Antifungal susceptibility testing of fluconazole by flow cytometry correlates with clinical outcome.

Susceptibility testing of fungi by flow cytometry (also called fluorescence-activated cell sorting [FACS]) using vital staining with FUN-1 showed a good correlation with the standard M27-A procedure for assessing MICs. In this study we determined MICs for blood culture isolates from patients with candidemia by NCCLS M27-A and FACS methods and correlated the clinical outcome of these patients with in vitro antifungal resistance test results. A total of 24 patients with candidemia for whom one or more blood cultures were positive for a Candida sp. were included. Susceptibility testing was performed by NCCLS M27-A and FACS methods. The correlation of MICs (NCCLS M27-A and FACS) and clinical outcome was calculated. In 83% of the cases, the MICs of fluconazole determined by FACS were within 1 dilution of the MICs determined by the NCCLS M27-A method. For proposed susceptibility breakpoints, there was 100% agreement between the M27-A and FACS methods. In the FACS assay, a fluconazole MIC of <1 microg/ml was associated with cure (P < 0.001) whereas an MIC of > or =1 microg/ml was associated with death (P < 0.001). The M27-A-derived fluconazole MICs did not correlate with outcome (P = 1 and P = 0.133).

Inappropriate antibiotic therapy in febrile cancer patients with bacteremia.

OBJECTIVE: The aim of the study was to assess the outcome of inappropriately treated cancer patients with documented bacteremia. DESIGN/SETTING: 95 cases of inappropriately treated bacteremias in febrile cancer patients in a tertiary-care center were analyzed and compared with a group of appropriately treated bacteremias to assess risk factors for inappropriate therapy and outcome. RESULTS: Among 285 bacteremias, 95 (33.3%) were not treated appropriately, with 42 receiving the wrong antibiotics and 17 having too short a therapeutic course of appropriate antibiotics. In 13, therapy was delayed for more than 48 hours after the onset of fever. Twenty-three patients did not receive antibiotic therapy at all despite bacteremia. A group of 95 inappropriately treated bacteremias was compared to 190 appropriately treated bacteremias occurring in the same period. Microbiological cure after the initial course of therapy was achieved more often (76.8% vs 38.9%, P < .001) in the group of appropriately treated bacteremias in all cases and also in the subgroup of leukemic patients (P < .01). Overall and attributable mortality were significantly lower in patients who were treated appropriately. There was no difference in the number of antibiotics administered in appropriately versus inappropriately treated bacteremias. Cost of therapy between both groups was similar. CONCLUSIONS: Inappropriately treated bacteremic cancer patients had outcomes that were significantly worse than patients who were treated appropriately. The reasons for inappropriate therapy were selection of the wrong antimicrobials, too short a duration of therapy, delayed onset of therapy, or absence of antimicrobial therapy.

Predictors of mortality in bacteremic cancer patients: retrospective analysis of 64 deaths occurring among 262 bacteremic episodes.

A total of 262 bacteremic episodes were observed in cancer patients in a single cancer institution during the last 7 years, and the recorded outcome was death in 65. The 65 patients who died (24.8% overall mortality) were divided retrospectively into two subgroups: (a) those who died of underlying disease with bacteremia (45 cases, 16.9% crude mortality) and (b) those who died of bacteremia (20 patients, 7.7% attributable mortality). Comparison of several risk factors in subgroups of patients who achieved a cure (197 cases) and of those who died and whose deaths were attributable (20 cases) revealed six risk factors that were associated with attributable mortality: (1) chemotherapy-induced neutropenia (P < 0.03), (2) Acinetobacter/Stenotrophomonas spp. bacteremias (P < 0.001), (3) liver failure (P < 0.001), (4) inappropriate therapy (P < 0.0001), (5) organ complications (P < 0.003) and (6) multiresistant organisms (P < 0.001). Enterococci and Pseudomonas aeruginosa, surprisingly, were found more frequently in those who died of an underlying disease with bacteremia than among patients who were cured (17.6% vs 7.6%, P < 0.05 and 29.1% vs 13.8%, P < 0.02). Those who died of infection had higher numbers of positive blood cultures, with 2.05 per episode, than did those who died of underlying disease with bacteremia (1.82) or those who were cured (1.51). Other risk factors, such as underlying disease, type of chemotherapy, origin of bacteremia, age, and catheters did not predict either overall or attributable mortality within the study group.

Bacteremia due to methicillin-resistant staphylococci occurs more frequently in neutropenic patients who received antimicrobial prophylaxis and is associated with higher mortality in comparison to methicillin-sensitive bacteriemia.

