Douglas N. Fish and Scott W. Mueller
KEY CONCEPTS
An immunocompromised host is a patient with defects in host defenses that predispose to infection. Risk factors include neutropenia, immune system defects (from disease or immunosuppressive drug therapy), compromise of natural host defenses, environmental contamination, and changes in normal flora of the host.
Immunocompromised patients are at high risk for a variety of bacterial, fungal, viral, and protozoal infections. Bacterial infections caused by gram-positive cocci (staphylococci and streptococci) occur most frequently, followed by gram-negative bacterial infections caused by Enterobacteriaceae and Pseudomonas aeruginosa. Fungal infections caused by Candida and Aspergillus, as well as certain viral infections (herpes simplex virus, cytomegalovirus [CMV]), are also important causes of morbidity and mortality.
Risk of infection in neutropenic patients is associated with both the severity and duration of neutropenia. Patients with severe neutropenia (absolute neutrophil count < 500 cells/mm3 [<0.5 × 109/L]) for greater than 7 to 10 days are considered to be at high risk of infection.
Fever (single oral temperature of ≥38.3°C [101°F], or a temperature of ≥38°C [100.4°F] for ≥1 hour) is the most important clinical finding in neutropenic patients and is usually the stimulus for further diagnostic workup and initiation of antimicrobial treatment. Infection should be considered as the cause of fever until proven otherwise. Usual signs and symptoms of infection may be altered or absent in neutropenic patients. Appropriate empiric broad-spectrum antimicrobial therapy must be rapidly instituted to prevent excessive morbidity and mortality.
Empiric antimicrobial regimens for neutropenic infections should take into account patients’ individual risk factors, as well as institutional infection and susceptibility patterns. The significant morbidity and mortality associated with gram-negative infections require that initial empiric regimens for treatment of febrile neutropenia have good activity against P. aeruginosa and Enterobacteriaceae. Inpatient parenteral regimens most commonly recommended for initial treatment include monotherapy with an antipseudomonal β-lactam, or a combination regimen consisting of an antipseudomonal β-lactam, plus an aminoglycoside. Low-risk patients may be successfully treated with oral antibiotics (ciprofloxacin plus amoxicillin/clavulanate), with the treatment setting determined by the patient’s clinical status.
Neutropenic patients who remain febrile after 3 to 5 days of initial antimicrobial therapy should be reevaluated to determine whether treatment modifications are necessary. Common regimen modifications include addition of vancomycin (if not already administered) and antifungal therapy (amphotericin B or fluconazole). Therapy should be directed at causative organisms, if identified, but broad-spectrum regimens should be maintained during neutropenia.
The optimal duration of therapy for febrile neutropenia is controversial. The decision to discontinue antimicrobials is based on resolution of neutropenia, defervescence, culture results, and clinical stability of the patient.
Prophylactic antimicrobials are administered to cancer patients expected to experience prolonged neutropenia, as well as to both hematopoietic stem cell and solid-organ transplant recipients. Prophylactic regimens may include antibacterial, antifungal, antiviral, or antiprotozoal agents, or a combination of these, selected according to risk of infection with specific pathogens. Optimal prophylactic regimens should take into account individual patient risk for infection and institutional infection and susceptibility patterns.
Patients undergoing hematopoietic stem cell transplantation are at an extremely high risk of infection because of prolonged neutropenia following intensive chemotherapy ± irradiation, while solid-organ transplant recipients are at high risk because of prolonged administration of immunosuppressive drugs. Fungal (Aspergillus) and viral (CMV) infections are particularly troublesome in these populations, and prophylactic regimens directed against these pathogens are commonly used. When documented, these infections must be treated aggressively in order to optimize patient outcomes. Nevertheless, mortality rates are often high despite appropriate and aggressive antimicrobial therapy.
Immunocompromised patients must be continuously assessed for evidence of infection and response to antimicrobial therapy. Because a large number of antimicrobials may potentially be used, the occurrence of drug-related adverse effects must also be carefully assessed. Efforts should be directed at designing cost-effective treatment strategies that promote optimal patient outcomes.
An immunocompromised host is a patient with intrinsic or acquired defects in host immune defenses that predispose to infection. Advances in modern medicine have created more immunocompromised hosts than ever before. Historically, many of these patients died of their underlying diseases. Dramatic improvements in survival have been achieved by more aggressive therapy of underlying diseases and improved supportive care. However, because such aggressive therapy often renders patients profoundly immunosuppressed for long periods, opportunistic infections remain important causes of morbidity and mortality. This chapter focuses on risk factors for infection, common pathogens and infection sites, and prevention and management of suspected or documented infections in cancer patients (including hematopoietic stem cell transplantation [HSCT] patients) and solid-organ transplant (SOT) recipients. Chapter 103 discusses infectious complications associated with human immunodeficiency virus (HIV) infection.
RISK FACTORS FOR INFECTION/EPIDEMIOLOGY
Many factors influence the degree of immunosuppression and also influence the epidemiology of the associated infections.
Neutropenia
Neutropenia is defined as an abnormally reduced number of neutrophils circulating in peripheral blood. Although exact definitions of neutropenia can vary, an absolute neutrophil count (ANC) of less than 1,000 cells/mm3 (1.0 ×109/L) indicates a reduction sufficient to predispose patients to infection.1 ANC is the sum of the absolute numbers of both mature neutrophils (polymorphonuclear cells [PMNs], also called polys or segs) and immature neutrophils (bands). The absolute number of PMNs and bands is determined by dividing the total percentage of these cells (obtained from the white blood cell [WBC] differential) by 100 and then multiplying the quotient obtained by the total number of WBCs (expressed in cells/mm3).
The degree or severity of neutropenia, rate of neutrophil decline, and duration of neutropenia are important risk factors for infection.1–5 All neutropenic patients are considered to be at risk for infection, but those with ANC less than 500 cells/mm3 (0.5 × 109/L) are at greater risk than those with ANCs of 500 to 1,000 cells/mm3 (0.5 × 109 to 1.0 × 109/L). Most treatment guidelines use ANC less than 500 cells/mm3 (0.5 × 109/L) as the critical value in making therapeutic decisions regarding the management of suspected or documented infections.1–5 Risk of infection and death are greatest among patients with less than 100 neutrophils/mm3 (0.1 × 109/L) (“profound neutropenia”).1,2,5 In patients with chemotherapy-induced neutropenia, the risk of infection is also increased according to both the rapidity of ANC decline and duration of neutropenia. Patients with severe neutropenia of more than 7 to 10 days’ duration are considered to be at especially high risk for serious infections.3,5 The duration of chemotherapy-induced neutropenia varies considerably among subsets of cancer patients according to the specific chemotherapeutic agents used and the intensity of treatment. Patients undergoing HSCT may have no detectable granulocytes in peripheral blood for up to 3 to 4 weeks and are at particular risk for severe infections with a variety of pathogens.6
Bacteria and fungi commonly cause infections in neutropenic patients. Gram-positive cocci (Staphylococcus aureus, Staphylococcus epidermidis, and other coagulase-negative staphylococci, streptococci, and enterococci) have emerged as the most common cause of acute bacterial infections among neutropenic patients. Gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) traditionally were the most common causes of bacterial infection and remain frequent pathogens.4,7–9 Although now not as common as gram-positive bacteria, the incidence of gram-negative infections may again be increasing.3,8 Gram-negative infections are associated with significant morbidity and mortality, in large part due to increasing antibiotic resistance.7–9 Patients who are neutropenic for extended periods and who receive broad-spectrum antibiotics are at high risk for fungal infections, usually due to Candida or Aspergillus spp.2,3,10,11 Viral infections, although not as common as bacterial and fungal infections, also may cause severe infection in neutropenic patients.2,3,5,6 Successful treatment of infections in neutropenic patients depends on resolution of neutropenia.1–3,5
Although not readily quantifiable, abnormalities may exist in granulocyte function as well as in cell numbers. Defects in phagocyte function may be caused by underlying disease (e.g., leukemia) or its treatment (e.g., corticosteroids, antineoplastic agents, and radiation).3,12
Immune System Defects
In addition to neutropenia, defects in T-lymphocyte and macrophage function (cell-mediated immunity), B-cell function (humoral immunity), or both predispose patients to infection. Cellular immune dysfunction is the result of underlying disease or immunosuppressive drug therapy; these defects result in a reduced ability of the host to defend against intracellular pathogens. Patients with Hodgkin’s disease and transplant patients receiving a wide variety of immunosuppressive drugs, such as cyclosporine, tacrolimus, sirolimus, mycophenolate, corticosteroids, azathioprine, and antineoplastic agents, are at risk for a variety of bacterial, fungal, viral, and protozoal infections (Table 100-1). Although some of these pathogens are associated with asymptomatic or mild disease in normal hosts, they may cause disseminated, life-threatening infections in immunocompromised hosts.
TABLE 100-1 Risk Factors and Common Pathogens in Immunocompromised Patients
Underlying disease also frequently causes defects in humoral immune function. Patients with multiple myeloma and chronic lymphocytic leukemia have progressive hypogammaglobulinemia that results in defective humoral immunity. Splenectomy performed as a part of the staging process for Hodgkin’s disease places patients at risk for infectious complications. Disease states with humoral immune dysfunction predispose the patient to serious, life-threatening infection with encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
Destruction of Protective Barriers
Loss of protective barriers is a major factor predisposing immunocompromised patients to infection. Damage to skin and mucous membranes by surgery, venipuncture, IV and urinary catheters, radiation, and chemotherapy disrupts natural host defense systems, leaving patients at high risk for infection. Chemotherapy-induced mucositis may erode mucous membranes of the oropharynx and GI tract and establish a portal for subsequent infection by bacteria, herpes simplex virus (HSV), and Candida.3,5,6 Medical and surgical procedures, such as transplant surgery, indwelling IV catheter placement, bone marrow aspiration, biopsies, and endoscopy, further damage the integument and predispose patients to infection. Infections resulting from disruption of protective barriers usually are a result of skin flora, such as S. aureus, S. epidermidis, and various streptococci.1,3,5,12
Environmental Contamination/Alteration of Microbial Flora
Infections in immunocompromised patients are caused by organisms either colonizing the host or acquired from the environment. Microorganisms may be transferred easily from patient to patient on the hands of hospital personnel unless strict infection control guidelines are followed. Contaminated equipment, such as nebulizers or ventilators, and contaminated water supplies have been responsible for outbreaks of P. aeruginosa and Legionella pneumophilainfections, respectively. Foods, such as fruits and green leafy vegetables, which often are colonized with gram-negative bacteria and fungi, are sources of microbial contamination in immunocompromised hosts.3,6,13
Most infections in cancer patients are caused by organisms colonizing body sites, such as the skin, oropharynx, and GI tract.1,3,5,6,13 Approximately 80% of infecting bacterial pathogens are from the patient’s own endogenous flora.1,3 The GI tract is the most common site from which infections in immunocompromised hosts originate. Periodontitis, pharyngitis, esophagitis, colitis, perirectal cellulitis, and bacteremias are caused predominantly by normal flora of the gut; bloodstream infections are thought to arise from microbial translocation across injured GI mucosa.1,5,6,13 Normal flora may be significantly disrupted and altered; oropharyngeal flora rapidly change to primarily gram-negative bacilli in hospitalized patients. Many cancer patients may already be colonized with gram-negative bacilli on admission as a result of frequent prior hospitalizations and clinic visits. In hospitalized cancer patients, however, up to 50% of infections are caused by colonizing organisms acquired after admission.1,3
Although hospitalization and severity of illness are important risk factors for colonization by gram-negative bacilli, administration of broad-spectrum antimicrobial agents has the greatest impact on flora of immunocompromised hosts. Use of these agents disrupts GI tract flora and predisposes patients to infection with more virulent pathogens. Antineoplastic drugs (e.g., cyclophosphamide, doxorubicin, and fluorouracil) and acid-suppressive therapy (e.g., H2-receptor antagonists, proton-pump inhibitors, and antacids) also may result in changes in GI flora and possibly predispose patients to infection.1,3,13
Numerous factors, such as underlying disease, immunosuppressive drug therapy, and antimicrobial administration, determine the immunocompromised host’s risk of developing infection. Several risk factors are present concomitantly in many patients (see Table 100-1).
