar between cancer and surgical patients but significantly lower in children vs. adults (p < or = 0.009).

Long-term (15 years) results of extended field radiotherapy in Hodgkin's disease.

From 1975 to 1990, 214 patients with the pathological Stage IA, IB, IIA, IIB and IIIA of Hodgkin's disease were treated by supradiaphragmatic and/or infradiaphragmatic mantle technique. Complete remission was achieved in 70 patients (8%) by means of radiotherapy only. Partial remission was achieved in 9 patients (2%). The survival at 10 years was 86% and 15 years it was 66%. The most frequent late complications were hypothyreosis, Lhermitte's syndrome and radiation pneumonitis.

Longitudinal 10-year prospective survey of fungaemia in Slovak Republic: trends in etiology in 310 episodes. Slovak Fungaemia study group.

A 10-year prospective survey of fungaemia in the Slovak Republic, involving 31 microbiology laboratories and 71 hospitals, was conducted from 1989-1998 (10 years): 310 fungaemias were analyzed for etiology, clinical characteristics, therapy, and outcome. C. albicans was responsible for 191 (61.6%) fungaemias, non-albicans Candida spp. (NAC) for 97 (31.3%), non-Candida yeasts for 18 (5.8%) and moulds (Fulsarium spp.) for four fungaemias. The most frequent NAC isolated from blood cultures were C. parapsilosis--30 (9.7%), C. krusei--18 (5.8%), C. tropicalis--14 (4.5%), and C. glabrata--10 (3.2%). Secular trends in etiology showed a sustaining decrease of C. albicans (from 100% in 1989 to 50.7% in 1998) and increase of NAC (from 0% in 1989-1990 to 46.3% in 1998). Non-Candida yeasts and moulds showed a stable proportion during the investigated period. There were statistically significant differences in etiology of fungaemia various subgroups of patients: non-albicans Candida spp. was significantly more frequent observed among subgroups of patients with pancreatitis and coma (53.3% vs. 31.3%, p < or = 0.02) and less frequently in the subgroup of neonates (15.0% vs. 31.3%, p < or = 0.006). Vice versa, C. albicans appeared more frequently in neonates (85%).

National and local antibiotic policies in Central and Eastern Europe.

To assess the antibiotic policies of Central European countries, we performed an overview of antibiotic stewardship, prescription habits and antibiotic prescription regulatory procedures. Since most Central European countries have had centralized health care and drug policies, the situation 10 years after decentralization is surprising. Only 3 of 10 Central European countries have some regulation of prescription of antibiotics, only 4 restrict some antibiotics, only 5 have hospital and only 3 national antibiotic policies. In all but 3 countries physicians can prescribe quinolones and/or 3rd generation oral cephalosporins as first-line antibiotics. Information on local and national antibiotic policies in Central and Eastern European countries is given including prescription guidelines for antibiotic use in community and hospital.

Antifungal susceptibility of 262 bloodstream yeast isolates from a mixed cancer and non-cancer patient population: is there a correlation between in-vitro resistance to fluconazole and the outcome of fungemia?

The aim of this study was to test the antifungal susceptibility of 262 bloodstream yeast isolates (164 Candida albicans strain, 88 non-albicans Candida spp. and 10 non-Candida yeasts) recovered from 169 surgical, neonatal, critically ill intensive care unit patients (ICU), and cancer patients (mixed patient population) to amphotericin B (AmB), fluconazole (FLU), 5-flucytosine (5-FC), itraconazole (ITRA), ketoconazole (KETO), miconazole (MICO), and nystatin (NYS), in order to correlate in-vitro resistance to fluconazole with the outcome of fungemia. The agar disk diffusion test was used to assess the susceptibility of the 262 bloodstream yeasts isolates. In addition, 78 strains isolated from cancer patients were also tested with the E-test. There were no differences in the susceptibility of the various C. albicans strains tested, except in 40 isolates from surgery patients, which showed a somewhat lower susceptibility to KETO and MICO to (3.7-5.5% resistance). There were no C. albicans strains resistant to AmB, NYS, or FLU. There were slight differences in the susceptibility patterns of the 88 non-albicans Candida spp. (NAC) isolates. Resistance to AmB and NYS appeared in 1 strain of C. guillermondii (minimum inhibitory concentration; MIC to AmB; 4 microg/ml) and in 1 strain of C. parapsilosis (MIC to NYS, 8 microg/ml and MIC to AmB, 2 microg/ml). All other NACs were susceptible to both polyenes (AmB and NYS). Nine of the 11 strains of C. krusei were resistant to FLU (MIC >or= 64 microg/ml), the 2 exceptions showed, respectively, MICs for FLU of 6 and 32 microg/ml ("dose-dependent" susceptibility). However, only 2 of 29 C. glabrata strains were fully FLU-resistant (MIC >or= 64 microg/ml), 27 being susceptible with MIC values of 0.5-8 microg/ml. Apart from 9 C. krusei and 2 C. glabrata strains, 2 C. parapsilosis strains and 1 strain of C. tropicalis were also FLU-resistant. Among the 88 NACs, 17.04% were FLU-resistant and 3.7% were KETO- and ITRA-resistant. Resistance to 5-FC and AmB was minimal. We compared the outcomes of patients infected with FLU-resistant vs FLU-susceptible yeasts in 161 evaluable patients treated with FLU. Attributable mortality was significantly higher (19.0% vs 8.6%; P < 0.01) in patients infected with the FLU-resistant yeasts.

Bacteremia and fungemia in pediatric versus adult cancer patients after chemotherapy: comparison of etiology, risk factors and outcome.

One hundred and eighteen (118) episodes of bacteremia and fungemia in children with cancer were compared to 401 episodes of bacteremia and fungemia in adults with cancer to assess differences in etiology, risk factors and outcome. A retrospective univariate analysis was performed of all episodes of bacteremia in national pediatric and adult cancer institutions appearing in 1990-1996. A total of 519 episodes of bacteremia were assessed and compared. Both cancer centers differed in prophylactic antibiotic policies. About 50% of adults but less than 5% of children received quinolone prophylaxis during neutropenia, even though the empiric antibiotic therapeutic strategy was similar. There were differences in etiology between the groups: staphylococci and Stenotrophomonas maltophilia were more frequently observed in children (P<0.01), Pseudomonas aeruginosa and Acinetobacter spp. in adults (P<0.05). Gram-positive bacteremia was surprisingly more commonly observed in adults (65.7% vs 33.3%, P<0.01). Mixed polymicrobial bacteremia occurred more commonly in adults (31.8% vs 7.6%, P<0.001) than in children. Analysis of risk factors did not observe differences in risk factors except for underlying disease (acute leukemia was more frequently observed in children -48.3% vs adults 33.7%, P<0.05 and prophylaxis: (prior prophylaxis with quinolones was more common in adults (47.5%) than in children (2.5%) P<0.0001). Overall and attributable mortality in pediatric bacteremia was significantly lower than in adults (P<0.03).