Infection in the Patient With Cancer

Summary of Key Points

Cancer patients with fever and neutropenia require immediate evaluation, assessment of risk for complications, at least two sets of blood cultures (including one from a peripheral vein and one from any indwelling catheter), other appropriate cultures or tests to aid infection diagnosis, and prompt institution of empiric broad-spectrum antibacterial therapy within 2 hours of presentation. Appropriate empiric antibiotic regimens include those covering Pseudomonas aeruginosa, enteric gram-negative organisms, and common institutional pathogens, taking into consideration local antibiotic resistance patterns. Gram-positive active agents are not a standard component of the empiric treatment regimen for fever and neutropenia.
Risk factors for an infection and/or a complicated course of infection in neutropenic cancer patients include the presence of indwelling catheters, comorbid medical conditions such as diabetes or chronic obstructive pulmonary disease, recent surgery, malnutrition, and cellular and humoral immune defects from an underlying tumor and its treatment. Recent use of antibiotics and/or hospitalizations are risk factors for infections with antibiotic-resistant bacteria.
Risk assessment is an important tool for evaluation and treatment of patients with cancer who have fever and neutropenia. The Multinational Association of Supportive Care in Cancer (MASCC) scoring system is often used, with a cumulative score of 21 or higher indicating a low-risk patient who might be eligible for outpatient and/or oral antibiotic empiric therapy. In addition, patients expected to have neutropenia lasting more than 7 days, typically those undergoing allogeneic stem cell transplantation or therapy for acute leukemia, are considered at high risk for complications. Most patients with solid tumors will have neutropenia lasting fewer than 7 days and are considered to be at low risk.
Antibiotic prophylaxis with levofloxacin has been shown to decrease fever and infection in high-risk patients with acute leukemia or those undergoing stem cell transplantation, with neutropenia (<1000 neutrophils/mm ³ ) lasting more than 7 days, and a mortality benefit was demonstrated in one meta-analysis.
Mold-active triazole agents such as posaconazole and voriconazole, are effective prophylaxis against invasive fungal infections in high-risk patients, such as those undergoing induction for acute leukemia or who have high-grade graft-versus-host disease (GVHD). Fluconazole is considered adequate prophylaxis in all preengraftment hematopoietic stem cell transplantation (HSCT) patients.
Prophylaxis of opportunistic infections (e.g., zoster, Pneumocystis jiroveci ) may be indicated for some patients receiving purine analogues, steroids or other immunomodulating drugs, or new targeted therapies, and clinicians should be familiar with those indications and risks.
Clostridium difficile has emerged as a major cause of morbidity and mortality in many centers, and fluoroquinolone use is a risk factor. Oral vancomycin is the treatment of choice in most cases, although metronidazole may be adequate for patients with mild symptoms.
Empiric antifungal therapy has been traditionally recommended for neutropenic patients who are still febrile after 4 to 7 days of broad-spectrum antibiotic, but with the broad use of mold-active triazole prophylaxis in high-risk patients, this practice is less frequently used. Instead, a high-resolution computed tomography scan of the chest and serial galactomannan assay results may identify possible mold infections and guide antifungal management.
Patients scheduled for allogeneic HSCT should be screened for evidence of latent herpesvirus and hepatitis virus infections, and prophylaxis should be instituted accordingly.

Numerous disease-related and chemotherapy-induced factors render patients with cancer at increased risk for infection. These factors include the type of cancer (e.g., a solid tumor versus a lymphoma or acute leukemia); the severity and duration of neutropenia; impairments in cellular function caused by cytotoxic or immunosuppressive drugs; breaches in the integument from surgical procedures, the presence of indwelling plastic venous catheters, or mucositis of the gastrointestinal (GI) tract as a result of chemotherapy; and comorbid conditions such as malnutrition, deconditioning, or medical problems such as chronic obstructive lung disease or diabetes. Approaches to prevention, diagnosis, and management of infectious complications in patients with cancer are greatly influenced by the cumulative burden of these risk factors. Neutropenia remains one of the most important predisposing factors for infection, overriding many of the others. This chapter addresses current standards for the management of fever during neutropenia and also highlights contemporary guidelines for the prevention and treatment of common infectious complications in patients with cancer.

