Prevention of febrile neutropenia in cancer patients by probiotic strain Enterococcus faecium M-74. Pilot study phase I.

Febrile neutropenia (FN) remains a potentially life-threatening complication of anticancer chemotherapy. Bacterial translocation via intestinal mucosa is a significant mechanism of FN development. Competitive inhibition of bowel colonization by pathogenic microorganisms by lactic acid bacteria could be a useful prevention of FN. The aim of the study was the evaluation of dose and safety of probiotic strain Enterococcus faecium M-74 enriched with organic selenium in patients with solid and hematological malignancies. Eleven (9 M/2F) patients were included in the study. In the first phase six patients with germ cell tumors treated by chemotherapy were included. They received prophylaxis by nonpathogenic strain E. faecium M-74 during 2 cycles of chemotherapy. The planned daily dose was 6 x 10(9) bacteria. Regarding the insufficient colonization of the gut, the dose was further increased up to 18 x 10(9) tid. After safety evaluation, five patients were included with relapse of acute leukemia. In patients with germ cell cancer, severe neutropenia G3/4 was noted in 10 of 12 cycles of chemotherapy. The febrile episode was not observed in any of the patients. The gut colonization by enterococci reaches 10(6) CFU/g stool. In 5 patients with acute leukemia during 127 days of severe neutropenia 12 febrile episodes occurred. There was not noted any febrile episode or infection provoked by the tested strain. Tolerance of therapy was excellent without significant undesirable effects. Optimal dose was assessed and safety of probiotic strain was evaluated in neutropenic patients with solid, or hematological malignancies. Based on these results we plan phase II study to evaluate the effectiveness of this strain in FN prophylaxis.

Nosocomial breakthrough fungaemia during antifungal prophylaxis or empirical antifungal therapy in 41 cancer patients receiving antineoplastic chemotherapy: analysis of aetiology risk factors and outcome.

Forty-one episodes of breakthrough fungaemia occurring over a 7.5 year period in the National and St Elizabeth's Cancer Institutes in Bratislava, Slovakia, were analysed. Five of them occurred during prophylaxis with fluconazole (one Torulopsis glabrata, one Hansenula anomala, two Candida krusei and one Candida parapsilosis), ten with itraconazole (three Trichosporon pullulans, one Trichosporon beigelii, one Cryptococcus laurentii, three Candida albicans and two T. glabrata), 11 during prophylaxis with ketoconazole (one Candida norvegenesis, one C. parapsilosis, one C. krusei, one Candida tropicalis, five C. albicans, one Candida stellatoidea and one C. laurentii and 15 during empirical therapy with amphotericin B (ten C. albicans, two T. beigelii and three Candida lusitaniae). The most frequent risk factors for breakthrough fungaemia were neutropenia, previous therapy with multiple antibiotics and recent catheter insertion. Comparing these episodes with 38 non-breakthrough fungaemias (appearing at the same institute in the same period) differences in certain risk factors were noted: breakthrough fungaemias were more frequently observed in patients with acute leukaemia (39.0% vs 5.2%, P < 0.001), mucositis (34.2% vs 13.1%, P < 0.05), prophylaxis with quinolones (58.5% vs 15.8%, P < 0.0001) and catheter-associated infections (29.3% vs 2.6%, P < 0.003). In this subgroup overall mortality (36.6% vs 28.8%) or early attributable mortality (22.0% vs 23.6%) were not significantly different.

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%).

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.

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%).

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 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.

Funguria in cancer patients: analysis of risk factors, clinical presentation and outcome in 50 patients.

Fifty cancer patients with funguria of > 10(5) CFU/ml, dysuria and leukocyturia were retrospectively analyzed for etiology, risk factors and outcome. In 72% of cases Candida albicans and in 28% non-albicans Candida spp. (Candida krusei, Candida tropicalis) and non-Candida spp. yeasts (Blastoschizomyces capitatus) were isolated. Torulopsis glabrata was not found among these patients. The most frequent risk factors were: antibiotic therapy with more than one antibiotic agent (96%), concomitant fungal infection in other localizations than the urinary tract (36%), colonization with the same species (48%), catheterization with urinary catheter or nephrostomy (46%), prophylaxis with quinolones (50%) and previous therapy with corticosteroids (72%). Structural or anatomic malformations of the urinary tract (26%), neutropenia (28%), antifungal prophylaxis with azoles (22%), and diabetes mellitus (12%) were less frequently seen. Thirty of 36 patients treated with systemic antifungals were cured and six were not.

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).

Vancomycin plus imipenem ceftazidime or ciprofloxacin in second line therapy in patients with febrile neutropenia not responding to first line therapy.

137 patients with febrile neutropenia after cytotoxic therapy not responding to ceftazidime plus or ceftriaxone plus netilmicin in received additionally to the previous combination either vancomycin alone or combined with another anti-gram-negative compound: imipenem in those treated prophylactically with ofloxacin and ciprofloxacin in those without prophylaxis. The addition of vancomycin to the previously ineffective combination of a third generation cephalosporin plus aminoglycoside, and replacement of ceftriaxone plus netilmicin with ceftazidime plus amikacin plus vancomycin or with ceftazidime plus vancomycin seems to be less effective (71.8-75 vs. 87.5-90.9%, p < 0.02) and more toxic (20.5-7.2 vs. 0-5%, p < 0.0005) than vancomycin in combination with a different anti-gram-negative compound as previously used: imipenem or ciprofloxacin.

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

Ninety-nine patients with 101 bacteraemic episodes due to Pseudomonas aeruginosa (PA) within 6 years were divided into two groups according to their resistance to imipenem; of these 91 episodes were due to imipenem-sensitive (ISPA) and 10 due to imipenem-resistant (IRPA) strains. Risk factors, clinical course and outcome were evaluated and compared in the two groups. Acute leukaemia, long-lasting neutropenia, previous therapy with amikacin, third-generation cephalosporins, imipenem and prophylaxis with quinolones were significantly more frequently associated with IRPA than with ISPA. Imipenem-resistant PA bactereamias were associated with a higher incidence of septic shock (40% vs 19.8%) p. 161 0.02) and death 33.3%) than were ISPA bacteraemias. Since 1992, when first IRPA appeared, the incidence of imipenem-resistance increased tenfold, and in 1994, up to 10% of the PA populations causing bloodstream infections in cancer patients in our centre were imipenem-resistant.

Amphotericin B lipid complex to treat invasive fungal infections in cancer patients: report of efficacy and safety in 20 patients.

20 patients with proven or suspected fungal infections were treated with the amphotericin B lipid complex (ABLC) with a daily dose of 5 mg/kg for 1-25 days. 6 patients died during the therapy due to fungal infection (3) or underlying disease (3). One patient was not evaluable. 13 patients were cured and improved. ABLC was administered in patients with renal disease avoiding the use of conventional amphotericin B (AmB) because of nephrotoxicity or after failure with AmB. Except for hypokalemia persisting after AmB in 5 patients, no systemic adverse reaction appeared. ABLC is a promising, well-tolerated and effective drug for the therapy of fungal infections after the failure of a previous antifungal therapy or after toxic reactions due to AmB.