ETIOLOGY OF INFECTIONS IN NEUTROPENIC CANCER PATIENTS
Infection remains a significant cause of morbidity and mortality in neutropenic cancer patients. More than 50% of febrile neutropenic patients have an established or occult infection.1,5 Patients with profound neutropenia are at greatest risk for systemic infection, with at least 20% of these individuals developing bacteremia.1,5 Areas of impaired or damaged host defenses, such as the oropharynx, lungs, skin, sinuses, and GI tract, are common sites of infection. These local infections may progress to cause systemic infection and bacteremia.5 Febrile episodes in neutropenic cancer patients can be attributed to microbiologically documented infection in approximately 30% to 40% of cases, about half of which are due to bacteremia. Further, infections can be documented clinically (but not microbiologically) in another 30% to 40% of patients, with the remaining 20% to 40% of patients manifesting infection only by fever.3,4,8,12
Table 100-1 lists organisms commonly infecting immunocompromised patients. Approximately 45% to 70% of bacteremic episodes in cancer patients are the result of gram-positive organisms compared with less than 30% of episodes documented during the 1970s and 1980s.1,4,7,12,14,15 This shift is attributed to the frequent use of indwelling central and peripheral IV catheters, frequent use of broad-spectrum antibiotics with excellent gram-negative activity but relatively poor gram-positive coverage, higher rates of mucositis caused by aggressive cancer treatments, and prophylaxis with trimethoprim–sulfamethoxazole or quinolones.1,4,7,12 Staphylococci (especially S. epidermidis) account for most infections, but Bacillus spp. and Corynebacterium jeikeium are also important pathogens.1,5,12,15 Rates of infection due to methicillin-resistant Staphylococcus aureus (MRSA) have increased in the hospital and community setting.16,17 Viridans streptococci, which may be resistant to β-lactams, also have emerged as important pathogens, particularly in patients with chemotherapy-induced mucositis of the oropharynx.4,12,18,19Enterococci, including vancomycin-resistant strains, also may be problematic in many institutions.2,19 Bacteremia caused by vancomycin-resistant enterococci (VRE) in neutropenic patients is associated with a mortality rate exceeding 70%.4,20
Gram-positive infections do not always cause immediately life-threatening infections and are associated with somewhat lower mortality rates (approximately 5% to 10%) compared with gram-negative infections.1,12,15 However, increasing rates of antibiotic resistance have made treatment of gram-positive infections in immunocompromised patients more challenging.7,12 MRSA infections are associated with increased morbidity, mortality, and hospital costs compared with susceptible organisms.21 Methicillin resistance among coagulase-negative staphylococci, which may cause 40% to 80% of infections in certain populations, is common (70% to 90% of isolates).6,7,16 Organisms that are resistant to vancomycin are increasing in importance.1,5,7,19 Thus, prevention and timely diagnosis and treatment of gram-positive infections are clearly of great importance in the management of neutropenic cancer patients.
Gram-negative infections remain important causes of morbidity and mortality (approximately 20%) in immunocompromised cancer patients.12,15 However, the relative frequency of infection owing to specific pathogens has been shifting among gram-negative infections. E. coli and Klebsiella remain the most common isolates at many centers.15 Strains of Klebsiella producing plasmid-mediated extended-spectrum β-lactamases that hydrolyze extended-spectrum cephalosporins have emerged and are cause for concern.1,5,7,19 The frequency of infections resulting from other gram-negative organisms, such as Enterobacter, Serratia, and Citrobacter, has been increasing.1,5 Infections with these particular organisms may be difficult to treat because of the ease of β-lactamase induction and the more frequent development of resistance to multiple antibiotics.1,3,5,12,19
P. aeruginosa has long been an important pathogen in cancer patients. P. aeruginosa infection rates are decreasing in patients with solid tumors but not in patients with hematologic malignancies.4,7 Infections caused by P. aeruginosa are associated with significant morbidity and mortality in neutropenic patients, with mortality rates of 31% to 75% reported.12,15 The frequency of infection caused by difficult-to-treat organisms such as Stenotrophomonas maltophilia and Burkholderia cepacia appears to be increasing at many centers, probably because of selective pressures of broad-spectrum antimicrobial use.4,12 As with gram-positive organisms, antibiotic resistance among gram-negative organisms has continued to increase at alarming rates and has made appropriate antibiotic selection for treatment of febrile neutropenia more difficult.1,16 Although the GI tract is a common site of bacterial infection, severe infections caused by anaerobic organisms are relatively infrequent. Anaerobes are found most frequently in mixed infections, such as perirectal cellulitis and mucositis-associated oropharyngeal infections.12
In addition to bacterial infections, neutropenic cancer patients are at risk for invasive fungal infections. Patients with extended periods of profound neutropenia who have been receiving broad-spectrum antibiotics, corticosteroids, or both are at the highest risk for invasive fungal infection. Up to one third of febrile neutropenic patients who do not respond to 1 week of broad-spectrum antibiotic therapy will have a systemic fungal infection.1,5,12 Large autopsy studies have documented that up to 40% of patients with hematologic malignancies had deep fungal infections, fully 75% of which were undiagnosed prior to death. Causative pathogens were usually either Candida spp. (35%) or Aspergillus spp. (55%).22
Candida albicans is the most common fungal pathogen in neutropenic cancer patients.4,12,23 However, non-albicans species of Candida including C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei are being isolated with increasing frequency and are more common than C. albicans infections in some studies.11,23 Increased infections caused by pathogens such as Trichosporon spp., Fusarium spp., and Curvularia have also been reported.23–25 The shift toward more frequent infection with non-albicans Candida is important because of significantly decreased rates of susceptibility among many of these strains.26 Because Candida spp. are normal flora, alteration of body host defenses is an important risk factor for the development of these infections. Oral thrush is the most common clinical manifestation of fungal infection. Mucous membranes damaged from chemotherapy and radiation serve as areas of Candida surface colonization and subsequent entry into the bloodstream; disease then may disseminate throughout the body. Organs such as the liver, spleen, kidney, and lungs are commonly involved in disseminated disease.22,24Hepatosplenic candidiasis is a particularly important infection in patients with hematologic malignancies.3,22,24 Diagnosis of Candida infections is difficult and often requires invasive tissue sampling.6 In patients with invasive candidiasis, overall attributable mortality is as high as 35% to 50%.4,11,23
Invasive infections caused by Aspergillus are a serious complication of neutropenia, with mortality approaching 80% in patients with prolonged neutropenia and/or patients undergoing allogeneic HSCT.4,12These infections are particularly prevalent in patients with hematologic malignancies and in patients undergoing HSCT.4,24,25,27 Infections resulting from Aspergillus species (including A. fumigatus, A. terreus, A. flavus, and A. niger) usually are acquired via inhalation of airborne spores. After colonizing the lungs, Aspergillus invades the lung parenchyma and pulmonary vessels, resulting in hemorrhage, pulmonary infarcts, and a high mortality rate. Invasive pulmonary disease is the dominant manifestation of infection in patients with neutropenia. However, Aspergillus also may cause other infections, including sinusitis, cutaneous infection, and disseminated disease involving multiple organs, including the CNS.27 Prolonged neutropenia is the primary risk factor for invasive pulmonary aspergillosis in patients with acute leukemia; use of corticosteroids also may predispose patients to disease.27 Invasive aspergillosis should be suspected in neutropenic cancer patients colonized with Aspergillus (in sputum and/or nasal cultures) who remain persistently febrile despite at least 1 week of broad-spectrum antibiotic therapy.1,5,27
Chemotherapy-induced mucous membrane damage may predispose neutropenic cancer patients to reactivation of HSV, manifesting as gingivostomatitis or recurrent genital infections. Untreated oropharyngeal HSV infections may spread to involve the esophagus and often coexist with Candida infections. Clinical disease resulting from HSV occurs most often in patients with serologic evidence (e.g., serum antibodies to HSV) of prior infection. Both HSV-seropositive HSCT patients and HSV-seropositive leukemics receiving intensive chemotherapy are at high risk for recurrent HSV disease during periods of immunosuppression.3,4,5,6,12
Pneumocystis jiroveci and Toxoplasma gondii are the most common parasitic pathogens found in immunocompromised cancer patients. Patients with hematologic malignancies (i.e., acute lymphocytic leukemia, lymphoma, and Hodgkin’s disease) and those receiving high-dose corticosteroids as part of chemotherapy regimens are at the greatest risk of infection.3,4,6,12 Routine use of trimethoprim–sulfamethoxazole prophylaxis has reduced substantially the incidence of these infections.1,5,6
Because the majority of infecting organisms in cancer patients are from the host’s own flora, some centers have used routine surveillance cultures in an attempt to prospectively identify causes of fever and suspected infection. In a typical surveillance culture program, cultures of the nose, mouth, axillae, and perirectal area are performed twice weekly, and culture results are correlated with the clinical status of the patient. Because these cultures are costly and have low diagnostic yield, the utility of surveillance culture programs is believed to be limited.1,5 However, surveillance cultures are useful as research tools and in patients with prolonged profound neutropenia and in institutions that have high rates of antimicrobial resistance or have problems with virulent pathogens such as P. aeruginosa or Aspergillus spp. Surveillance cultures should be limited to the anterior nares for detecting colonization with MRSA, Aspergillus, and penicillin-resistant pneumococci and to the rectum for detecting P. aeruginosa, multiple-antibiotic-resistant gram-negative rods, and VRE.1,12
Knowledge of infection rates and local susceptibility patterns is essential for guiding optimal management of febrile neutropenia. These parameters must be monitored closely because the spectrum of infectious complications is related to multiple factors, including cancer chemotherapy regimens and antimicrobial therapy used for treatment and prophylaxis.
CLINICAL PRESENTATION
The most important clinical finding in the neutropenic cancer patient is fever. Because of the potential for significant morbidity and mortality associated with infection in these patients, fever should be considered to be the result of infection until proved otherwise.1–3,8,12 At the appearance of fever, the patient should be evaluated carefully for other signs and symptoms of infection.
TREATMENT
Management of patients with febrile neutropenia, including both treatment and prophylaxis of infectious complications, can be extremely challenging. Although published guidelines are available, the most optimal clinical management of these patients remains unclear in many aspects.
Febrile Episodes in Neutropenic Cancer Patients
Desired outcomes
The goals of therapy in neutropenic cancer patients with fever are the following: (a) protect the neutropenic patient from early death caused by undiagnosed infection; (b) prevent breakthrough bacterial, fungal, viral, and protozoal infections during periods of neutropenia; (c) effectively treat established infections; (d) reduce morbidity and allow for administration of optimal antineoplastic therapy; (e) avoid unnecessary use of antimicrobials that contribute to increased resistance; and (f) minimize toxicities and cost of antimicrobial therapy while increasing patient quality of life. Empirical broad-spectrum antibiotic therapy is effective at reducing early mortality.13
CLINICAL PRESENTATION Febrile Neutropenia1,3,4,6
General
• Due to high risk for serious infections, frequent (at least daily) careful clinical assessments must be performed to search for possible evidence of infection
• Physical assessment should include examination of all common sites of infection, including mouth/pharynx, nose and sinuses, respiratory tract, GI tract, urinary tract, skin, soft tissues, perineum, and intravascular catheter insertion sites
Symptoms
• Usual signs and symptoms of infection may be absent or altered in neutropenic patients owing to low numbers of leukocytes and an inability to mount an inflammatory response (e.g., no infiltrate on chest x-ray film, urinary tract infection without pyuria)
• Pain may be present at the infection site(s)
Signs
• Fever in this setting is defined as a single oral temperature ≥38.3°C (≥101°F) in the absence of other causes or temperature ≥38°C (≥100.4°F) for 1 hour or more. Other causes of fever unrelated to infection in this patient population include reactions to blood products, chemotherapeutic agents (and other drugs, including biologics), cell lysis, and underlying malignancy
• Usual signs of infection may be absent or altered; patients with bacteremia commonly exhibit no signs of infection other than fever
Laboratory Tests
• Neutropenia (ANC≤1,000 cells/mm3 [≤1.0 × 109/L])
• Blood cultures (two or more sets, including vascular access devices) for bacteria and fungi; cultures of other suspected infection sites (infection can be documented microbiologically in only about 30% of cases, about half of which are due to bacteremia)
• Other cultures should be obtained as indicated clinically according to the presence of signs or symptoms
• Recent surveillance cultures (nasal, rectal) should be reviewed, if available
• Complete blood count and blood chemistries should be obtained frequently to monitor neutropenia, plan supportive care, guide drug dosing, and assess patient’s overall status
Other Diagnostic Tests
• Chest x-ray film
• Aspiration, biopsy of skin lesions
• Other diagnostic tests as indicated clinically on the basis of physical examination and other assessments
Approach to Treatment
General guidelines for management of febrile episodes and documented infections in neutropenic patients are shown in Figures 100-1 and 100-2.1 Although many controversies remain regarding optimal management of these patients, updated evidence-based guidelines from the Infectious Diseases Society of America (IDSA) for the management of febrile neutropenia were published in 2010.1 Similarly, the National Comprehensive Cancer Network (NCCN) published updated clinical practice guidelines for the prevention and treatment of cancer-related infections in 2012.5 Selected specific recommendations are discussed in the following sections of this chapter, and their associated evidence-based rankings are summarized in Table 100-2.
FIGURE 100-1 Initial management of febrile episodes in neutropenic patients. (ANC, absolute neutrophil count; HSCT, hematopoietic stem cell transplantation; MASCC, Multinational Association for Supportive Care in Cancer; PO, oral.)
FIGURE 100-2 Subsequent management of febrile episodes in neutropenic patients who have already received empirical antimicrobial therapy for 2–4 days. (ANC, absolute neutrophil count; MDR, multidrug-resistant; PO, oral.)
TABLE 100-2 Summary of Evidence-Based Recommendations for Management of Febrile Episodes in Neutropenic Patients
Fever in the neutropenic cancer patient is considered to be caused by infection until proved otherwise. High-dose broad-spectrum bactericidal, usually parenteral, empirical antibiotic therapy should be initiated at the onset of fever or at the first signs or symptoms of infection. Withholding antibiotic therapy until an organism is isolated results in unacceptably high mortality rates. Undiagnosed infection in immuno-compromised patients can rapidly disseminate and result in death if left untreated or if treated improperly. Failure to initiate appropriate antibiotic therapy for P. aeruginosa bacteremia at the onset of fever in neutropenic cancer patients resulted in mortality rates of 15% and 70% within 12 and 48 hours, respectively.1,5 Empirical antibiotic therapy is 70% to 90% effective at reducing early morbidity and mortality.1,5,7,12 Therapy must be appropriate and initiated promptly. Antimicrobial therapy must also be initiated promptly in afebrile cancer patients with clinical signs and symptoms of infection.
