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Infections are a common cause of death and an even more common cause of morbidity in patients with a wide variety of neoplasms. Autopsy studies show that most deaths from acute leukemia and half of deaths from lymphoma are caused directly by infection.With more intensive chemotherapy, patients with solid tumors have also become more likely to die of infection. Fortunately, an evolving approach to prevention and treatment of infectious complications of cancer has decreased rates of infection-associated mortality and will probably continue to do so. This accomplishment has resulted from three major steps:


1. The concept of “early empirical” antibiotics reduced mortality rates among patients with leukemia and bacteremia from 84% in 1965 to 44% in 1972.With better availability (and early use) of broad-spectrum antibiotics, this figure has recently dropped to 20–36%.


2. “Empirical” antifungal therapy has lowered the incidence of disseminated fungal infection; in trial settings, mortality rates now range from 7–21%. An antifungal agent is administered—on the basis of likely fungal infection—to neutropenic patients who, after 4–7 days of antibiotic therapy, remain febrile but have no positive cultures.


3. Use of antibiotics for afebrile neutropenic patients as broad-spectrum prophylaxis against infections promises to decrease both mortality and morbidity even further. A physical predisposition to infection in patients with cancer (Table 11-1) can be a result of the neoplasm’s production of a break in the skin. For example, a squamous cell carcinoma may cause local invasion of the epidermis, which allows bacteria to gain access to the subcutaneous tissue and permits the development of cellulitis. The artificial closing of a normally patent orifice can also predispose to infection: Obstruction of a ureter by a tumor can cause urinary tract infection, and obstruction of the bile duct can cause cholangitis.


Part of the host’s normal defense against infection depends on the continuous emptying of a viscus; without emptying, a few bacteria present as a result of bacteremia or local transit can multiply and cause disease. A similar problem can affect patients whose lymph node integrity has been disrupted by radical surgery, particularly patients who have had radical node dissections. A common clinical problem after radical mastectomy is the development of cellulitis (usually caused by streptococci or staphylococci) because of lymphedema and/or inadequate lymph drainage. In most cases, this problem can be addressed by local measures designed to prevent fluid accumulation and breaks in the skin, but antibiotic prophylaxis has been necessary in refractory cases.


A life-threatening problem common to many cancer patients is the loss of the reticuloendothelial capacity to clear microorganisms after splenectomy. Splenectomy may be performed as part of the management of hairy cell leukemia, chronic lymphocytic leukemia (CLL), and chronic myelocytic leukemia (CML) and in Hodgkin’s disease. Even after curative therapy for the underlying disease, the lack of a spleen predisposes such patients to rapidly fatal infections. The loss of the spleen through trauma similarly predisposes the normal host to overwhelming infection for life after splenectomy.The splenectomized patient should be counseled about the risks of infection with certain organisms, such as the protozoan Babesia (Chap. 117) and Capnocytophaga canimorsus (formerly dysgonic fermenter 2, or DF-2), a bacterium carried in the mouths of animals (Chaps. 5 and 48). Since encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis) are the organisms most commonly associated with postsplenectomy sepsis, splenectomized persons should be vaccinated (and revaccinated; Table 11-2 and Chap. 3) against the capsular polysaccharides of these organisms.


Many clinicians recommend giving splenectomized patients a small supply of antibiotics effective against S. pneumoniae,N. meningitidis, and H. influenzae to avert rapid, overwhelming sepsis in the event that they cannot present for medical attention immediately after the onset of fever or other symptoms of bacterial infection. A few amoxicillin/clavulanic acid tablets are a reasonable choice for this purpose. The level of suspicion of infections with certain organisms should depend on the type of cancer diagnosed (Table 11-3). Diagnosis of multiple myeloma or CLL should alert the clinician to the possibility of hypogammaglobulinemia. Although immuno-globulin replacement therapy can be effective, in most cases prophylactic antibiotics are a cheaper, more convenient method of eliminating bacterial infections in CLL patients with hypogammaglobulinemia. Patients with acute lymphocytic leukemia (ALL), patients with non-Hodgkin’s lymphoma, and all cancer patients treated with high-dose glucocorticoids (or glucocorticoid-containing chemotherapy regimens) should receive antibiotic prophylaxis for Pneumocystis infection (Table 11-3) for the duration of their chemotherapy. In addition to exhibiting susceptibility to certain infectious organisms, patients with cancer are likely to manifest their infections in characteristic ways.