Neutropenia as a Risk Factor for Infection

The association between neutropenia and increased infection risk was first demonstrated by Bodey and colleagues in 1966 in a study of leukemic patients undergoing cytotoxic therapy. The data show that the frequency of infectious complications is inversely related to the degree and duration of neutropenia ( Fig. 34.1 ). Infection risk starts to increase when the absolute neutrophil count (ANC) decreases to less than 1000 cells/mm ³ and increases dramatically when the ANC count is less than 500 cells/mm ³ . Fewer than half of the neutropenic patients who become febrile will have an identified infection. In roughly 10% to 20% or more of patients with neutrophil counts less than 100 cells/mm ³ , a bloodstream infection will be identified. More than 50% of all episodes of fever and neutropenia represent “fever of undetermined origin,” with no clear infection source on physical and radiographic examination and cultures. In addition to the severity of the ANC nadir, the duration of neutropenia is also an important determinant of both infection risk and infection type. Brief durations of neutropenia, particularly for less than 7 days, are usually associated with a rapid and favorable response to empiric antibiotic therapy. Fever often may be of unknown origin during this early phase of neutropenia, but if a causative pathogen is identified, bacteria and viruses predominate. A neutrophil count persistently less than 500 cells/mm ³ for more than 7 days is associated with greater risk for infection-related morbidity and mortality and is the setting in which, in the absence of prophylaxis, Aspergillus and other invasive fungal infections (IFIs) most often occur. Other pathogens that may cause infection during the course of prolonged neutropenia (i.e., after 7 days) include antibiotic-resistant bacteria, Candida species, and other molds. Deaths during the state of neutropenia usually are due to these subsequent infections. Overall inpatient mortality for fever and neutropenia is approximately 8% for low-risk patients and approximately 9% for those with more prolonged duration of neutropenia.

Figure 34.1, The relationship between neutrophil count and infection in patients with acute leukemia.

In addition to cytotoxic chemotherapy, circulating neutrophil deficiencies can result from bone marrow incompetence disorders such as myelodysplastic syndrome or crowding out of normal granulocytic precursors by tumor cells. “Functional neutropenia” describes impaired neutrophil microbicidal activity that may be a consequence of the leukemia itself or may be due to therapies such as steroids. In these instances, ineffective neutrophil killing leaves the patient highly vulnerable to infection despite seemingly normal peripheral white blood cell counts.

Other Risk Factors for Infection

Disruption of integumentary, mucosal, and mucociliary barriers by cytotoxic therapies provides opportunities for invasion by colonizing bacteria on the skin, in the GI tract, or in the mucous membranes. Shifts in normal colonizing microbial flora at these sites occur as a result of chemotherapy, antibiotic use, and nosocomial exposures, leading to increased colonization with gram-negative and antibiotic-resistant pathogens. Indwelling catheters create a significant breach in host defense, permitting direct access of skin flora and other pathogens to blood or subcutaneous tissue. Tumor growth can disrupt normal anatomic structures, and cancer surgery may result in anatomic alterations and wounds, providing local sites for pathogen entry.

Underlying diseases and cancer therapies also play important roles in infection risk. For example, hypogammaglobulinemia often complicates chronic lymphocytic leukemia (CLL) or multiple myeloma, rendering patients at increased risk for severe pneumococcal infections or Haemophilus influenzae or Neisseria meningitidis infection. In contrast to patients with solid tumors, patients with acute leukemias are more likely to have overwhelming sepsis or IFIs because of prolonged periods of profound neutropenia related to the underlying leukemia. Patients with acute lymphocytic leukemia, Hodgkin disease, or non-Hodgkin lymphoma may have defects in cell-mediated immunity that predispose them to development of Pneumocystis jiroveci pneumonia (PCP), cryptococcal disease, or infections with intracellular organisms such as Salmonella or Listeria.

Steroid (glucocorticoid) therapy induces a broad immunosuppressive effect, including impaired chemotaxis and killing by neutrophils, impaired T-cell function and reduction in T-cell proliferation, and alterations in skin and mucosal barriers. Long-term or high-dose steroid therapy is a significant risk factor for IFIs, particularly with Cryptococcus and P. jiroveci (usually seen with tapering of the steroid regimen). Invasive Aspergillus infections typically occur in patients receiving high doses of steroids (>1 mg/kg/day) for graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Steroid therapy also may predispose affected patients to development of bacterial infections and Mycobacterium tuberculosis reactivation. High-dose cytosine arabinoside therapy causes mucositis that has been linked to development of life-threatening streptococcal bacteremias in neutropenic patients. Fludarabine and alemtuzumab cause prolonged suppression of CD4+ lymphocytes and attendant susceptibility to infections with Listeria, P. jiroveci, herpesviruses, and bacterial infections. The administration of temozolomide along with radiation for glioblastoma also is associated with increased susceptibility to P. jiroveci, in addition to profound myelotoxicity. Patients with myeloma who are treated with the proteasome inhibitor bortezomib are at increased risk for herpes zoster, and antiviral prophylaxis should be administered to those receiving the drug.

Bevacizumab, a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A), is linked to impaired wound healing and possibly to intestinal perforation in colon cancer patients.

