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).

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).

Influence of homology size and polymorphism on plasmid integration in the yeast CYC1 DNA region.

We studied the influence of homology size and polymorphism on the integration of circular plasmids into the yeast CYC1 region. The plasmids used also contained the URA3 gene, and the proportion of Ura+ transformants resulting from plasmid integration into the CYC1 region was determined by Southern-blot analysis. A size-dependent decrease in integration into the CYC1 region was observed from 858 bp to 363 bp of homology. However, with a homology size of 321, 259 or 107 bp, about 2% of the transformants still contained plasmid molecules integrated in the CYC1 region. A single point mutation in the 858-bp fragment decreased the proportion of integrations to the CYC1 gene, but the presence of additional mutations did not have a cumulative effect. For plasmids isolated in a single-stranded (ss) form, the presence of two or six point mutations did not influence integration. These results were compared with those obtained in other assays designed to study substrate requirements for homologous recombination.

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.

Bacteremia in cancer patients with solid tumors undergoing chemotherapy versus surgery: risk factors, etiology and outcome in 276 patients.

Etiology, risk factors, outcome and complications of bacteremia in 276 patients with solid tumors were analyzed. A group of 78 patients with solid tumors and surgical therapy only was compared with 172 patients with solid tumors who were treated with chemotherapy only. The most frequently observed risk factors of bacteremia in patients after surgery was urinary catheter insertion, wound as source of bacteremia, age > 60, staphylococci, enterococci and Enterobacteriaceae as etiologic agents. In comparison, viridans streptococci and Pseudomonas aeruginosa as etiologic agents as well as vascular catheters were significantly more frequently found in those treated with chemotherapy only. Patients with bacteremia after surgery only had a lower incidence of septic shock (6.4 vs. 16.9%, P < 0.03) and also lower mortality (5.6 vs. 14.9%, P < 0.04) attributable to shock than patients being treated for solid tumors with chemotherapy only.

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%).

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.

Viridans streptococcal bacteraemia due to penicillin-resistant and penicillin-sensitive streptococci: analysis of risk factors and outcome in 60 patients from a single cancer centre before and after penicillin is used for prophylaxis.

60 patients with 60 viridans streptococcal bacteraemic episodes (42 due to penicillin-sensitive and 18 due to penicillin-resistant viridans streptococci) were analysed in a population of 12,185 admissions and 1,380 bacteraemic episodes during a 7-year period in a National Cancer Institute. The incidence of viridans streptococci among bacteraemias decreased from 11.5% in 1989 to 2.5% in 1995 after penicillin was introduced for prophylaxis of febrile neutropenia in acute leukaemia in 1993. However, the proportion of penicillin-resistant viridans streptococcal bacteraemias increased from 0 in 1989 and 1990 before any prophylaxis was given, to 12.9-16.7% after quinolones were used for prophylaxis in 1991 and 1992, and to 44.4-81.8% in 1993-1995 after penicillin was added to the quinolones. Mortality rate was higher in the subgroup of penicillin-resistant viridans streptococcal bacteraemias (p < 0.05). Statistically significant risk factors in patients with penicillin-resistant (compared with penicillin-sensitive) viridans streptococcal bacteraemia were: acute leukaemia (p < 0.03), high doses of cytarabine (p < 0.05), mucocutaneous lesions (p < 0.004), breakthrough bacteraemia during prophylaxis with ofloxacine plus penicillin (p < 0.001). Multiple logistic regression analysis showed that only acute leukaemia (OR 2.05, CI 0.85-1.85, p < 0.00452) and penicillin-resistance (OR 0.71, CI 0.103-4.887, p < 0.0209) were significant independent predictors of inferior outcome. Breakthrough bacteraemia during empiric therapy with vancomycine occurred in 5 of 116 patients treated with vancomycine, and during therapy with ampicillin plus gentamicin in 6 patients of 18 treated.

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.

Do vancomycin serum levels predict failures of vancomycin therapy or nephrotoxicity in cancer patients?