When designing optimal empirical antibiotic regimens, clinicians must consider infection patterns and antimicrobial susceptibility trends in their respective institutions. Patient factors such as risk for infection, drug allergies, concomitant nephrotoxins, and previous antimicrobial exposure (including prophylaxis) must be considered.1,4,5 Assessment of the patient’s risk of infection will help determine the appropriate route and setting for antibiotic administration (Fig. 100-1). Neutropenic patients with fever can be divided into low- and high-risk groups for complications of severe infection. Risk stratification drives both type and setting of antimicrobial therapy. The Multinational Association for Supportive Care in Cancer (MASCC) risk-index score is recommended by many clinical guidelines to assess a patient’s risk of complications.1,5 Most experts agree that, in general, low-risk patients have an anticipated duration of neutropenia ≤7 days, are clinically stable, and have no or few comorbidities and no bacterial focus or systemic signs of infection other than fever. In contrast, high-risk patients are those with an anticipated duration of neutropenia >7 days or profound neutropenia, are clinically unstable or have comorbid medical problems (e.g., focal or systemic signs of infection, GI symptoms, nausea, vomiting, diarrhea, hypoxemia, and chronic lung disease), or have a high-risk cancer (e.g., acute leukemia) and/or have undergone high intensity chemotherapy. High-risk patients (MASCC <21) should be hospitalized for parenteral antibiotics whereas low-risk patients may be candidates for oral or outpatient antibiotics. Even with such classifications, careful selection of low-risk patients for oral outpatient management is important (discussed in “Oral Antibiotic Therapy for Management of Febrile Neutropenia” section below).1,5,28–30
The optimal antibiotic regimen for empirical therapy in febrile neutropenic cancer patients remains controversial, but it is clear that no single regimen can be recommended for all patients. Because of their frequency and relative pathogenicity, P. aeruginosa and other gram-negative bacilli and staphylococci remain the primary targets of empirical antimicrobial therapy.1,12 Although P. aeruginosa is documented in fewer than 5% of bloodstream infections in the population of hospitalized patients, adequate antipseudomonal antibiotic coverage still must be included in empirical regimens because of the significant morbidity and mortality associated with this pathogen.1,4,12,16 All empirical regimens must be carefully monitored and appropriately revised on the basis of documented infections, susceptibilities of bacterial isolates, development of more defined clinical signs and symptoms of infection, or a combination of these factors.
Although there are some differences among them, consensus guidelines generally recognize three different types of empirical parenteral antibiotic regimens: (a) monotherapy with an antipseudomonal β-lactam such as a cephalosporin (cefepime or ceftazidime), a carbapenem (imipenem–cilastatin, meropenem, or doripenem), or piperacillin–tazobactam; (b) two-drug combination therapy with an antipseudomonal β-lactam plus either an aminoglycoside or an antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin); and (c) monotherapy or two-drug combination therapy as above, plus the addition of vancomycin (Fig. 100-1).1,5 Each of these regimens has advantages and disadvantages, which are summarized in Table 100-3. There is no overwhelming evidence that any one of these regimens is superior to the others. The overall response to empirical antibiotic regimens in febrile neutropenic cancer patients is approximately 70% to 90% regardless of whether a pathogen is isolated or which antimicrobial regimen is used.1,4,5,7,12 Additionally, other alternative regimens may also appropriate based on specific patient characteristics or susceptibilities of suspected pathogens.
TABLE 100-3 Comparative Advantages and Disadvantages of Various Antibiotic Regimens for Empiric Therapy of Febrile Neutropenic Cancer Patients
β-Lactam Monotherapy
Monotherapy with an antipseudomonal β-lactam is recommended by IDSA 2010 and NCCN 2012 guidelines as initial parenteral therapy for management of febrile neutropenia without suspected or proven resistant organisms or complications (e.g., pneumonia, hypotension, vascular access infection, etc.)1,5 Several β-lactam antibiotics in current use have been evaluated as monotherapy for management of febrile episodes in neutropenic cancer patients, including antipseudomonal cephalosporins (ceftazidime and cefepime), piperacillin–tazobactam, and antipseudomonal carbapenems (imipenem–cilastatin and meropenem).1,3,5,12,14 Three different meta-analyses assessing as many as 46 clinical trials involving more than 7,600 patients found no significant differences overall between monotherapy and combination therapy (β-lactam/aminoglycoside) in rates of survival, treatment response, and bacterial/fungal superinfections.31–33 One study also found a higher rate of adverse effects in aminoglycoside-containing combination regimens.32 In addition, one analysis found that cefepime monotherapy was associated with a significantly higher risk of mortality compared with the other β-lactams evaluated.1,5,33 A follow-up analysis conducted by the FDA using additional studies and patient-level data failed to confirm an increased risk of mortality with cefepime, concluding that it is as efficacious as other β-lactams.1,5,34Significantly lower response rates for ceftazidime (but not cefepime) monotherapy have been reported in another review of the clinical literature.1,5 However, until the results of these studies can be validated, ceftazidime is still are among the monotherapy regimens routinely recommended as appropriate initial therapy of febrile neutropenic patients, although with a lower strength of evidence in 2012 NCCN guidelines.1,5,12,33,34 Institutional susceptibility patterns and patient characteristics should drive drug selection.
Doripenem has an appropriate overall spectrum of antibacterial activity with good activity against P. aeruginosa and other gram-negative organisms as well as many gram-positive pathogens. Neither the 2012 NCCN nor the 2010 IDSA consensus guidelines specifically recommend doripenem as appropriate for monotherapy due to a lack of supportive clinical evidence at the time the guidelines were written.1,5Doripenem is, however, considered by many clinicians to be appropriate for this use.
Use of monotherapy has several potential advantages and disadvantages (see Table 100-3). Perhaps the most common concerns are those regarding the selection of resistant strains of organisms, such as P. aeruginosa, Enterobacter spp., and Serratia spp., through extended-spectrum β-lactamases and type 1 β-lactamases, especially with ceftazidime.1,5,7,12,19 Activity against gram-positive organisms such as coagulase-negative staphylococci, MRSA, enterococci (including VRE), penicillin-resistant S. pneumoniae, and some strains of viridans streptococci is poor with some single β-lactams, but cefepime and antipseudomonal carbapenems have good activity against viridans streptococci and pneumococci.1,5 Although ceftazidime has been studied widely and used for treatment of febrile neutropenia, newer agents may be more effective owing to ceftazidime’s susceptibility to β-lactamase induction and lower activity against gram-positive organisms.1,7,19,33 Ertapenem, a carbapenem, and tigecycline, a glycylcycline antibiotic, have excellent activity against many gram-negative organisms but should not be used in the empirical treatment of febrile neutropenia due to their weaker activity against P. aeruginosa.
As with all empirical antibiotic regimens, patients receiving monotherapy should be monitored closely for treatment failure, secondary infections, and development of resistance. Use of mono-therapy may not be appropriate in institutions with high rates of gram-positive infections or infections caused by relatively resistant gram-negative pathogens such as P. aeruginosa and Enterobacter. The carbapenems are less susceptible to inducible β-lactamases and often may be used effectively in these institutions. Overall, similar efficacy has been observed with monotherapy with antipseudomonal β-lactams compared to aminoglycoside combination therapy for treatment of P. aeruginosainfections.1,5,12,32,33
Aminoglycoside Plus Antipseudomonal β-Lactam
Regimens consisting of an aminoglycoside plus an antipseudomonal β-lactam traditionally have been the most commonly used for empirical treatment of febrile neutropenia, although many such regimens may lack adequate gram-positive activity (see Table 100-3).1,5 This relative lack of activity remains a concern because of the increasing frequency of gram-positive infections. The choice of aminogly-coside and β-lactam for inclusion in empirical regimens should be based on institutional epidemiology and antimicrobial susceptibility patterns. Similar efficacy is observed with an antipseudomonal β-lactam in combination with an aminoglycoside.1,5
Combinations of broad-spectrum β-lactams and aminoglycosides often provide synergistic activity against bacteria commonly infecting neutropenic patients. The exact role of synergy in the outcome of febrile neutropenic patients treated with empirical antibiotic therapy is somewhat controversial, particularly in light of the efficacy of single-drug regimens. Nevertheless, synergistic combinations of antibiotics appear to be beneficial in patients with persistent profound neutropenia. Moreover, administration of antipseudomonal β-lactams in combination with an aminoglycoside may result in a lower rate of drug resistance.4
Aminoglycoside toxicity may be a concern in patients receiving these regimens who are already receiving other nephrotoxic drugs, such as cisplatin and cyclosporine. Administration of aminoglycosides in large single daily doses (once-daily dosing) may be as effective, less costly, and no more toxic than conventional dosing methods.41 Although once-daily aminoglycoside dosing regimens appear to be safe and effective in these patients, standard dosing regimens are recommended for infections where data are not sufficient to recommend once-daily dosing (e.g., endocarditis).1,5,12
Fluoroquinolones as a Component of Empirical Regimens
Because the fluoroquinolone antibiotics have broad-spectrum activity (particularly against gram-negative pathogens), rapid bactericidal activity, and favorable pharmacokinetic and toxicity profiles, these agents have been investigated as empirical therapy for febrile neutropenic patients. Ciprofloxacin is the preferred agent for use in this clinical setting because of its relatively better activity against P. aeruginosa and more extensive evidence-based support for its use.1,12 Response rates to quinolone-containing combination regimens are comparable to those obtained with the other regimens described previously.1,4,5 Ciprofloxacin is not recommended for monotherapy, however, because of its relatively poor activity against gram-positive pathogens, particularly streptococci, and variable response rates in clinical studies.1,5 Fluoroquinolones should also not be used as empirical therapy in patients who have received quinolones as infection prophylaxis because of the risk of drug resistance.1,5,12 Rates of fluoroquinolone resistance are increasing, and streptococcal treatment failures are a concern.16,19 Although fluoroquinolones are not generally considered first-line empirical therapy, they may be useful as one component of combination regimens in patients with allergies or other contraindications to first-line agents.1,5
Empirical Regimens Containing Vancomycin
The inclusion of vancomycin in initial empirical therapy of febrile neutropenic cancer patients is not currently recommended by IDSA 2010 or NCCN 2012 guidelines unless the patient has specific risk factors; however, this remains an ongoing debate. This controversy continues because of the increasing incidence of gram-positive infections in this population, particularly MRSA. One approach is to include vancomycin in the initial empirical antibiotic regimen, thereby providing early effective treatment of possible gram-positive infections. Inclusion of vancomycin in initial empirical regimens may be more appropriate today because of higher rates of MRSA infections as well as aggressive chemotherapy regimens causing significant mucosal damage that increases the risk for streptococcal infections. Decreased mortality from penicillin-resistant viridans streptococcal infections has been observed when vancomycin was included in initial therapy.1,5,12 A second approach is to withhold vancomycin from initial empirical regimens, later adding the drug if gram-positive organisms are isolated from cultures or if there is no response to initial therapy. Support for both these approaches can be found in the medical literature.1,5,12,35,36 Prospective studies and at least two meta-analyses have failed to document increased response rates or decreased mortality with the routine addition of vancomycin to initial empirical regimens, provided that vancomycin can be added later as needed.1,5,12,35,36 In addition to increased costs of therapy, vancomycin was also associated with increased adverse effects, including nephrotoxicity.35,36 Finally, concerns remain regarding selection of resistant gram-positive bacteria such as VRE with excessive vancomycin use.1,5,12
Vancomycin is currently recommended for inclusion in initial empirical regimens only in patients at high risk for gram-positive infection, particularly due to MRSA and coagulase-negative staphylococci (including patients with evidence of infection of central venous catheters and other indwelling lines), high risk for viridans streptococcal infection due to severe mucositis, or pneumonitis or soft tissue infection in hospitals with high rates of MRSA infections.1,3,5,7,12,35,36 Rates of β-lactam resistance among viridans streptococci range from 18% to 29%.5 Empirical vancomycin use may be justified in institutions using empirical or prophylactic antibiotic regimens without good activity against streptococci (e.g., ciprofloxacin) and in patients known to be colonized with MRSA or β-lactam–resistant pneumococci. In patients with preliminary culture results indicating gram-positive infection, empirical vancomycin is appropriate while the susceptibility results are pending. Lastly, empirical use of vancomycin may be recommended in patients with hypotension or other evidence of cardiovascular impairment or sepsis without an identified pathogen.1,5,35,36 If empirical vancomycin therapy is initiated and no evidence of gram-positive infection is found after 48 to 72 hours, the drug should be discontinued.1,4,5 Continuing vancomycin when not warranted results in higher costs, more toxicities, and greater risk of development of VRE.1,5
Other antimicrobial agents, such as quinupristin–dalfopristin, linezolid, daptomycin, telavancin, and ceftaroline, should be reserved for documented infections caused by multiresistant gram-positive pathogens that are not susceptible to, or are unresponsive to, vancomycin. The role of these drugs in the routine treatment of fever in neutropenic patients is undetermined, and linezolid is associated with myelosuppression.1,5
Oral Antibiotic Therapy for Management of Febrile Neutropenia
An individual patient’s risk for complications of severe infection determines appropriate antibiotic therapy and the proper setting for administration (see Table 100-3).1,4,5 Risk stratification is based on several parameters (e.g., MASCC score as mentioned above) as well as response to empirical antimicrobial therapy if IV therapy is initially given.1 Because of the excellent spectrum of activity and favorable pharmacokinetics of currently available oral antibiotics, particularly the fluoroquinolones, oral antibiotics have an important role in the management of selected patients. In patients at low risk for severe or complicated bacterial infection, empirical therapy with broad-spectrum oral antibiotic agents achieves similar patient outcomes as parenteral antibiotics, with response rates of 77% to 95%.1,4,12,28–30 This has made possible the treatment of febrile neutropenia in low-risk patients in the outpatient setting. Patients judged to be low risk with reliable follow-up may be appropriate candidates for oral antibiotic therapy administered on an outpatient basis.1,4,12,28–30 Ciprofloxacin in combination with amoxicillin–clavulanate (or clindamycin for penicillin-allergic patients) for enhanced gram-positive coverage has been most commonly studied for outpatient therapy in low-risk patients and is recommended by IDSA and NCCN guidelines.1,5 In general, monotherapy with ciprofloxacin should be avoided due to relatively poor gram-positive activity. Levofloxacin has been used as monotherapy for outpatient treatment of low-risk patients, due to enhanced gram-positive activity; however, this regimen has not been well studied and is not formally recommended by IDSA or NCCN guidelines. If used, only the higher-dose levofloxacin 750 mg regimen should be administered in order to provide adequate activity against organisms such as P. aeruginosa.1,5 Careful patient selection obviously is required for such management strategies. Important criteria include patient and provider comfort, a history of medication compliance, good caregiver support, a follow-up plan, and close proximity, prompt access and transportation to appropriate medical care around the clock in the event of failure to respond to outpatient antibiotic therapy. If a patient qualifies for oral therapy based on social and clinical status, the first dose of oral regimen should be given and the patient observed for 4 to 24 hours to ensure tolerance and the patient remains clinically stable. Benefits of oral therapy on an outpatient basis include increased convenience and quality of life for patients and caregivers and reduced exposure to multidrug-resistant institutional pathogens.1,5 Outpatient therapy of low-risk patients now is common practice in most institutions.