SYSTEM-SPECIFIC SYNDROMES SKIN-SPECIFIC SYNDROMES

Skin lesions are common in cancer patients, and the appearance of these lesions may permit the diagnosis of systemic bacterial or fungal infection. Although cellulitis caused by skin organisms such as Streptococcus or Staphylococcus is common, neutropenic patients—i.e., those with <500 functional polymorphonuclear leukocytes (PMNs)/ìL—and patients with impaired blood or lymphatic drainage may develop infections with unusual organisms. Innocent-looking macules or papules may be the first sign of bacterial or fungal sepsis in immunocompromised patients (Fig. 11-1). In the neutropenic host, a macule progresses rapidly to ecthyma gangrenosum, a usually painless, round, necrotic lesion consisting of a central black or gray-black eschar with surrounding erythema. Ecthyma gangrenosum, which is located in nonpressure areas (as distinguished from necrotic lesions associated with lack of circulation), is often associated with Pseudomonas aeruginosa bacteremia (Chap. 53), but may be caused by other bacteria. Candidemia (Chap. 107) is also associated with a variety of skin conditions and commonly presents as a maculopapular rash. Punch biopsy of the skin may be the best method for diagnosis. Cellulitis, an acute spreading inflammation of the skin, is most often caused by infection with group A Streptococcus or Staphylococcus aureus, virulent organisms normally found on the skin (Chap. 21).


Although cellulitis tends to be circumscribed in normal hosts, it may spread rapidly in neutropenic patients. A tiny break in the skin may lead to spreading cellulitis, which is characterized by pain and erythema; in the affected patients, signs of infection (e.g., purulence) are often lacking.What might be a furuncle in a normal host may require amputation because of uncontrolled infection in a patient presenting with leukemia. A dramatic response to an infection that might be trivial in a normal host can mark the first sign of leukemia. Fortunately, granulocytopenic patients are likely to be infected with certain types of organisms (Table 11-4); thus the selection of an antibiotic regimen is somewhat easier than it might otherwise be (see “Antibacterial Therapy” later in the chapter). It is essential to recognize cellulitis early and to treat it aggressively. Patients who are neutropenic or have previously received antibiotics for other reasons may develop cellulitis with unusual organisms (e.g., Escherichia coli, Pseudomonas, or fungi). Early treatment, even of innocent-looking lesions, is essential to prevent necrosis and loss of tissue. Debridement to prevent spread may sometimes be necessary early in the course of disease, but it can often be performed after chemotherapy, when the PMN count increases. Sweet’s syndrome, or febrile neutrophilic dermatosis, was originally described in women with elevated white blood cell (WBC) counts. The disease is characterized by the presence of leukocytes in the lower dermis, with edema of the papillary body.


Ironically, this disease now is usually seen in neutropenic patients with cancer, most often in association with acute leukemia, but also in association with a variety of other malignancies. Sweet’s syndrome usually presents as red or bluish-red papules or nodules that may coalesce and form sharply bordered plaques. The edema may suggest vesicles, but on palpation the lesions are solid, and vesicles probably never arise in this disease. The lesions are most common on the face, neck, and arms. On the legs, they may be confused with erythema nodosum. The development of lesions is often accompanied by high fevers and an elevated erythrocyte sedimentation rate. Both the lesions and the temperature elevation respond dramatically to glucocorticoid administration. Treatment begins with high doses of glucocorticoids (60 mg/d of prednisone) followed by tapered doses over the next 2–3 weeks.


