Bloodstream infections in haematological cancer patients colonized by multidrug-resistant bacteria.

Infections by multidrug-resistant (MDR) bacteria are a worrisome phenomenon in hematological patients. Data on the incidence of MDR colonization and related bloodstream infections (BSIs) in haematological patients are scarce. A multicentric prospective observational study was planned in 18 haematological institutions during a 6-month period. All patients showing MDR rectal colonization as well as occurrence of BSI at admission were recorded. One-hundred forty-four patients with MDR colonization were observed (6.5% of 2226 admissions). Extended spectrum beta-lactamase (ESBL)-producing (ESBL-P) enterobacteria were observed in 64/144 patients, carbapenem-resistant (CR) Gram-negative bacteria in 85/144 and vancomycin-resistant enterococci (VREs) in 9/144. Overall, 37 MDR-colonized patients (25.7%) developed at least one BSI; 23 of them (62.2%, 16% of the whole series) developed BSI by the same pathogen (MDRrel BSI), with a rate of 15.6% (10/64) for ESBL-P enterobacteria, 14.1% (12/85) for CR Gram-negative bacteria and 11.1% (1/9) for VRE. In 20/23 cases, MDRrel BSI occurred during neutropenia. After a median follow-up of 80 days, 18 patients died (12.5%). The 3-month overall survival was significantly lower for patients colonized with CR Gram-negative bacteria (83.6%) and VRE (77.8%) in comparison with those colonized with ESBL-P enterobacteria (96.8%). CR-rel BSI and the presence of a urinary catheter were independent predictors of mortality. MDR rectal colonization occurs in 6.5% of haematological inpatients and predicts a 16% probability of MDRrel BSI, particularly during neutropenia, as well as a higher probability of unfavourable outcomes in CR-rel BSIs. Tailored empiric antibiotic treatment should be decided on the basis of colonization.

Successful management of chronic disseminated candidiasis in hematologic patients treated with high-dose liposomal amphotericin B: a retrospective study of the SEIFEM registry.

PURPOSE: Chronic disseminated candidiasis (CDC) is a complication of Candida infection in immunocompromised patients, involving the liver and spleen, and rarely other organs. The aim of the study is to identify the best antifungal drug for hematologic immunocompromised patients with CDC. METHODS: In this multicentric retrospective study, the charts of 20 patients with CDC following cytotoxic agent protocols for hematological malignancies, diagnosed from 2003 to 2013, were analyzed. The response to systemic antifungal therapy within 90 days from CDC diagnosis and the possible delay in chemotherapy plan, due to the infection, were evaluated. RESULTS: Six patients were treated with high-dose (HD; 5 mg/kg/daily) liposomal amphotericin B (L-AmB), whereas three received standard-dose (SD) L-AmB (3 mg/kg/daily). Azoles were given to six patients; the remaining five were treated with echinocandins. All patients treated with HD L-AmB (6/6-100 %) achieved complete resolution of CDC; one of them had to interrupt the chemotherapy program for the infection. In the SD L-AmB group, treatment failed in the 100 % of cases and one patient had to delay chemotherapy for the infection. Of the six patients who received azoles, two achieved complete resolution of the infection, four experienced treatment failure, and only three performed chemotherapy as planned. Echinocandins treatment resulted in complete resolution of the infection in 2/5 cases, partial response in 2/5 cases, and failure in one case. In this group, 3/5 patients completed chemotherapy as planned. CONCLUSIONS: This study shows that HD L-AmB was particularly effective against CDC in hematologic patients, allowing most patients to continue cytotoxic agent program.

Multicentre surveillance study on feasibility, safety and efficacy of antifungal combination therapy for proven or probable invasive fungal diseases in haematological patients: the SEIFEM real-life combo study.

