Infection in Neutropenic Patients with Cancer

Transcription

1 Infection in Neutropenic Patients with Cancer Eric J. Bow, MD, MSc, D. Bacteriol, FRCPC a,b,c, * KEYWORDS Neutropenia Myelosuppression Febrile neutropenia Febrile mucositis Neutropenic sepsis syndromes First neutropenic fever Persistent neutropenic fever Recrudescent neutropenic fever KEY POINTS Neutropenic fever syndromes are common among patients receiving intensive cytotoxic therapy for cancer. Neutropenic fever syndromes include first neutropenic fevers, persistent neutropenic fevers, recrudescent neutropenic fevers, unexplained neutropenic fevers, clinically documented neutropenic fevers, and microbiologically documented neutropenic fevers. Patients with hematologic malignancies are at greatest risk for neutropenic fevers and for the consequences of sepsis syndromes that may require critical care services. Several recent guidelines have been published to help clinicians manage these infections. EPIDEMIOLOGY OF NEUTROPENIC FEVER SYNDROMES What Characterizes Patients with Cancer Who Require Critical Care Services Over the last quarter century there have been significant improvements in the outcomes of anticancer treatments. 1 More patients are living with cancer and are at risk of developing critical illness as a result of cancer-related complications or treatment-related adverse events. As a result of improved outcomes for critically ill patients who have cancer, greater numbers are being considered for referral to intensive care units (ICU) for critical care services. 2 Up to 1 in 5 patients admitted to an ICU for sepsis syndromes also have cancer. 3 Conflict of Interest: Previously a consultant for Pfizer, Astellas, Teva, Amgen, Merck-Frosst. a Department of Medical Microbiology and Infectious Diseases, The University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada; b Department of Internal Medicine, The University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada; c Infection Control Services, The Manitoba Blood and Marrow Transplant Programme, Cancer Care Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9, Canada * Corresponding author. Infection Control Services, Cancer Care Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9, Canada. addresses: EJBow001@shaw.ca; EJBow@cancercare.mb.ca Crit Care Clin 29 (2013) criticalcare.theclinics.com /13/$ see front matter Ó 2013 Elsevier Inc. All rights reserved.

2 412 Bow The distribution of underlying cancer diagnoses in patients referred for critical care services has ranged from 55% to 85% for solid tumors to 23% to 45% for hematologic malignancies. 4 7 Among the hematologic malignancies referred to ICU, approximately 38% are non-hodgkin lymphoma, 27% acute myeloid leukemia, 9% myeloma, 7% acute lymphoblastic leukemia, and about 20% are other clonal disorders such as chronic myeloid leukemia or myelodysplastic syndromes. 5 The incidence of referral for critical care services for febrile neutropenic patients with solid-tissue cancers is relatively low. As many as one-quarter of patients with solid tumors have advanced metastatic disease at the time of referral. 7 In a regional cancer center in the United Kingdom, an audit of 1649 cancer admissions demonstrated a rate of hospitalization for neutropenic fever syndromes associated with cytotoxic therapy for solid-tissue malignancies in only 32 patients (1.9%, or 19.4 per 1000 oncology admissions). 8 In order of prevalence, the most common cancers represented were breast (28%), lung and esophagus (16% each), ovarian (13%), brain and sarcoma (6% each), and pancreas, bladder, colorectal, thyroid, and melanoma (3% each). Hypotension as part of the neutropenic fever syndrome that may require ICU referral occurred in 13 patients (41%) of whom 6 (46%) died. Severe sepsis/septic shock was observed in 32 of 301 (10.6%) febrile neutropenic patients with solid-tissue malignancies or lymphoma. 9 The event rate for severe sepsis/septic shock in patients undergoing intensive cytotoxic therapy for acute myelocytic leukemia and who develop a neutropenic fever syndrome has been reported to be as high as 29% (95% confidence interval [CI] 21% 38%). 10 Three broad categories of criteria for admission of patients with cancer to the ICU have been offered: postoperative care for surgical interventions, management of critical illness due to the cancer or its treatment, and monitoring of patients during intensive complex anticancer therapies. 11 Benefit from critical care services seems most likely when the critical illness occurs at the initial diagnosis of the cancer, when there are promising treatments available for the cancer, and when the immediate crisis is not linked to active or progressing malignancy. 12 The most common reasons for referral to the ICU include onset of respiratory failure requiring mechanical or noninvasive ventilation, management of sepsis syndromes associated with hemodynamic compromise requiring fluid and vasopressor support, gastrointestinal bleeding, surgical emergencies, or other end-organ failure. Surgical emergencies have accounted for up to 70% of admissions in patients with solid tumors compared with only 20% in patients with hematologic malignancies. 7 Patients with solid tumors may require critical care services at presentation or at the time of tumor recurrence. They may present with bulky disease that is causing obstruction, compression, erosion, perforation, hemorrhage, or end-organ failure requiring resection, diversion, stenting, or embolization procedures for symptomatic control. Hematologic malignancies and hematopoietic stem cell transplantation are associated with a different spectrum of needs for critical care services to help manage the consequences of syndromes related to leukostasis, tumor lysis, coagulopathies, sepsis, respiratory failure, graft-versus-host disease, hematopoietic failure, and multiorgan failure. 12 Neutropenic sepsis syndromes with severe sepsis and septic shock figure prominently among patients who have cancer referred for critical care services. Neutropenic fever syndromes are often a function of the myelosuppressive and cytotoxic effects of systemic chemotherapies administered for the cancer. The circumstances and risk factors for neutropenic fever syndromes have recently been reviewed. 13 This following sections focus on the definition of neutropenia, the neutropenic fever syndromes, the definition of fever in this context, the diagnostic considerations in the workup of a neutropenic fever syndrome, and the management

3 Infection in Neutropenic Patients with Cancer 413 considerations in the context of critical illness in patients with cancer managed in the ICU. Timing of Neutropenic Fever Syndromes Relative to the Onset of Neutropenia Bodey and colleagues 14,15 at the MD Anderson Cancer Institute in Houston, Texas described the relationship between fever, infection, and the circulating absolute neutrophil count (ANC) almost 50 years ago. The risk of invasive infection, which is inversely related to the ANC, 14,16,17 increases as the ANC decreases to less than /L and, in particular, as it decreases to less than /L. 18 Severe neutropenia is defined by an ANC less than /L and profound neutropenia by an ANC less than /L. 17,19 An absolute lymphocyte count (ALC) of less than /L at day 1 of cytotoxic therapy has also been associated with an increased risk for neutropenic fever syndromes. 20,21 Automated leukocyte differential counts, which are performed routinely in hospital and clinic laboratories, can provide reliable estimates of the ANC and ALC. The median time to the first neutropenic fever corresponding to the time of the neutrophil nadir occurs at the end of the second week, typically between days 10 and 14, from the first day of cytotoxic therapy. 17,22 This also corresponds to the time of the maximum cytotoxic effect of anticancer chemotherapies on the intestinal mucosa and the time of maximal oral and gastrointestinal mucositis. 22,25 29 The magnitude of mucositis is related to the intensity of the cytotoxic therapy; however, the timing of these effects is independent of the regimen. 28,30 32 Cytotoxic antineoplastic therapy damages the oral and gastrointestinal mucosa by initiating an inflammatory cascade beginning with the activation of nuclear factor-kb, followed in sequence by release of proinflammatory cytokines causing increased epithelial cell apoptosis; increased mucosal permeability; translocation of microorganisms or their cell wall components from the pool of commensal bacteria and fungi colonizing the mucosal surfaces resulting in infection and fever; and cell repair and tissue healing Neutropenia, Systemic Inflammatory Response, and Sepsis Syndromes Sepsis may be defined by the presence of a systemic inflammatory response to a confirmed infection. 37 The systemic inflammatory response syndrome (SIRS) has been characterized by at least 2 of the following criteria: body temperature greater than 38 C or less than 36 C, heart rate greater than 90 beats per minute, respiratory rate greater than 20 breaths per minute (or PaCO 2 <32 mm Hg), total leukocyte count greater than 12 or less than /L, or less than 10% band forms in the leukocyte differential count. 38 There is an assumption of a continuum of inflammatory mechanisms from SIRS to sepsis, to severe sepsis, to septic shock. 39 A neutropenic fever syndrome may be defined by a minimum of 2 SIRS criteria. The presence of a greater number of SIRS criteria at presentation of a neutropenic fever syndrome is associated with a higher likelihood of progression to septic shock, 40 ranging from 0% to 3% to 30% for SIRS 2, 3, and 4, respectively. Neutropenia and ICU Outcomes In the past, critical care physicians have been reticent to accept febrile neutropenic patients with cancer into the ICU because of high hospital mortality rates in excess of 50% In a single-center experience of 160 patients with non-hodgkin lymphoma undergoing stem cell autografting, neutropenic fever syndromes developed in 150 patients (94%) and of these 13 (9%) developed a severe sepsis syndrome. Eight of the 13 patients (62%) with severe sepsis required ICU admission and