Data indicate that erythema multiforme with mucous membrane involvement is often associated with herpes simplex virus (HSV) infection and is distinct from Stevens-Johnson syndrome, which is associated with drugs and tends to have a more widespread distribution. Since cancer patients are both immunosuppressed (and therefore susceptible to herpes infections) and heavily treated with drugs (and therefore subject to Stevens- Johnson syndrome), both of these conditions are common in this population. Cytokines, which are used as adjuvants or primary treatments for cancer, can themselves cause characteristic rashes, further complicating the differential diagnosis.This phenomenon is a particular problem in bone marrow transplant recipients (Chap. 12), who, in addition to having the usual chemotherapy-, antibiotic-, and cytokineinduced rashes, are plagued by graft-versus-host disease.


CATHETER-RELATED INFECTIONS

Because IV catheters are commonly used in cancer chemotherapy and are prone to infection (Chap. 13), they pose a major problem in the care of patients with cancer. Some catheter-associated infections can be treated with antibiotics, whereas in others, the catheter must be removed (Table 11-5). If the patient has a “tunneled” catheter (which consists of an entrance site, a subcutaneous tunnel, and an exit site), a red streak over the subcutaneous part of the line (the tunnel) is grounds for immediate removal of the catheter. Failure to remove catheters under these circumstances may result in extensive cellulitis and tissue necrosis. More common than tunnel infections are exit-site infections, often with erythema around the area where the line penetrates the skin. Most authorities (Chap. 35) recommend treatment (usually with vancomycin) for an exit-site infection caused by a coagulase-negative Staphylococcus. Treatment of coagulase-positive staphylococcal infection is associated with a poorer outcome, and it is advisable to remove the catheter if possible. Similarly, many clinicians remove catheters associated with infections due to P. aeruginosa and Candida species, since such infections are difficult to treat and bloodstream infections with these organisms are likely to be deadly. Catheter infections caused by Burkholderia cepacia, Stenotrophomonas spp., Agrobacterium spp., and Acinetobacter baumannii as well as Pseudomonas spp. other than aeruginosa are likely to be very difficult to eradicate with antibiotics alone. Similarly, isolation of Bacillus, Corynebacterium, and Mycobacterium spp. should prompt removal of the catheter.


GASTROINTESTINAL TRACT–SPECIFIC SYNDROMES

Upper Gastrointestinal Tract Disease Infections of the Mouth The oral cavity is rich in aerobic and anaerobic bacteria (Chap. 65) that normally live in a commensal relationship with the host. The antimetabolic effects of chemotherapy cause a breakdown of host defenses, leading to ulceration of the mouth and the potential for invasion by resident bacteria. Mouth ulcerations afflict most patients receiving chemotherapy and have been associated with viridans streptococcal bacteremia. The use of keratinocyte growth factor (palifermin) in a daily dose of 60 ìg/kg for 3 days before chemotherapy and totalbody irradiation is of proven value in preventing mucosal ulceration after stem-cell transplantation.


Fluconazole is clearly effective in the treatment of both local infections (thrush) and systemic infections (esophagitis) due to Candida albicans.Newer azoles (such as voriconazole) are similarly effective. Noma (cancrum oris), commonly seen in malnourished children, is a penetrating disease of the soft and hard tissues of the mouth and adjacent sites, with resulting necrosis and gangrene. It has a counterpart in immunocompromised patients and is thought to be due to invasion of the tissues by Bacteroides, Fusobacterium, and other normal inhabitants of the mouth. Noma is associated with debility, poor oral hygiene, and immunosuppression. Viruses, particularly HSV, are a prominent cause of morbidity in immunocompromised patients, in whom they are associated with severe mucositis. The use of acyclovir, either prophylactically or therapeutically, is of value. Esophageal Infections The differential diagnosis of esophagitis (usually presenting as substernal chest pain upon swallowing) includes herpes simplex and candidiasis, both of which are readily treatable. Lower Gastrointestinal Tract Disease Hepatic candidiasis (Chap. 107) results from seeding of the liver (usually from a gastrointestinal source) in neutropenic patients.