UNLABELLED: This multicentre observational study evaluated the feasibility, efficacy and toxicity of antifungal combination therapy (combo) as treatment of proven or probable invasive fungal diseases (IFDs) in patients with haematological malignancies. Between January 2005 and January 2010, 84 cases of IFDs (39 proven and 45 probable) treated with combo were collected in 20 Hematological Italian Centres, in patients who underwent chemotherapy or allogeneic haematopoietic stem cell transplantation for haematological diseases. Median age of patients was 34 years (range 1-73) and 37% had less than 18 years. Acute leukaemia was the most common underlying haematological disease (68/84; 81%). The phase of treatment was as follows: first induction in 21/84 (25%), consolidation phase in 18/84 (21%) and reinduction/salvage in 45/84 (54%). The main site of infection was lung with or without other sites. The principal fungal pathogens were as follows: Aspergillus sp. 68 cases (81%), Candida sp. six cases (8%), Zygomycetes four cases (5%) and Fusarium sp. four cases (5%). The most used combo was caspofungin+voriconazole 35/84 (42%), caspofungin + liposomal amphotericin B (L-AmB) 20/84 (24%) and L-AmB+voriconazole 15/84 (18%). The median duration of combo was 19 days (range 3-180). The overall response rate (ORR) was 73% (61/84 responders) without significant differences between the combo regimens. The most important factor that significantly influenced the response was granulocyte (PMN) recovery (P 0.009). Only one patient discontinued therapy (voriconazole-related neurotoxicity) and 22% experienced mild and reversible adverse events (hypokalaemia, ALT/AST increase and creatinine increase). The IFDs-attributable mortality was 17%. This study indicates that combo was both well tolerated and effective in haematological patients. The most used combo regimens were caspofungin + voriconazole (ORR 80%) and caspofungin + L-AmB (ORR 70%). The ORR was 73% and the mortality IFD related was 17%. PMN recovery during combo predicts a favourable outcome. CLINICAL TRIALS REGISTRATION: NCT00906633.

A prospective survey of febrile events in hematological malignancies.

The Hema e-Chart prospectively collected data on febrile events (FEs) in hematological malignancy patients (HMs). The aim of the study was to assess the number, causes and outcome of HM-related FEs. Data were collected in a computerized registry that systematically approached the study and the evolution of FEs developing in a cohort of adult HMs who were admitted to 19 hematology departments in Italy from March 2007 to December 2008. A total of 869 FEs in 3,197 patients with newly diagnosed HMs were recorded. Fever of unidentified origin (FUO) was observed in 386 cases (44.4%). The other causes of FE were identified as noninfectious in 48 cases (5.5%) and infectious in 435 cases (50.1%). Bacteria were the most common cause of infectious FEs (301 cases), followed by fungi (95 cases), and viruses (7 cases). Mixed agents were isolated in 32 episodes. The attributable mortality rate was 6.7% (58 FEs). No deaths were observed in viral infection or in the noninfectious groups, while 25 deaths were due to FUO, 16 to bacterial infections, 14 to fungal infections, and three to mixed infections. The Hema e-Chart provided a complete system for the epidemiological study of infectious complications in HMs.

Molecular analysis of population structure and antibiotic resistance of Klebsiella isolates from a three-year surveillance program in Florence hospitals, Italy.

We report the results of a three-year surveillance program of Klebsiella spp. in six hospitals in Florence (Italy). A total of 172 Klebsiella isolates were identified and typed by AFLP: 122 were K. pneumoniae and 50 were K. oxytoca. Most K. pneumoniae (80%) and K. oxytoca (93%) showed unrelated AFLP profiles. Beside this heterogeneous population structure, we found five small epidemic clonal groups of K. pneumoniae. Four of these groups were involved in outbreak events, three of which occurred in neonatal ICUs. The fifth clonal group spread in three different wards of two hospitals. Only one non-epidemic clonal group of K. oxytoca was detected. The frequencies of isolates with multiple antibiotic resistances increased with time; at the end of the study period, most K. pneumoniae were resistant to all the antibiotics tested. A PCR analysis of seven ertapenem resistant isolates was unable to detect any of the major genes known to underlie carbapenem resistance in K. pneumoniae.

Fatal acute hepatitis C virus infection in patients with hematological malignancies.

Patients in hematology units are at risk of hepatitis C virus infection. In these patients acute infection is reportedly mild, presents only moderately increased ALT levels, is characterized by a significant delay in anti-HCV seroconversion and does not influence the course of the underlying disease. We describe two fatal cases of acute HCV infection occurring in patients with hematologic malignancies and we hypothesize that, in a subset of immunocompromised patients, acute HCV infection may play a still unrecognized but not marginal role in contributing to death. Prospective studies are needed to define the frequency of fatal acute HCV infection among hematologic patients undergoing chemotherapy.

Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey.

A prospective cohort study was conducted in nine hematology wards at tertiary care centres or at university hospitals located throughout Italy from January 2009 to December 2012. All of the cases of bacterial bloodstream infection (BBSI) occurring in adult patients with hematologic malignancies were included. A total of 668 bacterial isolates were recovered in 575 BBSI episodes. Overall, the susceptibility rates of Gram-negative bacteria were 59.1% to ceftazidime, 20.1% to ciprofloxacin, 79.1% to meropenem, 85.2% to amikacin, 69.2% to gentamicin and 69.8% to piperacillin/tazobactam. Resistance to third-generation cephalosporins was found in 98/265 (36.9%) of Enterobacteriaceae isolates. Among Klebsiella pneumoniae strains, 15/43 (34.9%) were resistant to carbapenems. Of 66 Pseudomonas aeruginosa isolates, 46 (69.7%) were multidrug resistant. Overall, the susceptibility rates of Gram-positive bacteria were 97.4% to vancomycin and 94.2% to teicoplanin. Among the monomicrobial cases of BBSI, the 21-day mortality rate was significantly higher for those caused by Gram-negative bacteria compared to those caused by Gram-positive bacteria (47/278, 16.9% vs. 12/212, 5.6%; p < 0.001). Among Gram-negative bacteria, the mortality rate was significantly higher for BBSI caused by K. pneumoniae, P. aeruginosa, and Acinetobacter baumannii. Our results confirm the recently reported shift of prevalence from Gram-positive to Gram-negative bacteria as causative agents of BBSIs among patients with hematologic malignancies and highlight a worrisome increasing frequency in antimicrobial resistance among Gram-negative bacteria.

Fluconazole versus amphotericin B as empirical antifungal therapy of unexplained fever in granulocytopenic cancer patients: a pragmatic, multicentre, prospective and randomised clinical trial.

Amphotericin B, despite its intrinsic servere toxicity, is the most commonly used empirical antifungal therapy in cancer patients with unexplained fever not responding to empirical antibacterial therapy. The aim of this study was to show whether fluconazole was as effective as, and less toxic than, amphotericin, with no effort made to compare the antifungal activity of the two drugs. A group of 112 persistently febrile (> 38 degrees C) and granulocytopenic (< 1000 cells/mm3) cancer patients, not receiving any absorbable antifungal antibiotic for prophylaxis, with a mean age of 27 years (range 1-73 years), undergoing chemotherapy for a variety of malignancies and with a diagnosis of unexplained fever after at least 96 h of empirical antibacterial therapy, were randomised to receive either fluconazole (6 mg/kg/day up to 400 mg/day) or amphotericin B (0.8 mg/kg/day) as empirical antifungal treatment. Patients were required to have normal chest X-rays at randomisation, no previous history of aspergillosis and negative surveillance cultures for Aspergillus. The intention-to-treat analysis showed defervescence and survival without treatment modification in 42 of 56 patients (75%) in the fluconazole group and in 37 of 56 (66%) in the amphotericin B group (P = 0.4). Duration of therapy was 6 days (95% CI = 4-8 days) in both groups. Death occurred in 3 patients (5%) in the fluconazole and in 2 (4%) in the amphotericin B group. No fungal death was documented in either group. Adverse events developed in 18 of 56 patients (32%) in the fluconazole group and in 46 of 56 (82%) in the amphotericin B group (P < 0.001). In the amphotericin B group, 5 patients had treatment discontinued because of toxicity, versus none in the fluconazole group, a difference which approached statistical significance (P = 0.06). This study shows that fluconazole is by far less toxic than amphotericin B and suggests that it might be as effective as amphotericin B, in pragmatical terms and for this specific indication. However, numbers are too small to allow definitive conclusions about efficacy, and the use of fluconazole for this indication remains experimental. Future studies should try to identify patients more at risk of fungal infections, with the aim of individualising antifungal approaches.

Human polyomavirus BK (BKV) load and haemorrhagic cystitis in bone marrow transplantation patients.