In patients at low risk for severe bacterial infection who were initiated on IV antibiotics, oral antibiotics may play a role in step-down therapy. Carefully selected neutropenic patients may be safely switched from broad-spectrum parenteral therapy to oral antibiotic regimens (e.g., ciprofloxacin plus amoxicillin–clavulanate) with response rates comparable to patients remaining on IV therapy.12,28–30 Patient selection criteria generally include defervescence within 72 hours of initiation of parenteral therapy, hemodynamic stability, absence of positive cultures or a discernible site of infection, and ability to take oral medications. Many of these patients are able to complete their course of therapy at home.1,5,12,28–30 Changing parenteral antimicrobials to oral regimens in carefully selected patients is now relatively common practice and allows for less expensive hospitalizations and earlier patient discharges.
Antimicrobial Therapy After Initiation of Empirical Therapy
After initiation of empirical antimicrobial therapy (Table 100-4), judicious assessment of febrile neutropenic cancer patients is mandatory to evaluate response, clinical status, laboratory data, and potential need for therapy adjustments. After 2 to 4 days of empirical antimicrobial therapy, the clinical status and culture results of febrile neutropenic patients should be reevaluated to determine whether therapeutic modifications are necessary (Fig. 100-2). Modifications of antimicrobial therapy should be based on clinical and laboratory data; antibiotic therapy should be optimized based on culture results. However, during periods of neutropenia, patients generally should continue to receive broad-spectrum therapy because of risk of secondary infections or breakthrough bacteremias when antimicrobial coverage is too narrow.1,5,12 The treatment duration for a documented infection should be appropriate for the particular organism and site, and should continue for at least the duration of neutropenia (until ANC ≥500 cells/mm3 [≥0.5 × 109/L]) or longer if clinically necessary.
TABLE 100-4 Drug Dosing Table a
In patients who become afebrile after 2 to 4 days of therapy with no infection identified, it is generally optimal to continue antibiotic therapy until neutropenia has resolved (ANC ≥500 cells/mm3 [≥0.5 × 109/L]). Some clinicians switch therapy to an oral regimen (e.g., ciprofloxacin plus amoxicillin–clavulanate) after 2 days of IV therapy in low-risk patients who become afebrile and have no evidence of infection. In high-risk patients, parenteral antibiotic regimens should be continued until resolution of neutropenia.1,5 However, in afebrile patients with prolonged neutropenia but no signs or symptoms of infection, consideration can be given to discontinuing antibiotic therapy or switching to fluoroquinolone prophylaxis (discussed in “Prophylaxis of Infections in Neutropenic Cancer Patients” below), provided that patients can be observed carefully and have ready access to medical care.
The optimal management of patients who remain febrile in the absence of microbiologic or clinical documentation of infection remains highly controversial. Persistently febrile patients should be evaluated carefully, but modifications generally are not made to initial antimicrobial regimens within the first 2 to 4 days of therapy unless there is evidence of clinical deterioration (see Fig. 100-1).1,4,5 It is important to note that the persistence of fever does not necessarily mean failure of a given antimicrobial regimen; up to 25% of neutropenic patients have fever due to noninfectious causes.8 This is particularly true if patients are otherwise clinically stable. Fever after 2 or more days of antibiotic therapy can be due to a number of causes, including nonbacterial infection, resistant bacterial infection or infection slow to respond to therapy, emergence of a secondary infection, inadequate drug concentrations, drug fever, fever at an avascular site (e.g., catheter infection or abscess), or noninfectious causes such as tumor or administration of blood products.1,4,5,12 Patients with documented infection who are receiving appropriate antimicrobial therapy (based on in vitro susceptibility tests) often remain febrile until resolution of neutropenia occurs. Therefore, the same antibiotic regimen can be continued in patients who remain febrile despite 2 to 4 days of antibiotic therapy but are otherwise clinically stable, especially if neutropenia is expected to resolve within 1 week. However, antibiotic regimens may require modification in patients experiencing toxicities (Table 100-5) as well as in patients with evidence of progressive disease, clinical instability, or documentation of an organism not covered by the initial regimen.1,3,4,5,12 If not already part of the regimen, vancomycin should be considered as warranted by clinical and laboratory findings. However, if vancomycin was included in the initial empirical regimen and the patient is still febrile after 2 to 3 days of therapy without isolating a gram-positive pathogen, discontinuation of vancomycin should be considered to reduce the risk of toxicities or resistance.1,5
TABLE 100-5 Drug Monitoring of Selected Antimicrobials for Febrile Neutropenia, HSCT, and SOT
Initiation of Antifungal Therapy
Neutropenic patients who remain febrile despite more than 4 to 7 days of broad-spectrum antibiotic therapy are candidates for antifungal therapy. A high percentage of febrile patients who die during prolonged neutropenia have evidence of invasive fungal infection on autopsy, even though many had no evidence of fungal disease before death.26 Persistence of fever or development of a new fever during broad-spectrum antibiotic therapy may indicate the presence of a fungal infection, most commonly due to Candida or Aspergillus spp.12,22 Blood cultures are positive in fewer than 50% of neutropenic patients with invasive fungal infections.12,25 Sensitivity and specificity of fungal galactomannan assay may vary and should only be used when Aspergillus is suspected. Rapid, sensitive diagnostic tests for fungi such as serum β–D-glucan or fungal DNA assay are not yet in common usage, and waiting for isolation of fungal organisms is associated with high morbidity and mortality. The empirical addition of antifungal therapy is thus justified in this clinical setting.1,12,25 Therefore, empirical antifungal therapy should be initiated after 4 to 7 days of broad-spectrum antibiotic therapy in persistently febrile patients if the duration of neutropenia is expected to be >1 week. Administered doses must be adequate to treat undiagnosed fungal infection and prevent fungal superinfection in high-risk febrile neutropenic patients.1,5,23
Evidence-based recommendations from published guidelines for management of suspected or documented fungal infections in neutropenic patients are summarized in Table 100-2.23,27 Empirical coverage for both Candida spp. and Aspergillus should be considered because these organisms are responsible for more than 90% of fungal infections in neutropenic cancer patients.6,22 Aspergillus is particularly common in patients with hematologic malignancies and in patients with hematologic malignancies undergoing HSCT; therefore, amphotericin B traditionally has been preferred for these patients.1,5,12,37 In the setting of febrile neutropenia, lipid-associated amphotericin B (LAMB) products are similar in efficacy to conventional amphotericin B while causing fewer toxicities. LAMB products are thus almost exclusively recommended over conventional amphotericin B despite the significantly higher cost without clear improvement in efficacy.1,5,23,27,37,38 Although the use of higher doses of LAMB has been advocated in an effort to improve efficacy, one study demonstrated that lower doses (3 mg/kg) of liposomal amphotericin B were as efficacious as higher doses (10 mg/kg) with lower cost and fewer toxicities.39
The azole compounds fluconazole, itraconazole, and voriconazole are also used in the management of febrile neutropenia.23,27,40 Despite the increased cost and toxicities of LAMB, concerns regarding the emergence of Candidastrains with decreased azole susceptibility and unclear efficacy advantages relative to other agents have prevented these agents from replacing amphotericin B as the gold standard in persistently febrile neutropenic patients.25,27,37Fluconazole has good efficacy against C. albicans but lacks activity against molds such as Aspergillus. The use of fluconazole as an alternative to amphotericin B for empirical antifungal therapy is thus perhaps most appropriate in hospitals in which infections due to Aspergillus or non-albicans strains of Candida are not common.1,5,37 If fluconazole is used as antifungal prophylaxis in cancer patients, it should not be included in empirical antifungal regimens. Voriconazole is effective in the treatment of documented invasive fungal infections and is recommended as a reliable option for febrile neutropenia despite failing to meet noninferiority criteria when compared against LAMB for empiric therapy in febrile neutropenic patients.1,5,25,37,40–42 Itraconazole has similar efficacy as amphotericin B, with fewer toxicities. However, current lack of a parenteral dosage form, sometimes erratic oral absorption that often necessitates the use of serum concentration monitoring, numerous potential drug–drug interactions, and availability of many other antifungal options limit the use of itraconazole for empiric therapy.40–42
The echinocandin antifungals (caspofungin, micafungin, and anidulafungin) are attractive agents for treatment of febrile neutropenia because of their broad spectrum of antifungal activity and favorable adverse effect profiles. Caspofungin is as effective as, and also generally better tolerated than, liposomal amphotericin B for empirical treatment of neutropenic patients with persistent fever.40–42 Therefore, caspofungin is considered an appropriate alternative to LAMB and voriconazole.1,5,23,25,27,37,41 Micafungin and anidulafungin have not been as well studied specifically in this capacity; however, some experts consider them likely as effective.1,5,23,27
Clinical Controversy…
As with antibiotic therapy, the optimal duration of antifungal therapy remains controversial. Most clinicians agree that antifungal therapy can be discontinued when neutropenia has resolved in clinically stable patients with no evidence of fungal infection. In neutropenic patients, antifungal therapy generally should be continued for at least 2 weeks in the absence of signs and symptoms of active fungal disease, but many experts advocate continuing therapy until resolution of the neutropenia.4,12,23,37 In neutropenic patients with documented fungal disease, antifungal therapy should be directed at the causative organism, and therapy should be continued for at least 2 weeks after clinical and culture data indicate resolution of the infection.23 In addition to fungal infections, other causes of persistent fever of unknown origin include resistant bacterial infection, tissue necrosis as a result of underlying tumor, nonbacterial and nonfungal infection (e.g., viral, mycobacterial, or parasitic), and drug or blood product administration. The persistence of fever should not be considered the sole indication for modification of antifungal regimens, assuming that an agent active against Aspergillus was initially selected.25,37 Treatment recommendations for specific fungal infections are given in Table 100-6.
Initiation of Antiviral Therapy
Febrile neutropenic patients with vesicular or ulcerative skin or mucosal lesions should be evaluated carefully for infection due to HSV or varicella-zoster virus (VZV). Mucosal lesions from viral infections provide a portal of entry for bacteria and fungi during periods of immunosuppression. If viral infection is presumed or documented, neutropenic patients should receive aggressive antiviral therapy to aid healing of primary lesions and prevent disseminated disease. Acyclovir traditionally has been used in this population. However, the newer antivirals valacyclovir and famciclovir have better oral absorption and more convenient dosing schedules. Routine use of antiviral agents in the management of patients without mucosal lesions or other evidence of viral infection generally is not recommended.1,5 Treatment recommendations for viral infections are given in Table 100-6.
