Miriam Weinberger

Antifungal Prophylaxis in Cancer Patients After Chemotherapy or Hematopoietic Stem-Cell Transplantation: Systematic Review and Meta-Analysis

PURPOSEnTo evaluate the effect of antifungal prophylaxis on all-cause mortality as primary outcome, invasive fungal infections (IFIs), and adverse events. Many studies have evaluated the role of antifungal prophylaxis in cancer patients, with inconsistent conclusions.nnnMETHODSnWe performed a systematic review and meta-analysis of randomized, controlled trials comparing systemic antifungals with placebo, no intervention, or other antifungal agents for prophylaxis in cancer patients after chemotherapy. The Cochrane Library, MEDLINE, conference proceedings, and references were searched. Two reviewers independently appraised the quality of trials and extracted data.nnnRESULTSnSixty-four trials met inclusion criteria. Antifungal prophylaxis decreased all-cause mortality significantly at end of follow-up compared with placebo, no treatment, or nonsystemic antifungals (relative risk [RR], 0.84; 95% CI, 0.74 to 0.95). In allogeneic hematopoietic stem-cell transplantation (HSCT) recipients, prophylaxis reduced all-cause mortality (RR, 0.62; 95% CI, 0.45 to 0.85), fungal-related mortality, and documented IFI. In acute leukemia patients, there was a significant reduction in fungal-related mortality and documented IFI, whereas the difference in mortality was only borderline significant (RR, 0.88; 95% CI, 0.74 to 1.06). Prophylaxis with itraconazole suspension reduced documented IFI when compared with fluconazole, with no difference in survival, and at the cost of more adverse events. On the basis of two studies, posaconazole prophylaxis reduced all-cause mortality (RR, 0.74; 95% CI, 0.56 to 0.98), fungal-related mortality, and IFI when compared with fluconazole.nnnCONCLUSIONnAntifungal prophylaxis decreases all-cause mortality significantly in patients after chemotherapy. Antifungal prophylaxis should be administered to patients undergoing allogeneic HSCT, and should probably be administered to high-risk acute leukemia patients.

Listeria monocytogenes infection in Israel and review of cases worldwide.

Listeria monocytogenes, an uncommon foodborne pathogen, is increasingly recognized as a cause of life-threatening disease. A marked increase in reported cases of listeriosis during 1998 motivated a retrospective nationwide survey of the infection in Israel. From 1995 to 1999, 161 cases were identified; 70 (43%) were perinatal infections, with a fetal mortality rate of 45%. Most (74%) of the 91 nonperinatal infections involved immunocompromised patients with malignancies, chronic liver disease, chronic renal failure, or diabetes mellitus. The common clinical syndromes in these patients were primary bacteremia (47%) and meningitis (28%). The crude case-fatality rate in this group was 38%, with a higher death rate in immunocompromised patients.

Nontyphoid Salmonella Bacteremia: Age-Related Differences in Clinical Presentation, Bacteriology, and Outcome

In a retrospective study, 80 episodes of nontyphoid salmonella (NTS) bacteremia in children were compared with 55 episodes in adults over a 10-year period. The study disclosed major differences in the predisposition, clinical presentation, and outcome as well as the microbiology of NTS bacteremia in relation to age. Adults were more likely than children to have predisposing diseases (95% vs. 15%, respectively; P < .0001) and to receive prior medications (95% vs. 23%, respectively; P < .0001), particularly immunosuppressive agents (58% vs. 5%, respectively; P < .0001). In most adults (67%), NTS infection presented as a primary bacteremia and was associated with a high incidence of extraintestinal organ involvement (34%) and a high mortality rate (33%). In children, NTS bacteremia was usually secondary to gastroenteritis (75%) and caused no fatalities. Although group D Salmonella (78%) and the serovar Salmonella enteritidis were the predominant isolates from adults, the emergence of infections due to group C Salmonella (46%) and the serovar Salmonella virchow in children was noted.

Possible benefit of intravenous immunoglobulin therapy in a lung transplant recipient with West Nile virus encephalitis

Abstract: During the summer of 2000, a countrywide epidemic of West Nile fever (WNF) occurred in Israel, with 417 confirmed cases and 35 deaths. Immunosuppressed patients had a 31% case‐fatality rate, which was significantly higher compared to non‐immunosuppressed patients (13%). We describe a 42‐year‐old male lung‐transplant recipient with serologically confirmed West Nile virus (WNV) encephalitis and deteriorating level of consciousness. He was treated with 0.4u2003g/kg intravenous immunoglobulin preparation from Israeli donors that contained a high titer of anti‐WNV antibodies (1u2003:u20031600). The patient showed rapid improvement within 24u2003h and complete disappearance of signs and symptoms within 48u2003h. This is the second case of an immunosuppressed patient responding to the same preparation of intravenous immunoglobulins. Larger studies are required in order to establish the therapeutic role of immunoglobulins in patients with WNF.