Sources of Infection

Colonization by bacteria, fungi, or viruses with the potential to cause disease is generally is a prerequisite for clinical infection to occur. Accordingly, endogenous bacterial and fungal flora and latent herpesvirus infections account for a majority of initial infections in neutropenic patients with cancer. These infections include skin colonizers such as Staphylococcus aureus and coagulase-negative staphylococci, viridans group streptococci (VGS), and herpes simplex virus (HSV) from the oropharynx, in addition to gram-positive bacteria and enteric gram-negative bacteria from the skin and GI tract, respectively. Candida species infections often are derived from the skin or the GI or female genital tract. Latent infections that may reactivate during immunosuppression include those due to herpes simplex or varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B and C viruses, M. tuberculosis, and Toxoplasma gondii.

Exogenous sources of infection often are found in the hospital and home environments. Contaminated blood products, hospital equipment, and water sources and nosocomial spread of organisms from health care workers represent less common, albeit significant, sources of infection. Common hospital-acquired infections include those due to Clostridium difficile, respiratory viruses, vancomycin-resistant Enterococcus (VRE), and other multidrug-resistant (MDR) gram-negative bacteria. Water sources such as faucets and shower heads have been implicated in the spread of Legionella and Aspergillus. Outbreaks of Klebsiella and Enterobacter infection related to intravenous solutions have been well documented .

Foods can be a potential source of infection, particularly unwashed fruits and vegetables. In general, neutropenic patients are advised to follow safe food-handling guidelines, which include washing fruits and vegetables thoroughly, cooking eggs until the whites and yolks are completely hard, and cooking meat until it is well done. Potted plants, mulch, and excavation and building or renovation sites have been implicated as sources of Aspergillus and other molds that may cause disease.

Approach to Fever in the Neutropenic Patient

Fever often is the only reliable sign of significant underlying infection in the neutropenic patient. No specific clinical features, such as hypotension, chills, or the magnitude of fever can accurately distinguish between fever due to an infection and that due to a noninfectious cause. Nor are laboratory tests such as C-reactive protein or procalcitonin levels considered specific or sensitive or enough to be relied on for making decisions about the use of antibiotics at the time of presentation. Therefore all febrile neutropenic patients should receive empiric broad-spectrum β-lactam, antipseudomonal antibiotics, ideally within 1 hour of presentation. Although a clinically or microbiologically documented source of fever is not found in a majority of febrile neutropenic patients, the rapid initiation of empiric antibiotic therapy remains an important standard of care for all patients in this setting. The choice of specific antibiotic regimens depends on an assessment of the patient's infection risk during neutropenia, which, in turn, is a function of many factors, including the depth and duration of neutropenia, the underlying cancer type and status (remission, relapse, or recurrence), type of cancer treatment, and comorbid medical conditions. Clinical criteria that may alter the empiric antibiotic regimen are shown in Table 34.1 .

Table 34.1

Approach to Management of Fever and Neutropenia

History and Physical Findings	Indicated Modifications in Antimicrobial Coverage or Diagnostic Test
Fever during neutropenia, stable patient	Escalation approach: antibiotic monotherapy with an antipseudomonal β-lactam agent in hemodynamically stable patients with mild to moderate burden of illness; if the patient is receiving antibiotic prophylaxis, then empiric therapy must be based on an agent of a different class from that used for prophylaxis (e.g., if the patient is receiving fluoroquinolone-based prophylaxis, then switch to a β-lactam–based regimen)
Hypotension, signs of severe sepsis or septic shock	De-escalation approach: initial broad-spectrum antimicrobial coverage with a triple-antibiotic regimen (e.g., carbapenem plus vancomycin plus an aminoglycoside) is recommended; if cultures are negative for gram-positive organisms, consider discontinuing vancomycin after 3 days
Fever that is persistent or recrudescent on or after day 5 of antibiotic therapy	Empiric antifungal therapy: add an amphotericin B product, an echinocandin, or voriconazole if the patient is not already receiving prophylaxis with a mold-active agent; a CT scan of the chest may help identify fungal infection; consider a CT scan of the chest and frequent galactomannan testing during neutropenia to guide preemptive treatment as an alternative strategy to empiric antifungal treatment
Severe oral or esophageal mucositis	Send a swab for viral (HSV) culture; add antiviral coverage (if not already being given); consider antiviral resistance to prophylaxis if esophagitis occurs late in the course of neutropenia; add an antifungal agent for possible Candida esophagitis; switch streptococcal coverage to vancomycin; esophagoscopy may be indicated
Catheter exit site or tunnel erythema, tenderness, or discharge or cellulitis at any site	Culture any discharge; add vancomycin; for tunnel infection (erythema and tenderness 2 cm above exit site), catheter removal and surgical débridement generally are required
Possible anaerobic infection	Add metronidazole if broad-spectrum antibiotics without activity against anaerobes are being used
Abdominal pain, especially right lower quadrant, suggestive of neutropenic enterocolitis; oropharyngeal or neck or soft tissue swelling	Perform a CT scan of the affected area Supportive care: avoid surgical intervention if possible in a neutropenic patient
New pulmonary infiltrate	Bronchoscopy (with or without biopsy) is the preferred method for evaluating new infiltrates in high-risk patients Nodular: add mold coverage with voriconazole, posaconazole, or amphotericin B preparation Alveolar: broaden gram-negative coverage and add Legionella coverage (quinolone or macrolide) Interstitial: send specimen for diagnostic studies for both respiratory viruses, PCP, and herpesviruses, particularly CMV Review patient history for risk factors for tuberculosis or infection with endemic fungi
Upper respiratory symptoms of coryza, congestion during fall or winter	Send nasal wash or swab for respiratory viral studies (e.g., culture, PCR, rapid antigen testing)
Hemorrhagic cystitis	Indicated studies include urine viral culture and BK virus PCR assay (for hematopoietic stem cell transplant recipients)