4 414 Bow 7 (88%) died of septic shock at a median of 2.5 days (range 1 12 days) after admission to the ICU. 44 Several reasons have been offered for declining access to critical care services for patients with cancer. In a multicenter French study, 1 in 4 patients with cancer were refused admission to the ICU. 45 The reasons cited included the patient was too well to benefit in more than half (55%) of the cases, too ill to benefit in more than onethird (37%), full occupancy (7%), and patient or family refusal (about 1%). 45 It has been argued that the presence of severe neutropenia on ICU admission is an adverse risk factor against survival in patients with cancer. 46 In a study of 348 oncology patients admitted to the ICU, Kress and colleagues 6 reported hospital mortality rates of 53% among those who were neutropenic (n 5 77) and 37% who were not (n 5 271; P 5.01). However, neutropenia may not have as great an impact on mortality in the setting of septic shock. In 1 study, ICU mortality rates of 56% and 52% were observed among neutropenic and nonneutropenic patients with cancer with septic shock. 47 The presence of early acute noninfectious comorbidities in febrile neutropenic patients with cancer with severe sepsis or septic shock may have a greater influence on hospital mortality. The results of a large retrospective study of 428 febrile neutropenic patient with cancer and severe sepsis or septic shock examining factors affecting inhospital mortality from 1998 to 2008 demonstrated that the presence of at least 1 early acute noninfectious comorbid process (eg, cardiovascular events, neurologic syndromes, hemorrhagic events, tumor-driven tissue damage, treatment-driven tissue damage, or drug-related adverse reactions), older age, septic shock, acute respiratory, neurologic, or hepatic failure, all independently increased mortality. 48 In contrast, factors that reduced mortality included early removal of indwelling catheters, the inclusion of an aminoglycoside in combination with a b-lactam agent for the initial antibacterial management on admission to the ICU, and ICU admission between 2004 and The development of respiratory compromise plays an important role in the likelihood that febrile neutropenic patients with cancer may require ICU services. Of 65 patients receiving intensive induction therapy for acute leukemia, 30 (46.2%, 95% CI 34.6% 58.2%) developed new respiratory events (defined as any new respiratory symptom or sign such as dyspnea, cough, sputum production, rales, chest pain, new pulmonary infiltrate on a chest radiograph, or oxygenation impairment). Twenty of these patients (66%) developed acute respiratory failure (defined by a PaO 2 /FiO 2 ratio of <200 mm Hg) and 12 (60%) required ICU services. Seven (58%) of the 12 patients died in the ICU. 49 Of the original cohort of 65 patients, ICU services were required in 12 (18.5%, 95% CI 10.9% 29.6%). Allogeneic hematopoietic stem cell transplant (HSCT) recipients are a subpopulation of patients with cancer with a higher likelihood of needing ICU services during their treatment. An overall rate of referral of patients undergoing HSCT to critical care services has been estimated to be approximately 16%. 50 Adult recipients of cord blood allografts (CBT) have been observed to have high rates of ICU referral. In 1 series of 44 adults undergoing CBT, 25 (57%) required ICU care at a median of 42 days (range days) after transplant, and of whom 18 (72%) died. 51 The most common reason for referral was respiratory failure due to pneumonia in 13 of the 25 patients. Factors enhancing the likelihood of referral for critical care services included use of a myeloablative conditioning regimen (66% vs 22%, P 5.03) and lower nucleated cell dose ( vs nucleated cells/kg body weight, P 5.05). Factors associated with ICU mortality included the need for vasopressors (12 of 13 vs 6 of 12, P 5.03), higher Acute Physiology And Chronic Health Evaluation (APACHE III)

5 Infection in Neutropenic Patients with Cancer 415 score ( vs , P ), lower platelet count ( vs /L, P 5.03), and a shorter time from transplant until ICU admission ( days vs days, P 5.09). Autologous HSCT is associated with a lower risk of requiring critical care services. Experience from a large Canadian transplant center demonstrated a referral rate of only 3.3% of 1034 patients within 100 days of undergoing stem cell autografting during the period from January 2001 to January The median time from transplant to referral was 10 days. The referral rates by underlying diagnosis were 2.8% each for 615 and 199 patients with myeloma and non-hodgkin lymphoma, respectively, 0.9% of 112 patients with Hodgkin lymphoma, 28.2% of 39 patients with amyloidosis, 5.9% of 17 patients with acute myeloid leukemia, and 6.4% of 31 patients with other diagnoses. The reasons for ICU referral for the 34 patients included sepsis syndrome in 11 cases, respiratory failure requiring mechanical ventilation in 10 cases, acute cardiac failure in 9 cases, and gastrointestinal bleeding and neurologic syndrome in 2 cases each. Of the 13 patients who died (38%), 11 had multiorgan failure, 9 of whom also had intercurrent infection with invasive gram-negative bacillary disease (6 cases), candidemia (2 cases), and Clostridium difficile-associated diarrhea (1 case). Factors associated with death included the failure of more than 2 end organs (85% mortality), need for mechanical ventilation (85% mortality), vasopressor dependence (54% mortality), and gram-negative infection (42% mortality). Sequential Organ Failure Assessment scores ( vs ) and APACHE II scores ( vs ) were significantly higher among those who died. Factors associated with better outcomes for ICU referral among HSCT recipients include protocol-driven hematopoietic growth factor support for earlier engraftment, use of peripheral blood rather than bone marrow as the source of stem cells for hematopoietic reconstitution, protective strategies for acute lung injury, and early goal-directed therapy in the management of sepsis syndromes. 53 DIAGNOSIS Assessment of Neutropenia in Patients with Cancer The magnitude of the physical signs of inflammation and infection are directly related to the ANC. 16 Localizing findings such as erythema, swelling, exudate, fluctuance, ulceration, fissure formation, and focal tenderness may be muted in patients with severe neutropenia; however, they are useful and reliable signs of infection nonetheless. Integumental surfaces of the upper and lower respiratory tracts, upper and lower gastrointestinal tracts, and the skin are the anatomic sites most often involved with infection in neutropenic patients. 16,34 Accordingly, the clinician s initial assessment of a febrile neutropenic patient must focus on signs and symptoms related to the oropharynx and periodontium, the ears and sinuses, lungs, focal pain and tenderness in the abdomen, and skin, particularly at site of biopsy or venous access devices. As noted earlier, the microorganisms most often associated with invasive bloodstream infections occur in neutropenic patients derived of the normal microflora colonizing integumental surfaces damaged by surgical interventions and cytotoxic therapy. For example, damaged periodontal and oral tissues give rise to invasive viridans (alpha hemolytic) group streptococcal infections. Similarly, gastrointestinal mucositis increases the risk for facultatively anaerobic gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae,orenterobacter spp; microaerophilic gram-positive cocci such as Enterococcus spp (often referred to as nonhemolytic streptococci before genus and species identification) and Staphylococcus spp (including thermonuclease-positive Saureusand thermonuclease-negative