TABLE 100-6 Infectious Complications During Neutropenia, and After Hematopoietic Stem Cell and Solid-Organ Transplantation: Syndromes of Disease and Treatment Guidelines
Duration of Antimicrobial Therapy
The optimal duration of antimicrobial therapy in the neutropenic cancer patient remains controversial. Decisions regarding discontinuation of empirical antimicrobial therapy often are more difficult and complex than those regarding initiation of therapy (see Fig. 100-1). One point on which experts agree, however, is that the most important determinant of the total duration of antibiotic therapy is the patient’s ANC.1,3,5,12 If ANC is ≥500 cells/mm3 (≥0.5 × 109/L) for two consecutive days, if the patient is afebrile and clinically stable for 48 hours or more, and if no pathogen has been isolated, then antibiotics can be discontinued. Some clinicians advocate that patients with ANC less than 500 cells/mm3 (0.5 × 109/L) be maintained on antibiotic therapy until resolution of neutropenia, even if they are afebrile. However, prolonged antibiotic use has been associated with superinfections resulting from resistant bacteria and fungi and increases the risk of antibiotic-related toxicities.1,5,12 If low-risk patients are stable clinically with negative cultures but the ANC still is less than 500 cells/mm3 (0.5 × 109/L) antibiotics may be discontinued after a total of 5 to 7 afebrile days. However, patients with profound neutropenia (ANC <100 cells/mm3 [<0.1 × 109/L]), mucosal lesions, or unstable vital signs or other risk factors should continue to receive antibiotics until ANC has increased ≥500 cells/mm3 (≥0.5 × 109/L) and the patient is stable clinically.1,5,12
Patients who are persistently neutropenic and febrile, but who are stable clinically with no active site of infection, often can be successfully discontinued from antimicrobials after at least 2 weeks of therapy. However, these patients must be monitored carefully because reinstitution of antibiotics may be necessary.1,5,12 An alternative approach is to place these patients on antimicrobial prophylaxis (discussed in “Prophylaxis of Infections in Neutropenic Cancer Patients” below). Patients with documented infections should receive antimicrobial therapy until the infecting organism is eradicated and signs and symptoms of infection have resolved (at least 10 to 14 days of therapy).
Consensus guidelines provide useful information regarding the management of febrile episodes in cancer patients with neutropenia.1,5 However, therapy (including initial empirical regimens, modifications, and duration of treatment) must be individualized based on individual patient parameters and response to therapy.
Colony-Stimulating Factors
Because resolution of neutropenia is arguably the most important determinant of patient outcome from both febrile episodes and documented infections, numerous studies have evaluated hematopoietic colony-stimulating factors (CSFs) (sargramostim [granulocyte-macrophage colony-stimulating factor] and filgrastim [granulocyte colony-stimulating factor]) as adjunct therapy to antimicrobial treatment of febrile neutropenic cancer patients.43 These studies consistently found that use of CSFs reduces the total duration and severity of chemotherapy-related neutropenia; some studies have also shown fewer hospitalizations and decreased hospital length of stay.1,5,43,44 However, these studies have failed to demonstrate consistent benefits of CSFs compared with placebo in relation to important outcomes such as decreased overall mortality or infection-related mortality.5,44 Evidence-based guidelines from the IDSA, American Society of Clinical Oncology (ASCO), and the NCCN recommend that CSFs should not be routinely initiated in patients with uncomplicated fever and neutropenia.1,5,43,44 However, CSFs should be considered in patients who are at high risk for infection-associated complications, or who have factors that are predictive of poor clinical outcomes.5,43,44 These factors are summarized in Table 100-7. Patients with prolonged neutropenia and documented severe infections who are not responding to appropriate antimicrobial therapy may also benefit from treatment with CSFs.43,44 Clinical judgment must be exercised in determining which patients may benefit from judicious use of these expensive agents.
TABLE 100-7 Recommendations for Use of Colony-Stimulating Factors in the Management of Neutropenic Cancer Patients and Those Undergoing Hematopoietic Stem Cell Transplantation
Direct transfusion of neutrophils has also been studied for treatment of febrile neutropenia or documented infections.45,46 Routine use of neutrophil transfusions is not generally supported by data demonstrating improved clinical outcomes. However, use may be considered in patients with profound prolonged neutropenia with severe documented infections and in whom causative organisms have not been eradicated with appropriate antimicrobial therapy in combination with CSFs.1,5,45 At present, the use of neutrophil transfusions is considered investigational and is not recommended for routine management of febrile neutropenic patients.45
Prophylaxis of Infections in Neutropenic Cancer Patients
Owing to the potential morbidity and mortality of infections in neutropenic cancer patients, environmental modifications and prophylactic antimicrobial regimens have been implemented to prevent these complications. The overall goal of antimicrobial prophylaxis in cancer patients is to decrease the number and severity of systemic infections during prolonged periods of neutropenia. As with febrile neutropenia, patient risk factors for development of infection and complications should be assessed prior to initiation of prophylaxis (Table 100-8).
TABLE 100-8 Risk-Based Prophylactic Strategies for Patients with Neutropenia
General Measures
Because approximately 50% of pathogens infecting neutropenic cancer patients are acquired in the hospital, reducing acquisition of infectious organisms from the environment is a basic component in controlling nosocomial infections.1,2,5,6,12 Neutropenic patients should be placed in reverse isolation (isolation to protect patients from contracting infections after exposure to others) with standard barrier precautions, and strict adherence to infection control guidelines by hospital personnel.1,5,6,12 Plants and fresh or dried flowers are usually prohibited as part of standard neutropenic precautions in order to minimize risk of exposure to pathogenic bacteria. Proper meticulous handwashing by hospital personnel is a simple yet very effective infection control measure. Most neutropenic patients do not require specific room ventilation; however, HSCT recipients should be placed in a private positive-pressure room with >12 air exchanges per hour and HEPA filtration.1,5,6,12
Bacterial Infections
Combinations of oral nonabsorbable antibiotics, such as gentamicin, nystatin, vancomycin, polymyxin B, and colistin, have been widely studied as a means of reducing colonization of the GI tract with virulent pathogens. Although clinical trials have demonstrated that selective intestinal decontamination with oral nonabsorbable antibiotics successfully reduces infections, these regimens are not routinely recommended for prophylaxis because of problems that include unpalatability, high cost, frequent adverse effects (e.g., nausea, vomiting, and diarrhea), and development of resistance.1,2,4–6,12
Many prospective clinical trials have shown that prophylaxis with orally administered, systemically available antibiotics such as trimethoprim–sulfamethoxazole and fluoroquinolones is more effective and better tolerated than nonabsorbable antibiotics.1,5 Although trimethoprim–sulfamethoxazole is effective as prophylaxis against P. jiroveci, its lack of activity against P. aeruginosa is worrisome when used as prophylaxis against bacterial infection, particularly in institutions where pseudomonal infections are frequent.1 Other concerns with trimethoprim–sulfamethoxazole prophylaxis include selection of resistant organisms, predisposition to development of oral fungal infections, and delay in bone marrow recovery resulting in prolonged neutropenic episodes.1,5,6
Numerous studies have shown that oral fluoroquinolones are more effective than placebo, nonabsorbable antibiotics, or trimethoprim–sulfamethoxazole in preventing gram-negative infections in neutropenic cancer patients.47,48Fluoroquinolone prophylaxis during periods of neutropenia decreases the incidence of fever and microbiologically documented gram-negative infections and may decrease the risk of death in these patients.47,48 However, there are several potential limitations to their use. In particular, ciprofloxacin may lack adequate gram-positive activity and may not be the preferred fluoroquinolone for this reason. Although fluoroquinolone prophylaxis has been associated with the development of resistant gram-negative organisms, two meta-analysis reports suggest that the risk of infection with resistant pathogens is not significantly increased.47,48 Also the risk of colonization or infection with strains resistant to the prophylactic agent is lower with fluoroquinolones than with trimethoprim–sulfamethoxazole. However, patients experiencing breakthrough infection during fluoroquinolone prophylaxis should not be subsequently placed on a fluoroquinolone-containing empirical antibiotic regimen.1,5
Although studies have concluded that the benefits of prophylaxis with fluoroquinolones outweigh the potential risks in neutropenic patients with intermediate to high risk for infection (Table 100-8), antibacterial prophylaxis in general remains somewhat controversial due to continued concerns regarding the potential for development of resistant bacteria, high cost, and lack of impact on patient survival.1,2,5 Therefore, antibacterial prophylaxis is not recommended routinely for all neutropenic patients. Prophylaxis with ciprofloxacin or levofloxacin generally is indicated for intermediate- to high-risk patients expected to be profoundly neutropenic for more than 1 week, such as HSCT patients.1,5,6 High dose levofloxacin may be preferred by some clinicians due to enhanced gram-positive activity, but many other clinicians consider them similar in efficacy. If fluoroquinolone prophylaxis is used, strategic monitoring of gram-negative resistance to the drugs should be employed. Neutrophil recovery eliminates the need for continued prophylaxis, and recovery may be facilitated by use of CSFs.43 CSFs have also been formally recommended by the ASCO and the European Organisation for Research and Treatment of Cancer (EORTC) for primary prevention of febrile neutropenia in high-risk patients (see Table 100-7).43,49
Fungal Infections
Because neutropenic patients are at risk for mucocutaneous and invasive fungal infections that are difficult to diagnose and treat in this population, antifungal prophylaxis can be considered in intermediate- to high-risk patients at institutions where fungal infections in cancer patients occur frequently.1,5 The goal of antifungal prophylaxis is to prevent development of invasive fungal infections during periods of risk, thereby reducing morbidity and mortality. A meta-analysis of antifungal prophylaxis in 38 trials involving more than 7,000 cancer patients reported a decrease in the use of parenteral antifungal therapy, superficial and invasive systemic fungal infections, and fungal infection-related mortality rate.50 Antifungal prophylaxis in these studies resulted in decreased mortality in patients with prolonged neutropenia and HSCT but no effect on rates of invasive Aspergillus infections.
Although the choice of antifungal prophylaxis agents remains controversial, fluconazole prophylaxis has been particularly well studied and reduces the incidence of both superficial and systemic fungal infections; it also significantly decreases mortality from fungal infections in patients with leukemia and HSCT recipients.5,50 However, use of fluconazole prophylaxis has contributed to the emergence of infections caused by C. krusei and C. glabrata, pathogens that frequently are resistant to fluconazole and other azole-type antifungal agents.5,26 Therefore, antifungal prophylaxis with oral fluconazole, itraconazole, posaconazole, caspofungin, or micafungin is now recommended starting with induction chemotherapy.23 The choice of a specific agent should be determined by the types of fungal isolates at individual institutions.1,5,23 Patients in whom prophylaxis should be considered include those at intermediate to high infection risk as shown in Table 100-8. After initiation, anti-fungal prophylaxis should be continued until resolution of neutropenia or the need for institution of antifungal therapy for suspected/documented infection.23
Itraconazole, low to moderate doses of amphotericin B, intranasal and aerosolized amphotericin B, LAMB products, voriconazole, and the echinocandin agents have been investigated for Aspergillusprophylaxis in neutropenic patients.6,27,51 Posaconazole was more effective than either fluconazole or itraconazole in the prevention of Aspergillus and other invasive fungal infections in patients with hematologic malignancies and prolonged neutropenia.5,27,51However, outside of the HSCT setting, posaconazole is currently only recommended for routine prevention of Aspergillus infections in neutropenic patients with hematologic malignancies.27
Other Infections
Use of trimethoprim–sulfamethoxazole in cancer patients at risk for P. jiroveci pneumonia has substantially reduced the incidence of this protozoal infection.1,5 Antiviral prophylaxis with acyclovir, valacyclovir, or famciclovir is used in most centers to reduce the risk of HSV reactivation in patients with acute leukemia undergoing intensive chemotherapy. Varicella vaccine provides good protection (90%) in leukemic children and may be useful in seronegative adults, although the vaccine has been less well studied in this population.
When considering use of antimicrobial (antibacterial, antifungal, antiprotozoal, and antiviral) prophylaxis in neutropenic patients with cancer, the risks and benefits of prophylaxis must be weighed against issues with development of resistance, toxicities, and other concerns.
Evaluation of Therapeutic Outcomes
Close monitoring of febrile neutropenic patients, including both clinical and laboratory parameters, is essential for early detection and treatment of infectious complications. Three general therapeutic outcomes have been defined in the setting of febrile neutropenia: (a) success (survival during the febrile episode until resolution of neutropenia by judicious selection of empirical antimicrobial therapy), (b) success with modification (same as [a] but with additions/modifications to empirical therapy), and (c) failure (death during febrile neutropenia).13 Because many of the drugs that can be used in this setting (e.g., aminoglycosides and amphotericin B) have significant toxicity potential, careful attention must be paid to prevention and management of drug-related adverse effects. Evaluations of the parameters given in the Clinical Presentation are appropriate to help monitor and guide therapy. In addition, the NCCN guidelines for febrile neutropenia provide comprehensive recommendations on clinical/laboratory monitoring parameters, including schedules.5 The reader is referred to individual chapters within this book for more detailed discussions of monitoring parameters related to specific types of infections (e.g., pneumonia and urinary tract infections).
INFECTIONS IN PATIENTS UNDERGOING HSCT
Infection remains a major barrier to successful HSCT.52,53 Recipients of HSCT are at enhanced risk for infection because of prolonged periods of neutropenia. In addition, patients receiving allogeneic or matched unrelated donor transplants receive prolonged immunosuppressive drug therapy for prevention and treatment of graft-versus-host disease (GVHD). Intensive pretransplant conditioning regimens (high-dose chemotherapy and total-body irradiation), as well as GVHD itself, often disrupt protective barriers, such as mucous membranes, skin, and the GI tract, placing patients at further risk of infection. Although infectious complications are still associated with considerable morbidity and mortality, studies have documented significant reduction in mortality after HSCT in association with reductions in disease caused by bacterial, fungal, and viral infections.53
Etiology and Clinical Presentation of Infections
The timing with which specific types of infections typically occur following HSCT is shown in Figure 100-3, but the relative incidence and importance of specific pathogens vary greatly according to the specific type of HSCT performed. Patients receiving allogeneic transplants are at greatest risk for infection after HSCT and are predisposed to earlier and more severe infections with opportunistic pathogens such as Aspergillus. The presence of GVHD also has an impact on the incidence and timing of various infections, including invasive fungal infections.