Bacteriemia due to coagulase-negative staphylococci (CNS) resistant to methicillin and sensitive only to glycopeptides in 220 cancer patients was prospectively analyzed for risk factors and outcome. A group of 33 cases of bacteriemia with CNS-sensitive only to glycopeptides was compared with a group of 187 cases with CNS sensitive to methicillin. All cases appeared in two affiliated major cancer institutes in Bratislava with the same antibiotic policy. Univariate analysis showed differences in recorded risk factors: acute leukemia (48 vs. 33%, P < 0.05), neutropenia (57 vs. 32%, P < 0.045), previous prophylaxis with quinolones (30 vs. 11%, P < 0.01) and penicillin-V (15 vs. 3%, P < 0.02) and previous colonisation with CNS (27 vs. 3%, P < 0.01) were more frequently associated with bacteriemia resistant to methicillin and sensitive only to glycopeptides. Attributable mortality was also higher in this subgroup in comparison to bacteriemias with CNS sensitive to methicillin (12 vs. 3%, P < 0.05) however, overall mortality was similar. Bacteriemias due to CNS caused by sensitivity only to glycopeptides occurred more frequently in neutropenic patients (1), with acute leukemia (2), receiving quinolone and penicillin prophylaxis (3), and previously colonized (4), patients and had worse prognosis in comparison to those with methicillin-sensitive staphylococcal bacteriemias.

Eight-year surveillance of non-albicans Candida spp. in an oncology department prior to and after fluconazole had been introduced into antifungal prophylaxis.

From 1989 until 1996, during the last 8 years, the proportion of Candida (C.) krusei, and other non-albicans Candida spp. isolated from surveillance cultures and from sterile body sites, was analyzed among 13,758 admissions in a National Cancer Institute. During these admissions a total of 9,042 isolates were prospectively collected from surveillance cultures, and 126 from blood cultures. The proportion of C. krusei among all organisms was 12.7% to 16.5% in 1989 through 1991, i.e., before fluconazole was introduced into prophylactic protocols. After the introduction of fluconazole into prophylaxis in acute leukemia in 1992 the incidence of C. krusei was 7.9% to 8.6% during 1994 to 1996. After 5 years of using this drug for prophylaxis, the incidence of C. krusei was lower than before this drug was introduced in our institute. Among yeasts, the most frequently isolated pathogen was still Candida albicans (72.2% of all isolated fungal organisms). Among molds, Aspergillus spp. was the most frequently isolated agent. Analyzing the etiology of proven fungal infections (fungemias) confirmed by positive blood cultures, C. albicans was the most common causative organism in 53.8% of cases. The incidence of fungemia due to Torulopsis (C.) glabrata and C. krusei before and after fluconazole introduction did not change. Of 126 organisms isolated from blood cultures, there was no increase in T. (C.) glabrata or C. krusei after introduction of fluconazole for prophylaxis and therapy, and the quoted 6.4% of fungemic episodes remained stable with an incidence of 1 fungemia/year since 1991. The proportion of C. krusei and C. glabrata among Candida spp. was decreasing in our center between 1989 and 1996. Also, the proportion of non-albicans Candida spp. among isolates decreased from 25.7% in 1990 to 11.9% in 1996.

Analysis of 553 episodes of monomicrobial bacteraemia in cancer patients: any association between risk factors and outcome to particular pathogen?

Relationships between aetiology, various risk factors (such as neutropenia, catheter insertion, endoscopy, therapy with corticosteroids, therapeutic use of antimicrobials, antibiotic prophylaxis, source of infection), symptomatology and outcome were studied in 553 monomicrobial bacteraemic episodes in cancer patients observed within 7 years at the National Cancer Institute of the Slovak Republic. The ratio of gram-positive to gram-negative bacteraemia was 1:1 (43.5% vs 43.8%), and yeasts caused 7.2% of monomicrobial episodes. The highest mortality was associated with Pseudomonas aeruginosa (19.2%), non-albicans Candida yeasts (25%) and Bacteroides fragilis (22.6%). Independent risk factors for particular pathogens were investigated by a computerized logistic regression model. The only independent risk factor for staphylococcal and enterococcal bacteraemia was vascular catheter insertion (OR = 1.95 and 2.05, CI = 95%, P = 0.035 and 0.044, respectively). However, there were no independent specific risk significant factors for viridans streptococcal bacteraemia and bacteraemia due to Enterobacteriaceae or Ps. aeruginosa. Neutropenia was found to be an independent predictor for development of Acinetobacter spp. bacteraemia (OR = 3.84, CI = 95%, P = 0.044). Prior therapy with third-generation cephalosporines was a predictive, independent risk factor for the development of fungaemia (OR = 1.99, CI = 95%, P = 0.028) but not of enterococcal bacteraemia. We also did not observe any association between prior therapy with imipenem and Stenotrophomonas maltophilia bacteraemias. Multivariate analysis confirmed that fungaemia may be independently associated with higher mortality than bacteraemia caused by Enterobacteriaceae and staphylococci. However, the mortality of fungaemia was statistically no different from that of Ps. aeruginosa, Stenotrophomonas spp. and viridans streptococci bacteraemias.

