Kent A. Sepkowitz

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.

Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.

In the past decade, modifications in HCT management and supportive care have resulted in changes in recommendations for the prevention of infection in HCT patients. These changes are fuelled by new antimicrobial agents, increased knowledge of immune reconstitution, and expanded conditioning regimens and patient populations eligible for HCT. Despite these advances, infection is reported as the primary cause of death in 8% of autologous HCT patients and 17 – 20% of allogeneic HCT recipients [3]. The major changes in this document, including changes in recommendation ratings, are summarized here. The organization of this document is similar to the previous guidelines. Specifically, the prevention of exposure and disease among pediatric and adult autologous and allogeneic HCT recipients is discussed. The current recommendations consider myeloablative and reduced intensity conditioning for allogeneic HCT similarly since data on infectious complications following reduced intensity conditioning compared to myeloablative conditioning are sparse [4–7]. However, increased information regarding post-transplant immune recovery highlighting differences between myeloablative and reduced intensity HCT are included. The sections of the document have been re-arranged in an attempt to follow the time course of potential infectious risks for patients receiving HCT. Following the background section, information on hematopoietic cell product safety is provided. The subsequent sections discuss prevention of infection by specific micro-organisms. Following organism-specific information, the sections then discuss means of preventing nosocomial infections as well as “do’s and don’ts” for patients following discharge post-transplant. Finally, information on vaccinations is provided. This will hopefully allow the reader to follow the prevention practices needed from the time a donor is selected until the patient regains immune competence. Several topics are new or expanded from the prior document (Table 2). These include information on multiple organisms which were previously not discussed but have seemingly become more clinically relevant in HCT patients over the past decade. Data, and where possible, recommendations are provided regarding the following organisms that were not included in the previous document: Bordetella pertussis; the polyomaviruses BK and JC; hepatitis A, B, and C viruses; human herpesviruses 6, 7, and 8; human metapneumovirus; human immunodeficiency virus; tuberculosis; nocardiosis; malaria; and leishmaniasis. In recognition of our global society, several organisms are discussed that may be limited to certain regions of the world. Included in that section are also those infections that may be ubiquitous but occur infrequently, such as Pneumocystis jiroveci and Nocardia. Table 2 Summary of Changes compared to the Guidelines published in 2000 [1]. Several other changes should be noted. For bacterial infections, these guidelines now recommend quinolone prophylaxis for patients wth neutropenia expected to last as least 7 days (BI). Additionally, the recommendations for contact precautions (AIII), vaccination (BI), and prophylaxis patients with GVHD (AIII) against Streptococcus pneumoniae have been strengthened. The subsection on central line associated blood stream infections is now in the bacterial section. The vaccination section has been dramatically expanded. Changes include the recommendations for PCV rather than PPSV-23 for pneumococcal vaccination, starting some vaccinations earlier post-transplant, and the addition of recommendations for Varivax, HPV vaccine, and (the non-use of) Zostavax vaccine are included. Two additional appendices were added to provide information on desensitization to sulfa drugs and visitor screening questionnaires. Finally, the dosing appendix has merged both adult and pediatric dosing and provides recommendations for several newer antimicrobial agents that were not previously available. In summary, the changes and expansion to this document reflect the growing body of literature detailing infectious complications in HCT patients.

Effect of Daily Chlorhexidine Bathing on Hospital-Acquired Infection

BACKGROUND Results of previous single-center, observational studies suggest that daily bathing of patients with chlorhexidine may prevent hospital-acquired bloodstream infections and the acquisition of multidrug-resistant organisms (MDROs). METHODS We conducted a multicenter, cluster-randomized, nonblinded crossover trial to evaluate the effect of daily bathing with chlorhexidine-impregnated washcloths on the acquisition of MDROs and the incidence of hospital-acquired bloodstream infections. Nine intensive care and bone marrow transplantation units in six hospitals were randomly assigned to bathe patients either with no-rinse 2% chlorhexidine-impregnated washcloths or with nonantimicrobial washcloths for a 6-month period, exchanged for the alternate product during the subsequent 6 months. The incidence rates of acquisition of MDROs and the rates of hospital-acquired bloodstream infections were compared between the two periods by means of Poisson regression analysis. RESULTS A total of 7727 patients were enrolled during the study. The overall rate of MDRO acquisition was 5.10 cases per 1000 patient-days with chlorhexidine bathing versus 6.60 cases per 1000 patient-days with nonantimicrobial washcloths (P=0.03), the equivalent of a 23% lower rate with chlorhexidine bathing. The overall rate of hospital-acquired bloodstream infections was 4.78 cases per 1000 patient-days with chlorhexidine bathing versus 6.60 cases per 1000 patient-days with nonantimicrobial washcloths (P=0.007), a 28% lower rate with chlorhexidine-impregnated washcloths. No serious skin reactions were noted during either study period. CONCLUSIONS Daily bathing with chlorhexidine-impregnated washcloths significantly reduced the risks of acquisition of MDROs and development of hospital-acquired bloodstream infections. (Funded by the Centers for Disease Control and Prevention and Sage Products; ClinicalTrials.gov number, NCT00502476.).