6 416 Bow S epidermidis); opportunistic yeasts such as Candida spp; and less commonly obligate anaerobic gram-positive (Clostridium spp, Lactobacillus spp) and gramnegative (Bacteroides spp) bacteria, or afermentative obligately aerobic gramnegative bacilli )Pseudomonas spp, Stenotrophomonas spp, or Acinetobacter spp). Assessment of Fever in Neutropenic Patients with Cancer in the ICU An increased body temperature may be the earliest and only sign of infection in the neutropenic patient with cancer. 16 This observation is the trigger that initiates a rapid workup and administration of empiric systemic antibacterial therapy to avoid progression to a severe sepsis or septic shock syndrome and possibly death. Accordingly, the accurate and reliable clinical recognition of a febrile state in neutropenic patients is critical. Fever may be a function of infectious and noninfectious processes, and causes patient discomfort and imposes metabolic stress. The presence or absence of fever is used as a surrogate of the activity of infection. 54 The observation of a relative bradycardia in patients with temperatures of 38.9 C or more (the pulse-temperature deficit) who are not receiving b-blocker therapy and who have a negative chest radiograph suggests a drug fever syndrome. 55 Single isolated temperature increases rarely indicate infection; the most common association is with administration of blood products. 55 Fever in critically ill patients with neurologic or neurosurgical disease is common and may have infectious or noninfectious causes. The latter include neuronal injurydriven release of endogenous pyrogens, and the presence of blood in the cerebral parenchyma, ventricles, or subarachnoid space. 56 The origins of the definition of normal body temperature are somewhat obscure. 57 In 1868, Wunderlich defined the normal body temperature based on axillary readings in 25,000 patients to be 37 C (98.6 F) with a range of 36.2 C (97.2 F) to 37.5 C (99.5 F). He observed that temperatures higher than 38.0 C (100.4 F) were suspicious for a febrile state In a series of publications between 1845 and 1945 reviewed by Horvath, Menduke, and Piersol, 61 the mean of all mean normal oral body temperatures reported was C (98.34 F) with a range of C (97.2 F) to C (99.0 F). The upper limit of normal was 38 C (100.4 F); a higher temperature fulfilled the definition of fever. 62 More than 5 generations after Wunderlich s publication, almost 90% of medical professionals still define the normal oral body temperature as 37 C (98.6 F) or as a narrow range about this mean. 63 Studies in the early 1950s examining the relationship between oral and rectal temperatures confirmed Wunderlich s observations of the diurnal variation in body temperature; the lowest temperatures were noted in the morning (06:30 07:15 AM) and highest in the late evening (10:00 12:00 PM). 61 Moreover, these studies noted gender differences; the morning temperatures were higher in women than in men. 61 Forty-two years later, a study of 148 healthy men and women at the University of Maryland reported that the mean of 700 baseline oral temperatures was C ( F) with a range of 35.6 C (96.0 F) to 38.2 C (100.8 F). According to these observations, the upper limit of normal would be 38.2 C (100.8 F). The temperature of 37 C accounted for only 8% of all readings and was outside the 99.9% confidence limit for the sample mean. 58 It is known that circadian rhythms and menstrual cycles may vary the normal body temperature by 0.5 C to 1.0 C and that exercise may increase the body temperature by 0.3 C to 0.6 C. 64 Given these considerations, several guidelines have been published to provide some direction regarding the definition of a febrile state in neutropenic patients with cancer. The College of Critical Care Medicine and the Infectious Diseases Society of America have defined a febrile neutropenic episode as a single oral temperature

7 Infection in Neutropenic Patients with Cancer 417 of more than 38.3 C (101 F) or a temperature of more than 38.0 C (100.4 F) sustained for more than 1 hour. 19,65 Other international guidelines from North and South America, Europe, and Asia have provided similar definitions The Japan Febrile Neutropenia Study Group and the Asia-Pacific febrile neutropenia guidelines group have recommended that a single oral temperature of 38.0 C or higher or a single axillary temperature of 37.5 C or higher be accepted as the definition of a febrile state. 69 Based on the observations pertaining to the range of normal temperatures from the University of Maryland, most North and South American and European guidelines have adopted the standard of a single oral temperature of 38.3 C or higher as the definition of pyrexia in the setting of neutropenic patients with cancer. The technique by which body temperature is measured is important. Core body temperature is most accurately measured by a thermistor attached to a standard pulmonary artery catheter (PAC) or by in situ urinary bladder thermometry. 65 Oral, infrared tympanic membrane, axillary, and rectal thermometry represent surrogates of core body temperature. Rectal and axillary thermometry correlate most and least accurately with PAC thermometry, respectively. 71 Although rectal temperatures may vary from pulmonary artery temperatures by as much as 0.47 C, axillary temperatures may vary by as much as 0.9 C. 72 Rectal temperatures have the disadvantages of being poorly tolerated by patients, being difficult to obtain due to patient positioning, imparting a small risk for rectal perforation, and transmitting antibiotic-resistant organisms on the probe. Axillary temperatures have tended to be 0.2 C to 0.4 C higher than PAC thermometry 73,74 thus overestimating patient temperature. Although oral thermometry in alert cooperative patients is safe and convenient, mouth breathing, hot and cold oral fluids, heated oxygen delivery, and cytotoxic therapy-induced mucositis may distort the reading. 65,75 Infrared tympanic membrane thermometry is also noninvasive and convenient; however, inaccuracies due to observations obtained from the dependent ear, 76 multiple user error, 77 operator technique and equipment maintenance, and failure to remove cerumen in the external auditory canal 81 confound the ability to detect fever. False-negative and false-positive observations resulting in possible delayed interventions or in unnecessary interventions have been observed for axillary thermometry (15.3% and 21.1%, respectively) and tympanic thermometry (28.8% and 37.8%, respectively). 73 An accurate measurement is desirable because the decision to initiate an aggressive protocol of neutropenic fever management may be based on a difference of 0.5 C. 82 Fever in the ICU setting is common. A recent Canadian study demonstrated that almost 1 in 4 (24%) patients admitted for critical care services were febrile at the time of admission and a further 27% developed fever within 1 to 3 days. 54 The differentiation of infectious and noninfectious fevers in patients with cancer may be difficult. Noninfectious fevers have many possible explanations 83 including the hyperthermia syndromes when body temperature may exceed 41.1 C (106 F) 84 (eg, heatstroke 85 ; drug-induced syndromes such as the neuroleptic malignant syndrome associated with the use of neuroleptic agents, 86 the autosomal dominant malignant hyperthermia syndrome triggered by inhalational anesthetic agents such as halothane, 87 and the serotonin syndrome associated with the use of serotonin reuptake inhibitors 88 ; and the endocrinerelated syndromes such as thyrotoxicosis, pheochromocytoma, and the adrenal crisis syndrome); hematologic conditions (blood product transfusion, acute hemorrhage or deep body site hematomas, deep venous thrombosis, pulmonary emboli with infarction, hematophagocytosis syndrome, and stem cell transplant-related graft-vs-host reactions); drug hypersensitivities including drug fevers; intra-abdominal processes such as acalculous cholecystitis, acute pancreatitis, and solid-organ transplant rejection; pulmonary conditions such as the fibroproliferative phase of acute respiratory distress