CMV, Cytomegalovirus; CT, computed tomography; HSV, herpes simplex virus; PCP, Pneumocystis jiroveci pneumonia; PCR, polymerase chain reaction.

Definitions

Guidelines for evaluating antimicrobial therapy for fever and neutropenia have been developed by the Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network. Fever is defined as a single temperature measurement of 38.3°C (101°F) or greater in the absence of other obvious causes; a temperature of 38°C or greater sustained for an hour or longer is considered to represent a “febrile state” that requires prompt evaluation and intervention in the setting of neutropenia. Neutropenia is defined as an ANC less than 1000 cells/mm ³ in some centers but more often is designated by a neutrophil count of less than 500 cells/mm ³ , which is a level associated with a much higher risk for infection. For practical purposes, an ANC less than 500 cells/mm ³ , or a count that is anticipated to fall below that level within 48 hours, constitutes a state of neutropenia.

Occasionally, a neutropenic patient who is afebrile may exhibit signs or symptoms of infection (e.g., abdominal pain, severe mucositis, and perirectal pain) and should be considered to have an active infection. The concomitant administration of corticosteroids also may initially blunt the fever response in cancer patients. Afebrile neutropenic patients who show signs or symptoms suggestive of an infection should receive empiric antibiotics immediately because of their increased risk for serious invasive infections.

Initial Evaluation

The initial evaluation of the febrile neutropenic patient should be directed toward determining the possible sites of infection and causative organisms and assessing the patient's level of risk for infection-related complications during the course of neutropenia. A thorough site-specific review of systems is essential. Pertinent history includes recent antibiotic therapy, recent surgery or other invasive procedures such as biopsies or catheter placement, and possible exposure to infections from close contacts and household members, foods, animals, or travel.

The physical examination should focus on common potential sites of infection. It is essential to be aware that the manifestations of infection are often muted in the absence of inflammatory cells. The usual signs and symptoms of infection seen in immunocompetent hosts may be absent. Examination of the oropharynx may reveal mucosal ulcerations that could represent chemotherapy-induced mucositis but might also be due to HSV. Catheter sites require careful assessment for erythema, tenderness, or discharge. With bacterial cellulitis of the skin or perirectum, induration and erythema may be minimal; pimples or pustules are uncommon without neutrophils to create pus. Bacterial pneumonia may yield few respiratory signs or symptoms despite the infiltrates being apparent on the chest radiograph. A urinary tract infection may not be associated with dysuria. GI tract mucositis due to cytotoxic chemotherapy can lead diarrhea that mimics infections. Abdominal pain in neutropenic patients may signify a wide variety of problems, including intestinal tumor necrosis and neutropenic enterocolitis, both of which can result in intraabdominal catastrophe or sepsis.

Initial laboratory evaluation should include a complete blood cell count and differential white cell count to determine the degree of neutropenia, liver and renal function tests, oxygen saturation determination, and urinalysis. Chest radiography should be reserved only for patients who have symptoms of respiratory tract infection. At least two blood culture samples, each consisting of 20 to 40 mL of blood, should be obtained from both a peripheral vein and from an indwelling catheter lumen. An adequate volume of blood taken for culture will enhance the chances of recovering a pathogen.