It is most common in patients being treated for acute leukemia and usually presents symptomatically around the time the neutropenia resolves.The characteristic picture is that of persistent fever unresponsive to antibiotics; abdominal pain and tenderness or nausea; and elevated serum levels of alkaline phosphatase in a patient with hematologic malignancy who has recently recovered from neutropenia. The diagnosis of this disease (which may present in an indolent manner and persist for several months) is based on the finding of yeasts or pseudohyphae in granulomatous lesions. Hepatic ultrasound or CT may reveal bull’s-eye lesions. In some cases, MRI reveals small lesions not visible by other imaging modalities. The pathology (a granulomatous response) and the timing (with resolution of neutropenia and an elevation in granulocyte count) suggest that the host response to Candida is an important component of the manifestations of disease. In many cases, although organisms are visible, cultures of biopsied material may be negative.


The designation hepatosplenic candidiasis or hepatic candidiasis is a misnomer because the disease often involves the kidneys and other tissues; the term chronic disseminated candidiasis may be more appropriate. Because of the risk of bleeding with liver biopsy, diagnosis is often based on imaging studies (MRI, CT). Amphotericin B is traditionally used for therapy (often for several months, until all manifestations of disease have disappeared), but fluconazole may be useful for outpatient therapy. The use of other antifungal agents and combination therapy is less well studied. Typhlitis Typhlitis (also referred to as necrotizing colitis, neutropenic colitis, necrotizing enteropathy, ileocecal syndrome, and cecitis) is a clinical syndrome of fever and right-lowerquadrant tenderness in an immunosuppressed host. This syndrome is classically seen in neutropenic patients after chemotherapy with cytotoxic drugs. It may be more common among children than among adults and appears to be much more common among patients with acute myelocytic leukemia (AML) or ALL than among those with other types of cancer; a similar syndrome has been reported in patients infected with HIV type 1. Physical examination reveals right-lower-quadrant tenderness, with or without rebound tenderness. Associated diarrhea (often bloody) is common, and the diagnosis can be confirmed by the finding of a thickened cecal wall on CT, MRI, or ultrasonography. Plain films may reveal a right-lower-quadrant mass, but CT with contrast or MRI is a much more sensitive means of making the diagnosis. Although surgery is sometimes attempted to avoid perforation from ischemia, most cases resolve with medical therapy alone.


The disease is sometimes associated with positive blood cultures (which usually yield aerobic gram-negative bacilli), and therapy is recommended for a broad spectrum of bacteria (particularly gram-negative bacilli, which are likely to be found in the bowel flora). Surgery is indicated in the case of perforation. Clostridium Difficile–Induced Diarrhea Patients with cancer are predisposed to the development of C. difficile diarrhea (Chap. 43) as a consequence of chemotherapy alone. Thus they may have positive toxin tests before receiving antibiotics. Obviously, such patients are also subject to C. difficile– induced diarrhea as a result of antibiotic pressure. C. difficile should always be considered as a possible cause of diarrhea in cancer patients who have received antibiotics.


CENTRAL NERVOUS SYSTEM–SPECIFIC SYNDROMES

Meningitis The presentation of meningitis in patients with lymphoma or CLL, patients receiving chemotherapy (particularly with glucocorticoids) for solid tumors, and patients who have received bone marrow transplants suggests a diagnosis of cryptococcal or listerial infection. As noted previously, splenectomized patients are susceptible to rapid, overwhelming infection with encapsulated bacteria (including S. pneumoniae, H. influenzae, and N. meningitidis). Similarly, patients who are antibody-deficient (such as patients with CLL, those who have received intensive chemotherapy, or those who have undergone bone marrow transplantation) are likely to have infections caused by these bacteria. Other cancer patients, however, because of their defective cellular immunity, are likely to be infected with other pathogens (Table 11-3). Encephalitis The spectrum of disease resulting from viral encephalitis is expanded in immunocompromised patients.


