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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

Cover of Holland-Frei Cancer Medicine

Holland-Frei Cancer Medicine. 5th edition.

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Chapter 157Infections in Patients with Cancer

, MD and , MD.

Infection continues to be a significant problem in patients with cancer. Recent advances in medical technology, such as bone marrow and hematopoietic stem cell transplantation and the use of intensive chemotherapeutic regimens, have added substantially to the number of patients who are able to survive neoplastic disorders but do so with seriously impaired host defense mechanisms that compromise their ability to resist or contain infections. The spectrum of bacterial infection continues to change. Newer opportunistic pathogens are being recognized with increasing frequency.1 The emergence of antimicrobial resistance in common bacterial pathogens during the past decade is also of great concern.2,3 Fungal, viral, and protozoal infections are becoming increasingly common in immunosuppressed patients, are difficult to recognize and treat in a timely manner, and are often refractory to therapy.4,5 Time is critical for the successful management of these patients, and delays in the administration of appropriate therapy can jeopardize a favorable outcome. Because of the difficulty in treating many of these infections, attempts at reversing the immunologic deficit and strategies for infection prevention are of the utmost importance.6

The frequency of infection is related to the type of underlying neoplastic disease, and most infections occur in patients who are no longer responding to the therapy of their neoplasm. About 80% of patients with acute leukemia, 75% of patients with lymphoma, and 50% of patients with multiple myeloma develop infection during the course of their disease, and infection is the proximate cause of death in a substantial fraction of these patients.7,8 Serious infections also occur in patients with solid tumors in the absence of significant immunosuppression. Multiple episodes of infection in the same patient are not uncommon. In severely immunosuppressed patients, the usual signs and symptoms associated with infection may be altered, suppressed, or even absent. Therefore, it is often not possible to make a specific diagnosis, and empiric therapy is generally administered in high-risk patients who are suspected of having an infection. A thorough knowledge of the many factors that predispose these patients toward the development of infections is essential.

Factors Responsible for increased Susceptibility to Infections

Many factors increase the susceptibility of immunosuppressed cancer patients to infection. Each of these factors is associated with a unique set of infections, although there is some overlap between predisposing factors and certain infections. Also, multiple predisposing factors might exist in the same patient, widening the spectrum of potential infections. Recognition of these factors enables the astute clinician to make an accurate prediction of the potential pathogen(s) in a particular patient or setting and to institute appropriate empiric therapy promptly. Table 157.1 lists the predominant defects in host defense mechanisms associated with various cancers and the infections most commonly seen as a consequence of those defects.

Table 157.1. Defects in Host Defense Mechanisms and Common Infections Associated with Malignant Diseases.

Table 157.1

Defects in Host Defense Mechanisms and Common Infections Associated with Malignant Diseases.

Neutropenia

Neutropenia remains the most common predisposing factor for infection in cancer patients.9 While some diseases, such as hematologic neoplasms, cause neutropenia, it occurs most often as a result of the myelosuppression caused by antineoplastic chemotherapy, especially when such therapy is administered at doses designed to achieve maximum antitumor activity. The relationship between neutropenia and infection has been studied most extensively in patients with acute leukemia.10 Both the degree and the duration of neutropenia influence the development of infection. The risk of infection does not begin to increase until the neutrophil count decreases to levels below 1,000/mL of blood (Fig. 157.1). This risk increases substantially as the neutrophil count decreases further. The currently accepted, standard definition of neutropenia is an absolute neutrophil count of ≤ 500/mm3. Most serious infections including bacteremias develop during episodes of severe and prolonged neutropenia, and virtually every patient whose neutrophil count is less than 100/mL for 3 weeks or more will develop an infection, indicating a direct relationship between the risk of infection and the duration of neutropenia.

Figure 157.1. Relations between granulocyte count and infection in patients with acute leukemia.

Figure 157.1

Relations between granulocyte count and infection in patients with acute leukemia. Percentage of days spent with infection is inversely related to the level of circulating granulocytes.

Patients undergoing initial remission-induction therapy for acute leukemia are at great risk for developing infections associated with neutropenia since the duration of neutropenia in such patients is generally 21 to 25 days, with about 12 to 15 days at levels below 100/mL. Also, patients undergoing bone marrow or hematopoietic stem cell transplantation have essentially no circulating neutrophils for a period of 3 weeks following transplantation and are at great risk of developing infections until engraftment occurs and the neutrophil count begins to rise. For the majority of solid tumors, therapy usually results in shorter periods of less severe neutropenia. However, some solid tumors, such as testicular carcinoma, small cell carcinoma of the lung, and some lymphomas and sarcomas, are being treated with increasingly intensive chemotherapeutic regimens, which produce significant periods of severe neutropenia.

Neutropenic patients often fail to develop the characteristic signs and symptoms of infection, since they are unable to mount an adequate inflammatory response.11 For example, purulent sputum was produced by only 8% of patients with severe neutropenia (less than 100/mL) who developed pneumonia compared with 84% of patients with adequate neutrophils (> 1,000/mL). Likewise only 11% of the former had pyuria during episodes of urinary tract infection compared with 97% of the latter. Inflammatory exudates in neutropenic patients may be devoid of neutrophils and may contain only a few lymphocytes and macrophages. Neutropenic patients who develop pneumonia may not have pulmonary infiltrates on chest radiographs or may fail to demonstrate meningismus when they develop meningitis.

Infection can disseminate widely and rapidly in patients with severe neutropenia. Nearly all episodes of bacteremia and disseminated fungal infection complicating neoplastic diseases arise in patients with neutrophil counts of less than 100/mL. An autopsy study of pneumonia in 40 children who died of cancer illustrates the relationship between neutropenia and the development of bacteremia. None of the children with neutrophil counts above 1,000/mL developed bacteremia in association with pneumonia compared with 64% of children with less than 1,000 neutrophils/mL and 80% of children with 100 neutrophils/mL or less.

The most common sites of infection in neutropenic patients include the lung, oropharynx, blood, urinary tract, skin, and soft tissues, including the perirectal area. Infections are generally caused by organisms already colonizing the patient, although some of these organisms are acquired after admission to the hospital. These hospital-acquired pathogens are more likely to be resistant to commonly used antimicrobial agents because of the pressure of heavy antibiotic usage.

Patients with adequate levels of circulating neutrophils may be susceptible to infection due to impaired neutrophil function secondary to their disease or its therapy. Inadequate neutrophil function has been described in patients with acute and chronic leukemia and Hodgkin’s disease. Defects include the inability to migrate to sites of inflammation, impaired phagocytosis, and reduced killing of ingested bacteria. Abnormalities in neutrophil maturation and bactericidal activity have been reported in patients with acquired immunodeficiency syndrome (AIDS). The frequency of infection in acute leukemia is higher among patients whose neutrophils have reduced bactericidal capacity in vitro than among patients whose neutrophils function normally.

Not all neutropenic patients have the same risk for developing infection or for developing complications when they do become febrile. It is now possible to recognize high-, moderate-, and low-risk neutropenic patients, using clinical criteria during the initial phases of their febrile episode.12 Many patients with solid tumors that are responding to antineoplastic therapy and in whom neutropenia is relatively short lived (≤ 7 days) are considered low risk when they develop their febrile episode while receiving chemotherapy without being hospitalized, particularly if they are hemodynamically stable and do not have comorbidity factors, such as thrombocytopenia with clinical blending, respiratory insufficiency, hypertension, congestive heart failure, hypercalcemia, or central nervous system involvement. These patients have a high response rate (> 95%) to antibacterial therapy and a low complication rate (< 2%). Newer strategies for their management, such as early discharge from hospital and outpatient oral antibiotic therapy, are being developed.13–15

Cellular Immune Dysfunction

Those aspects of the immune response that are regulated by T lymphocytes or mononuclear phagocytes are collectively referred to as cell-mediated immunity (CMI). T cells are derived from bone marrow precursors (prothymocytes) that migrate to and eventually mature in the thymus. T lymphocytes mediate specific immune functions and also modulate the activity of other cells in the immune system. Activation of T cells occurs after recognition of specific antigens via cell surface receptors and results in replication and/or mediation of one of three functions—cytotoxicity, by direct killing of specific target cells; helper function, by stimulating the immune responses of other cells; and suppressor function, by inhibiting the immune responses of other cells. The cytotoxic and suppressor functions are mediated by cells that express the CD8 (T8) surface antigen, whereas the helper functions are mediated by a subset of T cells that express the CD4 (T4) surface antigen.16 The mononuclear phagocyte system includes bone marrow precursors (promonocytes) and their end products, the circulating monocytes, and macrophages. The growth and maturation of promonocytes in the bone marrow is governed by specific colony-stimulating factors (CSFs). Monocytes are released into blood within 24 hours of maturation and migrate into tissues after circulating in the blood for 1 to 4 days. In the tissues, they differentiate into macrophages and persist primarily in the spleen, liver, lungs, and connective tissue. Their activation is dependent upon T4 helper cell–derived lymphokines.

Defects in the T lymphocyte and/or mononuclear phagocytic system result in an increased susceptibility to infection. Cell-mediated immunity plays a primary role in protecting against intracellular pathogens.17 However, T4 lymphocytes have an impact on practically all aspects of immunity due to their ability to induce specific immune responses in other cells. Thus, the functions of B lymphocytes, which are primarily involved with maintaining humoral immunity, and granulocytes, which engulf and kill microorganisms, are regulated by T4 helper cells.

T-lymphocyte function is impaired in a variety of disorders. The human immunodeficiency virus (HIV) selectively ablates the T4 cell, which results in severe immune deficiency. Patients with Hodgkin’s disease also have evidence of impaired CMI, and, to a lesser degree, so do patients with chronic and acute lymphocytic leukemia. Defects in the mononuclear phagocytic system have been described in patients with monocytic leukemia. Immunosuppressive therapy with agents such as cyclosporine, tacrolimus azathioprine, corticosteroids, certain cytotoxic agents (fludarabine), and irradiation produces dysfunction in cellular immunity. These patients are especially susceptible to infection with intracellular organisms such as those listed in Table 157.2.

Table 157.2. Common Infectious Agents in Patients with Cancer.

Table 157.2

Common Infectious Agents in Patients with Cancer.

Humoral Immune Dysfunction

The immune response that is mediated by antibodies, which are immunoglobulins with a binding specificity for microbial antigens, is referred to as humoral immunity. B cells are lymphocytes that are derived from the bone marrow and are responsible for antibody production. Activation of B lymphocytes occurs in response to stimulation by specific antigens. This is followed by a proliferative phase and differentiation of activated cells into nondividing plasma cells that produce large quantities of immunoglobulins. Immunoglobulins promote phagocytosis and destruction of microorganisms by various mechanisms, such as opsonization of organisms for destruction by phagocytic cells, neutralization of toxins, and lysis of susceptible organisms.18 Immunoglobulins also have the capacity to block the adherence of certain bacteria to mucosal surfaces, thereby reducing the potential of such organisms to produce disease.

In disorders such as multiple myeloma, Waldenström’s macroglobulinemia, and the various “heavy chain diseases,” overproduction of a specific subcomponent of an immunoglobulin occurs as a consequence of malignant proliferation of plasma cells or their precursors. As this pool of malignant plasma cells expands, it does so at the expense of normal cells, resulting in low levels of normal immunoglobulins. Hypogammaglobulinemia is also present in 30 to 40% of patients with chronic lymphocytic leukemia, and infection occurs in nearly 90% of these patients compared with only 15% in patients with normal gammaglobulin levels. Infection is the cause of death in approximately 60% of patients with multiple myeloma. Patients with multiple myeloma and chronic lymphocytic leukemia are especially susceptible to infections caused by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae because specific opsonizing antibodies that play a major role in the defense against such pathogens are greatly reduced. Infections caused by gram-negative bacilli have also become frequent in these patients because they develop chemotherapy-induced neutropenia.

Bone Marrow Transplantation

Infection is one of the major complications associated with bone marrow and/or hematopoietic stem cell transplantation. During the initial period of neutropenia, which lasts from approximately 1 week before infusion to about 3 weeks after transplantation, patients are at risk of developing bacterial infections. Fungal infections caused by Candida spp. and Aspergillus spp. also occur during this period. The risk of these infections decreases after recovery of the neutrophil count, but neutrophil and macrophage function remain abnormal. Patients undergoing allogeneic transplantation also have suppressed CMI. As a consequence, infections with herpes viruses (herpes simplex virus [HSV], varicella-zoster virus [VZV], cytomegalovirus [CMV], Epstein-Barr virus [EBV], respiratory syncytial virus [RSV], and adenoviruses), protozoan organisms (such as Pneumocystis carinii and Toxoplasma gondii), and bacteria (such as Legionella spp., and S. pneumoniae) are common. These infections generally occur after the initial period of neutropenia has elapsed, and patients remain at risk until the regenerating immune system matures and restores normal immunity. This depends a great deal on whether or not graft-versus-host disease (GVHD) can be prevented or controlled. Multiple (polymicrobial) infections are not uncommon in this setting.

Local Factors

Local factors, such as tumor metastases, that produce obstruction and operative procedures that result in disruption of normal anatomic barriers play an important role in infections occurring in cancer patients. In an autopsy study of children with metastatic carcinoma, 80% of the cases of pneumonia were associated with pulmonary metastases, aspiration, or tracheostomy. Pneumonia and pulmonary abscesses frequently develop distal to tumors, causing obstruction of major bronchi, and these infections respond poorly to antibiotic therapy, unless adequate drainage is established. Obstruction of the biliary tract secondary to cancer can result in ascending cholangitis, especially in patients with T-tube drainage.19 Likewise, urinary tract infections are common in patients with tumors, such as bladder or prostatic carcinoma, that obstruct a ureter or the bladder neck causing retention of residual urine. Hydronephrosis, pyonephrosis, chronic pyelonephritis, and cystitis are not uncommon complications in patients with cancer of the genitourinary tract. In these situations, the infection is generally caused by one or more of the microorganisms colonizing the site of obstruction. Antibiotics seldom eradicate these infections in the presence of persistent structural abnormalities but do ameliorate the systemic symptoms of acute infection.

Damage to mucosal surfaces (particularly the gastrointestinal mucosa) occurs frequently as a result of antineoplastic chemotherapy and provides a portal of entry for infecting organisms. Radiation therapy results in depression of CMI, which can last for several months. Radiation also causes local tissue damage, which can predispose to secondary infection. Foreign bodies, such as urinary and venous catheters, also damage or circumvent normal anatomic barriers, thereby facilitating entry of microorganisms into tissues and the bloodstream.

Intravascular Devices

Surgically implanted central venous catheters are utilized extensively in patients who require frequent vascular access. These catheters (Hickman, Broviac, and long lines) can have up to three lumens, greatly facilitate a variety of functions, including the drawing of blood, and may remain in the same location for prolonged periods, ranging from several weeks to months. Three separate types of device-related infection have been described: infection of the entry site, tunnel infection, and catheter-related bacteremia or fungemia.20 Gram-positive organisms cause these infections most often, but gram-negative bacilli are not infrequent. Fungemia is most often due to Candida spp. Localized Aspergillus infection has also been described.

Splenectomy

Patients who have undergone splenectomy, such as those with Hodgkin’s disease, are at greater risk of developing infections than those with intact spleens. This is due to the fact that the spleen performs several important host defense functions, including antibody production and the removal of poorly opsonized or unopsonized pathogens.21 The infections commonly seen in such patients are due to S. pneumoniae, H. influenzae, Neisseria meningitidis, Babesia spp., and Capnocytophaga spp. These infections can be extremely severe. The syndrome of overwhelming pneumococcal sepsis, for example, is much more common in splenectomized individuals and can be rapidly fatal. These individuals need to be immunized by administration of the pneumococcal vaccine (preferably prior to splenectomy) and should also have personal access to antibiotics that are active against pneumococci. The emergence of penicillin-resistant pneumococci has had a significant impact on this aspect of the management of splenectomized patients.

Chemotherapeutic Agents

Chemotherapeutic agents predispose to the development of infections in a variety of ways. Many agents produce severe mucositis, particularly of the gastrointestinal tract, facilitating entry of microorganisms into tissues and the bloodstream.22 Agents that are myelosuppressive produce neutropenia, which is a well-recognized risk factor for infection. Chemotherapeutic agents are also known to interfere with cell-mediated and humoral immunity even when administered in doses that do not generally produce significant myelosuppression. Recently, it has been demonstrated that patients receiving interleukin-2 (IL-2) develop grampositive infections more frequently, and patients with chronic lymphocytic leukemia being treated with fludarabine are especially prone to developing infections that are common in patients with defective cell-mediated immunity.23,24

Bacterial Infections

The spectrum of bacterial infections continues to change as newer antimicrobial agents become available and as therapeutic interventions for neoplastic diseases continue to evolve.

During the past 7 to 10 years, there has been a resurgence in gram-positive infections and a decrease in documented gram-negative infections.1,22,25,26 The incidence of gram-positive infections has increased from approximately 20% in the mid-1970s to 50% in the mid-1990s (Table 157.3). Although the exact reasons for this epidemiologic shift remain unclear, several factors may be partly responsible. The most important factor is the increased use of catheters (i.e., central venous, peripheral, arterial), resulting in a parallel increase in catheter-related infections. Also, the use of antimicrobial regimens directed predominantly against gram-negative pathogens may reduce the incidence of (or the recovery of) such organisms from culture specimens. Prophylactic regimens using agents such as the fluoroquinolones have been effective in reducing the incidence of gramnegative infections but have not had a significant effect on, or occasionally have led to an increase in, gram-positive infections, particularly streptococcal infections.27

Table 157.3. Distribution of Bacterial Infection in 3,762 Febrile Episodes in Neutropenic Cancer Patients.

Table 157.3

Distribution of Bacterial Infection in 3,762 Febrile Episodes in Neutropenic Cancer Patients.

Approximately 15 to 25% of infections are polymicrobial in nature. They occur most often in patients with acute leukemia, although almost any underlying cancer may be present. The majority of these infections have substantial tissue involvement and include pneumonias, neutropenic enterocolitis, and perirectal infections. Catheter-related infections are also polymicrobial in 5 to 15% of patients. In a recent review of polymicrobial septicemias, 80% of episodes included at least one gram-negative bacillus, and 33% of these included only gram-negative bacilli.28 Infections involving only gram-positive, anaerobic, or fungal organisms occurred infrequently. Eighty-six percent of septicemias involving fungal organisms developed during hospitalization, whereas polymicrobial septicemia involving other organisms occurred with similar frequency in patients with hospital- or community-acquired infection. Infections involving gram-negative and fungal organisms were far more frequent in patients with hematologic neoplasms than those with solid tumors. Polymicrobial infections are associated with higher mortality (sometimes in excess of 50%) than infections caused by single organisms.