Drawing blood samples from both a vascular catheter and a peripheral vein can help determine whether the catheter is a source of infection. If the differential time to culture positivity between catheter- and venipuncture-derived cultures is greater than 2 hours, the catheter is implicated as a source. In patients with cancer, however, one study showed that catheter-drawn blood cultures without concomitant peripheral cultures do have very good negative predictive value and fairly good sensitivity (89%) and specificity (95%). A positive culture result for coagulase-negative staphylococci—a common contaminant—requires two positive blood culture sets to be considered a “true positive.”

Cultures of any suggestive sites of infection should be performed: Diarrheal stools should be tested for the presence of C. difficile toxin, and additional polymerase chain reaction (PCR)–based multiplex testing may identify pathogens such as norovirus or adenovirus. Specimens from oral or perineal lesions suspected to harbor HSV should be sent for viral cultures. PCR testing (preferred) or culture and rapid antigen testing should be performed for respiratory viruses on nasal wash or swab specimens in patients with suggestive signs or symptoms during the winter season.

Risk Assessment

Patients with fever and neutropenia may have a variety of clinical outcomes. Over 90% of them will receive broad-spectrum empiric antibiotics and survive the episode without major incident. In a minority of patients, significant infections will develop or they will experience other life-threatening medical events. The level of risk for complications is driven largely by the duration of neutropenia expected after a particular chemotherapy regimen. Specific historical and physical characteristics also play a key role, including age, type and stage of cancer, performance status, medical comorbidities, outpatient or inpatient status at presentation, and vital signs at presentation ( Table 34.2 ). In general, clinical features of low-risk patients include neutropenia anticipated to last less than 7 days, absence of serious medical comorbidity, and outpatient status at onset of fever. Typically, patients receiving chemotherapy for solid tumors fit into a low-risk category, with few complications anticipated. Oral antibiotics given outside of the traditional hospital setting may be appropriate for a subset of these low-risk patients. High-risk patients, in contrast, generally have an expected duration of neutropenia of 7 days or longer and/or have serious medical comorbid conditions. Recipients of allogeneic hematopoietic stem cell transplants, patients with acute leukemia who are receiving induction or consolidation therapy, and patients with myelodysplasia or aplastic anemia are considered at high risk for complications during neutropenia. High-risk patients should be always admitted to the hospital for antibiotic therapy if they develop fever and neutropenia. Persons who have received autologous hematopoietic stem cell transplants or those treated with certain regimens for CLL or lymphoma are sometimes considered to be at intermediate risk for infections, even though they may have prolonged durations of neutropenia (i.e., longer than 7 days).

Table 34.2

Risk for Infectious Complications After Cytotoxic Chemotherapy: Clinical Features Defining Risk Status and Risk Prediction in Patients With Fever and Neutropenia

Modified from Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):e56–93.

GENERAL CLINICAL FEATURES IN HIGH-RISK VS LOW-RISK PATIENTS
High risk Neutropenia anticipated to extend to or beyond 7 days Presence of any comorbid medical problems including but not limited to: Hemodynamic instability Oral or gastrointestinal mucositis that interferes with swallowing or causes severe diarrhea Abdominal pain or perirectal pain of new onset Nausea and vomiting Diarrhea (passage of six or more loose stools daily) Neurologic or mental status changes of new onset Intravascular catheter infection, especially catheter tunnel infection New pulmonary infiltrate or hypoxemia, or underlying chronic lung disease Evidence of hepatic insufficiency (defined as aminotransferase values greater than five times normal values) or renal insufficiency (defined as a creatinine clearance less than 30 mL/min) Low risk Neutropenia expected to resolve within 7 days Absence of any medical comorbidity as listed in high-risk criteria Adequate hepatic function and renal function
MASCC PREDICTION TOOL FOR DETERMINING HIGH AND LOW RISK FOR SERIOUS MEDICAL COMPLICATIONS
Characteristic	Weight (No. of Points) ^a
Age <60 yr	2
Outpatient status	3
Clinical status at presentation
No severe burden of febrile neutropenia
No or only mild symptoms	5
Moderate symptoms	3
No hypotension: systolic blood pressure >80 mm Hg	5
No dehydration requiring parenteral fluids	3
Medical history, underlying disease, and/or comorbidity
No chronic obstructive pulmonary disease	4
Solid tumor or hematologic malignancy without previous invasive fungal infection	4

MASCC, Multinational Association of Supportive Care in Cancer.

a If relevant, points are added to yield a sum score. If the score is >20, the patient is predicted to be at low risk (<10%) for the development of serious medical complications during the course of febrile neutropenia.