8 418 Bow syndrome or aspiration pneumonitis; collagen-vascular or autoimmune diseases including, but not limited to, systemic lupus erythematosis or adult Still disease; malignancies such as Hodgkin and non-hodgkin lymphoma, multiple myeloma, leukemia, soft tissue sarcoma, neoplasms of the brain, pancreas, colon, and kidney 89 ; vascular disorders such as acute myocardial infarction and stroke; and tissue damage such as chemotherapy-induced oral mucositis 75 or trauma. Fever patterns remain a controversial adjunct for diagnosis 55,90 and may be described as intermittent (defined as temperatures that return to normal on most days), sustained (defined as temperatures that vary by less than a degree each day), remittent or continuous (defined as temperatures that do not return to normal each day), and hectic (an intermittent or remittent fever with a difference of more than 1.4 C between the highest and lowest values). 55,90 Single increases in body temperatures to 38.9 C to 41.1 C (102 F 106 F) that terminate spontaneously within 24 hours are more often associated with noninfectious causes such as blood product transfusions or central venous access catheter-related manipulations. 84 Drug Fever Syndrome Drug fevers, which may occur in 3% to 5% of adverse drug reactions, 91 pose a particular diagnostic challenge in critically ill patients that frequently leads to prolonged hospitalization, nondiagnostic investigations, and ineffective empiric therapeutic interventions with additional adverse reactions. 92,93 These fevers are defined by an increase in body temperature coincident with the administration of a drug and defervescence following discontinuance of that drug and by the failure to identify any other cause after thorough history, physical examination, and laboratory testing. 92,94 It is, therefore, a diagnosis of exclusion. Anti-infectives, particularly those commonly recommended for use in the ICU and for neutropenic fever syndromes (eg, antipseudomonal and semisynthetic antistaphylococcal penicillins, carbapenems, thirdgeneration cephlosporins, glycopeptides, antiherpetic nucleoside analogues, and amphotericin B-based products), 92 are the most common drug class associated with drug fevers. The lag times between initiation of a drug and onset of fever have been reported to be (median 6) days for antimicrobials, (median 0.5) days for antineoplastic agents, (median 10) days for cardiac drugs, and (median 16) days for central nervous system drugs. 94 The pattern of fever has not been diagnostic and eosinophilia has been observed in only approximately 1 in 5 subjects. Chills, myalgia, and hypotension have been reported in 53%, 25%, and 18% of patients, respectively. The observed peak temperatures and times to defervescence have been reported to be as high as C and days, respectively. 94 A high index of suspicion is the most important tool available to the clinician in making this diagnosis in a patient with cancer with a recrudescent neutropenic fever syndrome 32 occurring within 1 to 2 weeks of therapy, who seems discordantly well, and who may be unaware of the increased temperature. 91 A relative bradycardia (pulse rate 100/min in the presence of fever and in the absence of b-blocker therapy 94 ) may suggest a drug fever syndrome. 93 Laboratory Assessment The Infectious Disease Society of America, 19 the American Society of Clinical Oncology, 13 the European Society for Medical Oncology, 95 and the Infectious Diseases Working Party of the German Society for Hematology and Oncology 96 recommend that the initial laboratory assessment of a febrile neutropenic patient should include a complete blood count with leukocyte differential and platelet counts (this will confirm the state of neutropenia), serum electrolytes, blood urea nitrogen, serum

9 Infection in Neutropenic Patients with Cancer 419 creatinine, serum transaminases (aspartate and alanine transaminases), and total bilirubin. Many investigators also include the cholestatic enzymes (g-glutamyl transferase and the alkaline phosphatase) in allogeneic stem cell transplants where graftversus-host reactions or human Cytomegalovirus may drive a fever syndrome. Samples of blood should be obtained for microbiological culture from 2 or more separate sites. 19,95,96 Where a central venous catheter is in situ, each lumen of the catheter should be sampled simultaneously with a peripheral site. 97 In circumstances where coagulase-negative staphylococci are isolated from the catheter, the peripheral culture may help discriminate catheter-related infection from contamination. A chest radiograph is recommended when respiratory symptoms or signs suggest the lungs or airways as a focus. 19 Neutropenic Fever Syndromes Several neutropenic fever syndromes distinguished by the fever profile in patients with cancer have been described. 32 Each neutropenic fever episode may be characterized as an unexplained fever syndrome (defined by onset of a febrile episode characterized by the features of a SIRS but for which neither a clinical focus nor a pathogen can be identified), a clinically documented infection (defined as a febrile neutropenic episode for which a clinical focus of infection is identified but not a pathogen), or a microbiologically documented infection (defined as a neutropenic fever associated with both a clinical focus of infection and a causative pathogen). The first neutropenic fever syndrome is defined as the first fever (a temperature of 38.3 C by oral thermometry observed on a single occasion or a sustained temperature of >38.0 C observed over at least 1 hour) during a given neutropenic episode. 19 A persistent neutropenic fever (PNF) syndrome is defined as a febrile episode that fails to defervesce after at least 5 days of broad-spectrum antibacterial therapy in patient with cancer at high risk 98 for medical complications. The estimated event rate for the PNF syndrome has been reported to be from 20% 99 to as high as 69% in patients with leukemia. 32 Invasive fungal infections as a cause for PNF have been identified in only a minority of such patients (3.6%, 95% CI 2.9% 4.4%) Other infectious causes include persistent infection or superinfection with a microorganism outside the spectrum of activity of the initial empiric antibacterial regimen. Noninfectious causes include frequent blood product administration or cytotoxic therapy-induced intestinal mucosal damage causing oral and gastrointestinal mucositis. 22 Recrudescent neutropenic fever (RNF) syndrome is defined as a febrile episode that recurs following initial defervescence after broad-spectrum antibacterial therapy for the febrile neutropenic episode. 103 The event rate for this syndrome has been estimated to be 15% (95% CI 13% 18%) overall, and approximately 30% for each of unexplained fevers, clinically documented infections, and microbiologically documented infections. 103 Of the microbiologically documented infections, gram-positive bacteria were isolated in 50%, gram-negative bacteria in 8%, and fungi in 42% (of these more than half represented invasive fungal infections two-thirds of which were invasive mold infections). 103 The concern that an invasive fungal infection may be a cause of the PNF or RNF syndrome has driven the recommendation for empirical antifungal therapy under these circumstances. 19 The myeloid reconstitution syndrome 32 is characterized by new or progressing inflammatory foci coincident with neutrophil recovery after severe myelosuppression. This syndrome may be difficult to differentiate from a RNF without an understanding of the context in which it developed. The recognition should compel the clinician to consider investigations that would exclude other bacterial, fungal, or viral pathogens.