Several observations suggest an association between long-lasting haemorrhagic cystitis (HC) in bone marrow transplantation (BMT) recipients and human polyomavirus BK (BKV) reactivation, but no conclusive evidence has been obtained so far. The amount of BKV measured in the urine of BMT patients during an episode of HC was compared with that detected in the urine of BMT patients without HC and of immunocompetent individuals in order to better assess the association of BKV reactivation with HC. For this purpose a quantitative competitive PCR was developed. The application of this assay to clinical samples allowed us to distinguish asymptomatic reactivation both in healthy individuals and in immunocompromised patients from reactivation associated with HC, in almost all cases. Low levels, below the sensitivity of the quantitative assay, were shown in asymptomatic healthy individuals and in about 50% of immunocompromised patients. A significantly higher viral load than in the urine of asymptomatic immunocompromised patients was detected in the urine of patients with HC. These data strengthen the hypothesis that BKV reactivation can cause, together with other factors, the majority of late HC in BMT recipients as well as in patients treated for acute refractory lymphoblastic leukemia.

Monitoring of polyomavirus BK viruria in bone marrow transplantation patients by DNA hybridization assay and by polymerase chain reaction: an approach to assess the relationship between BK viruria and hemorrhagic cystitis.

An association between long-lasting hemorrhagic cystitis (HC) in bone marrow transplantation (BMT) patients and viral infections, mostly with reactivation of the human polyomavirus BK (BKV), is suggested by several previous reports. We have carried out a prospective study in 55 (30 allogeneic, 24 autologous, 1 syngeneic) BMT recipients with the aim of evaluating the role of BKV in this frequent complication after BMT. To overcome the well known difficulties in BK virus isolation in cell cultures, a DNA hybridization assay and the polymerase chain reaction (PCR) were used for the detection and monitoring of viral urinary shedding, respectively. The presence of human polyomavirus JC and adenovirus DNA was also sought in urine specimens. BK viruria was demonstrated in 52.7% of patients (in 53.3% allogeneic and in 54.1% autologous BMT), whereas JCV and adenovirus were seldom present. Seven cases of HC (20% in allogeneic and 4% in autologous BMT) occurred and in all cases the clinical event was associated with BKV urinary shedding. This study suggests that BKV infection alone does not invariably lead to HC in BMT patients; for HC to occur the presence of other, at present unidentified, factors seems to be necessary.

Aplastic anemia due to B19 parvovirus infection in cadaveric renal transplant recipients: an underestimated infectious disease in the immunocompromised host.

Parvovirus B19 has been identified as the etiological agent of "fifth disease" in childhood. It is also a rarely reported cause of anemia in transplanted patients. During a period of 18 months we observed four cases (2 male and 2 female; 53 +/- 4.24 years) of severe aplastic anemia due to parvovirus B19 in kidney transplant patients. The overall incidence of the disease was 6.3% of all our transplanted patients. Symptoms of the disease occurred 22.5 +/- 9.75 days post-operatively. Serum creatinine was 1.5 +/- 0.35 mg/dl. Hb was 6.58 +/- 0.6 g/dl. All patients recovered with 15 days of high doses of commercial immunoglobulins. We conclude that B19 parvovirus infection is probably an underestimated disease in transplant patients. It is a first-period infection, probably donor-transmitted. High dose immunoglobulins are an effective but costly therapy.

Ticarcillin-clavulanic acid plus amikacin versus ceftazidime plus amikacin in the empirical treatment of fever in acute leukemia: a prospective randomized trial.

We evaluated the efficacy of ticarcillin-clavulanic acid plus amikacin (TCA) with ceftazidime plus amikacin (CFA) as empiric therapy of fever in acute leukemia in a total of 127 episodes. The overall success rate of the therapy (survival) was 93% in TCA group and 92% in CFA group. Success without therapy modifications (afebrile at 72 hours) was 39% for TCA, 31% for CFA; success with modifications was 55% and 61% respectively. Failure (death due to documented or presumed infection) was 6% for TCA and 8% for CFA. Differences were not statistically significant. The success without modifications was higher in the group of patients with fever of unknown origin (FUO) than in documented infections (DI), mainly with CFA. No differences were documented in the resistance rate and in clinical outcome during severe neutropenia (ANC <100 microl). In our experience TCA is as effective as CFA as first-line treatment in severe neutropenic patients with acute leukemia, although in both regimens patients with DI are likely to require modifications in treatment.