Enterobacteriaceae

The gastrointestinal tract serves as an important source of infection in neutropenic patients, and organisms that are normal inhabitants of the gastrointestinal tract are isolated frequently from blood and other clinical specimens in febrile neutropenic patients. Although the overall frequency of documented gram-negative infections has declined over the past decade, the proportion of gram-negative infections caused by Enterobacteriaceae has remained remarkably constant.29 Data from several large surveillance studies conducted at major cancer centers both in the United States and Europe indicate that Enterobacteriaceae cause approximately 65 to 80% of documented gram-negative infections in these patients, with Escherichia coli and Klebsiella spp. consistently being among the three most common species to be isolated. Thus, antimicrobial regimens used for prophylaxis and for empiric therapy in neutropenic patients have stressed the need for potent activity against Enterobacteriaceae (and other gram-negative bacilli). The bloodstream is the most frequent site of infection, followed by the urinary tract and the lung. Central venous catheters and other vascular access devices can get secondarily seeded during episodes of bacteremia and can serve as a continuing source of infection, unless the episodes are resolved. Fever is the only consistent manifestation of infection. Other manifestations depend on specific sites of infection (lung, urinary tract) and are often blunted in severely neutropenic/immunosuppressed patients. The majority of these infections respond to standard antimicrobial therapy. However, polymicrobial infections and those infections that are complicated by deep tissue involvement (pneumonia, enterocolitis, perirectal infections) are associated with greater morbidity and mortality.28 The emergence of resistance to beta-lactam antimicrobial agents as a result of the production of type 1 and extended-spectrum beta-lactamases (ESBL) is of great concern. The widespread use of fluoroquinolone prophylaxis has also resulted in the development of resistance among E. coli and other Enterobacteriaceae.30 Routine prophylaxis with the fluoroquinolones in afebrile neutropenic patients is, therefore, not recommended and should be considered only in patients whose risk of developing gram-negative infections is high.31

Pseudomonas aeruginosa

P. aeruginosa has been a leading cause of infection in the immunocompromised host and is associated with significant morbidity and mortality. The majority of Pseudomonas infections occur in patients with severe neutropenia. Pneumonia and bacteremia occur most often, although various clinical sites including the skin, gastrointestinal tract, and urinary tract are also frequently infected. During the early 1960s, P. aeruginosa was responsible for 35% of fatal infections in patients with acute leukemia. Since the introduction of carbenicillin and gentamicin, less than 10% of fatal infections are caused by this organism. In recent years, there has been a decline in the overall incidence of gram-negative infections in neutropenic patients.1 However, the proportion of gram-negative infections caused by P. aeruginosa has not declined and remains at approximately 15 to 20%.29 Pseudomonas is now being recognized with increasing frequency in patients with AIDS.32

The lung is the most frequent site of Pseudomonas infection. Animal experiments have demonstrated that Pseudomonas is cleared less readily from the lung by host defense mechanisms than other gram-negative bacilli. The typical radiographic pattern is that of a diffuse and often bilateral bronchopneumonia. The signs and symptoms include confusion, apprehension, chills, fever, toxic appearance, cough, and dyspnea. Small areas of radiolucency caused by microabscesses may be seen. Pathologically, the lesions consist of firm, well-defined hemorrhagic nodules with necrotic centers, frequently located subpleurally. Microscopically, they are characterized by central coagulative necrosis, surrounded by hemorrhagic necrosis and edema, associated with vasculitis of small arteries and veins. The walls of the vessels and especially the media and adventitia are invaded with myriads of organisms.

Several reviews of Pseudomonas bacteremia in cancer patients have been published.33,34 The largest reviewed 410 episodes that occurred over a 10-year period.33 The overall rate of Pseudomonas bacteremia was 4.7 cases per 1,000 admissions. Neutropenia was the most important predisposing factor, with 69% having an initial neutrophil count of < 1,000/mm3 and 40% being severely neutropenic with counts < 100/mm3. Fever was the most common sign of infection and was present in approximately 95% of patients. A substantial number (33%) of patients developed shock as a manifestation of their infection. Other important sites of infection in patients with bacteremia included the respiratory and urinary tracts, the oropharynx, the skin and soft-tissues, including the perianal region and catheterentry sites.

Localized Pseudomonas infection may occur in any organ. Skin lesions are present in approximately 20% of cases of bacteremia. Ecthyma gangrenosum, the characteristic skin lesion, may be located anywhere but is found most commonly in the axilla, groin, and perianal region. Single or multiple lesions at various stages might be present with extensive tissue damage (Fig. 157.2). Ecthyma gangrenosum may occur in the absence of detectable bacteremia. P. aeruginosa can be cultured from these lesions, and histologically, the lesions represent a bacterial vasculitis without thrombosis, with dense bacillary infiltration of the media and adventitia of blood vessels.

Figure 157.2. Multiple skin lesions (ecthyma gangrenosum) in a patient with Pseudomonas aeruginosa bacteremia.

Figure 157.2

Multiple skin lesions (ecthyma gangrenosum) in a patient with Pseudomonas aeruginosa bacteremia.

P. aeruginosa is widespread in the hospital environment, since it thrives in moist areas, such as faucets, sink drains, shower stalls, hydrotherapy tanks and water pitchers, and in respiratory equipment, such as respirators and nebulizers. It can also persist in soaps, shampoos, germicidal solutions, and ophthalmic solutions. Epidemics of P. aeruginosa infection have been observed in cancer patients. About 25% of patients with acute leukemia are stool carriers of P. aeruginosa on admission to hospital. This figure rises to 50% at the end of the first month of hospitalization in patients who are not receiving antimicrobial prophylaxis. The widespread use of antimicrobial prophylaxis probably reduces Pseudomonas carriage substantially. The frequency of Pseudomonas infection is twice as high in carriers as in noncarriers. The greater the length of Pseudomonas carriage, the greater the chances of acquiring infection.

In recent years, major advances have been made in the therapy of P. aeruginosa infections. Many potent antipseudomonal agents are now available, including antipseudomonal penicillins, extendedspectrum cephalosporins, aminoglycosides, new beta-lactam agents, such as monobactams and carbapenems, and the newer quinolones. The appropriate use of these agents has resulted in response rates in the range of 70 to 75%, even in neutropenic patients with Pseudomonas infections. White blood cell transfusions may be of some benefit and are being evaluated.35

Stenotrophomonas

Stenotrophomonas maltophilia are gram-negative bacilli that have emerged during the past decade as important nosocomial pathogens, particularly in patients with impaired host defense mechanisms.36 As in the case of P. aeruginosa, moist hospital environments, such as sink drains and water faucets, are potential sources of infection. Broad-spectrum antimicrobial therapy, which favors the selection and overgrowth of relatively resistant microorganisms, such as S. maltophilia, and the presence of central venous catheters have been found to significantly increase the likelihood of infection.37 Also, patients previously colonized with S. maltophilia are at greater risk of developing infection than those not colonized. These organisms cause a wide spectrum of disease. Bacteremia (often related to central venous catheters) and pneumonia are the most common manifestations of infection. Urinary tract infection, skin and soft tissue infection (including surgical wound infection), endocarditis, mastoiditis, and meningitis have also been reported. Clinical manifestations of S. maltophilia infection are indistinguishable from those caused by other gram-negative rod infections. It is also often difficult to distinguish colonization from infection. Substantial mortality occurs in neutropenic patients, especially if the infection goes unrecognized or a delay in appropriate antimicrobial therapy occurs. Monotherapy using broad-spectrum agents, such as the carbapenems (imipenem, meropenem), to which S. maltophilia isolates are generally resistant, is a common form of therapy in neutropenic patients. Empiric coverage against S. maltophilia should be considered in patients who fail to respond to such regimens. The majority of strains are susceptible to trimethoprim/sulfamethoxazole (TMP-SMX), although increasing resistance to this agent is being reported. Alternative agents include ticarcillin/clavulanate, minocycline, rifampin, the newer fluoroquinolones, and extended-spectrum cephalosporins. Most of these agents are less active than TMP-SMX, and susceptibility testing in each individual patient is recommended. Combination antibiotic therapy may be beneficial in patients from whom a relatively resistant strain has been isolated or who fail to respond to initial therapy with a single agent.38

Acinetobacter Species

Acinetobacter species are acknowledged to be opportunistic pathogens and usually cause disease in debilitated patients and those with severe underlying conditions, including cancer. These organisms are widely distributed in nature and have the ability to colonize normal or devitalized tissue. They are often found in areas of moist skin, including the axilla, groin, and interdigital pockets. Although infections caused by Acinetobacter species are relatively infrequent, infections of nearly all body sites (lungs, meninges, skin, heart valves, biliary tract, urinary tract, bones and joints, peritoneum, skin and soft tissue, and blood) have been reported. It may occasionally be difficult to distinguish infection from colonization. In the past, the anitratus subspecies were reported to be more commonly associated with infection, whereas the lwoffi subspecies were reported more often from sites of colonization or as contaminants.39 Recent data indicate that this trend has been maintained, and using current nomenclature, A. baumannii remain the predominant species isolated from clinical specimens.40

Outbreaks of infection caused by Acinetobacter species have been traced to intravascular access devices, contaminated respiratory therapy equipment, and contaminated bedding materials. Nosocomial transmission via the hands of hospital personnel has been documented. In cancer patients, up to 80% of bacteremic infections caused by Acinetobacter species are related to indwelling central venous catheters.39–41 The most common clinical finding is the presence of fever. The clinical course may range from benign transient bacteremia to fulminant septic shock (< 5%), which is seen more often in severely neutropenic patients. Polymicrobial infections from which Acinetobacter species are isolated appear to be increasing.40 Appropriate therapy includes the administration of antimicrobial agents to which the organisms are susceptible, and removal of the offending catheter in catheter-related infections. Multi-drug resistance is common among these organisms and may complicate the treatment of serious infections. Recently, there have been disturbing reports of increased resistance among Acinetobacter spp. to many antimicrobial agents, including aztreonam, ceftazidime, imipenem, and the fluoroquinolones. Infection control measures that limit the nosocomial spread of these pathogens are, therefore, exceedingly important.40–43

Salmonella Species

  There has been a substantial increase in the incidence of nontyphoidal Salmonella infections in the recent years. This is at least partly due to the increased incidence of these infections in patients with AIDS (with or without lymphoma or Kaposi’s sarcoma). Fifteen to 25% of serious Salmonella infections occur in patients with cancer. Patients with lymphoma, leukemia, or carcinoma of the gastrointestinal and genitourinary tract are most susceptible. Salmonella typhimurium and Salmonella enteritidis are the most frequently isolated species. Although typical gastroenteritis, which is usually self-limited, may occur in cancer patients, about one-half of the infections involve other organ systems. Pneumonia, urinary tract infection, peritonitis, osteomyelitis, meningitis, and wound infection have been observed. Bacteremia and disseminated infections occur more frequently in cancer patients than other patients with salmonellosis. Patients with AIDS have recurrent bouts of Salmonella bacteremia, despite appropriate antibiotic therapy for the initial episode. A small percentage of patients continue to harbor Salmonella in stools or urine for periods > 1 year following an acute infection and are considered chronic carriers. Uncomplicated, nontyphoidal, Salmonella gastroenteritis generally requires no antibiotic therapy, but severely immunocompromised patients who are at risk of developing bacteremia or disseminated infection might benefit from antibiotic therapy. Ampicillin, chloramphenicol, and TMP-SMX were considered standard agents for the treatment of Salmonella infections. These agents are now suboptimal due to the emergence of widespread resistance to them and also due to the incidence of untoward reactions associated with some of them. Currently, the most reliable agents are the fluoroquinolones, the extended-spectrum cephalosporins, and the carbapenems.44 Resistance to even these agents is being reported, and it may be prudent to administer more than one class of agent to seriously ill patients with salmonellosis until susceptibility determinations can be performed. Patients with AIDS who have high relapse rates often require several weeks or even months of oral suppressive therapy with an agent such as ciprofloxacin following parenteral therapy for the initial infection in an attempt to avoid repeated episodes of bacteremia.

Streptococcus Species

Many streptococcal species are important pathogens in cancer patients. Streptococcus pneumoniae causes infection primarily in patients who have undergone splenectomy, those with multiple myeloma, those with acute or chronic lymphocytic leukemia, and allogeneic bone marrow transplant (BMT) recipients. The syndrome of overwhelming pneumococcal sepsis occurs in patients with splenectomy and often follows a fulminant course resulting in death. Disseminated intravascular coagulation may occur, and S. pneumoniae are often demonstrated in peripheral blood smears.45 Defects in antibody formation and clearing of the organisms from the bloodstream are probably responsible for this clinical syndrome.21 Prompt and effective antimicrobial therapy is critical. Penicillin G remains the drug of choice for the treatment of pneumococcal infections caused by susceptible strains. However, penicillin-resistant pneumonococci are being reported with increasing frequency and need to be treated with alternative agents.46,47 Most penicillin-resistant strains are susceptible to the extended-spectrum cephalosporins (ceftriaxone, ceftazidime, cefepime) although pneumococcal strains resistant to these and other beta-lactam agents have been recognized. The carbapenems (imipenem, meropenem) have also been reported to be active against penicillin-resistant strains. These strains are uniformly susceptible to vancomycin, which is often included in empiric regimens until the results of susceptibility testing become available. Newer generation, expanded-spectrum quinolones (sparfloxacin, trovafloxacin, gatifloxacin, moxifloxacin, clinafloxacin), some of which are still under evaluation, have potent activity against penicillin-resistant pneumococci, and are being used with increasing frequency to treat these infections. Clinical experience with most of these agents for the treatment of serious infections caused by penicillin-resistant pneumococci in cancer patients, is limited.

Prior to the emergence of penicillin-resistance, it was recommended that high-risk patients be given a personal supply of antibiotics with antipneumococcal activity (e.g., amoxicillin/clavulanic acid, Agumentin [reg], which is also active against H. influenzae) so that they may initiate antibiotic therapy at the first sign of infection, even prior to seeking medical attention. With current rates of penicillin-resistance running as high as 60% in some communities, the usefulness of this strategy has been severely limited. The newer generation quinolones are the only oral agents with reliable activity against these organisms. Their use in this setting instead of amoxicillin/calvulanate might be prudent, and occasionally life saving, but has not been fully evaluated.

The rationale for immunizing high-risk individuals with pneumococcal vaccination is provided by the increased incidence and severity of pneumococcal infection in such patients and the occurrence of drug-resistant pneumococcal isolates. Immunization with the currently licensed polyvalent vaccine is recommended for high-risk individuals with a variety of chronic systemic illnesses and for persons 64 years or older. The highest levels of antibodies are developed by healthy young adults, and the existence of immunosuppressive disorders results in suboptimal antibody production. Vaccination should be given prior to splenectomy, if possible. Vaccination after splenectomy and in patients with continued immunosuppression results in low level antibody production but is still considered beneficial. A new conjugate pneumococcal vaccine is due to become available early in the year 2000 and is likely to be an improvement on the currently available vaccine.

Alpha-hemolytic (viridans) streptococci have recently emerged as important pathogens in cancer patients, particularly in patients with acute leukemia undergoing intensive chemotherapy and in bone marrow transplant recipients.48 Alpha-hemolytic streptococci colonize the oral cavity, and the most consistent predisposing factor for the development of infection appears to be high-dose chemotherapy with drugs, such as cytosine arabinoside, that induce severe mucosal damage, thereby facilitating entry of these organisms into the bloodstream. Other probable predisposing factors include antimicrobial prophylaxis, particularly with fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) that might encourage the selection and overgrowth of these organisms, and the treatment of chemotherapy-induced gastritis with antacids or histamine type 2 (H2) antagonists.49 Streptococcus mitis, Streptococcus sanguis, and Streptococcus salivarius are the predominant species. Bacteremia is the most common manifestation of viridans streptococcal infections. In some patients, a rapidly progressive disseminated infection occurs involving the bloodstream, lungs, central nervous system, and skin (Fig. 157.3). Septic shock is often present, and the clinical picture resembles that of staphylococcal “toxic shock syndrome.” This syndrome (which is also caused by Streptococcus pyogenes) has been termed the “toxic-strep syndrome” or the streptococcal toxic shock syndrome. Overwhelming infection produces substantial morbidity, and mortality in the range of 25 to 35% occurs despite prompt and aggressive antibiotic therapy.

Figure 157.3. Invasive infection caused by alpha-hemolytic (viridans) streptococci.

Figure 157.3

Invasive infection caused by alpha-hemolytic (viridans) streptococci. Note the hemorrhagic nature of the lesions in this patient with thrombocytopenia.

Of increasing concern are reports that 20 to 60% of alpha-hemolytic streptococci are now penicillin resistant at some institutions. This has limited the utility of penicillin G and other penicillins for the prevention and treatment of such infections. All isolates are currently susceptible to the glycopeptides vancomycin and teicoplanin, although tolerance to these agents has been described, and the use of antibiotic combinations (vancomycin + rifampin ± gentamicin) is sometimes necessary.48 Clearly, viridans streptococci have become formidable pathogens in neutropenic patients with hematologic malignancies, and newer strategies for infection prevention and therapy are needed.

Beta-hemolytic streptococci belonging to Lancefield groups A, B, C, F, and G also cause infections in cancer patients but less often than S. pneumoniae and viridans streptococci. Bacteremia is the most common manifestation of these infections, although infections involving any organ site can occur. Like viridans streptococci, S. pyogenes has been associated with a rapidly progressive, toxic-shock-like syndrome. The management of these infections is similar to that of other streptococcal infections previously discussed. Penicillin G remains the drug of choice for susceptible isolates. Increasing resistance to the penicillins is being described.

Staphylococcus Species

During the past 15 years, a marked increase in the incidence of infections caused by gram-positive organisms has been reported from most major cancer treatment centers. The majority of these are caused by Staphylococcus species. During this time, there has been a slight decline in infections caused by S. aureus but a considerable increase in the incidence of infections caused by coagulase-negative staphylococci.1,22,26 The predominant species is S. epidermidis, although S. hominis and S. haemolyticus are also often isolated. Increased use of vascular access devices and other conditions that usurp mechanical barriers to infection (surgery, trauma) are predominantly responsible for the increase in the recovery of these organisms, since they commonly inhabit normal skin. The gastrointestinal tract, however, also serves as an important source for coagulasenegative staphylococci in febrile neutropenic patients. Bacteremia, including those associated with central venous catheters, is the most common manifestation of staphylococcal infection. Skin and soft tissue infections, including surgical wound infections, are also common. Although frequently regarded as contaminants or organisms associated with low virulence, coagulase-negative staphylococci have been associated with considerable morbidity in neutropenic patients. Serious complications, including septic thrombophlebitis and lung and splenic abscesses, can occur and can occasionally be fatal. It is, therefore, prudent to regard as significant the recovery of these organisms from properly obtained blood cultures.

The therapy of staphylococcal infections depends on the antimicrobial susceptibility of the organisms isolated. The majority of S. aureus isolates in the United States are still methicillin susceptible. Infections caused by such isolates should be treated by a parenterally administered, penicillinase-resistant, semisynthetic penicillin (nafcillin, oxacillin). In patients with penicillin allergy, or when dealing with methicillin-resistant isolates, vancomycin appears to be the agent of choice. Catheter removal appears warranted in most patients with a catheter-related S. aureus bacteremia. In contrast to S. aureus, most coagulase-negative staphylococcal isolates are resistant to methicillin. Vancomycin is the most logical choice for therapy. Infected catheters should be removed, whenever feasible, although antibiotic therapy without catheter removal has also been shown to be successful. Recurrent infection will occur in 20 to 30% of patients in whom infected catheters are not removed.50

Enterococcus Species

Enterococcal infections were distinctly uncommon until the mid- to late 1970s. Since then the frequency of enterococcal infections has risen steadily, and they are currently the second most common gram-positive organisms (after coagulasenegative staphylococci) isolated from neutropenic patients. This increased frequency has been seen in parallel with and is probably related to the increased use of extended-spectrum cephalosporins (cefoperazone, ceftazidime), to which these organisms are intrinsically resistant.51,52 The most common infections caused by enterococci are those of the bloodstream, urinary tract, wounds, and intra-abdominal infections, although occasionally endocarditis, meningitis, pneumonia, and other infections may be seen. Enterococcus faecalis is the predominant enterococcal species accounting for 75 to 80% of clinical enterococcal isolates. Most isolates of E. faecalis are susceptible to clinically achievable concentrations of penicillin, ampicillin, and vancomycin although these agents may lack bactericidal activity. Consequently, synergistic combinations of these agents with aminoglycosides, such as gentamicin, are recommended for serious enterococcal infections.