FIGURE 100-3 Timetable for the occurrence of infections in hematopoietic stem cell transplantation (HSCT) and solid-organ transplant patients. (UTI, urinary tract infection.)
After administration of intensive conditioning regimens to eliminate malignant cells and prevent rejection of donor cells, patients may remain profoundly neutropenic for 3 to 4 weeks. During this preengraftment period, patients are at risk for the same types of infectious complications that occur in other granulocytopenic cancer patients (e.g., bacterial and fungal infections) and should be managed accordingly (see Table 100-1). Table 100-6 lists regimens for treatment of specific infections.
HSCT recipients remain at high risk for infection after bone marrow engraftment has occurred.5,52,53 Significant defects in neutrophil function and cell-mediated and humoral immunity, persisting for several months after transplantation, predispose patients to infectious complications. Acute and chronic GVHD also result in prolonged periods of immunosuppression and increased infection rates.
Patients undergoing HSCT are at significant risk for serious bacterial infections.52–54 The risk of bacterial infection is particularly increased in patients undergoing allogeneic transplantation and those with GVHD. Gram-negative bacteremia occur in approximately 20% of patients, and mortality rates may reach 25%.54
Fungal infections, especially those caused by Candida and Aspergillus spp., are serious and often result in fatal complications. Fungi remain a serious cause of infection, particularly in allogeneic HSCT recipients, for up to 1 to 2 years following transplantation and may occur in as many as 20% of patients.52,53,55 Mortality rates associated with invasive aspergillosis infections may be as high as 90%.52,53,55,56
HSCT recipients are also at risk for serious viral infections, particularly HSV and cytomegalovirus (CMV). HSV infections may include gingivostomatitis, esophagitis, genital lesions, and, rarely, pneumonia during the first month after transplant.52,57 Clinical disease is more common in patients with serologic evidence of prior exposure and latent HSV infection pretransplant. Therefore, reactivation of latent disease during periods of immunosuppression is the most common etiology of HSV infection. Without prophylaxis, as many as 80% of HSV-seropositive patients experience mucocutaneous disease after intensive chemotherapy compared with less than 25% of seronegative patients.10,52,57 HSV infections often coexist with Candida infection and mucositis secondary to chemotherapy, radiation, or both.10,57Painful swallowing associated with these conditions often makes it difficult for patients to take oral medications and maintain adequate nutritional intake. Because of the considerable morbidity associated with HSV reactivation after transplantation, the HSV serologic status of patients should be determined prior to transplant.
HSCT recipients are at high risk for CMV infections during the early postengraftment period. Infections range in severity from asymptomatic infection with viral shedding (urine, throat, and lungs), to life-threatening disseminated disease and interstitial pneumonia.10,52,57
As with HSV, patients seropositive for CMV before transplantation are at high risk for reactivation of infection during periods of immunosuppression; up to 70% of seropositive patients develop reactivation after transplantation compared with only 3% of seronegative patients.10,52,53,57 Other risk factors for CMV infection in HSCT patients include advanced age, human lymphocyte antigen mismatch, total-body irradiation, multiagent conditioning regimens, and presence of GVHD.57 Patients without evidence of latent CMV infection (CMV-seronegative) before transplantation may develop primary CMV infection after receiving bone marrow or blood products from CMV-seropositive donors. Although the typical onset of both primary and recurrent CMV infection is 1 to 2 months after transplantation, late-onset infections may occur more than 100 days after transplantation.10,52,53,57 Patients receiving allogeneic transplants are at highest risk for CMV reactivation, with progression to clinical disease in approximately 10% of patients.10,52,53,57
The most serious clinical manifestation of CMV disease and the leading cause of infectious death in HSCT recipients is interstitial pneumonia, which is associated with an 85% mortality rate if left untreated.52,57 This clinical syndrome manifests as fever, dyspnea, hypoxia, nonproductive cough, and diffuse pulmonary infiltrates. As many as 40% of allogeneic HSCT patients will develop interstitial pneumonia; up to 40% of these cases are caused by CMV.52,57 Interstitial pneumonia also may result from other infectious (P. jiroveci, VZV) and noninfectious causes (pulmonary damage by radiation and chemotherapy).52,57
During the late postengraftment period (beginning approximately 180 days after transplantation), infections remain a major problem in patients suffering from chronic GVHD. Infections common during the late postengraftment period include those caused by encapsulated bacteria, such as S. pneumoniae and H. influenzae, fungi, and viruses, including CMV and VZV.52,57 Patients not undergoing allogeneic transplantation or suffering from chronic GVHD generally have few infections in this period.
Up to 50% of all patients surviving up to 10 months after transplantation develop an infection caused by VZV.52,57 Infection with VZV is most common in allogeneic HSCT recipients with acute or chronic GVHD.10,57 Both primary (varicella) or recurrent disease (herpes zoster) usually present as skin lesions, most of which remain contained to local areas; however, 30% to 45% of these infections may disseminate to other cutaneous areas or body organs, causing mortality as high as 50%.10,57
TREATMENT
Desired Outcomes
The goals of therapy in managing HSCT recipients include the following, from the neutropenic period through the late postengraftment period: (a) protect the patient from early death caused by undiagnosed infection; (b) employ effective prophylactic therapy to prevent common bacterial, fungal, viral, and protozoal/parasitic infections; (c) effectively and aggressively treat established infections; (d) avoid unnecessary use of antimicrobials that contribute to increased resistance; and (e) minimize toxicities and cost while increasing patient quality of life.
Prophylaxis and Management of Infections in Recipients of HSCT
The overall goal of prophylaxis and treatment of infection in HSCT patients is prevention of infectious morbidity and mortality. Specific goals of antimicrobial drug use in HSCT patients include (a) prevention of bacterial, fungal, viral, and protozoal infections during preengraftment and postengraftment periods and (b) effective treatment of established infections. These goals must be achieved at the lowest possible toxicity and cost. Prophylactic therapy should be aimed specifically at pathogens known to cause a high incidence of infection within the HSCT population, the specific institution, or both. In addition, prophylactic therapy should be limited to regimens proved to be effective through well-designed clinical trials.
Appropriate immunizations should be a primary consideration in the prevention of infections in HSCT recipients. Immunizations against common bacterial and viral pathogens are timed to avoid periods of severe immunosuppression following HSCT when the protective response to vaccination potentially would be decreased.5,6 Current recommendations for immunization of HSCT patients include three doses each of diphtheria–pertussis–tetanus or diphtheria–tetanus, inactivated polio, conjugated H. influenzae type b, and hepatitis B vaccines at 12, 14, and 24 months after transplantation. The 23-valent pneumococcal vaccine should be administered at 12 and 24 months after HSCT, and the influenza vaccine should be administered prior to HSCT, resumed at least 6 months after transplantation, and continued annually for life. Family members, close contacts, and healthcare providers of HSCT patients also should be vaccinated annually against influenza. Finally, the measles–mumps–rubella vaccine should be administered no sooner than 24 months after HSCT when the patient is considered to be immunocompetent. The varicella vaccine is contraindicated for administration to HSCT patients owing to the live-attenuated nature of the product and the risk of VZV infection. The injectable inactivated influenza vaccine is preferred both before and after HSCT due to severe underlying illnesses pretransplant and contraindication of the live-attenuated intranasal product posttransplant.1,5,6
Bacterial Infections
Prophylaxis of infections in HSCT patients is similar in many ways to that used in other neutropenic patients. Antibacterial prophylaxis with oral antimicrobials is used commonly; considerations are the same as those discussed previously in the “Prophylaxis of Infections in Neutropenic Cancer Patients” section. Although many studies have shown decreased rates of bacteremia and other bacterial infections after HSCT, overall mortality rates have not been consistently reduced.1,5,6,57 Therefore, routine use of prophylactic antibiotics in HSCT is still controversial but should be considered in patients at moderate to high risk of infection (Table 100-8). Fluoroquinolones are the most frequently used agents, with levofloxacin preferred over ciprofloxacin due to enhanced gram-positive activity.1,5,6,57 These regimens usually are started either within 72 hours of beginning the chemotherapy conditioning regimens or on the day of hematopoietic stem cell infusion and continued throughout the neutropenic period. Patients who become febrile while receiving prophylaxis should be managed according to general guidelines for febrile neutropenic patients.
Clinical Controversy…
Prophylaxis of infection in HSCT patients with parenteral vancomycin has been studied because of the high incidence of gram-positive infections following transplantation. Vancomycin prophylaxis appears to decrease the overall incidence of gram-positive bacterial infections, number of days of empirical antimicrobial therapy, and cost of therapy.5,6 However, important mortality benefits have not been demonstrated consistently, and there are significant concerns regarding the selection of vancomycin-intermediate S. aureus and VRE. Thus, prophylactic vancomycin use is not recommended except in institutions with high rates of MRSA infection among HSCT recipients.1,5,6 There currently is no defined role in prophylaxis for other agents with anti-MRSA activity (e.g., linezolid).
Antibiotic prophylaxis against bacterial infection is also recommended in the late postengraftment period (>100 days after transplantation) in certain high-risk patients, specifically allogeneic transplant recipients with chronic GVHD.5,6 Antibiotics should be targeted against encapsulated bacteria, particularly S. pneumonia, and should be selected based on local susceptibility patterns for these organisms; penicillin is preferred in areas with low rates of penicillin-resistant pneumococci.5 Patients receiving trimethoprim–sulfamethoxazole for prophylaxis of other opportunistic infections may be protected adequately and do not necessarily require an additional antibiotic.5,6Prophylaxis should be continued as long as the chronic GVHD is being actively treated.