A predisposition to infections with intracellular organisms similar to those encountered in patients with AIDS (Chap. 90) is seen in cancer patients receiving (1) high-dose cytotoxic chemotherapy, (2) chemotherapy affecting T-cell function (e.g., fludarabine), or (3) antibodies that eliminate T cells (e.g., anti-CD3) or cytokine activity. Infection with varicella-zoster virus (VZV) has been associated with encephalitis that may be caused by VZV-related vasculitis. Chronic viral infections may also be associated with dementia and encephalitic presentations, and a diagnosis of progressive multifocal leukoencephalopathy should be considered when a patient who has received chemotherapy presents with dementia (Table 11-6). Other abnormalities of the central nervous system (CNS) that may be confused with infection include normal-pressure hydrocephalus and vasculitis resulting from CNS irradiation. It may be possible to differentiate these conditions by MRI.


Brain Masses Mass lesions of the brain most often present as headache with or without fever or neurologic abnormalities. Infections associated with mass lesions may be caused by bacteria (particularly Nocardia), fungi (particularly Cryptococcus or Aspergillus), or parasites (Toxoplasma). Epstein-Barr virus (EBV)–associated lymphoproliferative disease may also present as single or multiple mass lesions of the brain. A biopsy may be required for a definitive diagnosis.


PULMONARY INFECTIONS

Pneumonia (Chap. 17) in immunocompromised patients may be difficult to diagnose because conventional methods of diagnosis depend on the presence of neutrophils. Bacterial pneumonia in neutropenic patients may present without purulent sputum—or, in fact, without any sputum at all—and may not produce physical findings suggestive of chest consolidation (rales or egophony). In granulocytopenic patients with persistent or recurrent fever, the chest x-ray pattern may help to localize an infection and thus to determine which investigative tests and procedures should be undertaken and which therapeutic options should be considered (Table 11-7). The difficulties encountered in the management of pulmonary infiltrates relate in part to the difficulties of performing diagnostic procedures on the patients involved. When platelet counts can be increased to adequate levels by transfusion, microscopic and microbiologic evaluation of the fluid obtained by endoscopic bronchial lavage is often diagnostic. Lavage fluid should be cultured for Mycoplasma, Chlamydophila, Legionella, Nocardia, more common bacterial pathogens, and fungi. In addition, the possibility of Pneumocystis pneumonia should be considered, especially in patients with ALL or lymphoma who have not received prophylactic trimethoprim-sulfamethoxazole (TMP-SMX).The characteristics of the infiltrate may be helpful in decisions about further diagnostic and therapeutic maneuvers.


Nodular infiltrates suggest fungal pneumonia (e.g., that caused by Aspergillus or Mucor). Such lesions may best be approached by visualized biopsy procedures. Aspergillus spp. (Chap. 108) can colonize the skin and respiratory tract or cause fatal systemic illness. Although Aspergillus may cause aspergillomas in a previously existing cavity or may produce allergic bronchopulmonary aspergillosis, the major problem posed by this genus in neutropenic patients is invasive disease due to A. fumigatus or A. flavus. The organisms enter the host after colonization of the respiratory tract, with subsequent invasion of the blood vessels. The disease is likely to present as a thrombotic or embolic event because of the organisms’ ability to invade blood vessels.The risk of infection with Aspergillus is correlated directly with the duration of neutropenia. In prolonged neutropenia, positive surveillance cultures for colonization of the nasopharynx with Aspergillus may predict the development of disease. Patients with Aspergillus infection often present with pleuritic chest pain and fever, which are sometimes accompanied by cough. Hemoptysis may be an ominous sign. Chest x-rays may reveal new focal infiltrates or nodules.