Although E. faecalis remains the predominant enterococcal species, infections caused by E. faecium are rising, particularly in neutropenic and other immunosuppressed patients.53 These isolates often express high-level resistance to the aminoglycosides, thereby eliminating the synergistic interaction with the penicillins, high-level resistance to ampicillin, and (with increasing frequency) resistance to vancomycin. The most problematic infections occur when all these resistance patterns are seen within the same strains. Vancomycin resistance was first described in 1988 and may now be seen in up to 17 to 25% of enterococcal isolates from high-risk populations.54 Risk factors for infection with vancomycin-resistant enterococci (VRE) include gastrointestinal colonization with these strains, and the use of antimicrobial agents with significant activity against anaerobes (metronidazole, clindamycin, imipenem).53 The administration of vancomycin (both oral and parenteral) is also a frequently cited risk factor for subsequent colonization with VRE.3 Infections caused by VRE are much more common in patients with severe neutropenia (acute leukemia; bone marrow transplantation prior to engraftment) and are seldom seen in patients with solid tumors receiving conventional chemotherapy, in whom neutropenia is generally short lived. VRE are associated more often with recurrent infections, higher rates of refractory infections, and higher rates of serious morbidity and mortality, all of which are partly mediated by the lack of effective therapy.55

For strains of VRE that are moderately susceptible to ampicillin (MIC ≤ 32 μg/mL), the administration of high doses of ampicillin (20–24 g/day) in combination with gentamicin might be worthwhile. When faced with an infection caused by a strain with high-level resistance to the aminoglycosides and amipicillin, there are very few established therapeutic options. Individual susceptibility testing is recommended under these circumstances and should include agents like the fluoroquinolones, rifampin, minocycline, tetracycline, chloramphenicol, TMP-SMX, and the macrolides. Anecdotal reports have suggested the clinical utility of various combinations (ciprofloxacin + gentamicin + rifampin; imipenem + ampicillin) but there is very little collective clinical experience with such regimens.56 Newer agents that are currently under investigation for the treatment of VRE include a new pristinamycin combination (Synercid), newer glycopeptides (daptomycin , LY 333328), oxazolidinones (linezolid), and everninomycins. Many of these agents appear to be promising and are eagerly awaited.57

Attempts at eradicating gastrointestinal colonization with VRE have been singularly unsuccessful. Thus, infection control measures to reduce the transmission of VRE are of over-riding importance. These measures are more aggressive than standard infection control practices (Table 157.4) and strict compliance by hospital personnel is a prerequisite for their success.56,58,59

Table 157.4. Infection Control Measures Designed to Limit Nosocomial Spread of Vancomycin-Resistant Enterococci in High-Risk Areas (Oncology Units).

Table 157.4

Infection Control Measures Designed to Limit Nosocomial Spread of Vancomycin-Resistant Enterococci in High-Risk Areas (Oncology Units).

Listeria monocytogenes

L. monocytogenes is a gram-positive bacillus that causes meningitis, encephalitis, septicemia, and endocarditis in humans. Outbreaks of listerial infection have been reported following consumption of contaminated food products, such as milk, cheese, and cole slaw. While the majority of Listeria infections arise in previously healthy individuals, they are frequently seen in immunocompromised patients, including those with lymphoma.60 Most lymphoma patients are receiving adrenal corticosteroids or antitumor agents when they become infected. The administration of fludarabine and prednisone is associated with an increased incidence of listeriosis in patients with chronic lymphocytic leukemia and may be the result of a depletion in CD4 cells.23 Whereas type IVb L. monocytogenes causes the majority of infections in the general adult population of the United States, type I causes most of the infections in cancer patients and neonates. Meningitis accounts for over 60% of cases in cancer patients and septicemia without meningitis for about 30%. Rarely, infection in other sites, such as pleural effusion or septic arthritis, are found. Meningismus is present in only one-half of the cancer patients with meningitis, and occasionally the cerebrospinal fluid is normal. When pleocytosis is present, either neutrophils or mononuclear cells predominate. The organisms may be initially difficult to culture from the cerebrospinal fluid and may be occasionally misidentified as either hemolytic streptococci or diphtheroids. While these organisms are susceptible in vitro to various antibiotics, ampicillin or penicillin remains the drug of choice for therapy. These agents are frequently used in combination with an aminoglycoside, since experimental laboratory results have demonstrated synergism between penicillins and aminoglycosides against L. monocytogenes. If an aminoglycoside is administered for central nervous system infection, both systemic and intrathecal routes can be used. Although these organisms are susceptible, in vitro, to the extended-spectrum cephalosporins, these agents are not effective for the therapy of L. monocytogenes meningitis. TMP-SMX is bactericidal against the majority of these isolates and has been used successfully in penicillin-allergic patients with listeriosis, including those with Listeria meningitis.

Mycobacterial Species

  Protection against mycobacterial infection is mediated by cellular immunity. Mycobacterial infections, therefore, occur more frequently in patients with impairment of the cellular component of the host defense mechanisms. Tuberculosis has been considered a common complication of advanced Hodgkin’s disease, and in the past, as many as 20% of these patients developed tuberculosis. In recent years, however, this infection has been found in only 1 to 2% of patients. The diagnosis of tuberculosis is often difficult to establish with certainty because the usual manifestations of fever, weight loss, pulmonary infiltrates, and hepatosplenomegaly may be due to Hodgkin’s disease. Furthermore, these patients are often anergic to the tuberculin skin test. Tuberculosis is no more frequent in patients with leukemia than in the general population. However, when infection arises in these patients, it is likely to disseminate widely and rapidly. Substantial changes in the blood and bone marrow including lymphocytosis, monocytosis, eosinophilia, thrombocytopenia, and pancytopenia, may accompany tuberculous infection.

In recent years, the spectrum of neoplastic diseases associated with tuberculosis has changed. Infection is frequent in patients with carcinoma of the head, neck, and lung and in patients with lymphoma. Patients with lymphoma are more likely to develop acute tuberculous pneumonia or disseminated infection that is associated with a high mortality rate.

Until 1984, there was a yearly decline in the incidence of tuberculosis in the United States. This decline was halted and reversed by 1985. By 1991, 39,000 cases of tuberculosis in excess of the number predicted had occurred. This increased incidence of tuberculosis has been partly ascribed to the ongoing worldwide epidemic of AIDS.61 Approximately half the excess cases have resulted from co-infection with HIV and Mycobacterium tuberculosis, primarily in African American and Hispanic American individuals between the ages of 20 and 45 years. It was initially thought that the majority of these cases represented recrudescence of previously latent infection. Subsequent studies have established that HIV-infected individuals are not only predisposed to reactivation of latent infection but often acquire new infection from the environment and transmit tuberculosis to HIV-negative individuals as well. At particular risk are health-care workers who have been exposed to HIV-infected individuals with tuberculosis. More recent data indicate that the tide is beginning to turn, and that there is a reduction in the case rate of tuberculosis in large urban areas such as New York and San Francisco.62–64

Extrapulmonary and disseminated tuberculosis occurs frequently in HIV-infected individuals as a result of decreased immunologic competence. Common sites of involvement include the peripheral, hilar, or mediastinal lymph nodes and the bone marrow. Other sites from which the organisms can be cultured include urine, blood, cerebrospinal fluid, brain, liver, spleen, joints, skin, abdominal wall, psoas abscesses, and the gastrointestinal mucosa.

The most alarming feature of tuberculosis in HIV-infected individuals has been the appearance and spread of multi-drug–resistant (MDR) isolates.65 These organisms (resistant to both isoniazid and rifampin and occasionally to streptomycin and ethambutol) have caused several outbreaks of tuberculosis in hospitals and prisons in New York and Florida.61 More than 90% of these infections occur in HIV-infected individuals, and the case fatality rate is 80%. Factors contributing to the emergence of MDR tuberculosis include poor compliance with standard therapeutic regimens, delayed diagnosis, delayed recognition of drug resistance and ineffective therapy for prolonged periods, and failure to observe recommended isolation procedures.

Anergy is frequent in patients with cellular immune defects, and positive tuberculin skin tests may be seen in only 10 to 30% of patients. The acid-fast stain is the only widely available test for a rapid presumptive diagnosis of tuberculosis. Traditional culture techniques, followed by biochemical testing, take up to 4 to 8 weeks to identify M. tuberculosis. This process is shortened considerably (1–3 weeks) by the use of radiometric culture methods followed by a DNA-probe for an M. tuberculosis-specific ribosomal RNA sequence. The DNA probe can be used in mycobacterial cultures but is not sensitive enough to detect organisms in clinical samples. Newer methods based on polymerase chain reaction (PCR) offer great promise and have the potential of providing a specific diagnosis within 24 hours.

Standard therapy for drug-susceptible tuberculosis includes the administration of isoniazid, rifampin, and pyrazinamide daily for 2 months, followed by isoniazid and rifampin for 4 months, either daily or biweekly.66 Cure rates of greater than 95% are achieved by this regimen. Treatment with isoniazid, rifampin, ethambutol, and pyrazinamide three times a week for a period of 6 months is also effective.67 Because of the increasing frequency of drug resistance, the initial use of four-drug regimens is preferable until susceptibility determinations can be made. Cure rates of 90% can be achieved by using regimens containing isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin for 6 to 12 months in patients with an isoniazid-resistant isolate. Up to 18 months of therapy may be required in HIV-infected individuals. Resistance to both isoniazid and rifampin markedly reduces the efficacy of therapeutic regimens, and failure rates of 40 to 70% have been reported. Quinolones, such as ofloxacin and ciprofloxacin, have been found to be useful in MDR tuberculosis. Individualized drug regimens, based on results of susceptibility testing. should be employed, generally using at least three drugs to which the isolate is susceptible.66,68 Directly observed therapy (DOT) is recommended for all drug-resistant tuberculosis and for patients who are known to be noncompliant or unreliable.

Some cancer patients are prone to developing infection with mycobacteria other than M. tuberculosis. Patients with hairy-cell leukemia are particularly prone to developing disseminated infection caused by Mycobacterium avium-intracellulare complex (MAC).69,70 Recent data indicate that MAC infections are not uncommon in patients with solid tumor as well.71 Unlike MAC infection in patients with AIDS, cancer patients present predominantly with pulmonary involvement. Bacteremia and disseminated disease are uncommon. In the past, disseminated MAC infections have been difficult to treat because the organisms are resistant to standard antitubercular agents. Multiple drug regimens (4–6 agents) have been used with little therapeutic benefit, and substantial toxicity. However, regimens developed in the last 3 to 4 years appear to be much more effective and much less toxic, producing response rates in the 60 to 80% range. Commonly used agents include ethambutol, rifabutin, clarithromycin, azithromycin, and streptomycin.72,73 Refractory cases may respond to therapy with inferferon-gamma (INF-γ) in combination with drug therapy.74

Mycobacterium kansasii also causes infection both in patients with hematologic malignancies and in patients with solid tumors.75 Most patients have pulmonary disease which is indistinguishable from that caused by M. tuberculosis. The organisms are generally susceptible to standard antituberculous agents, and most patients respond to therapy.

The pathogenic, rapidly growing mycobacteria (M. chelonei and M. fortuitum) are environmental organisms, commonly found in water and soil. The two most common infections caused by these organisms in cancer patients include catheter-related bacteremia and pulmonary infection.76,77 In the former, antibiotic therapy in addition to catheter removal is generally effective. In pulmonary or disseminated infection, prolonged therapy with combination regimens is necessary.78,79 The organisms have variable susceptibility to agents such as the quinolones, the tetracyclines, the macrolides, amikacin, cephalosporins, and TMP-SMX.

Disease caused by mycobacteria can mimic cancer or present a diagnostic dilemma in patients with cancer who have been effectively treated and subsequently present with a pulmonary lesion. The assumption that this lesion is a metastatic or recurrent neoplasm should not be made, and patients should be carefully evaluated for tuberculosis or fungal infection before cancer chemotherapy is instituted. Elderly patients with evidence of old tuberculosis infection should also receive isoniazid (INH) prophylaxis when cancer chemotherapy is initiated to prevent reactivation of latent tuberculosis.

Legionella pneumophila

Since its initial description in 1976, Legionella pneumophila has been recognized as an important cause of community acquired and nosocomial pneumonia in healthy and immunosuppressed persons, including bone marrow transplant recipients.80 In addition to severe pneumonia, pleural effusion, empyema, and lung abscess formation, are recognized complications of L. pneumophila infection and occur more often in the immunosuppressed host.81 Case fatality rates for treated legionnaires’ disease depend on factors such as the immune status of the patient (higher case fatality in immunosuppressed patients), and whether the disease was acquired in the community, or in the hospital (nosocomial disease associated with greater fatality rates). Mortality rates as high as 80% have been documented in solid organ transplant recipients and others who are immunosuppressed. Renal failure, another well-recognized complication of L. pneumophila infection, is also associated with increased mortality.

A specific diagnosis of L. pneumophila infection might be difficult to establish. The organisms are fastidious and require special Legionella-selective culture media to promote growth (buffered charcoal yeast extract [BCYE] agar). Other diagnostic methods include serologic testing, direct fluorescent antibody (DFA) staining, DNA probes, and the detection of urinary antigen.

Erythromycin was considered the treatment of choice for legionellosis. In patients failing to respond to erythromycin, combinations with rifampin or TMP-SMX appeared to be useful. Recent evidence from in vitro and animal-model studies and preliminary clinical experience indicate that the time has come to change the standard chemotherapy for legionellosis. Azithromycin is more active than erythromycin and clarithromycin against both intracellular and extracellular L. pneumophila and should be used as a front-line agent for legionellosis.82 The newer fluoroquinolones are also very active against L. pneumophila and some experts consider these agents (ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin, trovafloxacin) to be the drugs of choice for the treatment of this infection.82 Adding rifampin to azithromycin or a quinolone probably provides little further benefit. The quinolones are the agents of choice for the treatment of legionellosis in patients receiving immunosuppressive therapy with cyclosporin or tacrolimus, since, unlike the macrolides and rifampin, the quinolones do not alter the metabolism of cyclosporin or tacrolimus.

Fungal Infections

Fungal infections began to emerge as a significant problem among cancer patients once effective antibacterial agents became available and immunocompromised patients were surviving for prolonged periods. Initially, Candida spp. accounted for the vast majority of fungal infections, but in recent years, other organisms, especially Aspergillus spp., have been responsible for the continuing increased frequency. Most fungal infections occur in patients with hematologic neoplasms.83 At the present time, 40 to 50% of fatal infections are due to fungi. Fungal infections occur in about 10% of patients with lymphoma but remain an infrequent complication in patients with metastatic carcinoma. A disturbing observation in recent years is the increasing frequency of systemic fungal infections in patients undergoing initial remission induction chemotherapy for acute leukemia and lymphoma. In the past, these infections tended to occur predominantly in patients with far-advanced neoplasms who were no longer responding to chemotherapy.

Fungal infections occurring in cancer patients can be divided into two major categories: the pathogenic fungi (Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis) and the opportunistic fungi (Candida spp., Aspergillus spp., and other fungi). The former organisms cause infections in the general population but are more likely to cause disseminated infection in the cancer patient. Acute infection during cancer therapy often represents reactivation of latent infection. Patients with lymphoma are most susceptible to these infections. Opportunistic fungi usually cause only superficial infection in immunocompetent hosts but are the most common cause of systemic fungal infection in patients with impaired host defense mechanisms.

Fungemia is uncommon even in patients with disseminated infection. Most cases of fungemia are due to Candida spp. In the past, the majority of infections were due to Candida albicans, but in recent years Candia tropicalis, Candida glabrata, Candida parapsilosis, and other species have emerged as significant pathogens.84 Aspergillus spp. and Mucorales are rarely cultured from the blood even in patients with widely disseminated infection. Fungi that are cultured from blood specimens of patients with disseminated infection more often include C. neoformans, H. capsulatum, Fusarium spp. and Trichosporon beigelii. The extensive use of intravascular catheters has resulted in an increased frequency of fungemia, especially caused by Candida spp. Since 70 to 80% of these patients have evidence of deep-seated infection, all these patients should be given antifungal therapy. Since the duration of fungemia during therapy is prolonged if intravascular catheters are not removed, it is advisable to remove them, whenever possible. If the infection is caused by C. parapsilosis, therapy is rarely effective without removal of the catheter. 85 Local infections due to Aspergillus spp. and Rhizopus spp. may occur at catheter sites and progress to pulmonary or disseminated disease.

The setting in which fungal infection develops is complex, and multiple factors are responsible for the rapid increase in these infections. Frequently, this has been attributed to the widespread use of broad-spectrum antibiotics. Bacteria that inhibit the growth of Candida spp. are suppressed by antibiotic therapy permitting the overgrowth of Candida spp. Antibiotics probably do not directly predispose patients to fungal infections; they facilitate fungal overgrowth in the oropharynx and gastrointestinal tract. At high concentrations, Candida spp. have been shown to cross the intact gastrointestinal mucosa and enter the circulation by a process known as persorption.

Adrenal corticosteroids can interfere with macrophage function, and the macrophage is one of the primary defenses against fungal invasion. Prolonged and severe neutropenia also predisposes to fungal infection. Neutrophils ingest and kill Candida spp. in vitro and serve as a major defense against systemic infection. In an animal model of aspergillosis, it was demonstrated that the macrophage represents the primary defense mechanism against spores and that the neutrophil represents the primary defense mechanism against mycelia.86 The administration of adrenal corticosteroids interferes with macrophage function, allowing ingested spores to germinate. The administration of nitrogen mustard (and many other cancer chemotherapeutic compounds) causes neutropenia, which facilitates establishment of infection by activated mycelia.

Fungal infections often become established at sites of previous infection or necrosis. For example, over 70% of cases of pulmonary aspergillosis occur in association with a previous or concomitant bacterial pneumonia. Candida spp. often infect gastrointestinal ulcerations caused by antitumor agents, or herpes or bacterial infection. The availability of effective antitumor agents and supportive care measures has prolonged the survival of many patients with severely compromised host defense mechanisms, permitting the development of fungal infections in patients who previously would have died of bacterial infections.

Candida Species

Most superficial fungal infections of the oropharynx and gastrointestinal tract are caused by C. albicans. Oropharyngeal candidiasis occurs in about 25 to 30% of cancer patients undergoing chemotherapy and is even more frequent in patients with acute leukemia. This infection is especially prevalent in patients receiving antitumor agents or radiotherapy that causes mucosal damage, patients receiving adrenal corticosteroids, and patients already colonized with Candida spp. at the onset of chemotherapy. Some patients with solid tumors develop mild, asymptomatic infection following chemotherapy that is not recognized and resolves without therapy. Also, patients with oropharyngeal candidiasis may have associated esophageal candidiasis that is asymptomatic.87 The lesions appear as white or grayish white plaques surrounded by an erythematous halo (Fig. 157.4). The plaques are friable with a freely bleeding base. These lesions may be difficult to differentiate from the necrotic mucosa caused by antitumor agents, such as methotrexate. Candida plaques may occur in association with herpes simplex infection. Topical agents, such as nystatin, are often of minimum benefit, and not infrequently, the lesions progress. Orally absorbable antifungal agents, such as fluconazole and itraconazole solution, are generally effective. Occasional patients may require a short course of parenteral amphotericin B, which produces dramatic improvement in most cases after the initial dose.