Risk factors, aetiology, therapy and outcome in 123 episodes of breakthrough bacteraemia and fungaemia during antimicrobial prophylaxis and therapy in cancer patients.

One hundred and twenty-three breakthrough bacteraemias (BB) were defined during a 5-year period in a National Cancer Centre, among 9986 admissions and a total of 979 bacteraemic episodes analysed. Of 123 bacteraemias in 103 patients, 77 were polymicrobial and 116 of the 323 organisms isolated were resistant to currently administered antimicrobial agents. Sixty-seven of the bacteraemic episodes were catheter-associated, as confirmed by the isolation of the same organisms from both blood and catheter tip. The strains isolated most frequently were coagulase-negative staphylococci (30.5%), corynebacteria (10%), Pseudomonas aeruginosa (10%), Enterococcus faecalis (9%) and viridans streptococci (8.5%). Gram-positive aerobes accounted for two-thirds of all micro-organisms isolated during breakthrough bacteraemic and fungaemic episodes. Polymicrobial episodes were associated more frequently with vascular catheters and neutropenia, and had a less favourable outcome than monomicrobial infections. Relapse was associated more frequently with catheter-related episodes, but the overall mortality rate was similar and independent of catheter insertion. Breakthrough bacteraemic and fungaemic episodes were associated more frequently with acute leukaemia. Catheter removal, as an independent variable, and modification of antimicrobial therapy were essential for better outcome.

Bacteremia due to Enterobacter spp. in cancer patients--analysis of 51 episodes.

Fifty one episodes of bacteremia due to Enterobacter spp. appearing within 7 years among 12 301 admissions in a single cancer institution were studied for risk factors, clinical presentation and outcome. Fifteen episodes were due to Enterobacter aerogenes, 23 due to E. cloacae and 13 due to E. agglomerans. The proportion of bacteremia due to Enterobacter spp. among Gram-negative bacteremias was 10.1% and infection associated mortality was 13.8%. The incidence in 1989-1995 varied from 3.7 to 8.7% and was relatively stable. Most common risk factors were: solid tumors as underlying disease, central venous catheter insertion, prior surgery and prior chemotherapy within 48 h. Neutropenia and urinary catheters were not at high risk in either one of the patients subgroups. Comparing two subgroups of 51 bacteremias, monomicrobial and polymicrobial (when Enterobacter spp. was isolated from blood culture with other microorganism), previous chemotherapy, vascular catheter insertion and prior endoscopy were more frequently associated with polymicrobial Enterobacter spp. bacteremia. There was also differences in infection associated mortality: bacteremias due to Enterobacter spp. only had significantly lower mortality in comparison to polymicrobial Enterobacter spp. bacteremias (3.3 vs. 29.3%; P<0.02). Susceptibility of Enterobacter spp. strains isolated from 51 episodes was stable and showed only two episodes due to quinolone-resistant strains, both in 1992 despite of the use of ofloxacin in prophylaxis of neutropenic patients since 1990 in our institute. Ninety-two to 94% of all strains were susceptible to aminoglycosides, 96-98% to ofloxacin and ciprofloxacin, respectively and 94.9% to meropenem but only 75.5% to ceftazidime.

Resistance pattern of 2816 isolates isolated from 17631 blood cultures and etiology of bacteremia and fungemia in a single cancer institution.