Viral Infections
Prophylaxis of recurrent HSV infection is recommended for all HSV-seropositive patients undergoing HSCT.1,5,6,57 Approximately 0% to 10% of HSV-seropositive patients receiving acyclovir experienced viral shedding, clinical symptoms of viral reactivation, or both compared with 60% to 80% of patients receiving placebo.6,57 IV acyclovir therapy eventually is necessary in many patients because of the development of severe mucositis from conditioning regimens. However, oral acyclovir, valacyclovir, or famciclovir is effective and considerably less expensive in patients who can take oral medications. Valacyclovir has replaced acyclovir as first-line therapy in many institutions.5,6,57,58 The antiviral agent usually is started at the time of the conditioning regimen and continued until bone marrow engraftment or resolution of mucositis (approximately 30 days after HSCT), although longer durations of prophylaxis may be considered in allogeneic HSCT recipients with GVHD or frequent HSV reactivations before transplantation.5,6,57,58 In addition to preventing recurrence of HSV disease, acyclovir prophylaxis may reduce the incidence of CMV reactivation.5,6 Patients receiving ganciclovir or foscarnet for prophylaxis or treatment of CMV infection do not need additional antiviral therapy for prevention of HSV or VZV.5 Patients developing active HSV or VZV infection should be treated with high-dose acyclovir.57
Oral acyclovir or valacyclovir given for up to 12 months after transplantation also significantly reduces reactivation of VZV infections and prevents the occurrence of severe VZV disease.1,5 Patients receiving either allogeneic or autologous HSCT may therefore be considered for long-term (up to 1 year after transplantation) prophylaxis against VZV.5 Patients who received HSCT within the previous 24 months, or those more than 24 months after HSCT who have chronic GVHD or are undergoing immunosuppressive therapy, should receive varicella-zoster immunoglobulin 625 units intramuscularly within 48 to 96 hours after close contact with persons with chickenpox or shingles for prevention of VZV-related disease.6
Acyclovir-resistant HSV has been reported occasionally in HSCT patients receiving acyclovir prophylaxis. Foscarnet is a drug of choice for treatment of documented infection with acyclovir-resistant HSV and should be reserved for this use.5,6,57
Prevention of CMV disease has been studied extensively in HSCT patients and is a well-accepted indication for prophylaxis because of the high associated infectious morbidity and mortality. If possible, CMV-seronegative patients should receive donor cells and supportive blood products from seronegative donors only; however, CMV-seropositive patients are not at significant additional risk by receiving blood or donor cells from seropositive donors.57Although acyclovir has relatively poor in vitro activity against CMV, a decrease in CMV infection and an improvement in overall survival were reported in HSV- and CMV-seropositive allogeneic HSCT recipients receiving IV acyclovir.5,6
Ganciclovir has been well studied for prophylaxis because of its superior activity against CMV compared with acyclovir.5,6 Oral valganciclovir has also been well studied in the setting of HSCT.5,58Valganciclovir has excellent pharmacokinetics and produces serum levels of ganciclovir, which are at least similar to those achieved after IV administration.59 Valganciclovir is routinely used in many centers based on the favorable pharmacokinetic properties and convenience of oral dosing in certain patients.5,58,59 Although administration of prophylactic ganciclovir to CMV-seropositive patients may significantly decrease the occurrence of CMV disease, studies have found no clear survival benefit, and ganciclovir-related bone marrow suppression frequently was problematic. Therefore, ganciclovir prophylaxis is somewhat controversial and is not universally recommended for routine use.5,6,57 It may, however, be considered for allogeneic HSCT recipients for the first 100 days after transplantation.5,6,57
Perhaps a more appropriate role for ganciclovir and valganciclovir is preemptive therapy, in which ganciclovir is administered at first isolation of CMV from the blood or bronchoalveolar lavage fluid. Detection of CMV can be accomplished by use of either a monoclonal antibody-based test for viral antigens or by detection of viral DNA through polymerase chain reaction (PCR)-based tests. Preemptive therapy significantly reduced the occurrence of CMV disease (including CMV pneumonia) and improved survival significantly up to 180 days after transplantation.5,57 Because CMV viremia and bronchoalveolar lavage cultures are highly predictive of subsequent CMV disease, preemptive ganciclovir or valganciclovir therapy should be considered for autologous HSCT recipients within the first 100 days after transplantation or in allogeneic HSCT recipients at any time after transplantation.5,6,57 The doses of ganciclovir or valganciclovir for preemptive therapy are the same as those used for prophylaxis. Foscarnet can also be used for either prophylaxis or preemptive therapy of CMV disease in patients intolerant of ganciclovir. CSFs are beneficial in this setting (Table 100-6), providing benefits similar to those noted in neutropenic patients with acquired immunodeficiency syndrome receiving ganciclovir therapy for CMV retinitis.43,44
Prophylaxis of CMV disease with either IV immunoglobulin (IVIG) or cytomegalovirus hyperimmune globulin (CMVIG) produced variable and inconclusive results, and their use is not currently recommended.60,61
Ganciclovir or valganciclovir are the drugs of choice for treatment of active CMV infection in HSCT patients (see Table 100-5). Foscarnet also may be of benefit for treatment or prevention of infections in HSCT patients and may be used as an alternative to ganciclovir/valganciclovir because of its relative lack of bone marrow toxicity. Foscarnet-related nephrotoxicity may be problematic, however, especially in the posttransplant period when patients may be receiving other nephrotoxic agents. Cidofovir has not been well studied in HSCT patients and is also associated with nephrotoxicity, but this agent may also be considered for preemptive therapy or treatment of active disease.5
Numerous single-agent treatments, such as vidarabine, interferon, and ganciclovir, have been used unsuccessfully as treatment for CMV pneumonitis. However, the combination of high-dose IVIG and ganciclovir may decrease the mortality of the syndrome from 85% to only 30% to 50%.57,60,62 Ganciclovir plus hyperimmune CMVIG also is considered effective for treatment of CMV disease, although this regimen has not been studied as extensively in the HSCT population in a controlled fashion. The potential for ganciclovir-associated bone marrow suppression prior to marrow engraftment and in patients who are just recovering from granulocytopenia remains a concern, especially in patients with unstable renal function. Ganciclovir plus CMVIG is used widely as the treatment regimen of choice for severe or life-threatening CMV disease, this use being based on benefit-versus-risk considerations more than definitive clinical data.5 Ganciclovir plus IVIG may also be used, although CMVIG has replaced IVIG in many institutions.5,60,62
Fungal Infections
Prophylaxis with antifungal agents is efficacious and generally recommended for prevention of mucocutaneous and disseminated fungal infections in high-risk HSCT patients (Tables 100-2 and 100-8).5,6,23,25,51,57,63–66 Patients specifically recommended for prophylaxis include all allogeneic recipients and autologous transplant recipients who are expected to have prolonged neutropenia, have received intensive conditioning regimens associated with extensive mucositis, or have recently received fludarabine.5,6,23,25,51,57,63,64 Fluconazole is the most commonly used agent; it is started on the day of transplantation and continued until resolution of neutropenia or, in allogeneic HSCT, for at least 75 days after transplantation.5,6,23,57,64 The variable activity of fluconazole against non-albicans species of Candida may be problematic in this population, as is lack of activity against Aspergillus.25,26,51,64Prophylaxis with fluconazole (as well as itraconazole), although effectively reducing colonization and infection with yeasts, has not been consistently demonstrated to reduce overall mortality or invasive infections such as aspergillosis in HSCT recipients.5,25,51,57,63–66 Micafungin was more efficacious than fluconazole in the prevention of early-onset Candida infections in patients with neutropenia prior to engraftment, and also showed a trend to fewer episodes of invasive aspergillosis.5 Posaconazole was also more effective than fluconazole in the late prevention of invasive Aspergillus and other fungal infections in HSCT patients with GVHD. In a meta-analysis, prophylaxis with agents active against Aspergilluswere also associated with a 33% reduction in mortality related to invasive fungal infections compared to fluconazole.66 Fluconazole, posaconazole, and micafungin, along with itraconazole, voriconazole, and LAMB products, are all recommended for prophylaxis of fungal infections in HSCT. Posaconazole is the preferred agent in high-risk HSCT patients with GVHD (Table 100-2).5,25,27,51,63–65
Protozoal Infections
Pulmonary infection with P. jiroveci is a relatively infrequent complication of HSCT. However, mortality rates in this population are approximately 60% and are especially high in patients with GVHD.5,6,52Prophylactic trimethoprim–sulfamethoxazole is recommended for a period of 3 to 6 months after autologous HSCT, and for at least 6 months and while receiving immunosuppressive therapy after allogeneic HSCT. Toxoplasmosis is not a common infection in HSCT patients but is associated with mortality rates of approximately 70%.67 Toxoplasmosis should also be prevented by trimethoprim–sulfamethoxazole prophylaxis.5,6
Use of Colony-Stimulating Factors
Filgrastim, pegfilgrastim, and sargramostim have been studied in HSCT patients in an effort to speed bone marrow recovery, reduce the period of neutropenia, and decrease infectious complications. CSFs appear effective as well as safe following autologous transplantation, although increased rates of GVHD and mortality have been reported with use of CSFs following allogeneic transplantation.43 The use of CSFs is now routinely recommended to mobilize blood progenitor cells and reduce the period of neutropenia in autologous transplants (Table 100-6).5,43,44
Evaluation of Therapeutic Outcomes
Close monitoring of HSCT patients, including clinical and laboratory data, is essential for early detection and treatment of infectious complications. In addition, because many of the drugs commonly used in this setting (e.g., ganciclovir, amphotericin B, and trimethoprim–sulfamethoxazole) have significant toxicity potential in HSCT patients, careful attention must be paid to prevention and management of drug-related adverse effects. Monitoring parameters related to specific types of infections (e.g., pneumonia and urinary tract infections) should be applied as appropriate. The reader is referred to other chapters within this book for more specific information.
INFECTIONS IN SOLID-ORGAN TRANSPLANT RECIPIENTS
Solid-organ transplantation (SOT) has become an established mode of treatment for end-stage diseases of the heart, lungs, kidney, liver, pancreas, and small bowel. Patient and allograft survival rates have greatly improved due to improvements in immunosuppressive drug therapy, candidate selection, and transplant surgery techniques and more experience in the management of complications (including infection) in these patients. Despite advances in diagnostic techniques and antimicrobial therapy, infectious complications remain important causes of morbidity and mortality after SOT.
Risk Factors
Many risk factors for infection are present in SOT patients (see Table 100-1). The most important risk factor in this population is immunosuppressive drug therapy for prevention and treatment of allograft rejection. Risk of infection depends on specific immunosuppressive drug regimens as well as the intensity (dose) and duration of immunosuppression. Most opportunistic infections in transplant patients occur during the first 6 months after transplantation, when the intensity and total cumulative doses of immunosuppressive therapy are very high.68,69
Immunosuppressive drugs, often in escalated doses, are used to treat episodes of graft rejection include immunoglobulins directed against T cells (e.g., antithymocyte globulin), murine monoclonal antibodies (muromonab), antibodies against interleukin 2 receptors (daclizumab and basiliximab), T-cell–depleting antibodies (alemtuzumab), and high-dose corticosteroids. Rejection episodes often occur during the period 2 to 4 months posttransplant when the overall cumulative dose or net state of immunosuppression is highest.68,70 Therefore, patients already at risk for infection are placed at even higher risk if additional immunosuppressive therapy is needed to treat one or more episodes of graft rejection. Immunosuppressive drug therapy must be evaluated carefully when infections occur because, in many cases, immunosuppression may have to be reduced to allow patients to survive the infectious episode, at the expense of increased risk of graft rejection. Risk of increased infectious complications from immunosuppressive therapy used to treat rejection episodes is determined, at least in part, by the specific therapy used.68–70
Etiology
As with cancer patients, microorganisms infecting SOT patients are present before transplantation or are acquired from exogenous sources. All transplant recipients are at risk for mucocutaneous candidiasis from species colonizing body sites. Invasive fungal infection is less common following kidney and pancreas transplantation (5% to 15%) but may occur in 30% to 60% of heart, lung, liver, and small bowel transplant recipients. Rates are highest following lung, liver, and small bowel transplantation and are associated with mortality rates up to 60% to 80%.68,71–73 Approximately 50% to 90% of all systemic fungal infections in transplant recipients are caused by Candidaspp.68,71,72 Abdominal surgery, especially the more complex procedures required for liver and small bowel transplantation, predispose patients to serious fungal disease, most likely as a consequence of entering an area already colonized with Candida spp.71 Lung and heart transplant recipients are particularly at risk for invasive aspergillosis; these infections may occur in up to 10% of patients.71–73 Liver and lung transplant recipients are at high risk for serious gram-negative bacterial infections as a result of the technically difficult surgical procedures.68 Although opportunistic viral, fungal, and protozoal infections may occur commonly, bacterial infections remain the most frequent infectious complications after transplantation in all allograft recipients.
Organisms present as latent tissue infections may reactivate and cause clinical disease with administration of immunosuppressive drug therapy. Disease resulting from infection reactivation has been noted with viruses (HSV, human herpesvirus-6, CMV, VZV, Epstein–Barr virus), protozoa (T. gondii, P. jiroveci), and mycobacteria (Mycobacterium tuberculosis).74,75 Serologic or immunologic tests are performed prior to transplantation to assess the risk for reactivation infection and identify other subclinical infections (e.g., hepatitis B, hepatitis C, Legionella). Many patients with reactivated infection have no clinical symptoms; often the only evidence of active infection is a rise in antibody titer from the pretransplant baseline, positive culture, or histologic evidence. Reactivation of latent infection may result in severe life-threatening disease in immunosuppressed hosts.75
Exogenous sources of infection in transplant patients include environmental contamination and transmission of microorganisms via transplanted organs and blood products. Environmental sources of infection are similar to those noted in other immunocompromised hosts, such as cancer patients. Airborne pathogens, especially fungi such as Aspergillus and Cryptococcus neoformans, may cause infections in transplant patients; this is thought to be a direct cause of increased Aspergillus infections among lung transplant patients.68,71 Transplant patients are at high risk for nosocomial infections (P. aeruginosa, Acinetobacter). Optimal prevention and management of nosocomial infections in transplant patients require knowledge of the current epidemiology of infections and susceptibility patterns in the institution.
Infections transmitted via donor organs or blood products are major causes of morbidity and mortality in transplant patients and may include HSV, T. gondii, and hepatitis B and C. The most important infections transmitted from the donor, however, are caused by CMV. These infections may cause serious disease, and predispose patients to other opportunistic infections, and contribute to acute and chronic allograft dysfunction or rejection, posttransplant lymphoproliferative disorders, and cardiac complications and atherosclerosis in heart transplant recipients.68,76 In contrast to reactivation disease, transplant patients contracting primary CMV disease are at increased risk for serious life-threatening infections.68,77–79 The most important source of primary CMV infection in transplant patients is the donor organ. Efforts are made to avoid transplanting organs from CMV-seropositive donors into CMV-seronegative recipients because of the potentially severe consequences. With the relative scarcity of suitable organs and the rapidity with which transplant decisions often must be made, however, this is not always possible. The consequences of transplanting an organ from a CMV-seropositive donor into an already CMV-seropositive recipient are less clear. CMV reinfection (as well as reactivation) syndromes may occur in these patients.68,69,79 In addition to transmission from donor organs, primary CMV disease may be transmitted from seropositive blood products, although this is a much less common mode of transmission.
Organs from donors seropositive for T. gondii or HSV generally are not withheld from seronegative patients. Organs from known HIV-infected donors, however, are not used for transplantation. Asymptomatic HIV-seropositive individuals with CD4+ lymphocyte count greater than 400 cells/mm3 (0.4 × 109/L) may be considered for SOT (as well as HSCT) without prohibitively high risk for acceleration of HIV disease.80 However, this practice is not widespread because of the shortage of donor organs. The impact of protease inhibitors and highly active antiretroviral therapy on long-term outcome of HIV-infected patients following transplantation is not precisely known but is believed to have improved the overall feasibility of transplanting these individuals.80
Timing of Infections After Transplantation
As with HSCT, the overall time course for infections can be divided into three general periods after transplantation (see Fig. 100-3). Although risk of infection with specific pathogens varies with the type of transplant, the time course of infections is similar in all transplant recipients. During the early posttransplant period (within the first month after transplantation), patients are at risk for infections already present and brought forward from the pretransplant period (e.g., hepatitis B); postoperative infections, such as surgical wound and catheter infections; infection resulting from colonized donor organs (pneumonia following lung transplant); and reactivation of HSV.68,69,75In the intermediate posttransplant period (2 to 6 months after transplant), risk is highest for viral infections, including CMV, Epstein–Barr virus, and hepatitis B and C. The combination of these “immunomodulating” viruses plus sustained immunosuppressive therapy leads to a high risk for opportunistic infections with pathogens such as P. jiroveci, Aspergillus, and Nocardia asteroides.68,69,71,75 In the late post-transplant period (>6 months after transplant), patients are at risk for persistent infections (particularly viral) from earlier posttransplant periods, reactivation of VZV and C. neoformans, and routine infections affecting the general population.68 In addition, patients who required additional immunosuppression therapy for acute or chronic rejection are at continued high risk for opportunistic infections (Aspergillus and P. jiroveci).68,69,71 Although Figure 100-3 illustrates infection patterns common to all solid-organ transplants, the relative incidence and importance of a particular pathogen vary according to the type of transplant.