A validated risk assessment tool has been developed by the Multinational Association of Supportive Care in Cancer (MASCC) to identify high- and low-risk neutropenic patients at presentation with fever. The MASCC risk scoring system (see Table 34.2 ) uses a summation of weighted risk factors, including patient age, history, outpatient or inpatient status, acute clinical signs, the presence of medical comorbid conditions, and the severity of illness at presentation (referred to as “burden of illness”) to distinguish high-risk from low-risk patients with over 80% sensitivity and 60% negative predictive value. Low-risk patients are identified by a cumulative MASCC score equal to or greater than 21 points, whereas a score of less than 21 indicates that there is a high risk for complications during the course of febrile neutropenia. Patients with MASCC index scores of less than 15 demonstrate extremely high rates of complications and are more likely to die. A fundamental difficulty with the MASCC system is the nebulous nature of the “burden of febrile neutropenia” criterion, which is a subjective measure of how “sick” the patient appears to be at presentation. Despite this vagueness, MASCC-based risk assessment has been adopted as a standard management tool for patients with fever and neutropenia. In a large prospective validation study of the MASCC assessment tool among 277 febrile neutropenic patients, the rate of serious medical complications during the course of neutropenia was 12.9% in the low-risk group identified by MASCC score of 21 or higher (70% of all patients), compared with 43.3% of the high-risk group. Mortality rates were 1.9% and 9%, respectively, in low- and high-risk patients. In one study comparing the predictive potential of the MASCC risk index with biomarkers, including procalcitonin and C-reactive protein, a multivariate analysis revealed that MASCC score was the only independent variable that accurately predicted outcomes in febrile neutropenia; the biomarkers were all of limited value.

The MASCC risk index system may also be used as an adjunct to other factors to identify low-risk patients and aid in determining whether oral and/or outpatient empiric antibiotic management is appropriate.

Once pertinent historical data have been acquired, a physical examination and radiographic studies have been performed, risk has been assessed, and appropriate culture specimens have been obtained, then empiric antibiotics should be started promptly in all patients with fever and neutropenia. Preferably, all of these tasks should be completed swiftly, within 1 hour of patient presentation.

Empiric Antibiotic Therapy

For more than four decades, empiric antibiotic regimens that include a broad-spectrum antipseudomonal agent have been the standard approach to managing fever and neutropenia in both high-risk and low-risk patients with cancer. Use of cefepime, piperacillin-tazobactam, or an antipseudomonal carbapenem such as imipenem or meropenem, is the mainstay of empiric treatment recommended by various guidelines for most neutropenic patients with fever. Addition of either an aminoglycoside or ciprofloxacin, a mainstay agent, have shown no clear benefit of combination therapy over monotherapy. Escalation of the initial monotherapy regimen to include additional antibiotics, or changes in the initial agent, may be necessary as clinical and microbiologic information evolves, as outlined in Table 34.2 . This escalation approach, in which a single broad-spectrum antibiotic is initiated, is appropriate in febrile neutropenic patients with mild to moderate illness who have no clear source of infection and are hemodynamically stable. It is important to note that the specific choice of empiric agent(s) should be based on a review of local institutional bacterial susceptibility patterns in addition to previous exposure to broad-spectrum antibiotics; nosocomial infection, colonization or prior infection with resistant bacterial species (e.g., methicillin-resistant Staphylococcus aureus [MRSA], VRE, extended-spectrum β-lactamase (ESBL)–producing or antibiotic-resistant Enterobacteriaceae, Acinetobacter, Pseudomonas species, and Stenotrophomonas maltophilia ); intensive care unit stays; presence of urinary catheters; diarrhea; or serious illness such as pneumonia or sepsis.

Hypotension or septic shock in a neutropenic patient necessitates very broad empiric antibiotic coverage at the outset. This approach is warranted in view of the high mortality rate in neutropenic patients with the systemic inflammatory response syndrome, which can be incited by a wide variety of bacterial pathogens.

A multidrug regimen is recommended, with an antipseudomonal β-lactam (e.g., cephalosporin, carbapenem, or penicillin, depending on local susceptibilities) plus an aminoglycoside or ciprofloxacin (if the patient is not already receiving fluoroquinolone prophylaxis) plus vancomycin or another MRSA-active agent. Once the results of blood cultures and other tests are available and the clinical course evolves over several days, clinicians may de-escalate from the initial multidrug cocktail to a more simplified, tailored regimen (see Table 34.1 ).

Similarly, in the current era, a global increase in the incidence of MDR bacterial pathogens often merits a more expanded empiric antibiotic regimen for fever and neutropenia, and subsequent de-escalation can be pursued once more precise microbiologic and clinical data emerge. For example, if a pneumonia is identified at the outset, then adding an antipseudomonal fluoroquinolone (i.e., ciprofloxacin or levofloxacin) to the empiric β-lactam regimen provides broader coverage against potential gram-negative or atypical pathogens, such as Legionella. The initial regimen may be later modified or de-escalated according to clinical, radiographic, or culture data that become available, as outlined in Table 34.1 .