10 420 Bow ANTIMICROBIAL MANAGEMENT Initial Empirical Antibacterial Therapy Timely administration of effective antibacterial therapy active against suspected or proven pathogens is critical for patient survival. Among patients with severe sepsis or septic shock, the administration of effective antibacterial therapy within 1 hour of documented hypotension was found to be associated with 80% survival of the episode. However, for the first 6 hours, each hour delay in appropriate antibacterial therapy was associated with a reduction in survival of 7.6% (range 3.6% 9.9%). 104 Timely administration of appropriate initial antibacterial therapy is problematic, however. The mean time to implementation of initial effective therapy following the onset of recurrent or persistent hypotension has been as long as hours. 104 The delay in administering initial empirical antibacterial therapy to febrile neutropenic patients with cancer undergoing assessment in an emergency department setting has also been long (median 180 minutes, range minutes) Based on observations such as these, the American Society of Clinical Oncology, the Infectious Diseases Society of America, the American College of Critical Care Medicine, and the Surviving Sepsis Campaign Guidelines have recommended the standard of 1 hour from onset of the neutropenic sepsis syndromes to initial empirical antibacterial therapy. 13,65,111 The recommendations for initial empirical antibacterial therapy in most guidelines reflect the principle of broad-spectrum initial therapy focusing primarily on but not limited to aerobic gram-negative members of the family Enterobacteriaceae, Escherichia coli, Klebsiella spp, and Enterobacter spp; afermentative gram-negative bacilli such as Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter spp; and microaerophilic gram-positive cocci including, but not limited to, methicillin-susceptible Staphylococcus aureus, viridans group streptococci, and vancomycin-susceptible Enterococcus spp. Of concern is the increasing prevalence of multidrug-resistant organisms in the health care environment such as methicillinresistant Staphylococcus aureus (MRSA), vancomycin-intermediate S aureus, ampicillin-resistant Enterococcus faecium, vancomycin-resistant enterococci, Clostridium difficile, extended-spectrum b-lactamase producing gram-negative bacilli, and carbapenemase-producing gram-negative bacilli. The latter group of potential pathogens are resistant not only to all b-lactam agents but also typically carry resistance genes for other classes of antibacterials including the aminoglycosides, fluoroquinolone, and trimethoprim-sulfamethoxazole. 112 The correct choice of initial empirical antibacterial therapy is critical to the outcome of the patient with cancer with a neutropenic sepsis syndrome. In a retrospective analysis, inappropriate initial antibacterial therapy was associated with approximately fourfold reduction in hospital survival from 52% to 10.3%. 113 Another study of infections in hematology and oncology patients, 60% of whom were neutropenic, demonstrated 30-day all-cause mortality rates of 18% and 35% among those for whom the initial empirical antibacterial therapy was deemed appropriate or inappropriate, respectively. 114 A summary of the common antibacterial agents administered for neutropenic sepsis syndromes is shown in Table 1. Patients with cancer with neutropenic sepsis syndromes who are at high risk for medical complications attributable to the syndrome and who require ICU services should be initially treated with an antipseudomonal b-lactam antibacterial agent such as a third-generation or fourth-generation cephalosporin such as ceftazidime or cefepime, respectively, a carbapenem such as imipenem/cilastatin or meropenem, or a ureidopenicillin plus b-lactamase inhibitor combination such as

11 Infection in Neutropenic Patients with Cancer 421 piperacillin-tazobactam as monotherapy. 19 However, under defined circumstances, additional agents may be appropriate as part of the initial empirical regimen. For example, in environments with a high prevalence of MRSA, vancomycin should be considered when the patient has evidence of pneumonia, hypotension, or skin and skin stricture infection, including those related to central venous access devices where there is a high incidence of methicillin-resistant coagulase-negative staphylococci bloodstream infections. 97,115 Similarly, where vancomycin-resistant enterococci are prevalent and the patient manifests an intra-abdominal sepsis syndrome, inclusion of the lipopeptide, daptomycin, or an oxazolidinone, linezolid, to the b-lactam agent may be prudent. Although guidelines advocate initial empirical antibacterial therapy with a single agent (monotherapy) for febrile neutropenic patients with SIRS and sepsis syndrome, 13,19,95,96 the approach for those neutropenic fever syndromes characterized at the outset as severe sepsis or septic shock may require a broader approach with the inclusion of an aminoglycoside or fluoroquinolone with a broad-spectrum antipseudomonal b-lactam agent. 116 Prospective studies examining mortality among patients presenting with severe sepsis or septic shock managed with monotherapy have generally reported all-cause hospital mortality rates in excess of 25%. In contrast, studies examining mortality rates for sepsis without septic shock among monotherapy recipients have reported mortality rates of less than 15%. A recent systematic review with meta-analysis 117 examining the impact of combination therapy compared with monotherapy on mortality in patients with sepsis and septic shock failed to observe a combination therapy treatment effect on mortality overall (odds ratio [OR] 0.856, 95% CI , P ); however, in subsets of patients at high risk of death with monotherapy (>25%) combination therapy reduced mortality (OR 0.49, 95% CI , P<.0001). In contrast, among patients at lower risk of death (<15%) with monotherapy, exposure to combination therapy was associated with increased mortality (OR 1.53, 95% CI , P 5.003). This experience suggests that the survival benefit accruable from early combination antibacterial therapy requires selective application for those patients with septic shock. 118 This effect applies to patients with both invasive infection due to gram-negative bacilli and gram-positive cocci. Modification of the Initial Antibacterial Regimen Modification of the initial empirical antibacterial regimen is common practice and occurs in approximately 1 in 2 patients with cancer with neutropenic sepsis (49.3%, 95% CI 47.5% 51.1%). 119 Physicians make modifications to the initial empirical antibacterial regimen typically for 4 reasons: failure of the patient to defervesce within an expected time frame, recrudescent fever after initial defervescence, identification of a microorganism resistant to the initial empirical antibacterial regimen or progression of baseline infection, and the development of a regimen-related toxicity or end-organ damage that requires a change to the initial regimen. PNF and RNF Failure to defervesce within an expected time frame is 1 of the most common reasons cited for regimen modification. Among neutropenic patients with cancer at high risk for febrile neutropenic episode-related medical complications, the median time to defervescence is 5 days The most common first modification to the initial monotherapy regimen for persistent fever has been the addition of a glycopeptide, occurring in approximately half of the first modifications. 119 The second most common regimen modification for persistent fever is the addition of a systemic antifungal agent,

12 422 Bow Table 1 Antibacterial agents that may be considered for administration for the treatment of neutropenic fever syndromes Antibiotic Class Agent Dosing Comments b-lactam agents: penicillins Piperacillin-tazobactam mg/kg/d IV in 4 6 divided doses, or 4.5 g IV every 6 8 h 119 Combination of an antipseudomonal ureidopenicillin and a b-lactamase inhibitor Standard initial empiric monotherapy for neutropenic sepsis 19,96,160,161 Ticarcillin-clavulanate mg/kg/d IV in 4 6 divided doses b-lactam agents: Imipenem/cilastatin mg IV every 6 h, carbapenems a or 1 g IV every 8 h 163 Combination of an antipseudomonal carboxypenicillin and a b-lactamase inhibitor An alternative agent to piperacillin-tazobactam Alternative to b-lactam/b-lactamase inhibitor agents as initial empiric antibacterial monotherapy for febrile neutropenia 161 Agents of choice for ESBL-producing gram-negative infection Meropenem g IV every 8 h Similar characteristics to imipenem, but greater antipseudomonal activity Increased adverse effects such as nausea, vomiting, diarrhea, and a propensity for CDAD 119 Ertapenem 1 g IV daily Less active against enterococci and P aeruginosa Protein binding allows for once daily out-patient administration No studies on febrile neutropenia Doripenem mg IV every 8 h Similar efficacy to meropenem Antipseudomonal activity > imipenem and meropenem Limited experience in febrile neutropenia