The resistance pattern of 2816 isolates from 17631 blood cultures and the etiology of isolates causing bacteremia and fungemia among 14591 admissions were investigated in an 80-bed single cancer institute during seven years (1990-1996) under the same empiric therapeutic antibiotic policy but with different prophylactic strategies. No change was found in the proportion of Gram-positive versus Gram-negative bacteria isolated from bacteremias (70% vs. 30%) during the past seven years. Furthermore, the proportion of coagulase-negative staphylococci and enterococci was about the same before and after the introduction of ofloxacin in prophylaxis. However, the proportion of Pseudomonas aeruginosa and Stenotrophomonas maltophilia causing bacteremia increased. There was no increase in Candida krusei and Candida glabrata after the introduction of fluconazole into our prophylactic regimen in 1992. Penicillin-resistance in viridans streptococci increased after penicillin was introduced into prophylaxis in acute leukemia in 1993. Until 1995 no quinolone-resistant Enterobacteriaceae were observed. Susceptibility to quinolones did not significantly change within the past seven years in Enterobacteriaceae after their introduction to prophylaxis in 1991, but Pseudomonas aeruginosa decreased from 90 to 58.2%. Glycopeptide resistance in enterococci and staphylococci was minimal in the observed period (0.9-4.3%).

Fungemia in cancer patients undergoing chemotherapy versus surgery: risk factors, etiology and outcome.

26 patients with fungemia and cancer treated with chemotherapy (group A) were compared to 25 patients with fungemia and cancer treated with surgery (group B), to assess differences in etiology, risk factors and outcome. Candida albicans was responsible for 42% of fungemias in group A, and for 92% of fungemias in group B (p < 0.005). Breakthrough fungemia occurring during antifungal prophylaxis appeared in 46.6% of group A vs 12% of group B (p < 0.02). There was significant difference in outcome between the groups: 20% of patients after surgery vs 7.7% of those after chemotherapy died from fungemia (p < 0.04). Most common risk factors recorded in both groups were catheter insertion and previous therapy with broad spectrum antibiotics.

Bacteremia in neutropenic versus nonneutropenic cancer patients: etiology and outcome in 401 episodes.

Etiology, risk factors, symptomatology and outcome of 401 bacteremic episodes during the period of 6 years in a National Cancer Institute occurring among 9987 admissions were analyzed. Neutropenia as an independent risk factor was observed in 198 episodes, while 203 bacteremic episodes appeared in nonneutropenic patients. Both groups were compared in risk factors, etiology, clinical symptomatology and outcome. Proportion of particular pathogens did not show significant differences in both groups, except for E. faecalis occurring more frequently in the group of nonneutropenic patients in contrast to Enterobacteriaceae, occurring more frequently in neutropenic patients. There was significant by higher proportion of anaerobic bacteremia and fungemia in neutropenic than in nonneutropenic patients. Prior prophylaxis with quinolones with breakthrough bacteremia were also seen more frequently in the group of neutropenic patients. Septic shock and death due to bacteremia occurred more frequently in the group of neutropenic patients.

Breakthrough bacteraemic and fungaemic episodes during antimicrobial prophylaxis and therapy in cancer patients: analysis of risk factors, etiology, therapy and outcome in 123 episodes.

One hundred twenty three breakthrough bacteraemias (BB) during 5 years in a National Cancer Institute, among 9986 admissions and 979 bacteraemic episodes were analysed. 123 BB were caused by 323 microbes, only 116 were resistant (31.5%) to currently administered antimicrobials. Sixty seven of 123 bacteraemic episodes were catheter associated confirmed by isolation of the same organisms from the blood and catheter tip. 77/123 BE were polymicrobial. The most frequently isolated strains were coagulase negative staphylococci (30.5%), Corynebacteria (10%), Ps. aeruginosa (10%), Str. faecalis (9%) and Viridans streptococci (8.5%). Gram-positive aerobes accounted for two-thirds of all organisms isolated during breakthrough bacteraemic and fungaemic episodes. Mixed polymicrobial breakthrough bacteraemic and fungaemic episodes were more frequently associated with vascular catheter insertion and neutropenia, and had a less favourable outcome in comparison to monomicrobial infections. The relapse was associated more frequently with catheter related bacteraemic and fungaemic episodes, but the overall mortality rate was similar independently from catheter insertion. Breakthrough bacteraemic and fungaemic episodes were associated more frequently with acute leukaemia. Polymicrobial breakthrough bacteraemic and fungaemic episodes were associated more frequently in neutropenic episodes and in venous catheters. Regarding the outcome, an extraction of the catheter with no dependence on variable and modification of antimicrobial therapy were essential for the improvement in the prognosis. (Tab. 5, Ref. 20.).

Bacteremia and fungemia occurring during antimicrobial prophylaxis with ofloxacin in cancer patients: risk factors, etiology and outcome.