Chest CT may reveal a characteristic halo consisting of a mass-like infiltrate surrounded by an area of low attenuation. The presence of a “crescent sign” on a chest x-ray or a chest CT scan, in which the mass progresses to central cavitation, is characteristic of invasive Aspergillus infection but may develop as the lesions are resolving. In addition to causing pulmonary disease, Aspergillus may invade through the nose or palate, with deep sinus penetration. The appearance of a discolored area in the nasal passages or on the hard palate should prompt a search for invasive Aspergillus. This situation is likely to require surgical debridement. Catheter infections with Aspergillus usually require both removal of the catheter and antifungal therapy. Diffuse interstitial infiltrates suggest viral, parasitic, or Pneumocystis pneumonia. If the patient has a diffuse interstitial pattern on chest x-ray, it may be reasonable to institute empirical treatment with TMP-SMX (for Pneumocystis) and a quinolone (for Chlamydophila, Mycoplasma, and Legionella) or an erythromycin derivative (e.g., azithromycin) while considering invasive diagnostic procedures. Noninvasive procedures, such as staining of sputum smears for Pneumocystis, serum cryptococcal antigen tests, and urine testing for Legionella antigen, may be helpful. In transplant recipients who are seropositive for cytomegalovirus (CMV), a determination of CMV load in the serum should be considered.


Viral load studies (which allow physicians to quantitate viruses) have superseded simple measurement of serum IgG, which merely documents prior exposure to virus. Infections with viruses that cause only upper respiratory symptoms in immunocompetent hosts, such as respiratory syncytial virus (RSV), influenza viruses, and parainfluenza viruses, may be associated with fatal pneumonitis in immunocompromised hosts. An attempt at early diagnosis by nasopharyngeal aspiration should be considered so that appropriate treatment can be instituted. Bleomycin is the most common cause of chemotherapyinduced lung disease. Other causes include alkylating agents (such as cyclophosphamide, chlorambucil, and melphalan), nitrosoureas [carmustine (BCNU), lomustine (CCNU), and methyl-CCNU], busulfan, procarbazine, methotrexate, and hydroxyurea. Both infectious and noninfectious (drug- and/or radiation-induced) pneumonitis can cause fever and abnormalities on chest x-ray; thus the differential diagnosis of an infiltrate in a patient receiving chemotherapy encompasses a broad range of conditions (Table 11-7).


Since the treatment of radiation pneumonitis (which may respond dramatically to glucocorticoids) or drug-induced pneumonitis is different from that of infectious pneumonia, a biopsy may be important in the diagnosis. Unfortunately, no definitive diagnosis can be made in ∼30% of cases, even after bronchoscopy. Open-lung biopsy is the “gold standard” of diagnostic techniques. Biopsy via a visualized thoracostomy can replace an open procedure in many cases.When a biopsy cannot be performed, empirical treatment can be undertaken with a quinolone or erythromycin (or an erythromycin derivative such as azithromycin) and TMP-SMX (in the case of diffuse infiltrates) or with amphotericin B or other antifungal agents (in the case of nodular infiltrates). The risks should be weighed carefully in these cases. If inappropriate drugs are administered, empirical treatment may prove toxic or ineffective; either of these outcomes may be riskier than biopsy.


CARDIOVASCULAR INFECTIONS

Patients with Hodgkin’s disease are prone to persistent infections by Salmonella, sometimes (and particularly often in elderly patients) affecting a vascular site.The use of IV catheters deliberately lodged in the right atrium is associated with a high incidence of bacterial endocarditis, presumably related to valve damage followed by bacteremia. Nonbacterial thrombotic endocarditis has been described in association with a variety of malignancies (most often solid tumors) and may follow bone marrow transplantation as well. The presentation of an embolic event with a new cardiac murmur suggests this diagnosis. Blood cultures are negative in this disease of unknown pathogenesis.


ENDOCRINE SYNDROMES

Infections of the endocrine system have been described in immunocompromised patients. Candida infection of the thyroid may be difficult to diagnose during the neutropenic period. It can be defined by indium-labeled WBC scans or gallium scans after neutrophil counts increase. CMV infection can cause adrenalitis with or without resulting adrenal insufficiency. The presentation of a sudden endocrine anomaly in an immunocompromised patient may be a sign of infection in the involved end organ.