AIDS--the first 20 years.

In 1981, no one would have believed that unusual infections in five young men were the harbinger of a worldwide health catastrophe.

Opportunistic Infections in Patients with and Patients without Acquired Immunodeficiency Syndrome

In the next decade, longer survival of patients with cancer and more-aggressive therapies applied to common conditions, such as asthma and rheumatoid arthritis, will result in a larger population with significant immune system defects. Many in this population will be at risk for opportunistic infections, which are familiar to doctors who have treated people infected with human immunodeficiency virus (HIV). However, the epidemiology, presentation, and outcome of these infections in patients with an immune system defect, other than that caused by HIV infection, may be different than those encountered in patients with acquired immunodeficiency syndrome. Reviewed are 4 common opportunistic infections: Pneumocystis carinii pneumonia, cryptococcosis, atypical mycobacterial infection, and cytomegalovirus infection. Emphasized are the important differences among these groups at risk.

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.

The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and healthcare-associated bloodstream infections: Results of a quasi-experimental multicenter trial

Objective:Spread of multidrug-resistant organisms within the intensive care unit (ICU) results in substantial morbidity and mortality. Novel strategies are needed to reduce transmission. This study sought to determine if the use of daily chlorhexidine bathing would decrease the incidence of colonization and bloodstream infections (BSI) because of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) among ICU patients. Design, Setting, and Patients:Six ICUs at four academic centers measured the incidence of MRSA and VRE colonization and BSI during a period of bathing with routine soap for 6 months and then compared results with a 6-month period where all admitted patients received daily bathing with a chlorhexidine solution. Changes in incidence were evaluated by Poisson and segmented regression modeling. Interventions:Daily bathing with a chlorhexidine-containing solution. Measurements and Main Results:Acquisition of MRSA decreased 32% (5.04 vs. 3.44 cases/1000 patient days, p = 0.046) and acquisition of VREdecreased 50% (4.35 vs. 2.19 cases/1000 patient days, p = 0.008) following the introduction of daily chlorhexidine bathing. Segmented regression analysis demonstrated significant reductions in VRE bacteremia (p = 0.02) following the introduction of chlorhexidine bathing. VRE-colonized patients bathed with chlorhexidine had a lower risk of developing VRE bacteremia (relative risk 3.35; 95% confidence interval 1.13–9.87; p = 0.035), suggesting that reductions in the level of colonization led to the observed reductions in BSI. Conclusion:We conclude that daily chlorhexidine bathing among ICU patients may reduce the acquisition of MRSA and VRE. The approach is simple to implement and inexpensive and may be an important adjunctive intervention to barrier precautions to reduce acquisition of VRE and MRSA and the subsequent development of healthcare-associated BSI.

Selective CD4+ Lymphopenia in Melanoma Patients Treated With Temozolomide: A Toxicity With Therapeutic Implications

PURPOSE Standard schedule temozolomide (TMZ; daily for 5 days every 4 weeks) is often used in melanoma patients, but phase III data show that it is no more effective than standard dacarbazine. Extended TMZ dosing regimens may be superior by delivering the drug continuously at a higher dose over time. Using an extended dosing schedule, we noted a high incidence of lymphopenia and occasional opportunistic infections (OIs). Here we report our retrospective experience in the first 97 patients. MATERIALS AND METHODS TMZ was administered at 75 mg/m(2)/d orally for 6 weeks every 8 weeks, although nine patients were treated continuously without a break. Seventeen patients were treated with TMZ alone; 73 patients received TMZ with thalidomide; seven patients received TMZ with low-dose interferon alfa. RESULTS Median duration of TMZ treatment was 113 days; 29% received > or = 24 weeks of therapy. Lymphopenia was seen in 60% of patients (absolute lymphocyte count < 800/microL) with a median of 101 days to lymphopenia. TMZ did not cause significant neutropenia or thrombocytopenia. Lymphopenia was not more common in patients treated concomitantly with thalidomide. In all patients analyzed for lymphocyte subsets, lymphopenia induced by TMZ affected the CD4(+) compartment preferentially. There were two documented OIs (Pneumocystis and Aspergillus pneumonia) as well as other infections indicative of T-cell dysfunction in another 21 patients. CONCLUSION TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.