The authors analyzed 27 breakthrough bacteremias occurring during ofloxacin prophylaxis in afebrile neutropenia over 7 years in 9989 admissions and 979 bacteremic and fungemic episodes in a National Cancer Center in Bratislava, Slovak Republic. The most frequently isolated organisms in breakthrough bacteremias were gram-positive (71.3%), mainly coagulase-negative staphylococci (41.3%), enterococci (9.2%) and Corynebacteria (9.2%), followed by gram-negative rods-Pseudomonas aeruginosa (13.2%) and Stenotrophomonas maltophilia (9.2%). The outcome of breakthrough bacteremias during ofloxacin prophylaxis was not associated with the underlying disease, neutropenia, catheter insertion or resistance, but only with multiple risk factors. A higher failure rate was observed in those patients having a catheter infected with a resistant organism and during neutropenia. No patients with Hickman catheter were included in the study. Patients with mixed breakthrough bacteremia due to gram-negative and gram-positive organisms had higher failure rates than those with monomicrobial bacteremia. Catheter extraction and rapid institution of intravenous antibiotics in combination should be administered in breakthrough bacteremia.

Polymicrobial bacteremia in cancer patients: analysis of risk factors, etiology and outcome in 214 episodes.

Two hundred and fourteen episodes of polymicrobial bacteremia in 182 cancer patients in a period of 6 years in a 360-bed National Cancer Institute were analyzed for etiology, risk factors and outcome. Variables were compared with 187 episodes of monomicrobial bacteremias in 147 cancer patients to find statistical significance among risk factors, etiology and outcome. Urinary catheters and breakthrough bacteremia were the only risk factors associated with polymicrobial in comparison to monomicrobial bacteremia (P < 0.05). Concerning etiology, Enterococcus faecalis, Candida spp., Acinetobacter calcoaceticus and Stenotrophomonas maltophilia were more commonly isolated in polymicrobial than in monomicrobial bacteremic episodes. Polymicrobial bacteremia presented more frequently with septic shock (22.9% vs. 9.0%, P < 0.05) and/or organ complications (25.2% vs. 11.8%, P < 0.05). However, mortality due to bacteremia did not significantly differ between polymicrobial and monomicrobial, but when polymicrobial bacteremia with and without coagulase negative staphylococci were compared, mortality in polymicrobial bacteremia without staphylococci was higher (10% vs. 4.7%, P < 0.04).

Bloodstream infections due to anaerobic bacteria in cancer patients: epidemiology, etiology, risk factors, clinical presentation and outcome of anaerobic bacteremia.

Thirty one bacteremic episodes (BE) in 31 patients due to anaerobic bacteremia (AB) in 979 BE among 9986 admissions at a 360 beds National Cancer Institute within last 6 years were analyzed for time distribution, risk factors, clinical presentation and outcome. Overall incidence of AB was 3.6%, but the proportion to other groups of microorganisms is decreasing. 73% were Bacteroides fragilis, 10.8% Peptostreptococci and Propionibacteria and 5.4% Clostridia. The most common risk factor for AB was prior surgery, solid tumor as underlying disease, prophylaxis with quinolones and previous therapy with third generation cephalosporines. 48.4% of AB were polymicrobial. Infected wound was the most common source of infection in 38.7% of our cancer patients. Six patients (19.4%) presented septic shock, and 45.2% died, but only in 22.6% death was related to bacteremia. Comparing the groups of AB due to B. fragilis (BF) to non-Bacteroides spp. (NB)AB, infection-associated mortality was higher in BFAB in comparison to NBAB. Other risk factors such as hematologic malignancies, previous prophylaxis with quinolones, prior surgery and prior therapy with broad spectrum antimicrobials, were more frequently associated with BFAB.

Teicoplanin plus pefloxacine versus teicoplanin plus netilmicin in empiric therapy of febrile patients with cancer and neutropenia. A randomized study of two once daily regimens in patients with previously inserted catheters.

In a comparative randomized trial, teicoplanin 5 mg/kg plus either netilmicin 5 mg/kg or pefloxacine 10 mg/kg was administered in a once daily empiric therapy to 40 cancer patients with fever and neutropenia after cytotoxic chemotherapy. Both regimens were analyzed with respect to the localisation of the underlying disease, catheter presence and agents isolated from blood culture. The cure and improvement rate were 80% (teicoplanin plus netilmicin) and 85% (teicoplanin plus pefloxacin), with no statistically significant difference between the groups. Teicoplanin with either an aminoglycoside or a quinolone administered once daily seems to be a suitable approach in empiric therapy for fever in neutropenia and may prevent catheter insertion in cancer patients.