Figure 157.4. Severe oropharyngeal candidiasis in a patient with AIDS.

Figure 157.4

Severe oropharyngeal candidiasis in a patient with AIDS.

Candida esophagitis is no longer a rare infection in patients with hematologic neoplasms. The most common symptom is dysphagia, often accompanied by severe retrosternal pain, nausea, and vomiting, and occasionally, gastrointestinal bleeding. Rarely, this infection can lead to perforation. The pain during swallowing may become so severe that the patient is unable to eat. It may be present with or without oral candidiasis. A characteristic cobblestone or moth-eaten appearance of the esophageal mucosa is present on barium-contrast radiographic studies (Fig. 157.5). However, these abnormalities may be caused by other organisms, such as herpes simplex and cytomegalovirus. Furthermore, in 25% of cases, the radiographic studies are negative. The diagnosis is established by esophagoscopy, which reveals characteristic ulcerations with pseudomembrane formation. This procedure permits biopsy for definitive diagnosis. Appropriate therapy consists of an orally absorbable antifungal agent, but some patients may have difficulty swallowing these medications. Parenteral amphotericin B is dramatically effective within 24 to 48 hours, and about 80% of patients respond after a 5-day course of therapy. Fluconazole is an equally effective and less toxic parenteral preparation.

Figure 157.5. The characteristic “moth-eaten” appearance of the esophageal mucosa demonstrated on barium-swallow examination in a patient with esophageal candidiasis.

Figure 157.5

The characteristic “moth-eaten” appearance of the esophageal mucosa demonstrated on barium-swallow examination in a patient with esophageal candidiasis.

Superficial Candida infections of other areas of the gastrointestinal tract have been identified in about 3% of cancer patients. They are found at autopsy examination in 10% of patients with lymphoma, 15% of patients with acute leukemia, and only 2% of patients with carcinoma. Candidiasis may involve any portion of the gastrointestinal tract, and multiple sites are often involved.88 Usually, infection below the esophagus is asymptomatic and only diagnosed at autopsy examination.

Systemic Candida infections may be localized to a single organ, but usually multiple organs are involved.89 Occasional cases of chronic laryngitis due to Candida spp. have been recognized. Pulmonary infection is usually a manifestation of disseminated disease, but occasional primary infections of the lung occur due to aspiration of contaminated oropharyngeal secretions. It is difficult to establish the diagnosis of primary Candida pneumonia because there are no characteristic findings.90 Isolation of Candida spp. from the sputum does not establish the diagnosis because it may represent contamination from the oropharynx. Infections localized to the meninges, kidneys, and bone have been reported infrequently. Urinary candidiasis has been recognized as a complication of prolonged catheterization. Candida peritonitis may occur following intestinal perforation or in association with peritoneal catheters.

Disseminated candidiasis is found at autopsy examination in 20 to 30% of patients with acute leukemia, 2% of patients with lymphoma, and less than 1% of patients with metastatic cancer. About 55% of episodes are caused by C. albicans, 30% by C. tropicalis, and the remainder by other Candida spp. and T. glabrata.91 At some institutions C. albicans accounts for less than 50% of infections and C. tropicalis is as common or more common. Two patterns of organ involvement have been described. In one, occurring predominantly in patients with acute leukemia, the most frequent organs infected include the gastrointestinal tract, liver, spleen, and lungs. This pattern of involvement suggests the gastrointestinal tract as the primary site of origin. The second pattern of distribution involves predominantly the heart, kidneys, and lung, which is the pattern of distribution in animals following direct intravenous injection.

There are no characteristic physical signs and symptoms of disseminated candidiasis. Some patients present with the acute onset of tachycardia, tachypnea, and hypotension suggestive of endotoxin shock. In others, the onset may be insidious. Often, the only indications of this infection are a gradual worsening of the patient’s clinical condition, associated with fever unresponsive to antibiotic therapy. Some patients have ocular infection causing blurred vision, pain, scotomas, or loss of visual acuity. Ocular lesions include white fluffy retinal exudates with vitreous haze or hemorrhage, hypopyon, iritis, or conjunctivitis. About 10% of patients have characteristic erythematous macronodular skin lesions. These skin lesions may be single or multiple, localized or diffuse, often resembling a drug rash. Candida organisms can be identified in the subcutaneous tissue of skin biopsies of these lesions and can be cultured from the tissue in 50% of the cases. In occasional patients, these skin lesions are associated with a myositis in which the patient has exquisitely tender muscles.

Central nervous system involvement occurs in up to 50% of patients with disseminated candidiasis. It may be manifested as cerebritis, cerebral abscesses, or meningitis. Often the only symptom is mental obtundation. A stiff neck may be detected in some patients with meningitis, but often this sign is absent. Examination of the cerebrospinal fluid usually reveals nonspecific abnormalities such as an elevated protein and occasional mononuclear cells. Candida organisms are seldom visualized or cultured from the cerebrospinal fluid.

A chronic form of Candida infection known as hepatosplenic candidiasis—or, more appropriately, chronic disseminated candidiasis—has been described during the past 30 years. This infection typically occurs in patients with acute leukemia undergoing chemotherapy while they are experiencing prolonged severe neutropenia. They develop fever that fails to respond to broad-spectrum antibacterial antibiotics. They also fail to respond to antifungal agents while they remain neutropenic. During this phase of the infection, they usually remain asymptomatic, except for fever. Subsequently, their underlying leukemia remits and their neutrophil count recovers. Despite this recovery, the patients remain febrile and debilitated with substantial weight loss. Symptoms, including right upper quadrant or shoulder pain, may now appear. Hepatosplenomegaly may be detected. Characteristically, the alkaline phosphatase concentration becomes highly elevated, and other liver function tests may also become abnormal. Ultrasonography, magnetic resonance imaging (MRI), or computed tomography (CT) of the liver and spleen reveals multiple lesions (Fig. 157.6). Other organs may also be infected. Only 50 to 60% of these patients respond to amphotericin B plus flucytosine, and often therapy must be continued for several months before benefit is achieved. Studies suggest that fluconazole may be especially useful in the treatment of this condition.92 Interestingly, this type of Candida infection has virtually disappeared from institutions where fluconazole is used prophylactically in marrow transplant recipients and patients with acute leukemia.

Figure 157.6. Multiple “punched-out” lesions in the liver, spleen, and kidneys in a patient with chronic disseminated candidiasis.

Figure 157.6

Multiple “punched-out” lesions in the liver, spleen, and kidneys in a patient with chronic disseminated candidiasis.

Because the frequency of infections caused by Candida spp. other than C. albicans has increased substantially in recent years, unique features of some of these infections have been recognized. At some institutions C. tropicalis has surpassed C. albicans as the most common cause of disseminated infection. It appears to be more virulent since only 3 to 15% of neutropenic patients colonized by C. albicans subsequently develop disseminated infection compared to 40 to 80% of those colonized by C. tropicalis. Skin lesions and myositis are associated more often with C. tropicalis infection. C. parapsilosis is less virulent than C. albicans, and infection is nearly always associated with intravascular catheters and parenteral nutrition. Only 10% of patients with intravascular catheters who develop C. parapsilosis fungemia respond to antifungal therapy without removal of the catheter.86

Colonization and infection due to C. krusei and C. glabrata has been associated with the use of fluconazole prophylaxis.93 Unlike most other Candida spp., C. krusei has been isolated from many foods and beverages, but infrequently from normal humans. It is inherently resistant to fluconazole and may be more easily acquired from nosocomial and environmental sources in patients receiving fluconazole prophylaxis. C. glabrata is a common contaminant of the skin and urine. It has variable susceptibility to fluconazole, but many infections have been treated successfully with high doses of this drug. C. glabrata has been recovered more often than C. albicans in cases of breakthrough candidemia in patients receiving amphotericin B.94

The diagnosis of disseminated candidiasis is often not established before death. Only 50% of patients have abnormal chest radiographs at the onset of infection involving the lungs, although an additional 25% may develop pulmonary involvement as the infection progresses. Candida spp. are cultured from the blood of only 30 to 50% of patients with disseminated candidiasis. Culturing techniques, such as lysis-centrifugation may increase the yield of positive blood cultures in more than 70% of these patients. It is difficult to evaluate the importance of C. albicans isolated from the throat or urine specimens since many patients without disease are carriers of this organism. When a patient with hematologic neoplasm has persistent neutropenia and fever unresponsive to antibiotics, however, he has about a 60% chance of having disseminated candidiasis if C. tropicalis is cultured from his urine, stool, or throat.

A variety of methods have been developed to detect circulating Candida antigens and metabolites in order to enhance the ability to diagnose the presence of infections. Measurements of Candida antibodies are of no value since these are present in 70% of uninfected leukemic patients. Among the assays studied have been monoclonal antibodies to detect mannoprotein, enzyme-linked immunosorbent assay (ELISA) technique to detect enolase, rapid enzymatic assay to detect D-arabinitol and amebocyte lysate assay to detect 1, 3,β-D-glucans.95 Unfortunately, none of these approaches has been proven to be reliable, but the PCR may become a useful diagnostic tool in the future.

Amphotericin B has been effective for the treatment of disseminated candidiasis in patients with adequate numbers of neutrophils, but its efficacy in neutropenic patients has been disappointing. Very few patients with severe neutropenia who develop major organ or disseminated candidiasis recover from their infection unless the neutropenia resolves. Therapeutic efficacy may be enhanced, especially if the infection is caused by C. tropicalis, by combining 5-fluorocytosine with amphotericin B. In vitro and animal studies indicate that these agents interact synergistically against Candida spp. The myelosuppressive toxicity of 5-fluorocytosine can be problematic in patients whose marrow function has been compromised already by chemotherapy. Liposomal preparations of amphotericin B have reduced nephrotoxicity but do not appear to be more effective against Candida infections. Since most Candida infections do not require prolonged therapy, amphotericin B induced nephrotoxicity is usually not a major problem. Prospective, comparative trials have demonstrated that fluconazole is as effective and less toxic than amphotericin B for the treatment of disseminated candidiasis.96 One randomized trial and several open studies suggest that fluconazole is as effective as amphotericin B in neutropenic patients.97 Fluconazole and liposomal preparations of amphotericin B appear to be more effective than amphotericin B desoxycholate for the treatment of chronic disseminated candidiasis. The frequency of this type of candidiasis has greatly diminished at centers where fluconazole prophylaxis is used for neutropenic patients.98

Aspergillus Species

Aspergillosis has become an increasing problem in neutropenic patients and patients receiving chronic adrenal corticosteroid administration. Recent studies have reported a frequency of 20 to 50% among patients with acute leukemia. The most common pathogen is Aspergillus fumigatus. Other human pathogens include A. terreus, A. flavus, A. niger, A. glaucus, and A. nidulans. Infection is usually acquired by inhalation of spores, which are deposited in the paranasal sinuses or lungs.99 The hospital may serve as the source of microepidemics of aspergillosis, most of which are associated with construction within or adjacent to the hospital. Microepidemics have been described in this setting in patients with hematologic neoplasms and in bone marrow and renal transplant recipients. Studies have shown that the concentration of Aspergillus spores is much higher at construction sites within the hospital than at other hospital sites. Disturbance of dust above false ceilings represents a significant risk to susceptible patients, and they should be protected from such exposure.

Over 70% of infections involve the lungs, and about 35% of patients with pulmonary aspergillosis have hematogenous dissemination to other organs. Pulmonary infection may be manifested as necrotizing bronchopneumonia, hemorrhagic pulmonary infarction, solitary or miliary lung abscesses, lobar pneumonia, or bronchitis. A few patients will develop exsanguinating pulmonary hemorrhage early in the course of their infection. The classic clinical presentation of pulmonary aspergillosis is the sudden onset of pleuritic chest pain with fever, hemoptysis, and a pleural friction rub suggestive of pulmonary embolus and infarction. Unfortunately, this classic syndrome occurs in less than 30% of patients. Often, the only evidence of infection is prolonged fever with noncharacteristic pulmonary infiltrates that fail to respond to antibacterial therapy. Occasional patients present only with fever and a normal physical and chest radiographic examination. CT scans may reveal nodular lesions in the lungs of patients with normal chest radiographs.

The earliest abnormality on chest radiographic examination is the appearance of single or multiple rounded dense areas (Fig. 157.7). Patients with symptoms of pulmonary infarction may develop typical wedge-shaped lesions on radiographic examination. As the infection progresses, one of several patterns may emerge, including single or multiple abscesses with cavitation, lobar pneumonia, or patchy or diffuse pulmonary infiltrates located unilaterally or bilaterally. Patients whose infection is controlled often develop cavities with or without fungus balls. Patients with progressive unilateral pulmonary disease despite amphotericin B therapy have been salvaged by surgical resection.

Figure 157.7. Multiple rounded pulmonary infiltrates compatible with invasive pulmonary aspergillosis.

Figure 157.7

Multiple rounded pulmonary infiltrates compatible with invasive pulmonary aspergillosis.

Pathologically, pulmonary infection consists of nodular zones of consolidation surrounded by hemorrhage, abscess formation, or typical wedge-shaped infarcts. On microscopic examination, Aspergillus spp. appear as uniform septate hyphae, about 4 microns in diameter with dichotomous branching. These organisms have a propensity for invading blood vessels, causing thrombosis and infarction.

Aspergillus sino-orbital infection is being diagnosed with increasing frequency in patients with acute leukemia and in marrow transplant recipients, accounting for at least 15% of cases of aspergillosis (Fig. 157.8). Signs and symptoms include fever, retro-orbital pain, headache, circumorbital erythema, nasal obstruction, and necrotic encrustation of the nasal septum, palate, or external nares. Infections may erode through the base of the skull and invade the brain or cause destruction of the paranasal and facial structures and the eye. About half the infections disseminate to other organs. The fungus can often be isolated from nasal cultures. It can be visualized histopathologically and often cultured from biopsy specimens.

Figure 157.8. Pansinusitis caused by Aspergillus spp.

Figure 157.8

Pansinusitis caused by Aspergillus spp. in an allogeneic bone marrow transplant recipient with persistent fever.

Overall, about 35% of infections are widely disseminated. Organs involved include the lung, brain, gastrointestinal tract, liver, kidney, and thyroid.100 Aspergillus infection of the liver may cause multiple abscesses or vascular thrombosis and infarction, occasionally resulting in Budd-Chiari syndrome. The organism is seldom isolated from blood culture specimens.

Although central nervous system aspergillosis sometimes results from local extension of sinus infection, more often, it follows hematologic dissemination. Multiple lesions are usually present, with substantial vascular invasion leading to cerebral thrombosis, infarction, and abscess formation. These patients are lethargic and have focal neurologic signs indicative of the area of brain involvement. The cerebrospinal fluid is normal in most instances, although leukocytosis and increased protein concentrations may be found.

A localized form of aspergillosis has been described in association with intravascular catheters. Aspergillus spores may be deposited from the air at the time of insertion or may be impregnated in materials used for catheter dressings. These infections are potentially serious because they can disseminate. Skin lesions, manifested as sharply defined black eschars, occur in about 5% of patients with disseminated infection.

Many Aspergillus infections are diagnosed only at autopsy examination. Antemortem diagnosis is difficult because the organism is cultured from clinical specimens of less than 30% of infected patients. Although Aspergillus spp. can be cultured from normal subjects and is a potential laboratory contaminant, if this organism is isolated from the respiratory tract secretions of susceptible patients, it should be considered a significant finding. Serologic tests may be useful in supporting the diagnosis of aspergillosis but are not widely available at this time.

Amphotericin B is effective for the treatment of aspergillosis, provided the patient’s underlying deficiency in host defense mechanisms has been corrected. Patients with persistent deficiencies in host defense mechanisms, especially neutropenia, seldom respond to therapy. Since recovery often requires prolonged therapy with amphotericin B, which usually causes dose-limiting toxicity, a liposomal preparation is preferable to amphotericin B desoxycholate. There is suggestive, but not definitive, evidence that these preparations may be more effective. Although 5-fluorocytosine is not active against Aspergillus spp., some patients have appeared to benefit from the addition of this drug to amphotericin B therapy.

Itraconazole is an azole compound that has activity against Aspergillus spp. It has been effective in some leukemic patients but is not generally appropriate for initial therapy because it is available only as an oral preparation. Also, its efficacy in persistently neutropenic patients has not been established.101 It can be useful for maintenance therapy in patients who are responding to amphotericin B, but require prolonged treatment.

A major problem is the management of the patient who has recovered from pulmonary aspergillosis and has a persistent cavity with or without a fungus ball. Acute pulmonary hemorrhage can occur, leading to death. Furthermore, the potential for reactivation of infection interferes with subsequent cancer chemotherapy. Surgical excision of the residual cavity should be given consideration, but that may not always be technically possible due to the presence of multiple cavities or the location of the lesion. Amphotericin B should be administered during periods of neutropenia following subsequent courses of cancer chemotherapy and is preferable to itraconazole because some patients receiving itraconazole have experienced reactivation of infection during periods of neutropenia. The appropriate duration of such therapy is unknown, but it should be continued for a minimum of two courses.

Cryptococcus Species

Cryptococcosis is primarily a disease of patients with impaired cellular immunity, hence patients with lymphoma, Hodgkin’s disease, and other lymphatic malignancies are at risk from this infection. It accounts for about 25% of fungal infections in patients with Hodgkin’s disease. Occasionally, infection occurs in patients with solid tumors. Unlike candidiasis and aspergillosis, cryptococcosis is acquired prior to hospitalization. The organism is ubiquitous in animals and soil specimens. Infection begins in the lungs, where in healthy humans, it may remain asymptomatic and resolve without therapy. Dissemination is frequent in cancer patients, and central nervous system infection is a usual feature. Other organs involved in disseminated infection include the lymph node, liver, kidney, spleen, adrenal, bone, and skin.

Infection may be acute, subacute, or chronic and may arise suddenly or insidiously. Symptoms of central nervous system infection include headache, vertigo, nausea, and vomiting; physical findings consist of fever, meningitis, stupor, signs of increased intracranial pressure, and focal neurologic defects. Leukocytosis (predominantly with lymphocytes), hypoglycorrhachia, and elevated protein concentrations are usually found in the cerebrospinal fluid. Yeast cells can be visualized in the cerebrospinal fluid of nearly 60% of patients. The organisms may be confused with mononuclear cells, but they can be differentiated by an India ink preparation that defines the capsule of the yeast cells. Although C. neoformans usually is cultured easily from the cerebrospinal fluid of patients with meningitis, occasional cancer patients have normal cerebrospinal fluid, and the organism cannot be isolated from repeated culture specimens. The serologic test for detection of cryptococcal antigen in cerebrospinal fluid and blood is useful for rapid diagnosis of this infection, especially in cases where the organism cannot be visualized.

Since meningitis is usually associated with disseminated disease, the yeast may be isolated from blood, urine, or sputum culture specimens. Disseminated infection may involve multiple organs, but the skin and bone are frequent sites of involvement. Skin lesions of cryptococcosis are acneiform, nodular, plaque-like, or ulcerated and are present in about 10% of patients with disseminated infection. Cryptococcal pneumonia may be manifested as miliary, nodular, or cavitary lesions on chest radiographs. On pathologic examination, the typical lesions have a gelatinous appearance. The lesions consist of aggregations of encapsulated budding yeast cells with minimal inflammatory response. Granulomas may be present in some cases. Primary cryptococcal pneumonia may follow a fulminant course, leading to the death of the patient 1 to 2 weeks after onset of symptoms.