High-risk patients should always receive intravenous antibiotics in the inpatient setting. GI absorption may be too slow and inadequate to yield adequate serum concentrations of antibiotic rapidly in ill patients. Furthermore, high-risk patients are typically those with hematologic malignancies and heavy chemotherapy pretreatment leading to profound immunologic deficiencies; in addition, they may be colonized with resistant organisms as a result of prior antibiotic and nosocomial exposures, thus meriting close attention for breakthrough infections during the course of febrile neutropenia. Low-risk patients are generally less immunocompromised, and those who can tolerate oral agents may be treated with an oral fluoroquinolone-based regimen. Oral ciprofloxacin plus amoxicillin-clavulanate combination therapy proved as effective as intravenous broad-spectrum monotherapy in two randomized controlled studies among low-risk patients. Ciprofloxacin should not be used as a solo agent because of its poor coverage of gram-positive organisms. Levofloxacin has better activity than ciprofloxacin against gram-positive organisms, most notably VGS, and it appears to be an effective, well-tolerated oral agent for empiric therapy in low-risk patients.

Outpatient management has become an accepted standard of care in selected low-risk patients with fever and neutropenia, especially those with an MASCC risk score of 21 or greater. Oral antibiotics may be initiated in the outpatient setting for selected low-risk patients if fulminant infection is excluded on the basis of initial history and examination and laboratory and pertinent radiographic findings, if swallowing of pills is not impaired, and if round-the-clock family support is ensured. In one large series, oral outpatient treatment for low-risk fever and neutropenia was deemed to be successful in 80% of patients, with 20% of patients requiring readmission to the hospital, primarily for persistent fever. Factors predicting readmission included age greater than 70 years, grade of mucositis greater than 2, poor performance status, and ANC less than 100 cells/mm ³ at the outset of fever.

In patients who have been admitted to the hospital for initial empiric intravenous antibiotics but who have defervesced and remained hemodynamically stable, de-escalation of the broad-spectrum empiric regimen is recommended once susceptibility of pathogens from initial cultures is known. For example, if a susceptible Escherichia coli bacteremia is identified, then empiric cefepime may be narrowed to coverage with once-daily ceftriaxone for the duration of the neutropenic period. If cultures are negative but stable afebrile neutropenia persists, some experts advocate discontinuing broad-spectrum antibiotics in favor of a return to levofloxacin prophylaxis.

Use of Vancomycin or Other Gram-Positive Agents

Vancomycin or other agents with potent activity against drug-resistant gram-positive pathogens are not recommended for routine inclusion in the initial empiric regimen. Although a predominance of gram-positive pathogens is isolated in blood cultures from febrile neutropenic patients, these organisms rarely cause life-threatening infections. In 1992 a large prospective, randomized trial from the European Organisation for Research and Treatment of Cancer failed to show a clinical advantage in adults with fever and neutropenia of use of a regimen containing vancomycin compared with one that did not. Since then, vancomycin or similar gram-positive active drugs have not been included in the empiric regimen, except in limited circumstances, as shown in Table 34.3 . Other agents with activity against gram-positive pathogens include daptomycin, ceftaroline fosamil, and linezolid. Both linezolid and daptomycin are often effective against infections with VRE. Daptomycin has excellent activity in cases of S. aureus bloodstream infections, with some evidence suggesting superior outcomes compared with vancomycin. Ceftaroline fosamil also appears to show comparable activity in this setting. Caution is advised when prescribing these agents because each has significant adverse effects. Myelotoxicity has been associated with prolonged linezolid use (longer than 14 days), primarily in the form of thrombocytopenia and occasionally neutropenia. In the setting of HSCT or induction for acute myeloid leukemia, studies of hematologic parameters have revealed no delay in the times to neutrophil or platelet engraftment between control patients and those receiving linezolid.

Table 34.3

Appropriate Use of Gram-Positive Active Antibiotics in the Neutropenic Patient With Cancer

VANCOMYCIN OR ANOTHER GRAM-POSITIVE ACTIVE ANTIBIOTIC

Clinical situations for which the addition of vancomycin or another gram-positive active antibiotic is recommended include the following:
- Clinically apparent, serious catheter-related infection (e.g., tunnel or port pocket infection or any other skin or soft tissue infection)
- Blood culture positive for gram-positive bacteria before final identification and susceptibility testing
- Known colonization with methicillin-resistant Staphylococcus aureus
- Hypotension or septic shock without an identified pathogen (i.e., a clinically unstable patient)
- Risk factors for viridans streptococcal bacteremia, including severe mucositis (typically associated with high-dose cytarabine and with TMP-SMX or fluoroquinolone prophylaxis)