The purpose of this study was to determine if patients with high vancomycin (VAN) serum levels experience more toxicity than underdosed patients with lower (VAN) levels, and whether low VAN serum levels cause therapeutic failures in patients with gram-positive bacteremia. In 198 cancer patients trough and peak serum levels of VAN were measured. Acute toxicity (Red Man syndrome) appeared in 3 patients (1.5%). Patients previously or currently treated with other nephrotoxic compounds (134 patients) presented the same incidence of nephrotoxicity as those receiving VAN for the first time in monotherapy (64 patients). VAN did not increase the toxicity when patients were dosed simultaneously or previously with aminoglycosides or amphotericin B. Our second observation, when studying serum levels in our 198 patients was that high VAN trough serum levels (trough > 15 microg/mL) were associated with significantly more nephrotoxicity (33.3% vs. 11.1%, P < 0.03) than low levels in the subgroups of either pretreated patients or unpretreated with other nephrotoxic drugs. None of 198 patients who had trough levels below 15 microg/mL had peak levels exceeding 40 microg/mL. This suggests that only serum monitoring of trough levels may predict nephrotoxicity. A case control study was conducted to compare a group of 22 VAN failures with 22 successfully treated patients matched in underlying disease and neutropenia who were treated in the same period, under the same antibiotic policy, at the same cancer center, for gram-positive bacteremia. Persisting, enterococcal, or mixed enterococcal plus staphylococcal bacteremia were the only statistically significant risk factors which predicted therapy failure in cancer patients. Neither peak nor trough VAN serum levels predicted failure or cure of gram-positive bacteremia in cancer 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.).

Imipenem-resistant Ps. aeruginosa bacteraemia in cancer patients: risk factors, clinical features and outcome.

Ninety nine patients with 101 bacteraemic episodes due to Ps. aeruginosa (PA) within 6 years were divided into two groups according to their resistance to imipenem-91 due to imipenem sensitive (ISPA) and 10 due to resistant (IRPA). Risk factors, the clinical course and the outcome were evaluated and compared. Acute leukaemia, prolonged neutropenia, previous therapy with amikacin, third generation of cephalosporins, imipenem and prophylaxis by quinolones were significantly more frequently associated with IRPA. Imipenem resistant PA bacteraemia were associated with higher incidence of septic shock (40% vs 19.8%, p < 0.02) and death (33.3%) than ISPA bacteraemias. Since 1992, when first IRPA appeared, the incidence of imipenem resistance increased tenfold, and in 1994, up to 10% of PA causing bloodstream infections in cancer patients in our center were imipenem resistant. (Tab. 3, Ref. 8.).

Bacteremia in cancer patients with solid tumors undergoing chemotherapy versus surgery: risk factors, etiology and outcome in 276 patients.

Risk factors, etiology, symptomatology and outcome of bacteremia in 276 patients with solid tumors were evaluated. A group of 78 patients with solid tumors and surgical therapy was compared with 172 patients with solid tumors but treated solely by chemotherapy. The most frequently observed risk factors of bacteremia in patients after surgery were the vascular and urinary catheter insertions, wound as source of bacteremia, staphylococci, enterococci and Enterobacteriaceae as etiologic agents. Comparing the group of therapeutically treated patients with solid tumors, with the group of those treated only by chemotherapy, a statistically significant difference in risk factors between both groups was observed only in the incidence of catheter insertion (more frequently in surgically treated patients), neutropenia (more frequently in those treated by chemotherapy). Wound as source of bacteremia was more frequently observed in those after surgery. Enterobacteriaceae and enterococci were significantly more frequently observed in patients with solid tumors treated by surgery. Surprisingly, patients after surgery the mortality due to septic shock was lower in (6.4% vs 16.9%, p < 0.03) than in the control group of patients with solid tumors treated solely by chemotherapy. (Tab. 1, Ref. 5.).

Staphylococcal bacteremia in cancer patients: risk factors and outcome in 134 episodes prior to and after introduction of quinolones into infection prevention in neutropenia.

A total of 134 episodes of staphylococcal bacteremia (SBE) appearing among 9987 admissions, and 979 episodes of bacteremia in cancer patients within 5 years, were analyzed for risk factors, clinical course and outcome; 64 were monomicrobial and 70 polymicrobial. The most frequent risk factors were acute leukemia, catheter insertion, long-lasting neutropenia, and prior prophylaxis with quinolones. There was no significant difference between polymicrobial and monomicrobial SBE in risk factors. The two groups differed only in the source of bacteremia (gastrointestinal and respiratory-tract infections were more common in monomicrobial SBE) and etiology-Staphylococcus aureus appeared more frequently in monomicrobial than in polymicrobial bacteremia (20.3% compared to 4.3%, P < 0.05). More complications (14.3%) such as abscesses, endocarditis, etc. appeared in the group of polymicrobial SBE (P < 0.05). No difference was observed in clinical course and outcome between monomicrobial and polymicrobial SBE. The incidence of SBE has increased since 1991, when quinolones were first used in prophylaxis in afebrile neutropenia at our center; however, the infection-associated mortality in monomicrobial SBE was low (4.3%).

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.