13 b-lactam agents: cephalosporins b-lactam agents: monobactams Ceftazidime 2 g IV every 8 h A standard guideline-recommended monotherapeutic agent for initial empiric antibacterial therapy for febrile neutropenia 19,161 Limited gram-positive activity 19 including enterococci and anaerobic bacteria Ceftazidime-avibactam Combination of a third-generation antipseudomonal cephalosporin and a new non b-lactam b-lactamase inhibitor 165 now under development Avibactam is synergistic with ceftazidime against ESBL-producing and KPC-producing gram-negative bacilli Encouraging but no studies on febrile neutropenia Cefepime 2 g IV every 8 h A broad-spectrum fourth-generation antipseudomonal cephalosporin guideline-recommended monotherapeutic agent for initial empiric antibacterial therapy for febrile neutropenia 19,161 Inactive against enterococci and most anaerobic bacteria 161 Higher all-cause mortality in systematic reviews 119 Ceftriaxone 2 g IV every 24 h Efficacious in neutropenic sepsis at low risk for infections due to MRSA, enterococci, Enterobacter spp, and P aeruginosa 166 Advantage of single daily dosing when administered with an aminoglycoside Spectrum of coverage includes MSSA and viridans group streptococci (the second most common bacteremic isolate in neutropenic patients) and most aerobic gram-negative bacilli, except P aeruginosa 166 Not recommended for critically ill neutropenic patients with cancer with severe sepsis or septic shock Aztreonam 2 g IV every 6 h Recommended for use in combination with vancomycin for initial empirical antibacterial therapy for febrile neutropenia in patients with penicillin hypersensitivity 19 (continued on next page) Infection in Neutropenic Patients with Cancer 423

14 424 Table 1 (continued) Antibiotic Class Agent Dosing Comments Glycopeptides Vancomycin 1 g IV every 12 h In general, not indicated for initial empiric antibacterial therapy, with the following exceptions 19,160 Indicated initially for MRSA, SSSI, CVAD-related infection, pneumonia, septic shock syndrome 19,160 Teicoplanin Load 167 : 8 mg/kg/d 1, 7 10 mg/kg every 12 h for 3 5 doses, Similar indications and outcomes as for vancomycin 19,96,168 Fewer adverse events than vancomycin 168 or 400 mg every 12 h day 1 Maintenance 167 : 5 10 mg/kg/d or 400 mg/d Dalbavancin Similar outcomes as for vancomycin 168 No published studies on febrile neutropenia Televancin Similar outcomes as for vancomycin 168 No published studies on febrile neutropenia Lipopeptides Daptomycin 4 6 mg/kg/d IV Bactericidal, and effective for infections due to MRSA, VISA, VRE, and streptococci Administered as a modification to the initial empirical antibacterial therapy if these resistant bacteria are isolated, or as an alternative to vancomycin Rhabdomyolysis is the major toxicity; therefore, CPK monitoring is recommended 169 Should not be used for pneumonia due to inactivation by pulmonary surfactant 161 Oxazolidinones b Linezolid 600 mg IV/PO every 12 h Bacteriostatic agent against gram-positive cocci such as staphylococci (including MRSA), streptococci, and enterococci (including VRE due to E faecium) Equivalent efficacy to vancomycin in febrile neutropenia. 168 Time to defervescence shorter than vancomycin (6.6 d vs 8.5 d) but delayed neutrophil recovery (approximately day 8 vs 13, respectively) 170 Administered as an alternative to vancomycin, particularly for VRE Tedizolid 200 mg PO every 12 h Active against linezolid-resistant staphylococci 165 Less myelosuppression No studies in febrile neutropenia Radezolid Active against linezolid-resistant staphylococci 165 No studies on febrile neutropenia Bow

15 Fluoroquinolones Ciprofloxacin mg PO every 12 h, or 400 mg IV every 12 h Tetracyclines: glycylcyclines Polymyxins d Aminoglycosides Used in combination with a b-lactam agent as initial empirical antibacterial therapy for febrile neutropenia 171 Should be avoided for empirical therapy if administered as antibacterial prophylaxis 13,19 Levofloxacin mg IV/PO daily Limited experience as therapy in febrile neutropenia Should be avoided for empirical therapy if a fluoroquinolone has been administered as antibacterial prophylaxis Tigecycline c Colistimethate (polymyxin E) Gentamicin Tobramycin Amikacin 100 mg IV loading dose, Recommended for invasive infection due to MDR organisms including then 50 mg IV every 12 h ESBL-producing and KPC-producing or NDM-1-producing gramnegative bacilli, and VRE 19 As effective as vancomycin for gram-positive infections (SSSIs, MRSA, bacteremia) but more adverse effects mg/kg/d IV in Indicated for treatment of MDR gram-negative infections associated 2 4 divided doses with KPC and NDM-1 19 Nephrotoxicity and neurotoxicity are the major adverse events 172, mg/kg/d IV as a single dose 174,175 Recommended for use in combination with a b-lactam agent in febrile 20 mg/kg/d IV as a single dose 174,175 neutropenia associated with septic shock syndrome 19,118 Not recommended for use in combinations as initial empirical antibacterial therapy in otherwise uncomplicated febrile neutropenia 19 Not recommended for use as monotherapy in neutropenic patients 19 or in the setting of renal impairment 96 Abbreviations: CDAD, Clostridium difficile-associated diarrhea; CVAD, central venous access device; ESBL, extended-spectrum b-lactamase; IV, intravenously; KPC, Klebsiella pneumoniae carbapenemase; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis; MSSA, methicillin-susceptible Staphylococcus aureus; NDM-1, New Delhi metallo-b-lactamase type 1; PO, orally; SSTI, skin and skin structure infection; VISA, vancomycin-intermediate Staphylococcus aureus; VRE, vancomycin-resistant enterococci. a Carbapenems are active against most common community-acquired gram-positive cocci except for MRSA, MRSE, and enterococci. None of the carbapenems have activity against Enterococcus faecium. Similarly, this class is active against most aerobic and anaerobic gram-negative bacilli except Stenotrophomonas maltophilia (due to production of metallo-b-lactamases capable of inactivating all b-lactams, including carbapenems. This class is stable against ESBLproducing Escherichia coli and Klebsiella pneumoniae. b Oxazolidinones bind to the 50S ribosomal subunit and inhibits the initial phase of translation by blocking the incoming aminoacyl trna. 176 c Tigecycline, a bacteriostatic glycylcycline derivative of minocycline, occupies a binding site on the 30S ribosome, similar to tetracyclines, and also uniquely binds to site A of the ribosome that prevents the elongation of the polypeptide chain by blocking the entry of the aminoacyl trna to that site. 177 Active against a wide spectrum of gram-positive cocci including MRSA, MRSE, VRE, and Streptococcus pneumoniae, and gram-negative bacilli including Enterobacteriaceae, Acinetobacter spp, and Stenotrophomonas maltophilia. 177 d Polymyxins, discovered in 1947, are a group of 5 polypeptide antibiotic compounds (polymyxins A E). 172 They bind with the anionic lipopolysaccharides in the outer cell membrane of gram-negative bacteria by displacing calcium and magnesium resulting in increased permeability, leakage of cell contents, and death. 172 Infection in Neutropenic Patients with Cancer 425