Occupationally Acquired Infections in Health Care Workers: Part II

More than 10 years have elapsed since the last major consideration of occupationally acquired infections in health care workers [1, 2]. Since then, much has changednew infections have been identified, diagnostic tests for previously recognized diseases have been improved, the use of molecular epidemiologic techniques in outbreak investigations has increasingly become routine, and outpatient and home care have become more common. The topic of occupationally acquired airborne infections in health care workers was addressed in part I of this two-part review [3]. Infections such as occupationally acquired tuberculosis, varicella-zoster, measles, and respiratory syncytial virus infections were considered, as were ethical and historical concerns. Part II of this review discusses infections caused by bloodborne organisms (such as human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis C virus [HCV], cytomegalovirus [CMV], and Ebola virus), organisms spread through the oral-fecal route (such as salmonella and hepatitis A virus [HAV]), and organisms spread through direct contact (such as herpes simplex virus and Sarcoptes scabiei). It then summarizes known interventions, including handwashing, vaccination, and prompt placement of potentially infectious patients into appropriate isolation. The risks to health care workers inherent in health care delivery should be considered by planners of health care for the next century. Bloodborne Transmission Bloodborne transmission (Table 1) has received increased attention with the advent of the acquired immunodeficiency syndrome epidemic and, more recently, the outbreak of Ebola virus infection. Although many nonmedical occupational groups are at risk for diseases caused by organisms transmitted through the airborne or oral-fecal route, health care workers are one of the few groups at risk for the transmission of bloodborne pathogens. In addition to blood-to-blood transmission, some of these pathogens may be transmitted in saliva, as occurs with CMV and B virus infection. Table 1. Occupationally Acquired Infections Resulting from Bloodborne Transmission* HIV Infection The occupational risk for transmission of HIV has been the subject of numerous thorough reviews [9, 34-40] and is not considered in detail here. The rate of seroconversion after exposure ranges from 0.1% to 0.4% [4, 5, 35]. In general, a large inoculumincluding that from a source case with more advanced disease, a stick with a large-bore blood-containing needle, or a more severe injuryis associated with a higher rate of transmission [41]. Occupational transmission has been confirmed in 49 health care workers and may have occurred in 102 others [6] (Table 2). Percutaneous exposure alone was the source of transmission for most confirmed cases of infection (42 persons). The optimal management of health care workers after exposure remains unknown. A recent retrospective, casecontrol study examined risks associated with transmission in 31 case-patients and 679 controls [41]. In this analysis, the use of zidovudine was associated with a 79% risk reduction, although zidovudine failure has occurred [42]. Provisional Public Health Service recommendations include three antiretroviral drugs (zidovudine, lamivudine, and indinavir) for high-risk exposures [7, 43]. Table 2. Health Care Workers with Documented and Possible Cases of Occupationally Acquired HIV Infection in the United States, through 1995* Hepatitis B Hepatitis B virus was one of the first bloodborne pathogens to be recognized as an occupational risk among health care workers [44-46]. An early review [46] found a preponderance of cases of hepatitis B among pathologists, laboratory workers, and blood bank workers, alerting investigators to the risks of exposure to blood. Subsequent studies confirmed these early observations [47-63]. In general, the seroprevalence of HBV in health care workers is twofold to fourfold higher than that of blood donor controls [47, 61]; the highest rates are seen among dentists [8, 47]; physicians [8, 47, 61, 63]; laboratory workers [8, 47, 63, 64]; dialysis workers [63]; cleaning service employees [51, 62]; and nurses [8], including emergency department nurses [56]. Widespread transmission may occur from a single surgical procedure [65]. Many infections in health care workers are asymptomatic [48]. In prevaccine surveys, the annual incidence of hepatitis B was 5 to 10 times higher among physicians and dentists than among blood donors and more than 10 times higher among surgeons, dialysis workers, persons caring for the mentally handicapped, and laboratory workers exposed to blood [47, 61, 66]. The risk for transmission from a single needlestick varies according to E antigen status: 1% to 6% for E antigen-negative blood compared with 22% to 40% with E antigen-positive blood [8-10, 67]. However, transmission of E antigen-negative blood has caused fulminant hepatitis requiring liver transplantation [68]. Hepatitis delta virus has been transmitted to a surgeon [69]. The quality-adjusted loss in life expectancy is similar for persons who receive needlesticks involving a source patient who has HBV infection and for persons who receive needlesticks involving a source patient with HIV infection [70, 71]. Not all cases of HBV transmission are explained by needlesticks, suggesting that other modes of spread may be possible [8, 9, 72]. Infection control interventions, such as the segregation of dialysis recipients according to surface antigen status [73, 74] and vaccination [74, 75], have effectively reduced occupational acquisition of HBV. However, the Centers for Disease Control and Prevention (CDC) calculate that 6500 to 9000 new HBV infections occurred among health care workers in 1990 [8]. Given the natural history of HBV infection, 300 to 950 of these health care workers (5% to 10%) will eventually develop chronic HBV infection that will lead to death from cirrhosis in 100 to 150 persons and to fatal hepatocellular carcinoma in 25 to 40 persons [8]. Despite this, HBV vaccination of health care workers remains incomplete. In one study, 23% of health care workers were unvaccinated [52], a rate similar to that of anesthesiologists in the United Kingdom [76]. A three-vaccine series is 88% effective [77, 78]; decreased response is seen among recipients who are older, who smoke, or who are obese [77, 78]. Hepatitis C The 1990 introduction of a test for HCV infection has dramatically improved our understanding of disease epidemiology. Because HBV and HCV have similar modes of transmission, it was assumed that groups of health care workers at increased risk for hepatitis B also would be at risk for hepatitis C [19, 52, 60]. This, however, has not proven to be true for many groups, including dialysis workers [79-82], laboratory workers [83], persons who work with the mentally impaired [84], and surgical staff [83]. Indeed, although occupational exposure accounts for about 2% of all cases of hepatitis C [19], the seroprevalence of HCV among health care workers is roughly similar to that of the general population (about 1%) [83, 85-89]. Dentists do have increased risk [16, 17]: In one serosurvey [16], significantly more dentists (1.7%) than blood donors (0.13%) were seropositive for HCV; the highest rate of seroprevalence was seen among oral surgeons (9%). Seroconversion occurs in 1.2% to 10% of nonimmune health care workers who receive needlesticks from a source patient with hepatitis C [11-15]. Variation among control populations [90-92], variation in employee populations [18, 93, 94], and variation in the sensitivity of tests for HCV [19] have contributed to the lack of consensus about risk [14, 18, 94]. Optimal management of a needlestick is unknown, but the administration of immune globulin is not recommended [18, 40]. Cytomegalovirus Infection The prevalence of CMV infection in the United States varies according to geography, patient age, and group studied and ranges from 40% to 95%. The annual community incidence among adults is about 2% [21]. Transmission of CMV may occur through sexual contact or through contact with infectious blood. Respiratory secretions, saliva, and urine may also transmit CMV, as shown by increased rates of CMV infection among day care workers (8% to 10% per year) [95, 96]. Early incidence [97-99] and prevalence studies [100], as well as meta-analyses [101, 102] and reviews [103, 104], suggested that pediatric health care workers had elevated risk, similar to that of day care workers. Subsequent reports [20, 21, 35, 105, 106], however, have not shown this risk, perhaps because many recent studies were done in the era of universal precautions. Similarly, no increase in CMV infection among dialysis workers [107] or renal transplantation workers [108] has been found. Studies using molecular epidemiologic techniques have also shown that health care workers are at low risk for occupational transmission of CMV [109, 110]. No transmission was documented among 188 health care workers at a pediatric chronic care or neonatal unit in which many of the patients were heavy CMV shedders [110]. Molecular analysis of CMV recovered from one of two nurses who seroconverted showed discordance with CMV taken from a known occupational contact and concordance with CMV from a family member with new disease. Ebola Virus Infection and Other Viral Hemorrhagic Fevers The recent outbreak of Ebola virus infection in Zaire involved 296 cases and was associated with a 79% mortality rate [22-24]. At least 90 persons (32%) were health care workers [24, 25], a fact that led the CDC to issue recommendations for the management of persons with suspected viral hemorrhagic fevers [26]. Among the recommended practices were use of universal precautions, use of strict barrier protection, restriction of workers and visitors, and use of negative-pressure ventilation in the presence of respiratory symptoms. In a 1979 outbreak of Ebola virus infection