Patterns of infection in patients with aplastic anemia and the emergence of Aspergillus as a major cause of death.

Patterns of infection were studied in 150 patients with aplastic anemia who were admitted to the Clinical Hematology Branch, National Institutes of Health, between January 1978 and December 1989 for immunosuppressive therapy. Sixty percent of the patients were males, 71% were white, their mean age was 33.6 years (median, 27.5; range, 1-75), and 83% had severe aplastic anemia. One hundred three patients developed 1 or more febrile episodes during the study period. The risk factors for developing a febrile episode included a low Absolute Neutrophil Count (ANC) and Absolute Monocyte Count (AMC) at admission and the presence of an indwelling central venous catheter (Hickman-Broviack or Port-A-Cath). A total of 289 febrile events were studied, including unexplained fever (FUO) in 89 (31%), microbiologically documented infection (MBDI) in 137 (47%), and clinically documented infection (CDI) in 63 patients (22%). Compared to documented infections (MBDI) or CDI), FUO events were associated with a higher frequency of rigors, signs and symptoms of serum sickness, and treatment regimens known to cause fevers. None of the FUO events had a fatal outcome, even if the antibiotic therapy was discontinued before day 7. Among CDI events, bacteria were the most commonly defined etiologic agent (67%), followed by fungi (23%), viruses (7%), and parasites (3%). The patterns of bacterial infections in patients with aplastic anemia were similar to those observed in patients with cancer-related neutropenia. Twenty-one patients (15%) developed invasive fungal infections (aspergillus, 11; candida, 7; and both, 3), which were fatal in 19 (90%). Fungal infections accounted for 30% of the secondary infectious events and for 55% of fatal infectious events. The only identifiable risk factors for developing a fungal infection were the degree of neutropenia and monocytopenia at initial admission or final evaluation. Invasive pulmonary aspergillosis developed despite empirical amphotericin B therapy and was associated with a high incidence of fatal pulmonary hemorrhage (10 of 13 patients [77%]). Infection was responsible for 36 (62%) of the deaths observed during the study period and hemorrhage alone for 4 (7%). However, 20 of the patients who died of infection had concomitant hemorrhage. No significant drop in ANC, AMC, or platelet count could be demonstrated during a fatal infectious event as compared to a nonfatal infectious event. Invasive fungal infections, predominantly with aspergillus and candida, emerged in our study as the major causes of mortality in patients with aplastic anemia. Without bone marrow recovery the prognosis associated with invasive mycoses was grave.

Time to Blood Culture Positivity as a Marker for Catheter-Related Candidemia

ABSTRACT Candida spp. are important causes of nosocomial bloodstream infections. Around 80% of patients with candidemia have an indwelling central venous catheter (CVC). Determining whether the CVC is the source of candidemia has implications for patient management. We assessed whether the time to detection of Candida species in peripheral blood (time to positivity [TTP]) can serve as a marker for catheter-related candidemia. Prospective surveillance of Candida bloodstream infection was conducted in two medical centers. TTP was recorded by the BacT/Alert automated system. Sixty-four candidemia episodes were included. Fifty patients (78%) had an indwelling CVC. Thirteen patients (20.3%) had definite catheter-related candidemia. TTP was shorter for definite catheter-related candidemia (17.3 ± 2 h) than that for candidemia from other sources (38.2 ± 3 h; P < 0.001). A TTP cutoff of 30 h was 100% sensitive and 51.4% specific for catheter-related candidemia (area under the receiver-operator characteristic curve of 0.76). We conclude that TTP in peripheral blood is a sensitive but nonspecific marker for catheter-related candidemia and that a TTP of more than 30 h can help exclude an intravascular catheter as the possible source of candidemia.

Antibiotic Exposure as a Risk Factor for Fluconazole-Resistant Candida Bloodstream Infection

ABSTRACT Recent exposure to azoles is an important risk factor for infection with fluconazole-resistant Candida spp., but little is known about the role of antibacterial drug exposure in the emergence of drug-resistant Candida. We did a prospective nationwide surveillance study of candidemia in Israel and analyzed the propensity score-adjusted association between antifungal and antibacterial drug exposure and bloodstream infection with C. glabrata and fluconazole-resistant Candida isolates. Four hundred forty-four episodes of candidemia (450 Candida isolates, 69 [15%] C. glabrata isolates, and 38 [8.5%] fluconazole-resistant isolates) from 18 medical centers in Israel were included. C. glabrata bloodstream infection was strongly associated with recent metronidazole exposure (odds ratio [OR], 3.2; P < 0.001). Infection with a fluconazole-resistant isolate was associated with exposure to carbapenems, trimethoprim-sulfamethoxazole, clindamycin, and colistin (odds ratio, 2.8; P = 0.01). The inclusion of antibacterial drug exposure in a multivariable model significantly enhanced the models predictive accuracy for fluconazole-resistant Candida bloodstream infection. Our findings may be relevant to the selection of empirical antifungal treatment and broaden the scope of antibiotic-associated collateral damage.

