Alison G. Freifeld

Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

Prospective Surveillance for Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients, 2001–2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database

BACKGROUND The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. METHODS The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. RESULTS We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. CONCLUSIONS In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

Invasive fungal infections among organ transplant recipients: results of the transplant-associated infection surveillance network (Transnet)

BACKGROUND Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. METHODS The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. RESULTS During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. CONCLUSIONS We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

Clinical practice guidelines for the management of patients with histoplasmosis: 2007 Update by the Infectious Diseases Society of America

Evidence-based guidelines for the management of patients with histoplasmosis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 30:688-95). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. Since 2000, several new antifungal agents have become available, and clinical trials and case series have increased our understanding of the management of histoplasmosis. Advances in immunosuppressive treatment for inflammatory disorders have created new questions about the approach to prevention and treatment of histoplasmosis. New information, based on publications from the period 1999-2006, are incorporated into this guideline document. In addition, the panel added recommendations for management of histoplasmosis in children for those aspects that differ from aspects in adults.

A Double-Blind Comparison of Empirical Oral and Intravenous Antibiotic Therapy for Low-Risk Febrile Patients with Neutropenia during Cancer Chemotherapy

BACKGROUND Among patients with fever and neutropenia during chemotherapy for cancer who have a low risk of complications, oral administration of empirical broad-spectrum antibiotics may be an acceptable alternative to intravenous treatment. METHODS We conducted a randomized, double-blind, placebo-controlled study of patients (age, 5 to 74 years) who had fever and neutropenia during chemotherapy for cancer. Neutropenia was expected to be present for no more than 10 days in these patients, and they had to have no other underlying conditions. Patients were assigned to receive either oral ciprofloxacin plus amoxicillin-clavulanate or intravenous ceftazidime. They were hospitalized until fever and neutropenia resolved. RESULTS A total of 116 episodes were included in each group (84 patients in the oral-therapy group and 79 patients in the intravenous-therapy group). The mean neutrophil counts at admission were 81 per cubic millimeter and 84 per cubic millimeter, respectively; the mean duration of neutropenia was 3.4 and 3.8 days, respectively. Treatment was successful without the need for modifications in 71 percent of episodes in the oral-therapy group and 67 percent of episodes in the intravenous-therapy group (difference between groups, 3 percent; 95 percent confidence interval, -8 percent to 15 percent; P=0.48). Treatment was considered to have failed because of the need for modifications in the regimen in 13 percent and 32 percent of episodes, respectively (P<0.001) and because of the patients inability to tolerate the regimen in 16 percent and 1 percent of episodes, respectively (P<0.001). There were no deaths. The incidence of intolerance of the oral antibiotics was 16 percent, as compared with 8 percent for placebo (P=0.07). CONCLUSIONS In hospitalized low-risk patients who have fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin-clavulanate is safe and effective.

Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients

Context Cytomegalovirus is a common opportunistic infection among recipients of organ transplants. Contribution This meta-analysis summarizes 17 randomized trials of antiviral therapy for recipients of liver and kidney allografts. Universal prophylaxis for all high-risk patients and preemptive treatment for patients who had the virus detected during periodic monitoring reduced cytomegalovirus organ disease and allograft rejection more than did no treatment or placebo. Only universal prophylaxis reduced bacterial and fungal infections and death. Cautions Most trials were small and were not blinded. Implications Although the authors prefer universal prophylaxis over preemptive treatment, they recommend a large confirmatory trial to directly compare the 2 strategies. The Editors Despite advances in diagnosis and therapy, cytomegalovirus (CMV) is the most common opportunistic viral infection occurring after solid organ transplantation (1, 2). It causes substantial morbidity, prolongs hospital stay, increases health care costs, and increases risk for death (3-7). It is also associated with many adverse indirect effects, such as opportunistic bacterial and fungal infections (8-15), graft rejection (16-18), atherosclerosis (19-21), and post-transplantation lymphoproliferative disorders (22, 23). Two distinct approaches, preemptive and prophylactic, are used to prevent CMV disease in solid organ transplant recipients (24). The preemptive approach involves periodic monitoring of patients for development of CMV viremia (based on detection by culture, pp65 antigen [pp65], or polymerase chain reaction [PCR]) and therapeutic intervention when the virus is detected. The prophylactic approach involves systematic administration of an antiviral drug to all patients at higher risk (based on pretransplantation CMV seropositive status of either the donor or the recipient) for CMV infection. Both approaches have been used in different transplantation centers throughout the world, and no head-to-head comparison trials have resolved which strategy is optimal for preventing disease caused by CMV. Furthermore, the efficacy of each strategy in preventing the associated adverse indirect effects of CMV infection is controversial (1, 24). More important, the potential clinical superiority of using newer drugs with the most potent in vitro activity against CMV, such as ganciclovir and valganciclovir, rather than the older and less potent agent acyclovir still needs confirmation. In this systematic review, we summarize data about the efficacy of preemptive and universal prophylaxis strategies in preventing the development of organ disease associated with CMV infection in solid organ transplant recipients. We also evaluate whether these strategies prevent adverse indirect effects associated with CMV infection and try to assess the magnitude of the preventive effect associated with individual antiviral agents. Methods Literature Search We followed QUOROM guidelines for conducting and reporting systematic reviews (25). Specifically, we searched for English-language and nonEnglish-language reports of published and unpublished trials listed in MEDLINE (1966May 2005), EMBASE (1966May 2005), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (2004, Issue 4), and Evidence-Based Medicine (2000May 2005). We used the following keywords in the electronic searches: cytomegalovirus, transplantation, preemptive, prophylaxis, prevention, renal, kidney, kidney-pancreas, pancreas, hepatic, liver, small bowel, cardiac, heart, lung, heart-lung, other combined transplantations, and antiviral medications. When complementary information was required, one of us contacted the original authors of the included trials. The published results of references 66 and 67 were modified after contacting the authors. We also contacted pharmaceutical companies that have manufactured or are still producing anti-CMV medications to help identify unpublished trials and reviewed the abstracts from the 2003 and 2004 meetings of the Infectious Disease Society of America, Interscience Conference on Antimicrobial Agents and Chemotherapy, and American Transplantation Congress. Study Selection Two investigators independently screened the titles and abstracts of studies to identify those that met a priori-defined inclusion criteria. We selected randomized, controlled trials that evaluated the prevention of CMV in solid organ transplant recipients. We excluded trials that 1) used less than 2 g of acyclovir per day for universal prophylaxis; 2) used less than 3 g of ganciclovir per day for universal prophylaxis; 3) gave universal prophylaxis for fewer than 60 days; 4) gave preemptive therapy for fewer than 14 days; 5) aimed to test the efficacy of immunoglobulin, alone or in combination with antiviral drugs, as the primary end point; or 6) had a control group in which an active therapy was used to prevent CMV infections. Study Quality and Data Extraction We independently evaluated the quality of the trials with the Jadad scale, which includes yes-or-no items for scoring the reported method and concealment of randomization, the reported blinding of patients and investigators to the allocation of the intervention, and the reporting of patients who dropped out or withdrew from the study (26). We defined CMV organ disease as CMV viremia (defined by positive culture, pp65, or PCR) plus clinical or histologic involvement of an organ due to the same infection. Recognizing that CMV syndrome (symptomatic viremia with no end-organ involvement) and CMV organ disease are distinct entities with different rates of associated morbidity and mortality, we included only patients with CMV organ disease in the case definition. We disagreed in only 1 case definition and resolved the disagreement through consensus. (Of note, the sample size of each trial remained the same because patients with CMV syndrome were included in the sample without CMV disease.) We also abstracted data regarding the following secondary end points: allograft rejection, allograft loss, bacterial and fungal infections, non-CMV viral infections, time to CMV organ disease, CMV recurrence, CMV resistance, and death. Statistical Analysis We pooled data by using both the MantelHaenszel fixed-effects model (27) and the random-effects model of DerSimonian and Laird (28). In the absence of statistically significant heterogeneity (P< 0.10), we reported the results of the fixed-effects model. For studies with no outcome events (that is, no incidence of CMV organ disease) in 1 group, 0.50 was added to all cells. Because of the asymptotic approximation used with the aforementioned methods, we also examined the data by using the exact method, version 6 (StatXact, Cytel Software, Cambridge, Massachusetts). The results from the exact methods were similar to those from the asymptotic methods, and therefore, only the results from the asymptotic tests are presented. We used the BreslowDay method to assess statistical heterogeneity (29) and I2 analysis to detect the magnitude of variation attributable to heterogeneity rather than to chance (30). To estimate possible publication bias, we used the Egger regression approach (31). We planned a priori stratified analyses in the following subgroups: CMV serology mismatch (positive in donors and negative in recipients), type of allograft, type of CMV diagnostic method, type of immunosuppression regimen, type of drug used to prevent CMV, and length of follow-up. We also did several post hoc sensitivity analyses that excluded data from certain studies. We found that participants in one good-quality trial involving heart transplant recipients had been given universal prophylaxis for fewer than 60 days (32). We found 2 trials that met inclusion criteria that had different characteristics from those reported in most of the selected studies; 1 of these trials only included patients with donor-positive/recipient-negative CMV serostatus (33), and the other had used an acyclovir dosage of 2 g/d (34). Finally, we found 3 trials that met inclusion criteria whose authors could not be contacted for clarifications about discrimination between CMV syndrome and organ disease (35-37). Analyses were done with SAS, version 9.1 (SAS Institute, Inc., Cary, North Carolina), and Forest plots were built with Comprehensive Meta-Analysis, version 2 (BioStat, Englewood, New Jersey). Role of the Funding Source No funding was received in support of this study. Results The process of study selection is shown in Figure 1. Two studies (38, 39) met exclusion criterion 1, 1 study (40) met exclusion criterion 2, 4 studies (41-44) met exclusion criterion 3, and 14 studies (45-58) met exclusion criterion 6. A list of studies that met exclusion criterion 5 is available from the authors on request. Eleven trials involving 1582 patients (14, 32-37, 59-62) were selected for the universal prophylaxis analysis, and 6 trials involving 398 patients (63-68) were selected for the preemptive therapy analysis. One of the 11 universal prophylaxis trials only administered prophylaxis for 28 days (32). Three trials were double-blind (32, 35, 59), and 6 trials were placebo-controlled (14, 32, 35, 37, 59, 62). Allocation concealment was adequate in 5 trials (14, 32, 35, 59, 62) and was unclear or inadequate in the remaining trials. We assessed the length of follow-up as adequate in 7 trials (14, 33, 35, 59, 63-65) but noted that most trials did not report the exact timing of outcome events. Figure 1. Study selection. The characteristics of selected trials are shown in the Table. The median number of patients enrolled per trial was 73 (range, 32 to 616) for the universal prophylaxis analysis and 64 (range, 36 to 113) for the preemptive analysis. The proportion of patients with donor-positive/recipient-negative CMV serostatus and recipient-positive CMV serostatus (higher risk for CMV infection) were, respectively, 11.6% and 86.2%