Types of Infections and Clinical Presentation
Transplant patients are at risk for infections occurring at a variety of sites, including skin, surgical wound, urinary tract, lungs, blood, abdomen, and CNS. However, most infections occur at or near the site of the transplanted organ. For example, heart transplant and heart and lung transplant recipients most often are infected within the lungs or thoracic cavity. Urinary tract infections remain an important cause of morbidity in renal transplant patients, especially in the early posttransplant period. Administration of prophylactic antibiotics (e.g., trimethoprim–sulfamethoxazole) to these patients has reduced the incidence and severity of urinary tract infections.68,69 Serious bacterial and fungal infections originating from the abdomen and GI tract are most common after liver transplantation and are related to variables such as length of surgery and surgical procedures performed. Risk of bacteremia, usually originating from the gut, is highest in liver transplant patients. Renal transplant recipients are at the lowest risk for infections and infectious deaths, whereas patients receiving heart, lung, and liver transplants are at the highest risk for infection-related morbidity and mortality.68,69,71
In contrast to febrile neutropenic patients, the threshold for initiating empirical antimicrobial therapy is higher in febrile transplant patients. Appropriate therapy for the large numbers of pathogens that may cause infections in transplant patients varies greatly from organism to organism (Table 100-5). Therefore, careful attempts at definitive diagnosis of suspected infections must be made. If comprehensive workup reveals no source of infection, careful observation of the febrile transplant patient (rather than empirical therapy) is common practice. Surveillance cultures may be useful during the first 3 months for detecting CMV and HSV infections.68,71,77,78,81 Management and monitoring of documented infections are similar to that in other types of patients.
CLINICAL PRESENTATION Infections in Solid-Organ Transplant Patients
General
• Because transplant patients are at high risk for serious infections, frequent (at least daily), careful clinical assessments must be performed to search for evidence of infection
• Clinical presentation of infection is variable and depends on the type and site of infection, type of transplant, time after transplantation, immune status of the host, and dose and duration of immunosuppressive therapy
• Primary viral disease usually is more symptomatic and severe than disease caused by reactivation
• Physical assessment should include examination of all common sites of infection, including mouth/pharynx, nose and sinuses, respiratory tract, GI tract, urinary tract, skin, soft tissues, perineum, and intravascular catheter insertion sites
Symptoms
• Usual signs and symptoms of infection may be absent or altered in patients receiving intensive immunosuppressive regimens owing to an inability to mount a typical inflammatory response (e.g., no infiltrate on chest x-ray film, urinary tract infection without pyuria)
• Pain may be present at infection site(s)
Signs
• Fever is the single most important clinical sign indicating the presence of infection. Other causes of fever unrelated to infection in this patient population include reactions to blood products, drugs, embolic events, and ischemic injury
• Usual signs of infection may be absent or altered
• Signs of allograft dysfunction may be related to infection. Distinguishing fever caused by allograft rejection from that caused by infection often is difficult and frequently requires allograft biopsy
Laboratory Tests
• Blood cultures (at least two sets, including vascular access devices) for bacteria and fungi; cultures of other suspected or potential infection sites (urine, lungs, surgical wounds, and soft tissue infections)
• Other cultures should be obtained as clinically indicated according to the presence of signs or symptoms
• Complete blood count and chemistries should be obtained frequently to monitor allograft function, plan supportive care, guide drug dosing, and assess patient’s overall status
• Surveillance cultures for CMV and HSV may be useful during first 3 months after transplantation for early detection of infection
Other Diagnostic Tests
• Chest x-ray film
• Aspiration, biopsy of skin lesions
• Other diagnostic tests as indicated clinically on the basis of physical examination and other assessments
TREATMENT
Desired Outcomes
The goals of therapy in managing SOT recipients are similar to those in HSCT and include the following: (a) protect the patient from early death caused by undiagnosed infection, from the surgical procedure through the late postengraftment period; (b) employ effective prophylactic therapy to prevent common bacterial, fungal, viral, and protozoal/parasitic infections; (c) effectively and aggressively treat established infections; (d) avoid unnecessary use of antimicrobials; and (e) minimize toxicities and cost while increasing patient quality of life and avoiding harm to the engrafted organ(s).
Prevention of Infection in Solid-Organ Transplantation
The goals of antimicrobial drug use in solid-organ transplant recipients are (a) prevention of infectious complications in the immediate postoperative period, (b) prevention of late infectious complications associated with prolonged periods of immunosuppression, and (c) effective treatment of established infections in order to prevent graft dysfunction and rejection and decrease patient morbidity and mortality. All of these goals must be achieved at the lowest possible toxicity and cost.
Prevention of infection in the transplant patient can be accomplished in a number of ways. First, risk of environmental contamination should be minimized.82 Patients should be protected from institutional infectious outbreaks. Transplant patients should receive the pneumococcal vaccine once and the influenza vaccine yearly; however, their immunologic responses to these vaccines may be blunted by immunosuppressive therapy.68
Because the most important source of primary CMV infection is an infected donor organ, CMV-seronegative patients should not receive organs or blood products from seropositive donors if possible. A number of pharmacologic strategies have been studied in an attempt to prevent CMV infection. Prophylaxis with IV ganciclovir or oral valganciclovir is effective in reducing the incidence of both primary and reactivated CMV infection in SOT.58,62,68,69,76–79Ganciclovir prophylaxis also may significantly reduce reactivation of CMV infection in seropositive patients receiving antithymocyte globulin or muromonab for treatment of acute rejection.69,78,79 High-dose oral acyclovir effectively reduces the incidence of CMV infection and disease following renal transplantation. However, acyclovir is less efficacious in high-risk renal transplant patients (donor positive, recipient negative for CMV serum antibodies) and other nonrenal transplant types.68,69,76–79,83 Preemptive ganciclovir or valganciclovir (initiated after actual isolation of CMV from blood, urine, bronchoalveolar lavage fluid, or other site) is more effective than acyclovir in preventing CMV disease in liver transplant recipients. Preemptive ganciclovir effectively prevents CMV disease in other types of solid-organ transplants as well.77,78,81 Ganciclovir-related bone marrow suppression is not as problematic in solid-organ transplant recipients as in HSCT patients; most studies report that the drug is reasonably well tolerated.62,68,77,78,81,83
Whether prophylaxis or preemptive therapy is the best approach to preventing CMV disease is controversial.62,68,73,77–79,81,84–86 Prophylaxis is effective and easy to administer without the need for careful discrimination among suitable patients. However, universal prophylaxis results in unnecessary exposure of low-risk individuals to adverse effects of drugs, and there are concerns that prolonged exposure may increase the risk of viral resistance to drugs.77,78,83–85 Preemptive therapy is effective and results in exposure of fewer patients to drugs. Prophylactic therapy is recommended primarily in patients at highest risk of disease (i.e., seronegative patients receiving organs from seropositive donors), whereas other lower-risk patients are often recommended to receive only preemptive therapy.68,73,77,78,81,83–86 However, the risk of CMV infection and disease in lung transplant recipients is so high and is associated with such severe consequences (i.e., chronic graft dysfunction, decreased survival) that prophylaxis is routinely recommended for all lung transplant recipients.73,86 The duration of prophylactic therapy in SOT recipients is typically 100 days, although data suggest that the duration may be extended to 6 months in high-risk kidney transplant recipients and to 12 months in high-risk lung transplant patients.73,85,86
Clinical Controversy…
CMVIG may be valuable in decreasing the incidence and severity of CMV disease following kidney, heart, lung, and liver transplantation.62,68,76–79,82 Although prophylaxis with CMVIG has been strongly recommended for CMV-seronegative transplant recipients receiving organs from seropositive donors, the benefits of CMVIG relative to other therapies (e.g., prophylactic or preemptive ganciclovir) are not well known, and available studies have conflicting results. Whether the combination of CMVIG plus ganciclovir offers advantages over the use of either agent alone, either for primary prophylaxis or for treatment of established CMV disease, in SOT is unclear.62,68,77 However, some authorities recommend use of CMVIG in combination with ganciclovir for treatment of severe, life-threatening CMV pneumonitis in solid-organ transplant recipients.5,60,62
Although use of prophylactic acyclovir in HSV-seropositive patients undergoing HSCT is well accepted, prophylaxis in solid-organ transplant recipients remains controversial. Reactivation disease caused by HSV occurs in approximately 25% of HSV-seropositive patients who are not receiving prophylaxis.68 Oral or genital mucocutaneous disease is the most common presentation, but HSV pneumonitis also is seen occasionally and is associated with a mortality rate of approximately 75%.68 Acyclovir is therefore used at some centers because of the high incidence of clinical HSV infection after transplantation. Acyclovir for prophylaxis of HSV infection may be considered in patients following a preemptive strategy for management of CMV infection, but would not be necessary in patients receiving ganciclovir or valganciclovir for CMV prophylaxis.
Prophylactic antimicrobial agents are also of benefit to SOT patients in certain other clinical situations. Antibiotic prophylaxis, with agents such as cefazolin started perioperatively and continued for less than 24 hours, is considered to reduce wound infection rates effectively following renal transplantation.68,82 Although the benefits of perioperative prophylaxis have not been well demonstrated in other types of transplantation procedures, surgical prophylaxis usually is considered mandatory for liver, heart, lung, or small bowel transplant patients because of the high risk of perioperative bacterial infections.68,82Pulmonary infections are particularly common in lung and heart-lung transplant recipients. They often are caused by bacteria colonizing the airways of the diseased organs prior to transplantation. Therefore, perioperative antibiotics for lung and heart and lung procedures often are selected based on pretransplant sputum cultures and/or known colonizations.68,82 In addition, post-transplant antibiotic prophylaxis is effective in decreasing the number of bacterial infections in renal transplant patients. Prophylactic trimethoprim–sulfamethoxazole traditionally has been used because it is inexpensive and well tolerated; other antibiotics, such as the fluoroquinolones, also have been evaluated.68 Administration of oral low-dose trimethoprim–sulfamethoxazole (one double-strength tablet daily) for 6 to 12 months for prevention of P. jiroveci infection following heart and lung transplantation is common, although the efficacy and optimal duration are somewhat controversial.68,85 Selective bowel decontamination with nonabsorbable antibiotics in combination with a low-bacterial diet (no fresh fruits and vegetables) effectively reduces oropharyngeal and GI colonization with gram-negative aerobes and Candida in liver transplant patients. However, selective bowel contamination is less efficacious when administered for a period of less than 1 week prior to transplantation.82 Because liver transplantation usually is performed without advance notice as organs become emergently available, the practice of selective bowel decontamination remains controversial and is not recommended routinely.68,82
Because immunosuppressed transplant recipients are at risk for mucocutaneous fungal infections, prophylactic oral or topical antifungal agents may be indicated in these patients. Liver, pancreas, and small bowel transplant recipients are clearly at high risk for invasive fungal infections and should receive prophylaxis with fluconazole.23,68,71,85 Prophylaxis has also been suggested for lung and heart–lung transplant recipients due to the high incidence of invasive fungal infections in these patients. Prophylaxis with inhaled LAMB, high-dose fluconazole, itraconazole, voriconazole, and echinocandins have all been reported; however, data supporting either the general recommendation for prophylaxis or choice of specific agent are largely lacking and center-to-center variability is great.23,71,73,85 Concentrations of immunosuppressant drugs should be monitored closely in transplant patients receiving azole-type antifungal agents (fluconazole, itraconazole, and voriconazole).
Transplant patients, especially heart and heart and lung recipients, without serologic evidence of prior exposure to T. gondii who receive organs from seropositive donors are at high risk for toxoplasmosis.68,85Many of these patients will be receiving trime-thoprim–sulfamethoxazole for prophylaxis of P. jiroveci infection; this agent will also provide effective prophylaxis against T. gondii as well as N. asteroides. Although prophylaxis is not given routinely at all centers, this therapy may be justified in high-risk patients because of the delays in diagnosis and serious infections associated with toxoplasmosis.68,85
PERSONALIZED PHARMACOTHERAPY
Desired treatment outcomes in febrile neutropenia and in HSCT and SOT recipients are achieved through close monitoring and frequent patient assessment, including judicious evaluation of antimicrobial therapies based on suspected or documented infections. Treatment of known infections must be individualized based on documented pathogens and antimicrobial susceptibilities; effective treatment may require durations of therapy well beyond recovery of ANC in febrile neutropenic patients. High intensity of immunosuppression regimens in HSCT and SOT, as well as the presence of GVHD in HSCT, also dictate aggressive antimicrobial use with potentially long durations of therapy. However, such aggressive antimicrobial use must be balanced against unnecessary administration of drugs, which may lead to increased antimicrobial resistance, adverse effects, and cost. Proper evaluation of an individual patient’s risk of complications during febrile neutropenia or after transplantation allows for determination of proper prophylaxis regimens, selection of appropriate antimicrobials for treatment of infection, and selection of appropriate treatment settings (e.g., inpatient versus outpatient), all of which may allow for the most cost-effective therapy and contribute to an increased quality of life for the patient.
ABBREVIATIONS
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