Acinetobacter baumannii: emergence and spread in Israeli hospitals 1997-2002

n Summaryn n The incidence of multi-drug-resistant Acinetobacter baumannii bloodstream infections (BSIs) increased two- to four-fold in three Israeli hospitals between 1997 and 2002, accounting for 3.5–18% of all hospital-acquired BSIs. This was associated with increasing carbapenem resistance reaching 35–54%, and by a dramatic increase in carbapenem consumption. In-hospital fatality rates ranged between 47% and 58% and were significantly higher than those seen with other nosocomial Gram-negative pathogens. A. baumannii was not restricted to intensive care units, but had spread to all hospital wards. Multi-drug-resistant A. baumannii has the potential to reach endemicity in hospitals and warrants more vigorous and innovative efforts to limit its spread.n n

Recent trends in the epidemiology of non-typhoid salmonella and antimicrobial resistance: the Israeli experience and worldwide review

Purpose of review The epidemiology of non-typhoid Salmonella has changed significantly since the turn of the century. Interestingly, non-typhoid Salmonella epidemiology in Israel mirrors some important global trends, and these new trends are reviewed. Recent research that has shed more light on the true toll of non-typhoid Salmonella epidemic and resistance is also summarized. Recent findings After more than three decades of a persistent rise, reports from Israel, the US, and the UK indicate that the trend may be reversed and the incidence of NTS illnesses is starting to decline. In contrast, the rates of resistance and multidrug resistance are increasing and expanding worldwide. Of major concern are the increasing rates of multidrug resistance in Salmonella typhimurium, particularly definitive phage-type 104, the alarming increase in low-level ciprofloxacin resistance among several non-typhoid Salmonella serotypes, and the upsurge of high-level ciprofloxacin resistance, mainly in Taiwan. In Israel, high rates of resistance were reported for Salmonella virchow, which accounts for 16% of non-typhoid Salmonella illnesses, and is highly invasive in children. The true burden of Salmonella illnesses in the US was calculated as 520 cases per 100 000, compared with an annual incidence of 13.4 per 100 000 of laboratory confirmed cases. Hospitalization and death rates were 20% and 0.6%, respectively. Infection with resistant non-typhoid Salmonella isolates, and particularly S. typhimurium, increases the likelihood of hospitalization and death. Summary Many important trends of non-typhoid Salmonella epidemiology are not restricted to a single geographic location, but spread worldwide, reflecting the global nature of the epidemic. This epidemic imposes a heavy burden worldwide.

Epidemiology of bacteremia episodes in a single center: increase in Gram-negative isolates, antibiotics resistance, and patient age

Increased resistance among isolates causing bacteremia constitutes a major challenge to medical practitioners and institutions. Variability between institutes is substantial, and requires the individual analysis of local trends. An eight-year (1997–2004) surveillance study of episodes of bacteremia was conducted in an 850-bed university hospital in central Israel. Trends of incidence, resistance, age, and mortality were analyzed. We studied 6,096 patient-unique episodes of bacteremia, of which, 2,722 (45.3%) were nosocomial and 523 (9.2%) involved children less than 18xa0years of age. The overall incidence of bacteremia episodes has increased over the study years by 39% and the patient mean age by 7.5xa0years. Gram-negative organisms accounted for 72% of hospital-acquired cases and 69% of community-acquired cases. There was a substantial increase in the incidence of nosocomial episodes, predominantly due to Gram-negative isolates, mainly Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. Increased resistance to broad-spectrum antibiotics was noted among Gram-negative organisms, including quinolones (in K. pneumoniae), imipenem (A. baumannii and P. aeruginosa), piperacillin-tazobactam (K. pneumoniae), and amikacin (A. baumannii and P. aeruginosa). Increased resistance to oxacillin among coagulase-negative staphylococci was also noted. The all-cause mortality rates showed a significant rise. The patient age, intensive care unit (ICU) stay, and hospital acquisition were independently associated with mortality. We describe an increase in the incidence and resistance of Gram-negative organisms causing bacteremia and concomitant ageing of the patients with bacteremia. Similar patterns have been reported from other localities, and are of real concern.