Executive Summary: Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

NIH conference. Varicella-zoster virus infections. Biology, natural history, treatment, and prevention.

During the last 10 years, there have been major advances in the understanding of varicella-zoster virus and the diseases it causes. The molecular biology of the virus is being unraveled with the aid of new molecular technologies. Varicella, usually a benign manifestation of primary infection, and zoster, a result of reactivation of latent virus, can cause considerable morbidity in patients with immune impairment. Antiviral drugs, especially acyclovir, ameliorate severe infections but still have little role in the treatment of most normal patients with varicella or zoster. Varicella can be prevented when necessary by patient isolation and passive prophylaxis with varicella-zoster immune globulin. An experimental live vaccine also prevents varicella, but problems regarding its virulence for immunosuppressed patients and the durability of the protective response are still being addressed.Abstract During the last 10 years, there have been major advances in the understanding of varicella-zoster virus and the diseases it causes. The molecular biology of the virus is being unraveled wi...

Monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem.

PURPOSE To compare the efficacy of ceftazidime and imipenem monotherapy for fever and neutropenia, and to determine whether fewer antimicrobial modifications (additions or changes) are required by the broader-spectrum agent, imipenem. PATIENTS AND METHODS Adult and pediatric patients undergoing chemotherapy for solid tumors, leukemias, or lymphomas were randomized to receive open-label ceftazidime or imipenem on presentation with fever and neutropenia. Success with or without modifications of the initial antibiotic was defined as survival through neutropenia; failure was death due to infection. Comparisons were based on numbers of modifications made to each monotherapy during the course of neutropenia, in patients stratified as having unexplained fever or a documented infection. RESULTS Among 204 ceftazidime and 195 imipenem recipients, the overall success rate with or without modification was more than 98%, regardless of initial antibiotic regimen. Modifications occurred in half of all episodes, primarily in patients with documented infections on either monotherapy. Antianaerobic agents were more frequently added to ceftazidime (P < .001), but addition of other antibiotics, including vancomycin and aminoglycosides, was similar between the two monotherapy groups. Imipenem therapy was associated with significantly greater toxicity, manifested by Clostridium difficile-associated diarrhea and by nausea and vomiting, which required discontinuation of imipenem in 10% of recipients. CONCLUSION Ceftazidime and imipenem are both effective in the management of fever and chemotherapy-related neutropenia, provided that modifications are made in response to clinical and microbiologic data that emerge during the course of neutropenia. Imipenem, despite its broader antimicrobial spectrum, does not significantly decrease the overall need for antibiotic modifications and is more often complicated by gastrointestinal toxicity.

Invasive Non-Aspergillus Mold Infections in Transplant Recipients, United States, 2001-2006

Recent reports describe increasing incidence of non-Aspergillus mold infections in hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. To investigate the epidemiology of infections with Mucorales, Fusarium spp., and Scedosporium spp. molds, we analyzed data from the Transplant-Associated Infection Surveillance Network, 23 transplant centers that conducted prospective surveillance for invasive fungal infections during 2001-2006. We identified 169 infections (105 Mucorales, 37 Fusarium spp., and 27 Scedosporium spp.) in 169 patients; 124 (73.4%) were in HCT recipients, and 45 (26.6%) were in SOT recipients. The crude 90-day mortality rate was 56.6%. The 12-month mucormycosis cumulative incidence was 0.29% for HCT and 0.07% for SOT. Mucormycosis incidence among HCT recipients varied widely, from 0.08% to 0.69%, with higher incidence in cohorts receiving transplants during 2003 and 2004. Non-Aspergillus mold infections continue to be associated with high mortality rates. The incidence of mucormycosis in HCT recipients increased substantially during the surveillance period.