OTHER AGENTS FOR USE WITH KNOWN VANCOMYCIN RESISTANCE

Linezolid, quinupristin-dalfopristin, or daptomycin may be used in very selected clinical situations in which vancomycin-resistant pathogens (e.g., VRE) are identified or in patients for whom use of vancomycin is not a clinical option

GRAM-POSITIVE ACTIVE ANTIBIOTICS FOR GRAM-POSITIVE INFECTIONS ONLY

Vancomycin or another gram-positive active antibiotic should be discontinued in 2–3 days if no resistant gram-positive infection is identified

TMP-SMX, Trimethoprim-sulfamethoxazole; VRE, vancomycin-resistant Enterococcus.

Documented serious infections that are typically caused by gram-positive pathogens, such as cellulitis or obvious catheter-related infections, should be treated with vancomycin or another gram-positive active agent. Many catheter-related bloodstream infections are caused by coagulase-negative staphylococcal isolates with high-level β-lactam antibiotic resistance, and thus vancomycin is indicated. If vancomycin is started empirically because of concerns about drug-resistant gram-positive infections but cultures and examination do not identify infections with such organisms within 2 or 3 days, then empiric vancomycin therapy should be discontinued. Furthermore, in stable patients who remain persistently febrile and neutropenic after several days of empiric broad-spectrum antibiotics, the addition of vancomycin provides no benefit, and in fact yields greater renal toxicity.

In patients colonized with MRSA, a prospective study of 1770 pretransplant patients screened for MRSA colonization demonstrated that the risk of subsequent invasive disease in colonized patients ( n = 20) was vanishingly low when they become febrile and neutropenic. Therefore the addition of empiric coverage for MRSA in colonized patients is unlikely to be beneficial.

VGS bacteremia is uniquely associated with a syndrome of septic shock and acute respiratory distress syndrome (ARDS) in a small proportion of neutropenic patients. High-dose cytarabine or other intensive therapy that damages oropharyngeal mucosal barriers and allows translocation of VGS from its normal oral habitat is associated with an increased risk of overwhelming VGS sepsis. Prophylaxis with notoriously poor antistreptococcal agents, including ciprofloxacin or trimethoprim-sulfamethoxazole (TMP-SMX), may also predispose to VGS bacteremia and sepsis. Viridans streptococcal breakthrough infections may rarely occur during levofloxacin prophylaxis.

Approximately 18% to 29% of VGS bloodstream isolates from cancer patients are β-lactam resistant. Accordingly, vancomycin should be included in the initial empiric antibiotic regimen for hypotensive febrile neutropenic patients, or if VGS is identified from blood cultures, pending susceptibility testing.

Subsequent Modifications of Empiric Antibiotic Regimens

Modifications of the initial empiric antibiotic regimen are frequently made according to the escalation or de-escalation strategies outlined earlier. Additions, subtractions, or changes of antimicrobial agents may be required as the clinical course evolves and microbiologic information from cultures collected prior to antibiotic therapy becomes available. An important consideration is that the mean time to defervescence for febrile patients with neutropenia who receive appropriate initial antibiotic therapy ranges from 2 to 7 days. Therefore, in the absence of positive cultures to guide changes, at least 3 to 4 days of the initial antibiotic regimen should be given to otherwise stable patients, regardless of continued fever, to determine effectiveness. For patients with a documented infection, it is important to note that tissue-based infections such as pneumonia may take longer to respond to antimicrobial therapy.

Patients with fever persisting after 4 days of initial antimicrobial therapy and who have no identifiable site or source of infection should undergo reassessment of their initial antimicrobial therapy. Changes in antimicrobial agents should be based on the patient's clinical status, results of examination and cultures, and the likelihood of early marrow recovery. Although resolution of fever may be slow, persistent fever may suggest a range of possibilities: nonbacterial infection, a bacterial infection that is resistant to empiric antibiotics, the emergence of a secondary infection, a closed-space infection, inadequate antimicrobial serum levels, or drug fever. A careful search for these causes should be conducted. Frequent and arbitrary antibiotic changes for persistent fever in an otherwise stable patient are strongly discouraged. The clinically stable patient with persistent fever may be safely watched without altering the initial antibacterial therapy. If vancomycin was started earlier, it should be discontinued if the patient does not meet the criteria for its use (see Table 34.3 ). The addition of vancomycin without specific indications in a blind effort to suppress persistent fever has not been shown to be effective. If the fever persists beyond 4 to 7 days, initiation of empiric antifungal therapy should be considered (see the following section on empiric antifungal treatment).

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