Incidence and management of proven and probable fungal infections in patients with acute leukemia: a single center experience.

The incidence of fungal infections and the role of liposomal amphotericin B (Ambisome) in proven and probable infections were evaluated in acute leukemic patients, intolerant to conventional amphotericin B. During 1999-2002, 307 febrile episodes occurred in 231 patients. Fungi were responsible for 3% of bloodstream infections. Ambisome was employed in 5 fungal sepsis (1 Candida albicans, 1 C. famata, 1 C. tropicalis, 1 C. krusei, 1 Geotrichum capitatum) 2 Aspergillosis, 2 probable fungal pneumonia cases. A favorable response was achieved in 78% of patients (4 fungemia, 2 aspergillosis, 1 probable), an unfavorable response in 1 C. krusei fungemia and in 1 probable pneumonia. Our antimicrobial pattern documented a high resistance rate to azoles. We concluded that Ambisome is an effective and well tolerated agent and its introduction has changed the outcome for many patients, although in some refractory diseases other strategies must be considered.

Amphotericin B treatment of fungemia due to unusual pathogens in neutropenic patients: report of two cases.

Invasive fungal infections occur frequently in neutropenic patients although only in recent years has the role of emerging fungi been clearly established. We describe two cases of fungemia caused by Trichosporon beigelii and Rhodotorula glutinis respectively in two neutropenic patients with hematological malignancies who were treated with amphotericin B. The first patient, with refractory multiple myeloma, died following massive pneumonia despite therapy with amphotericin B and granulocyte-colony stimulating factor (G-CSF); the second patient, with relapsed acute lymphatic leukemia and persistent fever without any other clinical evidence, finally recovered. Amphotericin B continues to be considered the "gold standard" in the treatment of invasive mycoses although other approaches need to be tested for refractory infections.

The influence of ofloxacin versus trimethoprim-sulfamethoxazole on the aerobic flora in granulocytopenic subjects.

Ofloxacin (300 mg twice a day) and trimethoprim-sulfamethoxazole (TMP-SMZ) (160 mg trimethoprim and 800 mg sulfamethoxazole twice a day) were given prophylactically to 19 adult patients with acute leukemia undergoing induction chemotherapy. The influence of the two regimens on the bacterial aerobic flora was evaluated. Both of the prophylactic regimens conditioned the aerobic microflora of the patients. Both groups acquired new microorganisms, prevalently gram-positive cocci, but also gram-negative bacteria with the TMP-SMZ regimen. Both treatment groups acquired yeasts.

Management of fever in neutropenic patients with acute leukemia: current role of ceftazidime plus amikacin as empiric therapy.

To evaluate the current role of ceftazidime plus amikacin as empiric therapy in the management of fever in neutropenic patients with acute leukemia, we examined 172 febrile episodes in 106 patients enrolled during 1996-98. The overall success rate (survival of neutropenia, both with and without protocol modification) was 90%: 39% without modification and 51% with modification. We documented a significant difference in documented infections (DI) and fever of undetermined origin (FUO): success without modification was lower in DI and higher in FUO. Failure (death due to documented or presumed infection) was recorded in 10% of all episodes. Episodes with severe neutropenia were treated in 48% of cases without modification and in 41% with modification. No significant difference was observed in the status of underlying disease. 33% of gram-negative bacteria responsible for bloodstream infections were resistant to ceftazidime, of which 21% were multiresistant strains. We conclude that initial chemotherapy with ceftazidime plus amikacin remains a reasonable option for treating febrile and prolonged neutropenia, although patients with DI are likely to require additional or modified treatment. The emergence of resistant strains is an increasingly important issue.

Ondansetron versus chlorpromazine for preventing emesis in bone marrow transplant recipients: a double-blind randomized study.