Amphotericin B alone or in combination with 5-fluorocytosine is effective in about 60 to 70% of patients. 5-fluorocytosine can cause myelosuppression, especially when used in combination with amphotericin B, because it is excreted in the urine, and amphotericin B causes impaired renal function. In some cases of cryptococcal meningitis, it may be necessary to administer amphotericin B intrathecally at a dose of 0.5 mg every 3 days along with systemic therapy. Fluconazole is also effective against cryptococcosis but it does not sterilize the cerebrinospinal fluid as rapidly as amphotericin B. It is probably advisable to initiate therapy with amphotericin B plus 5-fluorocytosine and change to fluconazole after the patient starts improving. High dose fluconazole (800–1200 mg/d) plus 5-fluorocytosine probably is an acceptable alternative to amphotericin B plus 5-fluororcytosine as initial therapy.

Other Opportunistic Fungi

A variety of fungi of low pathogenicity have been recognized as cause of significant infection in occasional cancer patients. These organisms include Trichosporon beigelii, Blastoschizomyces capitatus, Fusarium spp., Pseudallescheria boydii, Geotrichum candidum, Bipolaris spp., and Malassezia furfur. In addition, members of the order Mucorales cause infection in occasional cancer patients. Most of these infections occur sporadically, although there have been clusters of Fusarium infections in recent years at some institutions. The majority of infected patients have hematologic neoplasms, especially acute leukemia.

Mucormycosis is infection caused by fungi of the order Mucorales. Rhizopus spp. cause the majority of these infections. Mucormycosis was first described in patients with diabetic ketoacidosis, in whom infection characteristically involves the sinuses, orbit, and brain. Pneumonia is the most common form of infection in cancer patients, although some patients develop sinusitis or cutaneous infection. Infection may become disseminated, involving the heart, kidney, gastrointestinal tract, liver, and spleen. The clinical presentation of mucormycosis is similar to that of aspergillosis.

Microscopically, these organisms appear as broad nonseptate branching hyphae. Like Aspergillus spp., Mucorales invade blood vessels, causing thrombosis and infarction. Most cases of mucormycosis in cancer patients are diagnosed at autopsy; consequently, therapeutic measures have not been evaluated extensively.

T. beigelii (cutaneum) can cause disseminated infection, primarily in patients with hematologic neoplasms but also in patients undergoing chemotherapy for metastatic carcinoma. The majority of patients have been severely neutropenic.102 A few patients, especially those with adequate neutrophil counts, develop localized pneumonia without dissemination. There are no characteristic signs and symptoms suggestive of Trichosporon infection. A variety of skin lesions have been described, and skin lesions occur in about 30% of infected patients. Portals of entry include the gastrointestinal tract, respiratory tract, and intravenous catheter sites. Trichosporon infection is often associated with other concurrent opportunistic infections. Although these organisms may be susceptible to amphotericin B, the azole compounds appear to be more effective therapeutic agents.

Fusarium spp. have emerged as significant pathogens in neutropenic patients during the past decade.103,104 These organisms produce a potent toxin that, when ingested, causes aplastic anemia. Localized infections of the lung, sinuses, and skin occur, but most patients have disseminated infection. Cutaneous and subcutaneous skin lesions are frequent in disseminated infection. Like Aspergillus spp., these organisms invade blood vessels, causing thrombosis and infarction. Usually Fusarium spp. can be isolated readily from blood culture or tissue specimens. It may be difficult to distinguish Fusarium from some other fungi on histopathologic examination. Recovery from this infection depends on resolution of neutropenia.

Antifungal Agents

For many years, amphotericin B was the only antifungal agent available against systemic infections. The major advantage of this agent is its wide spectrum of activity against infections that include candidiasis, aspergillosis, cryptococcosis, histoplasmosis, and coccidioidomycosis. Unfortunately, many of these occur in patients with impaired host defense mechanisms, whose response to amphotericin B therapy is suboptimal.105 For example, patients with acute leukemia seldom recover from disseminated candidiasis or aspergillosis, unless they achieve a remission of their underlying disease. A test dose of 1 mg probably should be given over 30 minutes to identify patients with acute idiosyncratic reactions, although this is debatable. If this dose is tolerated, it should be followed immediately with a dose of 0.3 to 0.5 mg/kg. The dose should be escalated over 1 to 2 days to 0.6 to 1.0 mg/kg/d, depending on the fungal infection. The lower dose can be used for Candida and Cryptococcal infections, whereas the highest dose is required for most other infections. Even doses higher than 1mg/kg/day have been used to treat aspergillosis, mucormycosis, and fusariosis.

Amphotericin B is associated with substantial toxicities. Idiosyncratic toxicities are the most serious and can consist of anaphylactic shock, acute liver failure, convulsions, or cardiac arrest. Acute toxicities during infusion include fever, chills, headache, anorexia, nausea, vomiting, muscle and joint pain, and thrombophlebitis. Many of these complications can be controlled with aspirin, small doses of adrenal corticosteroids, phenothiazine, or meperidine. During chronic drug administration, azotemia occurs in 80% of patients, hypokalemia in 20%, and normochromic anemia in 80%. Chronic toxicity is usually reversible, but occasional patients develop permanent nephrocalcinosis. The dosage of amphotericin B should be modified if the serum creatinine increases to above 3.0 mg/dL. Caution needs to be exercised when amphotericin B is administered with other nephrotoxic agents, such as aminoglycosides or cyclosporin. In some patients, hydration and sodium repletion prior to the administration of amphotericin B may reduce the risk of developing nephrotoxicity, but this has not been subjected to careful evaluation.

The administration of amphotericin B in lipid vehicles modifies the pharmacokinetics and distribution of this drug, permitting the administration of higher doses with less nephrotoxicity. Some animal studies have indicated that the higher doses of amphotericin B administered in lipid formulations are more effective. Currently, three preparations are available: ambisome (a liposomal formulation), Abelcet (ribbon-like lipid complexes), and Amphotec (disc-like lipid complexes). Each preparation has different amphotericin B concentrations and different pharmacokinetic properties.106 There are few comparative trials between any of these preparations and amphotericin B desoxycholate.107 Hence, it is uncertain whether any of these formulations are more efficacious than amphotericin B desoxycholate, even when given at much higher doses, although they are less nephrotoxic. Clinical trials have found response rates of 58 to 74% in candidiasis and 37 to 60% in aspergillosis. In comparative trials, lipid preparations have not been substantially more effective than amphotericin B desoxycholate for empiric therapy of fever in neutropenic patients, although in one study, there were fewer breakthrough fungal infections with ambisome.108 Ambisome appears to reduce the acute toxicities more reliably than the other lipid formulations. Other amphotericin B formulations and a lipid formulation of nystatin are undergoing investigation.

5-Fluorocytosine is a fluorinated pyrimidine that is converted to 5-fluorouracil in the fungal cell. Its spectrum of activity is primary against Candida spp. and C. neoformans. It interacts synergistically with amphotericin B and fluconazole against these fungi. Since some organisms are inherently resistant and other develop resistance during therapy, it is rarely used as monotherapy.109 Combination therapy is probably more effective than amphotericin B or fluconazole alone against cryptococcal infections. 5-Fluorocytosine plus amphotericin B may be more effective than amphotericin B for C. tropicalis infections. Some reports suggest that the addition of 5-fluorocytosine has been beneficial for some patients with aspergillosis who were failing to respond to amphotericin B. 5-Fluorocytosine can cause severe enterocolitis and myelosuppression. It can also delay recovery from the myelosuppressive toxicity of chemotherapeutic agents.

Ketoconazole is an oral imidazole that requires acid in the stomach for adequate absorption. It has been used successfully for the treatment of histoplasmosis, blastomycosis, coccidioidomycosis, and candidiasis. In comparative trials, ketoconazole has been more effective for the treatment of superficial Candida infections than topical agents, such as nystatin. It has also been used successfully for the prophylaxis of fungal infections in patients with acute leukemia, but absorption from the gastrointestinal tract may be compromised in some patients. While most patients tolerate ketoconazole, it can cause hepatotoxicity, which rarely can be fatal. Chronic administration may result in interference with steroid synthesis, resulting in gynecomastia and decreased testosterone levels. Drug interactions with anticoagulants, anticonvulsants, and cyclosporin can be troublesome. This drug has been replaced by fluconazole and itraconazole for the therapy of most fungal infections in cancer patients.

Fluconazole is an azole compound that is available as oral and intravenous preparations.110 The drug is well absorbed from the gastrointestinal tract and does not require gastric acid for its absorption. The drug has minimal toxicity even with prolonged use. It is very effective for the treatment of superficial Candida infections and superior to topical agents for the treatment of thrush. In comparative trials, it was as effective as amphotericin B for the treatment of candidemia and disseminated candidiasis, even in neutropenic patients, although the number of these patients was small.96,97 It is superior to amphotericin B for the therapy of chronic disseminated candidiasis and also Trichosporon infection.92 Although it is active against cryptococcal infections, it should not be used alone as initial therapy, but rather as continuing therapy in patients initially responding to amphotericin B. Fluconazole has been used effectively for prophylaxis of Candida infections in leukemic patients and bone marrow transplant recipients.111,112

There has been some concern about the emergence of resistance to fluconazole. C. krusei is inherently resistant and C. glabrata has variable susceptibility. Increased colonization and infection by these Candida spp. has been reported from institutions where fluconazole has been used extensively for antifungal prophylaxis. Emergence of resistance against C. albicans during therapy has been reported, but this has been almost entirely among patients with AIDS who have received repeated and prolonged therapy for thrush.113 Although standardized in vitro susceptibility testing is available, clinical response to fluconazole may not correlate with these results.114 It should also be recognized that occasional cancer patients with candidiasis have failed to respond to amphotericin B because the infecting organism was resistant.

Itraconazole is an azole compound whose absorption is somewhat dependent on gastric acidity. Early studies using itraconazole for antifungal prophylaxis in neutropenic patients demonstrated substantial variability in absorption. The oral solution is more reliably absorbed than the capsule. The drug is of special interest because of its activity against Aspergillus spp. and its minimal toxicity.101 In a review of 289 cases of aspergillosis reported in the literature, 63% showed a partial or complete response to itraconazole. The role of neutrophil recovery in infected neutropenic patients has not been described, nor are there comparative trials with amphotericin B. In neutropenic patients, therapy should be initiated with amphotericin B and replaced with itraconazole for chronic therapy after the neutrophil count has recovered. The liquid preparation is as effective as fluconazole for the treatment of thrush. Itraconazole has activity against C. krusei and some fluconazole-resistant strains of C. albicans. Its use for antifungal prophylaxis of neutropenic patients has not been adequately demonstrated.

The high frequency of fungal infections in neutropenic patients at autopsy examination and the inadequacy of diagnostic procedures have led to empiric administration of antifungal agents in patients suspected of having this infection. Empiric therapy should be considered in patients with neutrophil counts of less than 100/mm3 for greater than 1 week who develop fever that fails to respond to 4 to 7 days of broad-spectrum antibacterial therapy.115,116 Other supportive indications are indwelling catheters, chronic adrenal corticosteroid therapy, the presence of unexplained pulmonary infiltrates, and deteriorating renal or hepatic function. Responding patients probably should remain on antifungal therapy for at least 1 or 2 weeks. Empiric antifungal therapy is not indicated for a majority of patients who have only transient or modest degrees of neutropenia.

Viral Infections

Viral infections are prominent following bone marrow transplantation and are not uncommon in neutropenic patients with acute leukemia and lymphoma. Herpes viruses are identified most frequently, particularly herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV). Epstein-Barr virus (EBV), human herpes virus-6 (HHV-6), adenovirus, respiratory syncytial virus (RSV), influenza virus, and parainfluenzae viruses are encountered less often.117–119

Herpes Simplex Virus

Infections caused by HSV are the most common viral infections in patients with lymphoma and acute leukemia. More than 80% of bone marrow transplant recipients will have reactivation of latent HSV residing in the neuronal ganglia. Lesions caused by HSV are found most often on the lips and oral mucosa. In patients receiving antineoplastic chemotherapy these lesions tend to become large and painful, and severe mucositis with extensive ulceration of the oral mucosa is not uncommon. Secondary colonization or infection with bacteria or fungi may occur. Localized bleeding may be a complication in patients with severe chemotherapy-induced thrombocytopenia. Some patients develop chronic localized herpetic ulcers involving the nose, lips, or eyelids that begin as small papulovesicular lesions and gradually enlarge over several weeks. Herpetic lesions can extend from the oropharyngeal mucosa to involve the esophageal mucosa, producing symptoms that are indistinguishable from Candida esophagitis. Occasionally, esophagitis may occur without oropharyngeal lesions, and it may become necessary to perform invasive diagnostic procedures, such as endoscopy, and obtain a biopsy specimen in order to make an accurate diagnosis. Patients with herpetic esophagitis may also have lesions involving the larynx and trachea and occasionally may develop severe necrotizing tracheobronchitis. Localized HSV lesions may also be seen in other areas of the body, such as the genital and perianal areas, and may become quite destructive. Dissemination of HSV infection is uncommon and occurs most often in patients with Hodgkin’s disease. The liver, spleen, adrenal glands, kidneys, pancreas, lungs, brain, and gastrointestinal tract may be involved in disseminated infection. Acyclovir is effective for the treatment and prevention of HSV infections.120 Localized disease usually responds to 200 mg of acyclovir given orally, five times a day. Newer oral alternatives (valacyclovir, famciclovir), with better bioavailability than the oral acyclovir now available, should be used instead.121,122 Disseminated infection, encephalitis, and infection in immunocompromised patients generally require intravenous therapy with acyclovir (10 mg/kg/Q8h). Strains of HSV resistant to acyclovir may develop. In such cases, foscarnet is the treatment of choice.

Varicella-Zoster Virus

Primary infection with VZV causes approximately 4 million cases of chicken pox in the United States each year.123 VZV remains latent in the sensory ganglia for the lifetime of the host, and reactivates in 15% of persons to cause herpes zoster.124

Varicella has been recognized as a potentially serious infection in children undergoing cancer chemotherapy. Since it is a highly contagious infection, it is especially hazardous, and epidemics have occurred in pediatric cancer facilities. Serious complications arise in about 5% of otherwise healthy children who develop varicella, and the fatality rate is less than 0.5%. About 30% of children receiving cancer chemotherapy develop serious complications during varicella infection, and the fatality rate is around 7%. Most serious complications and deaths occur in children with hematologic neoplasms. The severity of infection is related to the extent of the underlying cancer and to antitumor therapy.

Characteristic manifestations of varicella include a generalized vesicular rash and fever. Lesions appear initially on the face and scalp and subsequently spread to the trunk and extremities. New lesions continue to appear as older lesions crust. Infection may be unduly prolonged in patients with cancer. The vesicles become hemorrhagic and necrotic in patients with thrombocytopenia. About 10% of children develop a bacterial superinfection. The disease is occasionally rapidly progressive, and in a few patients, this can lead to circulatory collapse and death shortly after the appearance of the vesicles. Disseminated infection may result in widespread pneumonia, and focal necrosis of the liver, pancreas, or adrenal glands. Fulminating encephalitis may develop occasionally. Dissemination generally develops within 1 week of the onset of skin lesions.

Herpes zoster occurs sporadically in the general adult population. Among cancer patients, it occurs most often in those with lymphoproliferative disorders. The risk for herpes zoster in HIV-infected individuals is increased about 20-fold. The infection is characterized by a unilateral vesicular rash in the distribution of one or two adjacent sensory dermatomes (Fig. 157.9). The thoracic, cervical, and lumbar dermatomes are most commonly involved. In about 20% of patients with cancer, herpes zoster lesions arise initially at sites where the tumor is in close proximity to a nerve trunk. In an additional 20% of the patients, eruption first appears at sites of recent radiation therapy. Initially, the lesions appear to be erythematous and maculopapular in nature but swiftly evolve into a vesicular rash. Vesicles may coalesce to form larger, bulbous lesions. Localized herpes zoster usually causes no unique problems in the cancer patient. Occasionally, the lesions heal slowly with necrosis and scarring. In others, lesion formation may continue for 10 to 15 days, and crusting or scabbing of lesions may not occur until about 3 to 4 weeks into the course of the disease. Occasional patients develop a generalized varicelliform eruption, without localization, at the onset of the disease. The rash is accompanied by pain (zoster- associated pain, ZAP) that often precedes the eruption by 2 to 3 days, and can last for several weeks or even months. Postherpetic neuralgia is ZAP that persists beyond 1 month.

Figure 157.9. Typical vesicular rash caused by varicella-zoster virus.

Figure 157.9

Typical vesicular rash caused by varicella-zoster virus. Note the dermatomal distribution, and the hemorrhagic nature of lesions in this patient with thrombocytopenia.

Cutaneous dissemination of herpes zoster occurs in about 35% of cancer patients compared with only 4% of those without cancer. Therapy with adrenal corticosteroids, radiation, or antitumor agents facilitates dissemination. Localized skin lesions may precede cutaneous dissemination by 2 to 15 days. Lesions may appear in the mouth, pharynx, labia, or anus. Visceral dissemination occurs infrequently but then commonly involves the gastrointestinal tract, liver, adrenals, pancreas, lungs, and brain, resulting in hepatitis, pneumonitis, and meningoencephalitis. Muscular weakness, motor paralysis, and postherpetic neuralgia seem to be more common in cancer patients. Multiple episodes of herpes zoster are much more common in immunosuppressed individuals than in persons who are immunocompetent.

Laboratory confirmation of the diagnosis is not required for most cases of varicella. VZV can be recovered from the vesicular fluid for a few days after the onset of the eruption but is recovered infrequently from other sites. Cultures are positive 30 to 60% of the time. Detection of VZV antigens in skin scrapings using fluorescence microscopy, and detection of VZV DNA, in the CSF or other tissues using PCR are more rapid and sensitive diagnostic techniques.

Controlled trials have demonstrated that acyclovir shortens viral shedding, accelerates healing of lesions, and reduces the frequency of visceral disease in both immunocompetent and immunocompromised patients with varicella.125,126 Acyclovir is superior to and has replaced vidarabine for the treatment of VZV. Most severely immunosuppressed patients need intravenous acyclovir, which usually requires hospitalization. The recommended dose of acyclovir for the treatment of VZV is 10 mg/kg administered every 8 hours, or 500 mg/m2 every 8 hours. Management of visceral complications, such as meningoencephalitis and pneumonitis, requires skilled supportive care in addition to antiviral therapy. Significant mortality may occur despite these measures. Therapy with foscarnet or combination therapy with foscarnet and acyclovir should be considered in severely immunosuppressed patients who fail to respond to acyclovir alone.127 Parenteral acyclovir therapy without hospitalization, or oral therapy with famciclovir or valacyclovir under close observation might be adequate and more cost effective in mildly immunocompromised patients.128

ZAP represents a continuum that includes prodromal pain, acute phase pain, and chronic pain (commonly referred to as postherpetic neuralgia). All these appear to be more common in the elderly and in immunosuppressed patients. Currently, no satisfactory therapy for ZAP exists, although a great deal of effort has been put into providing analgesic remedies to alleviate the range of pain experienced. Newer antiviral agents, such as famciclovir, may reduce the incidence and severity of ZAP but need to be more fully evaluated.