16 426 Bow occurring in about 1 in 3 cases of modification. 119 Regimen discontinuance due to an adverse event occurs in approximately 6% of cases of regimen modification. 119 The remaining modifications have consisted of the addition of or a change in an aminoglycoside or b-lactam, the addition of other agents such as metronidazole for anaerobic coverage, or antiviral therapy for Herpes group viral infection There seems to be differences in the times to modification among different physician groups. For example, in 1 international study, the median time to glycopeptide-based neutropenic fever modification for Canadian physicians was 11 days, for American physicians 6 days, and for Australian physicians 4 days (P ). 124 The antimicrobial susceptibilities of bacteria associated with subsequent recrudescent neutropenic sepsis syndromes (microbiologically documented infections) in hematology and oncology patients may change depending on the regimen chosen for the initial empirical therapy. In 1 study from an Israeli cancer center, 86% of gram-negative bacilli involved with the initial fever syndrome were susceptible to piperacillin-tazobactam; however, only 22% of gram-negative bacilli associated with subsequent febrile episodes in the same patients were susceptible to the same agent. 114 In contrast, 79% of the gram-negative bacilli causing subsequent febrile episodes were susceptible to a carbapenem. 114 Clinicians must be careful to document the subsequent recrudescent neutropenic sepsis syndromes so that such determinations can be made. RNF syndromes have been observed in 12% to 16% of febrile neutropenic patients responding to initial empirical antibacterial therapy. 103,121, In a review of 2 large randomized-controlled clinical trials of antimicrobial therapy in febrile neutropenic patients by the European Organization for the Treatment and Research of Cancer (EORTC), the distribution of these RNF syndromes was as follows: unexplained fevers in 30%; clinically documented neutropenic fever syndromes in 30%, of which 59% were respiratory infections; and microbiologically documented infections in 40%, of which 27% were bloodstream infections (gram-positive organisms in 20% and Candida spp in 7%), viral infections in 22% (Herpes simplex virus in 16%, and Cytomegalovirus in 6%), nonbloodstream invasive candidiasis in 14%, invasive mold infection in 14% (invasive aspergillosis in 10% and 4% non-aspergillus molds), and 16% nonbacteremic gram-positive infections (coagulase-negative staphylococci in 12%, and S aureus in 4%). 103 Such infections occur at a median of day 10 from the initial neutropenic sepsis syndrome and are associated with independent risk factors including adult age group, primary induction therapy for acute leukemia, a central venous access device in situ, ANC less than /L, and clinically documented infection as the first neutropenic fever syndrome. 103 In another single-center experience from Israel, 29% of the first neutropenic fever episodes were associated with persistent or recrudescent fever syndromes. Of these, 54% were microbiologically documented, 46% were bacterial (gram-negative bacilli in 33%, gram-positive cocci in 11%, and C difficile in 2%), and 7% were fungal. 114 Afermentative gram-negative bacilli (Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter spp) comprised almost one-third of the gram-negative bacillary infections. 114 These bacteria are often multidrug resistant 128 and associated with indwelling central venous access devices. 97 The addition of antifungal therapy for the empirical treatment of suspected occult invasive fungal infection as a cause of PNF despite 4 to 7 days of broad-spectrum antibacterial therapy has been an international standard of practice. 19,96, By these criteria, the prescription rate for empirical antifungal therapy (22% 69% in patients undergoing treatment of acute leukemia) far exceeds the event rate of 3.6% for proven or probable invasive fungal infection (95% CI 2.9% 4.4%) in persistently febrile neutropenic patients. 32 The Infectious Disease Society of America has acknowledged the

17 Infection in Neutropenic Patients with Cancer 427 lack of specificity of persistent fever as a surrogate marker of occult invasive fungal infection and has questioned the use of empirical antifungal therapy for every neutropenic patient for persistent fever alone. 19 Candidemia and invasive candidiasis in the ICU Given these considerations, investigators have tried to identify patients in the ICU setting who are at greater risk for invasive fungal infection such as invasive candidiasis, the most common invasive fungal infection in the ICU patient population. 132 Table 2 summarizes the risk factors for candidemia and invasive candidiasis (C/IC). Despite the availability of newer antifungal agents, the hospital all-cause mortality rate for patients with invasive candidiasis in the ICU often exceeds 40%. 133 Among 2890 patients admitted to an ICU, the ability to predict the likelihood of invasive candidiasis was increased from 3% to approximately 10% by the following criteria: administration of any antibacterial therapy or the presence of a central venous access device within 3 days of admission to the ICU, plus at least 2 of total parenteral nutrition, dialysis, any major surgery, pancreatitis, administration of corticosteroids, or administration Table 2 Risk factors for C/IC in patients with cancer referred for critical care services Risk Factor Comments Older age Increased number of comorbidities Immune suppression Administration of broad-spectrum Selection for mucosal colonization by antibacterial therapy opportunistic yeasts 178 Administration of previous antifungal Increased risk for Candida krusei or Candida therapy glabrata Candida colonization of mucosal surfaces Pool of microorganisms from which translocation is derived 133,179 Indwelling central venous access devices Contamination of catheters and catheter hubs and arterial catheters increase risk for access to circulation APACHE II score, >11 Increase in physiologic risk for C/IC 180 Extensive abdominal surgery Loss of bowel mucosal integrity as a result of trauma or surgery increases the likelihood of peritoneal contamination by Candida spp colonizing the damaged mucosal surfaces 137 Burns Integumental barrier damage leading to cytokine cascade Immunosuppression, especially corticosteroids Intensive cytotoxic anticancer therapy Organ transplantation Total parenteral nutrition Chronic renal failure and dialysis Prolonged ICU admission Abbreviation: C/IC, candidemia/invasive candidiasis. Interference with innate host immune defense mechanisms Cytotoxic therapy-induced intestinal epithelial damage leading to translocation of colonizing Candida spp Immunosuppression Increased risk for C/IC due to Candida parapsilosis Patients with chronic renal failure Increased incidence of C/IC after day 8 of admission with peak incidence at approximately day

18 428 Bow of other immunosuppressive agents. 134 The predictive value of the model has been improved by requiring that all of the following criteria be satisfied: mechanical ventilation, presence of a central venous access device, administration of broad-spectrum antibacterial therapy, and at least 1 other criterion. 135 The prognosis for C/IC has improved with the introduction of new safe antifungal agents including second-generation triazoles and echinocandins and with earlier diagnosis based on high indices of suspicion, prediction rules, and surrogate marker identification. 136,137 Guidelines have recommended that treatment of proven C/IC with several effective agents including lipid formulations of amphotericin B (liposomal amphotericin or amphotericin B lipid complex at 3 mg/kg/d) or an echinocandin (intravenous anidulafungin 200 mg load followed by 100 mg/d, intravenous caspofungin 70 mg load followed by 50 mg/d, or intravenous micafungin 100 mg/d). 137 Fluconazole may be considered an alternative for less severely ill patients with cancer who have not been receiving antifungal prophylaxis with an azole. 137 Mold infections in patients with cancer in the ICU Invasive mold infection, particularly invasive aspergillosis, in the critical care setting has been characterized by high crude mortality rates in excess of 80%, and attributable mortality rates of 48%. 138,139 A summary of the risk factors for invasive mold infections is shown in Table 3. An understanding of the true incidence of invasive mold infections such as invasive aspergillosis in the ICU setting is elusive. There are several reasons cited for this: the signs and symptoms of invasive aspergillosis such as fever unresponsive to broadspectrum antibacterial therapy, cough, dyspnea, hypoxia, and pleuritic chest pain are nonspecific in sedated, ventilated patients with cancer 132 ; it is difficult to interpret the significance of positive lower respiratory tract cultures for Aspergillus spp as representing invasive infection or colonization; the paucity of data from postmortem examinations regarding invasive mold infections 140 ; radiologic signs characteristic of invasive mold infection may be modified or absent in nonneutropenic patients with cancer in the ICU 141,142 and diagnosis may be confounded by intercurrent bacterial, viral, or Pneumocystis jirovecii pneumonia 143 ; the diagnostic usefulness of newer non culture-based antigen and genomic detection tests have not been standardized in ICU-based populations of patients with cancer ; and the diagnostic criteria based on host predisposition, clinical features, radiologic signs, and mycological testing 147,148 were designed for clinical trials rather than clinical practice. 149,150 Voriconazole is the agent of choice for the treatment of suspected, possible, probable, or proven invasive aspergillosis in immunocompromised patients Liposomal amphotericin B has been considered an alternative for this indication. 152,153 To date, primary therapy for invasive aspergillosis with combination antifungal therapy has not been recommended. 153 More recently, a randomized double-blind controlled trial in patients with leukemia and stem cell transplant demonstrated a survival advantage with primary therapy for invasive aspergillosis with a combination of voriconazole and an echinocandin, anidulafungin. 154 Impact of Antimicrobial Prophylaxis in Neutropenic Patients with Cancer Admitted to the ICU Among patients admitted to the ICU with sepsis syndromes, a history of antibacterial prophylaxis administration, together with an understanding of the patient s colonization profile and the local epidemiology of antimicrobial susceptibility patterns can influence the choice of subsequent antimicrobial therapy. Antibacterial prophylaxis, particularly with fluoroquinolone agents, is associated with the emergence of resistance. 112 In