Adverse outcomes associated with contact precautions: A review of the literature

BACKGROUND Contact Precautions (CP) are a standard method for preventing patient-to-patient transmission of multiple drug-resistant organisms (MDROs) in hospital settings. With the ongoing worldwide concern for MDROs including methicillin-resistant Staphylococcus aureus (MRSA) and broadened use of active surveillance programs, an increasing number of patients are being placed on CP. Whereas few would argue that CP are an important tool in infection control, many reports and small studies have observed worse noninfectious outcomes in patients on CP. However, no review of this literature exists. METHODS We systematically reviewed the literature describing adverse outcomes associated with CP. We identified 15 studies published between 1989 and 2008 relating to adverse outcomes from CP. Nine were higher quality based on standardized collection of data and/or inclusion of control groups. RESULTS Four main adverse outcomes related to CP were identified in this review. These included less patient-health care worker contact, changes in systems of care that produce delays and more noninfectious adverse events, increased symptoms of depression and anxiety, and decreased patient satisfaction with care. CONCLUSION Although CP are recommended by the Centers for Disease Control and Prevention as an intervention to control spread of MDROs, our review of the literature demonstrates that this approach has unintended consequences that are potentially deleterious to the patient. Measures to ameliorate these deleterious consequences of CP are urgently needed.