The administration of varicella-zoster immune globulin (VZIG) has been shown to be useful for postexposure prophylaxis in high-risk individuals and can also ameliorate established infection. VZIG must be given within 96 hours of exposure to be effective. The (OKA) vaccination strain of varicella vaccine is now available for universal immunization and postexposure prophylaxis.129,130 The vaccine is safe and effective in immuncompetent children. However, as a live attenuated virus, its administration to severely immunosuppressed individuals is risky and can result in severe vaccine-induced varicella.131 High-dose acyclovir (or famciclovir/valacyclovir?) administered as a 1-week course following exposure might be useful in this setting.132

Cytomegalovirus

CMV infections are common throughout the world. Primary CMV infection in immunocompetent persons is usually asymptomatic. Although uncommon, pneumonitis secondary to CMV infection has been described in otherwise healthy infants.133 Severe CMV infections are common in patients with AIDS and in recipients of organ transplants (including bone marrow). CMV pneumonia is a major cause of morbidity and mortality in allogeneic blood and marrow transplant recipients. Like other herpes viruses, CMV has the capacity to remain latent in host tissues after recovery from the initial acute infection. Up to 80% of seropositive patients undergoing marrow transplantation may reactivate latent virus. In seronegative patients, infection may be acquired from transplanted marrow or from unscreened blood products. The risk of developing CMV infection is greater in patients who develop GVHD. In marrow recipients, pneumonia and gastrointestinal infections are most common. Retinitis, which is common in patients with AIDS, is rare in marrow recipients. CMV pneumonia, which develops in approximately one-third of patients with CMV infection is fatal in 80 to 85% of cases, if left untreated. In elderly patients and those with GVHD, the mortality may be higher.

A number of tests are available for the diagnosis of CMV infections. ELISA tests for CMV antibody titers are readily available and are accurate for identification of prior infection or seroconversion. IgG antibodies persist for life and indicate prior infection, whereas IgM antibodies are usually associated with acute (primary or recrudescent) infection. The isolation of virus from body fluids or tissues indicates infection but not always symptomatic disease. Important recent advances enabling rapid diagnosis of CMV infection have been made. The shell-vial technique, using monoclonal antibody to stain infected cells in tissue cultures, is one such advance. The CMV pp65 antigenemia assay is a reliable and sensitive method for the diagnosis of CMV disease in immunocompromised patients and is considered to be more sensitive than shell-vial cultures for rapid detection of CMV in polymorphonuclear blood leukocytes.134–136 CMV pp65-positive cells are counted under a fluorescence microscope and results are generally expressed as the number of positive cells per 2×105 leucocytes examined. Results of CMV antigenemia assays are generally available within 5 hours of obtaining blood samples from patients.

Important advances have also been made in the treatment and prevention of CMV infection, although treatment remains suboptimal. Ganciclovir in combination with intravenous immune globulin (IVIG) has been shown to improve survival in transplant recipients with CMV pneumonia or gastroenteritis. The dose-limiting toxicity of ganciclovir is the development of neutropenia, which can increase the risk of bacterial and fungal superinfections. Ganciclovir-resistant CMV strains are uncommon but do occur. Foscarnet might be useful in the treatment of infections caused by such strains. Anecdotal evidence, particularly in AIDS patients, suggests that refractory CMV infections may respond to therapy using a combination of ganciclovir and foscarnet. Cidofovir is another antiviral agent with activity against CMV. Clinical experience with this agent in cancer and transplant patients is limited.

Primary CMV infection is preventable in patients who are CMV seronegative by using bone marrow and screened blood products from donors who are CMV seronegative. Two strategies are currently used to prevent CMV infection in seropositive patients who are at risk for reactivation. One is the prophylactic administration of ganciclovir.137 Although effective, prolonged ganciclovir administration often produces neutropenia. There is also evidence that prolonged ganciclovir prophylaxis inhibits the development of CMV-specific T cell lymphocyte responses and promotes the occurrence of late CMV pneumonia.138 The other approach involves pre-emptive therapy for subclinical CMV infection, on the basis of positive CMV antigenemia assays in blood or detection of CMV in bronchoalveolar lavage fluid (BAL).139,140 This strategy has the advantage that it targets patients with subclinical CMV infection. However, a small percentage of patients may present with CMV pneumonia without prior detection of the virus. Quantitation of CMV antigenemia also provides an estimate of viral load and may be useful in judging the efficacy of antiviral therapy.

Human Herpes Virus-6

HHV-6 is being recognized as an important pathogen in organ transplant (including bone marrow) recipients. Serologic reactivation accompanied by specific manifestations, including fever, rash, pneumonitis, hepatitis, myelosuppression, and neurologic dysfunction, have been described in recipients of bone marrow, kidney, and liver transplants. Ganciclovir and foscarnet inhibit viral replication, and therapy with these agents might be indicated in patients with severe infections.141

Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is an important cause of community-acquired and nosocomial pneumonia in young children. RSV pneumonia is uncommon in adults, although serious outbreaks have been reported among institutionalized young adults and elderly patients. RSV has recently been shown to be an important cause of upper respiratory tract and lower respiratory tract infection in immunocompromised adults, primarily transplant recipients.5,119 Presenting symptoms and signs include fever, cough, rhinorrhea, and nasal congestion, coupled with radiographic evidence of sinusitis and diffuse interstitial pneumonitis. The infection may progress rapidly and result in fulminant respiratory failure. Pneumonia tends to develop more often in bone marrow transplant recipients in whom engraftment has not yet occurred. The overall mortality rate in bone marrow transplant recipients is 50%, but it approaches 80% in patients with pneumonia. Early therapy with ribavirin may have a beneficial effect.

Influenza and Parainfluenza Viruses

Scant information exists regarding the incidence, clinical course, and outcome of influenza infections in immunosuppressed adults with cancer. Recent evidence indicates that during community outbreaks influenza is a frequent cause of acute respiratory illness in hospitalized adult bone marrow transplant recipients and patients with acute leukemia.5,142 Pneumonia is a frequent complication, and the mortality associated with pneumonia is 33%. The impact of therapy with drugs such as amantadine, rimantadine, or ribavirin is unknown. Because influenza infection is more readily prevented than treated, measures for adequate control should focus on prevention. Annual influenza immunization for all immunosuppressed patients, their families, and hospital staff is recommended. Contraindications for vaccination include a history of severe allergy to eggs and the presence of an acute febrile illness. Studies that better define the extent and nature of this infection and the optimal means of rapid diagnosis, treatment, and prevention of influenza in immunosuppressed patients are urgently needed.

The parainfluenza viruses are second only to RSV as a cause of serious lower respiratory tract disease in immunocompetent children. In the past 20 years, there have been scattered reports of the parainfluenza viruses causing serious, sometimes fatal pneumonias in children with leukemia, immunodeficiency syndromes, or bone marrow transplant. There is mounting evidence that, like RSV and the influenza virus, the parainfluenza viruses play an important role in the etiology of pneumonia in immunocompromised adults with cancer.118 Infection occurs mainly in recipients of autologous and allogeneic bone marrow transplant, both early and late after transplantation. Common clinical manifestations, the spectrum of disease, optimal methods for early detection, and the impact of therapy still need to be defined.

Measles Virus

Although measles is generally no more serious in children with cancer than in normal children, there have been a few exceptions. Children with cancer may develop hepatitis or encephalitis, and their course may be complicated by superimposed bacterial otitis or pneumonia. Giant cell pneumonia without the appearance of the typical skin rash has been observed. This may also occur after apparent recovery from the exanthem. Measles virus has been recovered from the throats of leukemic children for 3 or 4 weeks following onset of the rash, whereas it can no longer be recovered from the throats of normal children after 48 hours. Children who died of measles failed to develop complement-fixing or neutralizing antibodies 2 to 4 weeks after appearance of the rash, whereas normal children produce these antibodies within 1 week. Fatal infection involves the lung, heart, liver, pancreas, lymph nodes, thymus, and brain, causing focal necrosis with hemorrhage, inflammation, and giant cells with intranuclear and intracytoplasmic inclusions in the alveoli associated with mononuclear cells and small foci of fibroblastic proliferation. In patients with deficient cellular immunity, a chronic form of encephalitis, often with a concomitant pneumonia, has been reported.

No specific treatment for this infection is available. Supportive therapy, such as the administration of antipyretics and the maintenance of fluid balance, should be given as indicated. Patients should be observed carefully for signs of bacterial superinfections, which should be promptly treated with appropriate antimicrobial agents. Measles immune globulin (0.50 mL/kg, 1 mL, up to 15 mL) should be administered as soon as possible following exposure to a case of measles and must be given within 6 days of exposure. Live measles vaccine is contraindicated in persons with defects in CMI and should not be administered to children with cancer, since giant cell pneumonia may occur.

Hepatitis Viruses

Hepatitis B virus (HBV) infection is the most common cause of acute liver disease worldwide, and more than 300 million people have chronic infection with HBV.143 Chronic HBV infection leads to progressive liver disease, cirrhosis, and hepatocelluar cancer. Hepatitis C virus (HCV) has been estimated to infect 100 million persons worldwide and 4 million in the United States.144 Eventually 10 to 15% of these individuals will develop cirrhosis (chronic HCV infection is the leading indication for liver transplantation), and some will develop hepatocellular carcinoma.145 Recently, an association with HCV and non–Hodgkin’s lymphoma has been established.146 Many cancer patients develop elevation of transaminase levels indicating the presence of hepatitis, but it is often difficult to determine whether the disease is viral or drug induced. Although the current risk of transmission of HBV and HCV infection by the transfusion of screened blood is negligible, patients with acute leukemia and others who receive multiple transfusions may be at greater risk. The greatest threat to the safety of the blood supply are seronegative donors who donate blood during the infectious window period when they are undergoing seroconversion.147 However, the majority of HBV and HCV infections occur in individuals who use illegal drugs and/or engage in high-risk sexual behaviors.147 Drug-induced hepatitis is exceedingly common and a large number of agents commonly used in medicine can inflict liver damage. The latest example of rare but serious drug-induced hepatitis is that caused by the expanded-spectrum quinolone trovafloxacin, which is no longer available for routine use and must be considered only in life-threatening situations when no other alternative is available.

Hepatitis can be a serious problem in cancer patients for various reasons. Patients with impaired host defense mechanisms are more likely to develop fulminant infections. The presence of hepatitis may result in substantial delays in the administration of antineoplastic therapy, and may further interfere with nutrition in a group of patients where nutritional status is already impaired. Several reports have focused on the phenomenon of reactivation of quiescent liver disease due to HBV following immunosuppressive or cytotoxic therapy.148–150 The clinical picture is that of fulminant hepatic failure and some patients have required liver transplantation as a consequence. This syndrome has also been reported after withdrawal of low-dose methotrexate therapy, which has not been clearly established to be immunosuppressive.

Inferferon-alpha (INF-α) is currently the only approved treatment for HBV infection.151 Recent evidence indicates that the oral nucleoside analogue lamivudine produces substantial histologic improvement in many patients with chronic hepatitis.152 These approaches need further evaluation and long-term follow-up. Combination therapy might also be a consideration. Similarly, in patients with hepatitis C infection, INF-α in combination with ribavirin is effective in inducing virologic and histologic improvement and should be made available to such patients.153–155 Pre-exposure vaccination of persons at risk using recombinant hepatitis B vaccines affords protection against hepatitis B infection. Postexposure prophylaxis includes the administration of hepatitis B vaccine and hepatitis B immune globulin (HBIG). Measures for preventing hepatitis C need to be developed.

Protozoal Infections

P. carinii and T. gondii are protozoal organisms (although P. carinii has recently been reclassified as a fungus) that are capable of causing serious infections in cancer patients. Both organisms are ubiquitous and cause infection in a wide variety of animals. Antitumor agents and adrenal corticosteroids facilitate the establishment of these infections in experimental animals. In the past, the majority of cancer patients who developed these protozoal infections had received antitumor agents and/or adrenal corticosteroids. Beginning in 1981, the epidemiology of these infections changed dramatically, with the recognition that both P.carinii pneumonia (PCP) and toxoplasmosis develop with markedly increased frequencies in patients with AIDS.

Pneumocystis carinii

The first cases of PCP were described in Central Europe in the early 1950s and involved premature or debilitated infants. Prior to the AIDS epidemic, about 20% of P. carinii infections in the United States occurred in patients with leukemia and 15% in patients with other cancers. Most patients who develop this infection have evidence of immunosuppression, including a substantial number of children with acute leukemia who were in remission. PCP most often represents reactivation of latent infection but may occasionally represents newly acquired infection. An epidemic has been described among children with neoplastic diseases, and adults occupying the same hospital room have acquired the infection. There is also some evidence to indicate that the frequency of PCP in patients without AIDS increases during periods of normal contact (outpatient clinics, treatment rooms, hospital wards) with patients who have AIDS, suggesting person-to-person transfer of the organisms.156 Recent reports indicate that cases of PCP in patients with solid tumors (breast cancer) who have not been treated with corticosteroids, appear to be increasing.157,158

PCP may be insidious in onset or may progress rapidly. The most frequent presenting symptoms are unexplained fever, a nonproductive cough, and shortness of breath. The shortness of breath may occur initially only with exertion, but as the infection progresses, it is also present at rest, and the patient characteristically develops tachypnea, cyanosis, and tachycardia.159 Children may complain of anterior chest, substernal, or abdominal pain, associated with nausea or vomiting. Auscultatory findings are usually minimal. Bronchovesicular breathing is common. Dry rales may be heard, but findings indicative of consolidation are infrequent, except in advanced disease. The chest radiograph often reveals more extensive pulmonary involvement than is suggested by the clinical findings. The most common finding is that of a diffuse interstitial infiltration involving most portions of the lung relatively evenly, although asymmetry may occur. Pleural effusions are very uncommon and may indicate the presence of another disease process. In a small percentage of patients with proven PCP, the chest radiograph may be normal.

Abnormalities in lung function are common in patients with PCP. These include impairment in vital capacity and total lung diffusing capacity for carbon monoxide. Measurement of arterial blood gases is useful in determining the extent of pulmonary involvement. Hypoxemia is frequent, and an increased difference in the alveolar to arterial oxygen tension between rest and exercise measurements has also been described in patients with PCP.

In patients with normal chest radiographs and pulmonary function tests, whose symptoms are suggestive of PCP, gallium scanning has been found to be of use. There is generally diffuse uptake throughout the lung parenchyma, although focal uptake may also occur. These findings represent a fairly sensitive, but nonspecific test for the presence of PCP. Gallium scanning may also be helpful in determining relapse, when chest radiographic abnormalities cannot be determined to represent new or residual disease.

Several studies have demonstrated that examination of sputum can provide a noninvasive and inexpensive means of diagnosing PCP, particularly in patients with AIDS. Most patients with PCP, however, have a dry cough and rarely produce sputum. Adequate amounts of sputum can be induced by having patients inhale a mist of hypertonic saline produced by an ultrasonic nebulizer for a period of 10 to 20 minutes. Staining of the sample can be done by a variety of stains that detect P. carinii (Gomori methenamine silver, toluidine blue O, Giemsa, polychrome methylene blue) (Fig. 157.10). The sensitivity of this technique in a large number of AIDS patients has been shown to be 79% with a negative predictive value of 61%. The use of a fluorescei-tagged monoclonal antibody increases the sensitivity of the procedure to around 92%.160

Figure 157.10. Gomori methenamine silver (GMS) stain from a BAL specimen demonstrating multiple organisms in an AIDS patient with Pneumocystis carinii pneumonia.

Figure 157.10

Gomori methenamine silver (GMS) stain from a BAL specimen demonstrating multiple organisms in an AIDS patient with Pneumocystis carinii pneumonia.

Various invasive techniques for establishing the diagnosis of PCP are available. These include fiberoptic bronchoscopy with BAL and/or transbronchial lung biopsy. Needle lung biopsy and open lung biopsy are rarely necessary. The sensitivity and specificity of these procedures are greater than noninvasive techniques, but they are associated with complications, such as bleeding and pneumothorax. Many cancer patients suspected of having PCP are thrombocytopenic, and the hazards of performing invasive procedures in such patients are probably too great. Under these circumstances a therapeutic trial may be indicated if the patient has the typical pulmonary infiltrates on the chest radiograph and has rapidly progressive dyspnea and hypoxemia. Measurement of circulating P. carinii antigen and antibodies are of no help in diagnosis.

TMP-SMX and pentamidine isethionate appear to be equally effective for the treatment of PCP, both in patients with and without AIDS. In patients without AIDS, TMP-SMX represents the agent of choice since it is less toxic than pentamidine. The daily intravenous dosage of TMP-SMX recommended for the treatment of PCP is trimethoprim, 15 mg/kg, and sulfamethoxazole, 75 mg/kg. Pentamidine isethionate is administered by slow intravenous infusion at a dose of 4 mg/kg, as a single daily dose. Up to 50% of patients with AIDS experience untoward reactions related to TMP-SMX, and in many of these patients, therapy has to be discontinued prematurely.161 For patients who are intolerant to, or do not respond to, both TMP-SMX and pentamidine, the following alternatives exist. Trimetrexate, an inhibitor of protozoan dihydrofolate reductase at a dose of 45 mg/m2/d with leucovorin rescue is effective, both as first-line and as salvage therapy for PCP.162 Oral dapsone-trimethoprim has been found to be useful in AIDS patients with mild to moderately severe PCP. A combination of clindamycin and primaquine has also been used to treat mild to moderately severe PCP in humans.163 Another oral agent, atovaquone, a hydroxynaphthoquinone, has been approved for the treatment of mild to moderately severe PCP.164 It is as efficacious as pentamidine and TMP-SMX in this setting and is less toxic.165 The use of corticosteriods as adjunctive therapy for patients with moderate to severe PCP reduces the occurrence of respiratory failure and of mortality.166 Prednisone is generally administered as follows: 40 mg PO, b.i.d. for 5 days followed by 40 mg PO daily for 5 days and then 20 mg PO daily until the end of treatment. TMP-SMX has been found to be highly successful in protecting children who are at high risk from acquiring PCP. It is also used frequently for this purpose in patients with AIDS. Aerosolized pentamidine has recently found widespread use for the prevention of PCP in AIDS patients, particularly since it can be administered once a month. A small number of patients given aerosolized pentamidine will develop extrapulmonary (spleen, liver, bone marrow, eye) PCP. Other alternatives include dapsone, a combination of pyrimethamine and sulfadoxine (Fansidar), and possibly atovaquone.

Toxoplasma gondii

T. gondii, an obligate intracellular protozoan parasite, is among the most prevalent causes of latent infection of the central nervous system. The organism exists in three forms—tachyzoite (proliferative form), tissue cysts, and oocysts, each of which is potentially infectious for humans. T. gondii is found worldwide, and infection with it can result in acute or chronic manifestations. A variety of clinical syndromes have been described including asymptomatic infection, atypical pneumonia, chorioretinitis, congenital infection, encephalitis, and lymphadenitis. Lymphadenitis is common in systemic infection and frequently involves the cervical lymph nodes, although any lymph node group may be infected. Toxoplasmosis may first appear as myositis, myocarditis, hepatitis, pneumonitis, or encephalitis.

Cell-mediated immunity represents the primary arm of host defense against T. gondii. Serologic surveys in the United States indicate that up to 70% of healthy individuals have been infected with T. gondii. Patients with cancer, particularly those with defects in CMI, are at risk of reactivating latent infection or of developing newly acquired infection.167 Infection can be acquired by the ingestion of improperly cooked meat products, including pork and lamb. Toxoplasmosis may also be transmitted by blood transfusion, including transfusion of whole blood, platelets, or white blood cells.