19 Table 3 Factors associated with risk for invasive mold infections, including invasive aspergillosis, in neutropenic patients with cancers Risk Factor Host-Related Factors Older age Dectin-1 Y238X polymorphisms Tolllike receptor 4 polymorphisms in HSCT donors IL-10 promoter gene polymorphism APACHE II score >11 Increased iron stores Disease-Related Factors Unfavorable cytogenetic profile in AML Advanced underlying malignancy Relapse after HSCT Environmental Factors Month of transplantation Management in an HEPA-filtered protected environment Hospital construction or renovation Treatment-Related Factors Corticosteroid therapy Severe neutropenia (ANC < /L) >10 d T-cell suppressant therapy Failure to achieve CR in AML HSCT type HSCT, source of donor stem cells HSCT, CD34 stem cell dose HSCT, conditioning regimen HSCT, grade II-IV agvhd HSCT, CMV disease Impact of Risk Factor Increased risk for IMI: >55 y 12%, 55 y 5% 185 IA risk donor/recipient: WT/WT 18%, Y238X/WT 35%, WT/Y238X 33%, Y238X/Y238X 44% 186 Recipient IA risk when transplanted from donors with (22%) and without (5%) the polymorphism 187 IA risk: 0% vs 11.5% vs 19.7% for ACC/ACC, ACC/ATA, and ATA/ATA haplotypes, respectively 188 Increases the risk for IFI 180 IA risk: OR 12.3, 95% CI IA risk: 14% unfavorable vs 3% favorable or intermediate 185 Increased IA risk among patients with advanced disease (HR 1.5, 95% CI ) 189 Increased risk during April to September compared with October to March 190 Decreased risk for all-cause pneumonia 191 Decreased risk for IA 185,192 Increased environmental contamination with Aspergillus spp conidia 193 IA risk: 44% vs 24% 194 Mean duration 21 d in IA cases, vs 10 d in controls 195 IA risk: 29.5% vs 11.3% 196 IA risk: 19% vs 6% 185 IA risk: allogeneic > autologous 197 IA risk: alternative donor (unrelated donor or cord blood) > matched-related stem cell source 159 IFI risk: low dose (< CD34 cells/kg) prolongs time to engraftment and increases IFI risk 159 IA risk: MAC > RIC 198 IA risk: HR 11.1, 95% CI IA risk: HR 6.30, 95% CI Abbreviations: agvhd, acute graft-versus-host disease; CMV, Cytomegalovirus; CR, complete remission; HEPA, high-efficiency particulate air filter; HR, hazard ratio; HSCT, hematopoietic stem cell transplant; IA, invasive aspergillosis; IFI, invasive fungal infection; IMI, invasive mold infection; MAC, myeloablative conditioning regimen; RIC, reduced intensity conditioning regimen; WT, wild-type. Infection in Neutropenic Patients with Cancer 429

20 430 Bow neutropenic patients with cancer, fluoroquinolone-based chemoprophylaxis has been associated with breakthrough infections due to coagulase-negative staphylococci, viridans group streptococci (particularly S mitis), fluoroquinolone-resistant gram-negative bacilli, and opportunistic yeasts. Long-term use has been linked epidemiologically to colonization by MRSA, vancomycin-resistant enterococci, Clostridium difficile, and extended-spectrum b-lactamase producing and carbapenemase-producing gramnegative bacilli in cancer populations. Accordingly, clinical guidelines have recommended consideration of antibacterial prophylaxis in certain high-risk cancer populations such as those undergoing intensive cytotoxic therapy for acute leukemia or HSCT, and discouraged use for patients undergoing treatment of solid-tissue malignancies or lymphoma. 13,19 Antifungal chemoprophylaxis for the prevention of invasive candidiasis is recommended for high-risk patients with acute leukemia, HSCT, and specified solid-organ transplant patients. 19,137, The use of fluconazole for this purpose has been linked to a selection for invasive infections due to fluconazole-resistant Candida krusei and less susceptible strains of Candida glabrata or Candida albicans. Moreover, the clinician must be mindful of the lack of activity of fluconazole against molds such as Aspergillus spp. Previous administration of azole-based mold-active chemoprophylaxis to high-risk patients with cancer, particularly those who have undergone stem cell transplantation and who may have additional concomitant risk factors such as Cytomegalovirus infection or steroid-refractory graft-versus-host disease, may predispose to colonization and infection by azole-resistant molds such as members of the class Zygomycetes, order Mucorales, giving rise to infections such as mucormycosis. 158 Agents used for antimold chemoprophylaxis, particularly in patients with acute leukemia and stem cell transplant recipients, include itraconazole, voriconazole, and posaconazole. In addition, these agents have variable inhibitory effects on hepatic cytochrome P450 enzyme with significant potential for drug-drug interactions that may affect other immunosuppressive agents or agents commonly used in the ICU setting. 137,159 Patients who may be receiving azole-based mold-active chemoprophylaxis and who have suspected, possible, probable, or proven invasive mold infection should receive treatment with agents from another antifungal class such as an echinocandin or a polyene. 19 REFERENCES 1. Brenner H. Long-term survival rates of cancer patients achieved by the end of the 20th century: a period analysis. Lancet 2002;360(9340): Azoulay E, Afessa B. The intensive care support of patients with malignancy: do everything that can be done. Intensive Care Med 2006;32(1): Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34(2): Rosolem MM, Rabello LS, Lisboa T, et al. Critically ill patients with cancer and sepsis: clinical course and prognostic factors. J Crit Care 2012;27(3): Maschmeyer G, Bertschat FL, Moesta KT, et al. Outcome analysis of 189 consecutive cancer patients referred to the intensive care unit as emergencies during a 2-year period. Eur J Cancer 2003;39(6): Kress JP, Christenson J, Pohlman AS, et al. Outcomes of critically ill cancer patients in a university hospital setting. Am J Respir Crit Care Med 1999;160(6): Taccone FS, Artigas AA, Sprung CL, et al. Characteristics and outcomes of cancer patients in European ICUs. Crit Care 2009;13(1):R15.