Ondansetron, a selective 5-HT3 antagonist, is known to be effective for preventing emesis induced by cisplatin and other antineoplastic agents. We undertook a randomized double-blind study in a series of bone marrow transplantation (BMT) recipients to assess the antiemetic efficacy and the safety of ondansetron in comparison with chlorpromazine, which was being used at our institution, as the standard antiemetic agent for the conditioning regimen. Forty patients submitted to BMT (21 autologous, 19 allogeneic) were included in the study. Patients were randomly assigned to receive ondansetron (as a loading dose of 8 mg iv one hour before the beginning of the conditioning regimen followed by a continuous infusion of 1 mg per hour for the whole treatment period) or chlorpromazine 60 mg/m2/day given by continuous infusion for the same period (maximum 8 days). Twenty patients were assigned to ondansetron, while 20 were assigned to chlorpromazine. The response rate in terms of antiemetic efficacy and in nausea control was similar between the two treatment groups. On the contrary the two groups differed significantly in regard to side-effects: patients receiving ondansetron experienced significantly less sedation (p = 0.002), the absence of extrapyramidal reactions (p < 0.001) and no need for dose reduction (p < 0.001) as compared with patients treated with chlorpromazine.

An open evaluation of triple antibiotic therapy including vancomycin for febrile bone marrow transplant recipients with severe neutropenia.

Infectious complications still represent a major problem in patients submitted to bone marrow transplant (BMT); approximately 40% of febrile episodes are associated with infection and one-third of these are bacteremias. Opinions about the best appropriate empiric regimens are based on evaluation of cost, potential for adverse side-effects, development of bacterial resistance, prevalent nosocomial infections. In order to assess the clinical and microbiological effectiveness of an aggressive approach, we performed a prospective open study in 72 neutropenic febrile BMT patients, employing a triple antibiotic association including amikacin 500 mg x 8h, ceftazidime 2 g x 8 h, vancomycin 500 mg x 8 h as first-line empiric treatment. For the purpose of this study, a lasting return of temperature to normal and complete disappearance of either clinical or bacteriological signs of infection without any modification of therapy was considered as success; the persistence of fever after 72 hours or a protocol change was considered as failure. Eighty episodes were enrolled during the course of the study; bacteriological evidence of infection was obtained in 23 (28.7%) febrile episodes. Median duration of antibiotic administration and of febrile episodes were 5 and 2 days respectively. Overall response rate based on clinical responses was 87% and 91% in microbiological documented infections. Death due to sepsis nor toxicity were observed. This triple antibiotic combination appears to be a very effective regimen for the empiric treatment of febrile episodes in severely neutropenic BMT recipients.

Chemoprophylaxis of bacterial infections in granulocytopenic patients with ciprofloxacin vs ciprofloxacin plus amoxicillin.

Ciprofloxacin was compared to ciprofloxacin plus amoxicillin as antibacterial prophylaxis in 53 evaluable patients with neutropenic episodes, because an oral penicillin may help to decrease the incidence of gram-positive infections. The two groups were randomized and evaluated in a number of febrile episodes, in days at fever/at risk, in mean interval of first febrile episode, in duration of antibiotic therapy and in causative organisms in febrile episodes. In conclusion, no significant difference was observed between the two groups in prevention of gram-positive bacteremias.

Randomized trial comparing netilmicin plus imipenem-cilastatin versus netilmicin plus ceftazidime as empiric therapy for febrile neutropenic bone marrow transplant recipients.

The aim of this study was to compare the clinical and microbiological efficacy of netilmicin plus imipenem-cilastatin (Net + Imi) vs netilmicin plus ceftazidime (Net + Cef) as empiric antimicrobial therapy in bone marrow transplant (BMT) febrile neutropenic patients (pts). Sixty-six pts undergoing BMT for hematological malignancies and solid tumors were randomized to receive Net + Imi or Net + Cef as first-line antibiotic therapy. A lasting return of temperature to normal and complete disappearance of either clinical or cultural signs of infection without any modification of therapy was considered as improvement; the persistence of fever after 72 hours, the addition of a third antibiotic or a protocol change was considered as failure. Sixty-nine episodes were randomized during the course of the trial; bacteriological evidence of infection was obtained in 17 (25%) febrile episodes. Overall outcome based on clinical responses was as follows: 80% of pts on Net + Imi responded compared to 73% of those on Net + Cef. For microbiologically documented infections response rates were 70% in Net + Imi group and 43% in the Net + Cef group (p = ns). Neither septic death nor toxicity were observed. Both empiric regimens were shown to be effective; Net + Imi appeared to be more effective in microbiologically documented infections but there was no statistical significance. In conclusion, both Net + Imi and Net + Cef are active and safe as empirical treatment of febrile episodes in neutropenic BMT pts.