Toxoplasmosis is an infrequent infection even in immunosuppressed patients, except those with AIDS. Nearly half the cancer patients who develop toxoplasmosis have underlying Hodgkin’s disease. Sixty percent of patients with lymphoma who develop toxoplasmosis have central nervous system disease, although multiple other organs may be infected.168 Central nervous system disease may present as a nonspecific encephalopathy, diffuse meningoencephalitis, or a syndrome compatible with multiple space-occupying lesions. The usual signs and symptoms include drowsiness, disorientation, headache, vomiting, seizures, visual disturbances, and paresis. Fever and nuchal rigidity are seen in less than 50% of patients. The cerebrospinal fluid may be completely normal, or may contain a few white blood cells (usually lymphocytes) and have normal or slightly elevated protein levels and slightly decreased glucose levels.169

In patients who present with symptoms of toxoplasmic encephalitis, the CT scan is usually abnormal. Typically, multiple intraparenchymal lesions involving cerebral hemispheres, thalamus, or cerebellum are seen. Contrast-enhancement may demonstrate a ring-like or nodular pattern.170 Mild to moderate cerebral edema and a mass effect may be present. Occasionally solitary lesions may be present. Abnormalities demonstrated on the CT scan are not pathognomonic for toxoplasmosis, and similar lesions may be caused by other disease processes. MRI scanning appears to be more sensitive and may demonstrate the presence of lesions in patients with negative CT scans.

A specific diagnosis of toxoplasmosis is made by identification of the organisms in clinical specimens or by serologic methods. T. gondii have been identified microscopically in the blood, sputum, cerebrospinal fluid, and tissues of infected patients. Blood or body fluids may be inoculated into mice or tissue cultures and may demonstrate isolation of the organisms.171 This may take up to 6 weeks and is rarely helpful in the initial management of the patient.

A large number of serologic tests for the detection of antibody to T. gondii are available. The most useful tests for the measurement of immunoglobulin G (IgG) antibody are the Sabin-Feldman dye test, the indirect fluorescent antibody (IFA) test, and the modified direct agglutination test. The methods available for detection of IgM antibodies include the IgM-IFA test and the double sandwich IgM-ELISA. IgG antibodies appear within 7 to 14 days of acquisition of infection, whereas IgM antibodies appear during the first week. IgG antibodies generally peak within 30 to 60 days and then begin to fall but persist for life. IgM antibodies rise rapidly and then fall to low levels and disappear in a few months. Since the incidence of elevated antibody titers is high in the normal population, the diagnosis of toxoplasmosis can only be made if serial testing reveals increasing antibody titers. However, cancer patients have had toxoplasmosis without producing increases in antibody titers. The diagnosis of toxoplasmosis can also be established by demonstrating trophozoites in tissues, such as brain biopsy or endomyocardial biopsy specimens.

Toxoplasmosis can be treated successfully with a combination of pyrimethamine and sulfadiazine (or trisulfapyrimidines). The initial loading dose of pyrimethamine is 100 to 200 mg. This is followed by 25 to 50 mg daily for a period of 4 to 6 weeks. Sulfadiazine or trisulfapyrimidines are given at a dose of 6 to 8 g/d in four divided doses for 4 to 6 weeks. Folinic acid, 5 mg every other day, is generally administered in an attempt to reduce the myelosuppression associated with this regimen. Recently clindamycin has shown promise as an alternative to sulfadiazine in patients with toxoplasmosis and sulfonamide intolerance.172,173 It is well absorbed from the gut and has excellent tissue penetration, but achieves only erratic CSF and brain concentrations. In combination with oral pyrimethamine, clindamycin seems comparable in efficacy to pyrimethamine and sulfadiazine. Atovaquone also appears promising for the treatment of cerebral toxoplasmosis, but relapse rates approach 50% when this agent is used alone. The new macrolides azithromycin, roxithromycin, and clarithromycin have activity against T. gondii, but sufficient clinical data are lacking to recommend routine usage currently.174

Other Parasitic Infections

Opportunistic infections, including the syndrome of hyperinfection with the nematode Strongyloides stercoralis, occur most often in patients with T-lymphocyte impairment. Sporadic cases have been reported in patients with lymphoma and chronic lymphocytic leukemia. Infection with this parasite is common in the tropics, but it is worldwide in distribution. Usually, the parasite exists in the gut without causing severe disability. However, patients with impaired host defenses or those receiving antitumor and/or immunosuppressive agents may develop a serious infection. Large numbers of rhabditiform larvae may mature to filariform larvae and invade the gastrointestinal tract, causing ulceration. When hyperinfection occurs, pulmonary and gastrointestinal symptoms predominate.175,176 Pulmonary manifestations include dyspnea, cough, hemoptysis, chest pain, and cyanosis. Migration of the larvae into the lungs produces a diffuse pulmonary infiltrate. Gastrointestinal manifestations include abdominal pain and/or distension, nausea, vomiting, diarrhea, hematochezia, and hematemesis. Fever, rash, headache, chills, and shock may also be present. Coexisting bacterial infections, which are generally due to enteric gram-negative bacilli, are frequently present and may alert the astute clinician to the possibility of hyperinfection with S. stercoralis.

The crucial step in establishing the diagnosis of strongyloidiasis is the identification of larvae. They are usually demonstrated in stool samples and in pulmonary secretions. Duodenal aspiration might be necessary, if stool and pulmonary specimens fail to demonstrate larvae (Fig. 157.11). Eosinophilia is present in up to 50% of patients. Various immunologic tests are available including complement fixation tests, precipitin tests, indirect fluorescent antibody techniques, and direct passive hemagglutination tests. These tests are generally sensitive and specific but are limited by their lack of widespread availability. Thiabendazole (25 mg/kg twice daily for 2 days) is the agent of choice for the treatment of strongyloidiasis.177 Longer duration of therapy (5–14 days) may be necessary in seriously ill patients and those with hyperinfection. Ivermectin alone or in combination with thiabendazole may have a therapeutic role in refractory infections.178

Figure 157.11. Strongyloides stercoralis larvae in a specimen obtained through duodenal aspiration.

Figure 157.11

Strongyloides stercoralis larvae in a specimen obtained through duodenal aspiration. The patient had eosinophilia and chronic diarrhea.

Neither the presence of hematologic neoplastic disease nor therapy with antitumor agents appears to have any effect on intestinal parasites such as Necator americanus, Trichuris trichiura, or Hymenolepis nana.

Abdominal Infection

An acute abdomen is one of the most difficult problems for the physician caring for patients with cancer. Often, this complication occurs following the administration of chemotherapy when neutropenia and thrombocytopenia are complicating factors. Neutropenic patients often cannot mount an adequate inflammatory response and, therefore, may have peritonitis without significant symptoms. Usually, they have abdominal pain, distention, and diminished to absent bowel sounds, but guarding and rebound may be absent. Adrenocorticosteroids can also mask the characteristic signs and symptoms of peritoneal inflammation. Some of the potential causes of acute abdomen in the immunocompromised host include appendicitis, cholecystitis, peritonitis, hepatic or splenic abscesses, splenic infarcts, typhlitis, tumor lysis with perforation, and vinca alkaloid neuropathy.

Typhlitis or agranulocytic colitis is a disease that occurs in patients with neutropenia.179 It was originally described in children with acute leukemia but now is recognized in adults with acute leukemia and in occasional patients undergoing intensive chemotherapy for metastatic carcinoma. The common presenting signs and symptoms include fever, abdominal pain, and diarrhea. More than 60% of patients have bloody diarrhea.180 A substantial fraction of the patients have stomatitis, and 30% have vomiting. Physical examination reveals abdominal distention, tenderness often localized to the right lower quadrant, diminished to absent bowel sounds, and infrequently, rebound tenderness. Septicemia is present in 70% of the patients, and the most common organisms are aerobic gram-negative bacteria. Some of the cases have been associated with infection caused by Clostridium septicum. Complications include perforation and peritonitis.

Pathologically, typhlitis is a patchy inflammation of the bowel wall with well-demarcated ulcers, hemorrhage and masses of organisms with a paucity of inflammatory cells. Characteristically, the disease is limited to the cecum, but it can involve the entire lower gastrointestinal tract. The cause is unknown, but neutropenia is clearly a prerequisite. Chemotherapeutic agents may also play a role since they also cause mucosal ulceration.

Radiographic examination usually reveals evidence of a paralytic ileus with lack of bowel gas in the right lower quadrant, minimal distention of the terminal ileum, and thickening of the bowel wall. Ultrasonography or CT should be done to confirm the diagnosis and extent of disease. Initially, therapy should be supportive, consisting of nasogastric suction, intravenous fluids, and broad-spectrum antibiotics that include coverage for P. aeruginosa and anaerobes. Granulocyte transfusions can be an important component of the therapy, and since the infection may prove rapidly fatal, they may be administered simultaneously with antibiotics and not withheld until a response to antibiotic therapy alone is determined. Surgery is not indicated, unless it can be demonstrated that the process is localized and the patient is not responding to supportive therapy.181 In a study over 70% of patients survived with medical therapy only.180

Perianal Infections

Perianal infections are estimated to occur in 6% of patients with hematologic neoplasms and in as many as 23% of patients with acute leukemia undergoing chemotherapy.182 They are especially common in patients with acute monocytic and acute myelomonocytic leukemia, suggesting that leukemic infiltration of the tissues may play a role. A common predisposing factor is neutropenia, which is found in over 90% of these patients. The major presenting symptom is pain that is aggravated by defecation. Most patients are febrile, often with a hectic or septic temperature course. The lesion is erythematous, indurated, and ulcerated. Abscess formation occurs infrequently, but there may be extensive necrosis and sloughing extending into the rectum. Usually, the infection occurs at a site of a fissure or hemorrhoid, and, because of the absence of an inflammatory response, the extent of the infection may not be fully recognized.183

The majority of these infections are caused by aerobic gramnegative bacilli, especially P. aeruginosa and Escherichia coli. Pseudomonas infection can be especially devastating because the organism invades blood vessel walls causing a vasculitis that can lead to tissue necrosis. Undoubtedly, anaerobic organisms play an important role in these infections but are often not recognized because appropriate cultures have not been obtained. In most series, however, when septicemia occurs, anaerobes have only infrequently been cultured from the blood.

Initial therapy should be symptomatic, consisting of sitz baths or warm compresses, stool softeners, analgesics, and broad-spectrum antibiotics. Gut-sterilizing oral antibiotic regimens may be of some value in reducing contamination of ulcers by fecal flora. If an abscess is present, it should be incised and drained. Most physicians are reluctant to incise lesions without the presence of an abscess, but in one study, relief of symptoms and recovery were more likely to follow such an aggressive approach despite the absence of frank pus.184 Even when only scant watery or serosanguineous fluid was drained, it resulted in resolution of fever and healing. Radiotherapy has been evaluated in a prospective randomized trial and proven to be ineffective.

Mortality from these infections has varied from 10 to 35%, with most deaths being due to septicemic shock. In the neutropenic patient, resolution of infection often depends on recovery of the neutrophil count. Some patients may respond to initial antibiotic therapy, only to develop superinfection with a resistant organism. Patients with hematologic diseases who recover from perianal infections due to hemorrhoids or anal fissures should undergo surgical correction when they achieve a remission of their underlying disease, as otherwise, they may experience recurrent infections at a later date.185

Skin Infections

Skin infections may occur secondary to necrotic tumor masses, postoperative wound infections, extravasation of vesicant drugs, infected intravascular catheters, folliculitis, infected decubitus ulcers, or as manifestations of systemic infection or embolic lesions secondary to endocarditis. Advanced squamous carcinomas of the skin, head and neck carcinomas, breast carcinomas, and sarcomas become necrotic and ulcerated and can serve as a focus of infection. Although initially these infections may be caused by gram-positive organisms, eventually superinfection with gram-negative bacilli occurs and is impossible to eradicate with antibiotic therapy alone. These infections can pose a serious threat to patients undergoing myelosuppressive chemotherapy because of the risk of septicemia when they become neutropenic. Occasional patients develop gas-forming infections of large tumor masses, which may be due to anaerobes, aerobic gram-negative bacilli, or mixed organisms.

Neutropenic patients usually do not form abscesses at the site of skin infection but rather develop a spreading cellulitis, which often is associated with septicemia. A wide variety of aerobic gram-positive and gram-negative organisms can cause these infections, including skin contaminants such as Bacillus spp., Corynebacterium jeikeium, and Staphylococcus epidermidis. Efforts should be made to aspirate material from these infected sites, although cultures are frequently negative.

Systemic infections in cancer patients may be associated with skin lesions. An important skin lesion is ecthyma gangrenosum, which characteristically is found in the perianal area, groin, or axilla. Nearly always, it is caused by P. aeruginosa, but other gram-negative bacilli including Aeromonas and Serratia, fungi including Aspergillus or Mucorales, or S. aureus may be the cause.

Several fungi cause skin lesions as a manifestation of systemic infection. About 10% of patients with disseminated candidiasis develop characteristic macronodular skin lesions (Fig. 157.12). Disseminated aspergillosis and mucormycosis are infrequently associated with sharply demarcated lesions covered by a black eschar (Fig. 157.13). Skin lesions occur in cryptococcosis and histoplasmosis but are not characteristic. Fusarium causes a fungal infection that is frequently associated with a variety of skin lesions.

Figure 157.12. Characteristic macronodular cutaneous lesions in a patient with acute leukemia and disseminated Candida krusei infection.

Figure 157.12

Characteristic macronodular cutaneous lesions in a patient with acute leukemia and disseminated Candida krusei infection.

Figure 157.13. Disseminated aspergillosis and mucormycosis are infrequently associated with sharply demarcated lesions covered by a black eschar.

Figure 157.13

Disseminated aspergillosis and mucormycosis are infrequently associated with sharply demarcated lesions covered by a black eschar.

Widespread use of intravascular catheters in cancer patients has contributed to the changing spectrum of infection during the past decade. Whereas gram-positive infections accounted for less than 10% of cases of septicemia two decades ago, they now cause 60% of cases. Staphylococcus epidermidis has emerged as an important pathogen, and the frequency of S. aureus infection has increased substantially. Some of these infections are caused by Bacillus spp., Corynebacterium jeikeum, Enterococcus, Enterobacter spp., Acinetobacter, and fungi.1,39 Despite the widespread use of catheters, the infection rate seldom exceeds 15%, even in neutropenic patients.

In the past, the recommended policy was to remove the catheter whenever a patient developed fever and especially when it was associated with septicemia. Recent experience indicates that many cases of septicemia can be successfully treated without the removal of the catheter. Exceptions include fungi, S. aureus, Acinetobacter, Pseudomonas spp. other than P. aeruginosa, the atypical mycobacteria, and whenever there is cellulitis at the catheter site. However, if fever or bacteremia persists despite antibiotic therapy, catheters must always be removed. Because many of the gram-positive organisms associated with catheter infections are resistant to methicillin, vancomycin has become an important component of antibiotic therapy. Of great concern has been the recent emergence of vancomycin-resistant Enterococcus faecium as a cause of these infections.

The most serious catheter-related infections are septic thrombophlebitis and endocarditis.50,186 Septic thrombophlebitis is characterized by microabscess formation within a cannulated vein, which may be associated with repeated septic embolization. The majority of these infections is caused by S. aureus, Streptococcus, Bacteroides spp., and enteric gram-negative bacilli. As many as 70% of infections occur without local signs. Septic emboli occur in as many as 50% of the patients. This is a potentially life-threatening complication requiring prompt attention and should be suspected when a patient develops clinical evidence of sepsis with signs of local inflammation in the cannulated vein and positive blood cultures. The absence of pus within the vein does not preclude the diagnosis of septic phlebitis. Surgical exploration of the vein is necessary if the patient fails to respond to appropriate antibiotic therapy shortly after removal of the infected catheter. Endocarditis in the cancer patient presents no unique manifestations. Because the risk of endocarditis is greater in patients with valvular heart disease, catheters should not be routinely utilized in these patients for the administration of chemotherapy. Recently, antimicrobial impregnated catheters have become available that reduce the frequency of catheter-associated infections during short-term use.

Therapy of Infections in Neutropenic Patients

General Principles

The practice of initiating empiric broad-spectrum antimicrobial therapy when a neutropenic patient becomes febrile immediately after procuring all relevant cultures is now a well-accepted standard.187–189 Antibiotic therapy should be administered promptly, via the intravenous route, and at maximal therapeutic doses in order to achieve maximal efficacy. A large number of antimicrobial agents are available that can be used effectively in empirical regimens, and no specific antibiotic or combination of antibiotics is considered optimal.31 In general, an empiric regimen should provide a broad spectrum of activity against gram-negative organisms including P. aeruginosa, and gram-positive pathogens. This is usually achieved by administering antibiotic combinations (an aminoglycoside plus an antipseudomonal beta-lactam, or a combination of two beta-lactams), or broad-spectrum drugs used as single agents (monotherapy). The recent increase in gram-positive infections has led to the inclusion of vancomycin in some empiric regimens. When data obtained from blood and other specimens sent for culture at the initiation of antibiotic therapy become available, appropriate changes in the initial regimen should be made depending on the pathogen(s) isolated and the susceptibility pattern demonstrated in vitro.

A number of studies have demonstrated that serum bactericidal activity is of great importance when treating infections in neutropenic patients. In neutropenic patients a peak serum bactericidal titer of 1:16 or more was associated with a clinical success rate of 87%, while a peak serum bactericidal titer of 1:8 or less was associated with failure in 83% of bacteremias. The significant peak bactericidal titer for patients with adequate numbers of neutrophils was 1:8 with 98% success at or above this level and none below it.190

There is some evidence that antibiotic combinations that interact in a synergistic manner in vitro provide greater serum bactericidal activity and greater clinical efficacy than nonsynergistic combinations. Synergism may be of importance in patients with rapidly fatal underlying disease and severe and prolonged neutropenia who develop gramnegative septicemia. The enhanced activity of synergistic combinations is probably due to the lowering of the minimal inhibitory concentrations (MIC) of both drugs for the offending pathogen, thereby providing greater bactericidal activity in blood and tissues and, on occasion, rendering organisms that are resistant to the individual agents susceptible to the combination. Synergy occurs most often when an aminoglycoside is combined with an antipseudomonal penicillin and least often when two beta-lactam antibiotics are used in combination.

The importance of synergy has been questioned by some investigators.191 In many studies showing an advantage associated with synergistic combinations, often the nonsynergistic combination consisted of an aminoglycoside as the only agent to which the offending pathogen was susceptible. Several studies have shown that aminoglycosides are ineffective against gram-negative bacilli in neutropenic patients and should not be used alone.192 In severely neutropenic patients, better results may be obtained if the pathogen is susceptible to both agents of a combination rather than to only one, regardless of the presence or absence of synergy.

Antibiotic selection is also influenced by the potential toxicity associated with various agents. The aminoglycosides have long been associated with significant nephro- and ototoxicity and require frequent monitoring of renal function and serum levels, which can be expensive, time consuming, and uncomfortable to the patient. Elderly patients or those with pre-existing renal insufficiency are at greater risk for developing aminoglycoside-associated toxicity. The toxicity of the aminoglycosides can also be potentiated by other agents frequently used in cancer patients such as amphotericin B, cisplatin, and cyclosporin. Although the beta-lactam agents are associated with untoward reactions, such as hypersensitivity reactions and coagulation abnormalities, they are generally safer and better tolerated than aminoglycosides.

Local factors need to be considered when selecting antibiotics for initial empiric therapy. Certain pathogens may be endemic in a particular institution and must be included in the spectrum of the initial empiric regimen. Empiric therapy should include agents with antianaerobic activity in the case of intra-abdominal and pelvic infections (Table 157.5). Also, the susceptibility of various organisms may differ from one institution to another, and local susceptibility/resistance patterns must be kept in mind when designing empiric regimens.193

Table 157.5. Antimicrobial Agents Commonly Used in Neutropenic Patients.

Table 157.5

Antimicrobial Agents Commonly Used in Neutropenic Patients.

Patient Evaluation

Antimicrobial therapy in febrile neutropenic patients needs to be administered promptly, and a delay of even a few hours can result in substantially increased mortality.33 Pretreatment evaluation of the patient should therefore be performed as expeditiously as possible, yet it should be thorough. Although the inflammatory response may be blunted and physical signs of infection absent, a careful interview for historic information and a physical examination must be performed. Particular attention should be paid to sites that are frequently infected or serve as foci for the dissemination of infection. These include the oropharynx, lung, lower esophagus, perineum, paranasal sinuses, fingernails, and vascular catheter exit sites. Prior to the initiation of empiric antibiotic therapy, at least two sets of blood cultures and cultures from other appropriate sites (i.e., throat, urine, stool) should be obtained for examination for bacterial and fungal pathogens. In patients with central venous catheters, cultures should be obtained from the catheters and from a peripheral site. Material exuding from infected catheter exit sites should also be sent for Gram staining and culture. Cultures from appropriate sites should be repeated daily while patients remain febrile. All febrile neutropenic patients should undergo chest radiography to identify pulmonary lesions. In neutropenic patients with pneumonia, radiographs may appear normal. However, radiographs or CT scans of paranasal sinuses should be performed in patients in whom these sites are potential sources of infection. Other laboratory investigations include complete blood counts and determination of baseline values reflecting renal and hepatic function. These tests should be repeated at least twice a week while patients are receiving empiric antibiotic therapy. Imaging techniques, such as CT, MRI, ultrasonography, and radionuclide imaging, and invasive procedures, such as lung, liver, or skin biopsies, might be extremely useful at identifying sites of infection and isolating specific pathogens. The presence of thrombocytopenia often precludes the use of invasive diagnostic techniques. The absence of neutrophils precludes 199indium granulocyte localization studies. In this situation, gallium scanning may occasionally be helpful.

Initial Antibiotic Therapy

Antibiotic regimens that are frequently deployed in febrile neutropenic patients are listed in Table 157.6. These regimens provide broad-spectrum therapy and should be initiated promptly when neutropenic patients develop an elevated temperature. No single regimen is optimal, and the various factors discussed above need to be carefully considered before making a specific choice. The initial regimen may also need to be altered during the course of the febrile episode, depending on the susceptibility of microorganisms isolated from clinical specimens, the development of bacterial, fungal, or viral superinfections, or lack of apparent efficacy after administration of the regimen for 3 days.

Table 157.6. Common Antibiotic Regimens in Neutropenic Patients.

Table 157.6

Common Antibiotic Regimens in Neutropenic Patients.

Combinations of aminoglycosides and antipseudomonal penicillins have been extensively evaluated and are generally associated with overall response rates in the range of 65 to 85%. Aminoglycosides are often used in combination with extended-spectrum cephalosporins (ceftazidime, cefepime) and other beta-lactam agents (aztreonam, ticarcillin + clavulanic acid, piperacillin + tazobactam).31 The advantages of such combinations include the potential for synergy against gram-negative bacilli including P. aeruginosa, activity against many anaerobes, and minimal emergence of resistant organisms during therapy. Disadvantages of aminoglycoside–beta-lactam combinations include the potential for oto- and nephrotoxicity (particularly with repeated use, in elderly patients or those with underlying renal insufficiency, and when other potentially nephrotoxic agents, such as amphotericin B, are needed) and the lack of activity against many grampositive organisms. Once daily administration of aminoglycosides is associated with less toxicity than more frequent administration.194 Care must be taken to ensure that the aminoglycoside is not the only active agent against any gram-negative bacilli that are isolated, since these agents are not effective by themselves in neutropenic patients, even if the causative organisms are susceptible to them in vitro.

In an attempt to avoid aminoglycoside-associated toxicity, double beta-lactam combinations have been evaluated and found to be as effective but less toxic than aminoglycoside-containing combinations. Extended-spectrum cephalosporins are generally combined with antipseudomonal penicillins and provide a broad spectrum against gram-negative, anaerobic, and some gram-positive bacteria. Potential disadvantages of such combinations include high cost and the selection of resistant organisms and have reduced the impact of these regimens.

With the availability of broad-spectrum agents, such as carbapenems and extended-spectrum cephalosporins, it has become possible to initiate empiric therapy in febrile neutropenic patients using a single agent. Cefoperazone, ceftazidime, imipenem/cilastatin and meropenem have been used alone as initial therapy and have produced response rates similar to those obtained with combination regimens (see Table 157.6).195–197 Patients on single-agent therapy need to be carefully monitored and antibiotic changes made if the clinical situation or microbiologic data indicate the need.198

With the increased incidence of gram-positive infections, many of which are caused by methicillin- or multi-drug–resistant organisms, the inclusion of vancomycin in the initial regimen might become necessary.199,200 Most gram-positive infections are associated with low mortality, and several studies have shown that vancomycin can be safely added to the initial regimen if no response is obtained after 48 to 72 hours of therapy, or if a resistant organism is isolated, without adversely affecting the eventual outcome.25 This approach may reduce vancomycin-associated toxicity and costs and may decrease the potential for the emergence of vancomycin-resistant organisms. Fulminant gram-positive infection caused by alpha-hemolytic streptococci, S. pyogenes, or other gram-positive organisms have been described. It might be prudent to include vancomycin in the initial empiric regimen in institutions or specific patient populations (bone marrow transplant recipients) in whom these infections occur frequently.200

Low-Risk Patients

Antibiotic therapy for febrile neutropenic patients has traditionally been administered in the hospital because of the risk of infection-related and other complications. Although effective, this is an expensive, resource-consuming strategy if applied to all neutropenic patients who develop fever. Recently, simple clinical criteria and statistical prediction rules have made it possible to identify low-risk subsets among febrile neutropenic patients at the onset of the febrile episode.12 This development has enabled clinicians to evaluate not only the nature of therapy in such patients but also the setting (hospital, clinic, office, home) in which empiric antibiotic therapy is delivered.14 There is as yet, no universally accepted definition of low risk, and until better predictive models are developed, only clinically stable outpatients with solid tumors and expected duration of neutropenia ≤ 7 days should be considered low risk. Low-risk patients may be hospitalized initially, stabilized over 48 to 72 hours, and then discharged on home antibiotic therapy.15 The entire febrile episode might be treated in the outpatient setting using parenteral, sequential, or oral antimicrobial regimens.13,201 This approach is associated with substantial cost saving, a lower incidence of nosocomial superinfections, and improved quality of life for patients and convenience for their families. Careful patient selection and daily follow-up are essential components of the success of this novel approach. The Infectious Diseases Society of America (IDSA) and the National Comprehensive Cancer Network (NCCN) have recently published guidelines for the treatment of febrile neutropenic patients, which include suggestions for the outpatient management of low-risk patients.31,202

Duration of Therapy

Some authorities recommend continuation of antibiotic therapy in patients with documented infections until recovery of the neutrophil count, although overwhelming evidence indicates that this is not necessary. This approach is expensive, as it actually represents prophylaxis after resolution of infection and may result in an increased number of superinfections requiring numerous modifications of antibacterial therapy and/or the addition of antifungal therapy. Another approach is to continue antibiotics until all sites of infection have resolved, the causative pathogen, if isolated, has been eradicated, the patient has been treated for a minimum of 7 days and has remained free of significant symptoms or signs of infection for at least 4 days. Antibiotic therapy may be discontinued safely at this point despite the persistence of neutropenia.203 This approach may be associated with a low relapse rate and fewer superinfections.204

Fever of Unexplained Origin

The most perplexing group of patients are those with fever who display no clinical signs of infection and from whom no pathogen is isolated, that is, fever of unexplained origin (FUO). Many of these patients respond to the initial antibacterial regimens, suggesting that they do have bacterial infections. The widespread use of prophylactic antibiotics may, to an extent, be responsible for the failure to isolate the offending pathogens in such patients. Patients who remain febrile despite antibacterial therapy pose a difficult diagnostic and therapeutic challenge. These patients may have bacterial infections that are resistant to therapy or infections by nonbacterial pathogens (fungi, viruses, parasites). Drug-related or tumor fever may also be present. Aggressive, often invasive, diagnostic maneuvers are sometimes necessary for the management of such patients. In patients unable to tolerate invasive diagnostic procedures, continuation of antibacterial therapy and the addition of empiric antifungal, antiviral, or antiparasitic therapy might be necessary.

Other Therapeutic Modalities

About 15 to 25% of infections occurring in neutropenic patients fail to respond to appropriate antimicrobial therapy. In most cases, profound neutropenia persists, and patients remain febrile despite adjustments in antibacterial therapy and the addition of an antifungal agent. There was considerable interest in the use of white blood cell transfusions in the 1960s and 1970s. Early studies showed that optimum efficacy was achieved with the transfusion of 1011 neutrophils, an amount difficult to collect from normal donors. Dexamethasone was administered to donors to increase the number of neutrophils collected. Randomized trials in neutropenic patients with infections that failed to respond to appropriate therapy demonstrated that white blood cell transfusions increased the response rates. Interest in this therapeutic modality waned because of the difficulties in obtaining sufficient donors, alloimmunizaiotn of recipients when random donors were used, and the possibility of transmitting CMV infection from transfused cells. The availability of the hematopoietic growth factors has rekindled interest in this therapeutic modality because the administration of granulocyte colony-stimulating factor (G-CSF) to donors increases the number of neutrophils that can be collected.205 Preliminary clinical studies suggest that this approach to white blood cell collection has produced therapeutic benefit in about half the recipients.206

The administration of hematopoietic growth factors to patients receiving cancer chemotherapy reduces the severity and duration of neutropenia and, hence, the frequency of infectious complications. Guidelines for this use of these agents have been prepared by the American Society of Clinical Oncology (ASCO).207 The efficacy of these factors as adjuncts to antibiotic therapy for neutropenic patients after they have become infected has not been clearly established. It is reasonable to administer these agents to patients with neutrophil counts less than 500/mm3 who develop pneumonia, septic shock, sepsis syndrome, or fungal infection, since these patients have a poor prognosis without recovery of their neutrophils. Also, these agents should be considered for patients with documented infections who are failing to respond to appropriate therapy after 24 to 48 hours. INF-γ may be beneficial for therapy with nonviral infections that are not responding to appropriate therapy.208,209

Infection Prevention

The high frequency of infection in cancer patients during periods of myelosuppression has led to the development of programs for the prevention of infection. A number of studies have demonstrated that 80 to 85% of organisms that cause infection in cancer patients are derived from the endogenous microflora, and that up to 50% of these are hospital-acquired organisms. The two main strategies that are used for infection prevention are therefore directed toward suppressing the endogenous microflora and preventing the acquisition of new organisms from environmental sources. Suppression of the endogenous microflora is usually achieved by using prophylactic antibiotic regimens during periods of severe myelosuppression. In patients who are at risk for fungal, viral, or protozoal infections or in centers where such infections are relatively common, prophylactic regimens generally also include agents active against these groups of organisms. The prevention of acquisition of new organisms is accomplished by various techniques, including strict hand-washing precautions, use of well-cooked foods, which reduces contamination with gram-negative bacteria, and various isolation techniques or protected environments.6

Antimicrobial Prophylaxis

Prophylactic antimicrobial regimens achieve a major reduction in the patients’ microbial burden. TMP-SMX has been used in the past for this indication. Although most studies have shown a reduction in microbiologically documented infections and a reduction in the need for systemically administered antibiotics, the overall mortality has not been significantly altered. The use of TMP-SMX for prophylaxis has been associated with the emergence of resistant organisms, an increase in fungal colonization and infection, and prolongation of neutropenia. TMP-SMX remains the agent of choice for PCP prophylaxis.

The quinolones (norfloxacin, ciprofloxacin, ofloxacin) have virtually replaced TMP-SMX for antibacterial prophylaxis and are now the most commonly used agents for chemoprophylaxis.27 The use of these agents has been associated with significant reductions in the frequency of gram-negative infections, but they have little impact on, or may actually increase the frequency of, gram-positive infections (particularly with Streptococcus and Staphylococcus species). Quinolone prophylaxis has also resulted in the emergence of quinolone resistance among enteric gram-negative bacilli including E. coli.30 It is therefore not recommended for routine use in neutropenic patients but must be considered only in patients at high-risk for bacterial infection (i.e., those with prolonged periods of neutropenia).30,31

Antifungal and Antiviral Prophylaxis

Since fungal infections have become increasingly prominent in patients with cancer, antifungal prophylaxis has also been evaluated. Most prophylactic regimens have been aimed at reducing infections due to Candida species and are generally not effective in reducing other fungal infections (aspergillosis, mucormycosis). The most frequently evaluated agents have been nystatin, amphotericin B, and, more recently, miconazole, clotrimazole, ketoconazole, and fluconazole. In general, antifungal prophylaxis using these agents has been shown to produce a consistent decrease in superficial colonization with Candida species. Recently, fluconazole has been shown to decrease both superficial colonization and systemic Candida infection. A potential problem of antifungal prophylaxis is the selection of more resistant fungal organisms, such as Candida species other than C. albicans. As with antibacterial prophylaxis, the benefits of antifungal prophylaxis need to be weighed against the potential risks.

The availability of acyclovir and ganciclovir has made prophylaxis against herpes viruses possible. Acyclovir administered intravenously and/or orally has been shown to prevent reactivation of HSV infection in patients undergoing intensive chemotherapy with or without radiotherapy before bone marrow transplantation or induction therapy for leukemia or lymphoma. Recent data indicate that intravenous acyclovir may also reduce the incidence of CMV reactivation when used prophylactically. Ganciclovir is more active than acyclovir against CMV and has been demonstrated to be effective in reducing the incidence of CMV infection and disease in CMV-seropositive bone marrow transplant recipients. The occurrence of neutropenia is a limiting factor for ganciclovir prophylaxis. Foscarnet might be a useful alternative agent for this indication.

Isolation

Reduction of the acquisition of new organisms has been attempted by putting patients at risk into reverse isolation. Patients are also given well-cooked foods and are asked to avoid fresh fruits and vegetables (e.g., tomatoes, salads) that are naturally contaminated with gram-negative bacilli such as P. aeruginosa, Klebsiella pneumoniae, and E. coli. More elaborate regimens are expensive and time consuming and have not been shown to be more effective than strict adherence to hand-washing techniques.

Protected environments (PEs) provide a combination of the two approaches, that is, the use of isolation units to protect the patient against nosocomial contamination plus antibiotic regimens to reduce the patient’s endogenous flora. The PE generally consists of isolation units, which provide a barrier between the patient and the hospital environment, using aggressive decontamination techniques and filtered air. The most effective type of unit is the laminar airflow room, in which one wall or the ceiling comprises high efficiency air filters. Filtered air flows across the room with a laminar distribution, providing several hundred air exchanges per hour. All items used by the patient are sterilized before being placed in the unit, and various germicidal agents are used initially and during occupation of the units to maintain a sterile environment. The patient’s food is specially prepared or sterilized to minimize contamination. Disinfection of the patient is achieved by using intensive regimens, which include oral nonabsorbable antibiotics. Patients bathe with germicidal soaps and apply topical antibiotic ointments or sprays to areas of heavy microbial contamination.

Several studies have been conducted using the PE-prophylactic antibiotic program, particularly in patients undergoing remission induction therapy for acute leukemia. All these studies have demonstrated that patients treated with this program develop fewer serious infections than do controls.210 The proportion of days spent with infection at every level of circulating neutrophils is higher among control patients. This is not surprising since microbial contamination of the air and surfaces within laminar airflow rooms is 100-fold less than that of regular hospital rooms. However, PE programs are expensive and are difficult to tolerate for prolonged periods of time. They are, therefore, not used routinely, and only patients with severe and prolonged neutropenia (remission induction therapy for acute leukemia or bone marrow transplantation) are treated in protected environments.

Since attempts at suppressing the endogenous microflora and those at preventing the acquisition of organisms have not been overwhelmingly successful, other means for infection prevention need to be developed. The hematopoietic growth factors (granulocyte-macrophage [GM]-CSF and G-CSF) have been demonstrated to shorten the duration of neutropenia and to reduce the number of febrile days and of documented infections in selected subpopulations of neutropenic patients. Current guidelines suggest that the primary use of these agents is not indicated in previously untreated patients receiving most chemotherapy regimens.207 The secondary administration of growth factors can decrease the probability of febrile neutropenia after a documented occurrence in an earlier cycle. They can also reduce the period of neutropenia and the frequency of infectious complications in patients undergoing high-dose cytotoxic therapy with autologous marrow transplantation. Studies are being conducted in several other areas wherein CSF use might be beneficial, and their role is likely to expand as these data become available.211

Perspectives

Infection is still a frequent and serious complication for many cancer patients. The spectrum of bacterial infection continues to change, requiring continued vigilance, and the development of new strategies for infection prevention and optimal therapy. The emergence of newer pathogens, such as vancomycin-resistant enterococci and Stenotrophomonas maltophilia has posed serious challenges. Additionally, old adversaries such as Staphylococcus spp., Streptococcus spp. (S. pneumoniae, S. viridans), the Enterobacteriaceae, P. aeurginosa, and M. tuberculosis are becoming increasingly difficult to treat due to the acquisition of resistance to commonly used antimicrobial agents. Disseminated fungal infections are now the leading cause of death in patients with hematologic malignancies. Although the therapeutic armamentarium against fungi has expanded, and several newer antifungal agents are under investigation, resistant organisms, such as C. krusei, C. lusitaniae, C. rugosa, Fusarium spp., and Pseudallescheria boydii have appeared. The diagnosis and treatment of many fungal infections, particularly in the setting of persistent neutropenia, remain unsatisfactory. Viral infections are rapidly gaining importance, particularly in bone marrow transplant recipients and patients with acute leukemia. Although effective preventive measure and therapy for most herpes viruses (HSV-I, HSV-II, VZV, CMV) have been developed, serious infections caused by other viruses (RSV, influenza type B, adenoviruses, etc.) cannot be treated effectively. Reliable methods for the rapid diagnosis of these infections and effective means for their prevention and treatment still need to be developed. Parasitic infections are still uncommon, although they have increased in frequency since the onset of the AIDS epidemic. Although effective therapies are available, toxicity and the need for prolonged maintenance therapy can be problematic. Among the more positive developments is the availability of the hematopoietic growth factors (G-CSF, CM-CSF) and other cytokines. These agents play a significant role in preventing infections and are also potentially useful as therapeutic adjuncts for a wide variety of infections in cancer patients. The hematopoietic growth factors have also made it possible to transfuse large numbers of granulocytes by stimulating their growth in normal donors. The role of granulocyte transfusions is currently being re-evaluated in the treatment of serious bacterial and fungal infections. Recent advances have enabled clinicians to evaluate not only the nature of antimicrobial therapy but also the setting in which it is delivered. The ability to recognize with accuracy low-risk neutropenic patients at the onset of their febrile episode has encouraged the development of alternative treatment strategies, such as early discharge from hospital or outpatient antibiotic therapy, which appears to be as safe and effective as hospital-based therapy. These strategies are associated with a reduction in nosocomially acquired superinfections and an improved quality of life for patients and their families. Protected environments, prophylactic programs, infection control strategies, and the CSFs have reduced the risk of infection in cancer patients. The use of vaccines in high-risk patients affords protection against specific pathogens. Newer technologic advances should lead to further progress. However, the recognition, prevention, diagnosis, and treatment of infections in cancer patients will continue to challenge us in the foreseeable future, as we work toward the larger goal of eliminating cancer.

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