MUSCULOSKELETAL INFECTIONS

Infection that is a consequence of vascular compromise, resulting in gangrene, can occur when a tumor restricts the blood supply to muscles, bones, or joints.The process of diagnosis and treatment of such infection is similar to that in normal hosts, with the following caveats: 1. In terms of diagnosis, a lack of physical findings resulting from a lack of granulocytes in the granulocytopenic patient should make the clinician more aggressive in obtaining tissue rather than relying on physical signs. 2. In terms of therapy, aggressive debridement of infected tissues may be required, but it is usually difficult to operate on patients who have recently received chemotherapy, both because of a lack of platelets (which results in bleeding complications) and because of a lack of WBCs (which may lead to secondary infection). A blood culture positive for Clostridium perfringens—an organism commonly associated with gas gangrene— can have a number of meanings (Chap. 42). Bloodstream infections with intestinal organisms such as Streptococcus bovis and C. perfringens may arise spontaneously from lower gastrointestinal lesions (tumor or polyps); alternatively, these lesions may be harbingers of invasive disease.The clinical setting must be considered in order to define the appropriate treatment for each case.


RENAL AND URETERAL INFECTIONS

Infections of the urinary tract are common among patients whose ureteral excretion is compromised (Table 11-1). Candida, which has a predilection for the kidney, can invade either from the bloodstream or in a retrograde manner (via the ureters or bladder) in immunocompromised patients.The presence of “fungus balls” or persistent candiduria suggests invasive disease. Persistent funguria (with Aspergillus as well as Candida) should prompt a search for a nidus of infection in the kidney. Certain viruses are typically seen only in immunosuppressed patients. BK virus (polyomavirus hominis 1) has been documented in the urine of bone marrow transplant recipients and, like adenovirus, may be associated with hemorrhagic cystitis. BK-induced cystitis usually remits with decreasing immunosuppression. Anecdotal reports have described the treatment of infections due to adenovirus and BK virus with cidofovir.


ABNORMALITIES THAT PREDISPOSE TO INFECTION (Table 11-1)

THE LYMPHOID SYSTEM

It is beyond the scope of this chapter to detail how all the immunologic abnormalities that result from cancer or from chemotherapy for cancer lead to infections. Disorders of the immune system are discussed in other sections of this book. As has been noted, patients with antibody deficiency are predisposed to overwhelming infection with encapsulated bacteria (including S. pneumoniae, H. influenzae, and N. meningitidis). Infections that result from the lack of a functional cellular immune system are described in Chap. 90. It is worth mentioning, however, that patients undergoing intensive chemotherapy for any form of cancer will have not only defects due to granulocytopenia but also lymphocyte dysfunction, which may be profound. Thus these patients—especially those receiving glucocorticoid-containing regimens or drugs that inhibit T-cell activation or cytokine induction— should be given prophylaxis for Pneumocystis pneumonia.


THE HEMATOPOIETIC SYSTEM

Initial studies in the 1960s revealed a dramatic increase in the incidence of infections (fatal and nonfatal) among cancer patients with a granulocyte count of <500/ìL. More recent studies have cited a figure of 48.3 infections per 100 neutropenic patients (<1000 granulocytes/ìL) with hematologic malignancies and solid tumors, or 46.3 infections per 1000 days at risk. Neutropenic patients are unusually susceptible to infection with a wide variety of bacteria; thus antibiotic therapy should be initiated promptly to cover likely pathogens if infection is suspected. Indeed, early initiation of antibacterial agents is mandatory to prevent deaths. These patients are susceptible to gram-positive and gramnegative organisms found commonly on the skin and in the bowel (Table 11-4). Because treatment with narrowspectrum agents leads to infection with organisms not covered by the antibiotics used, the initial regimen should target pathogens likely to be initial causes of bacterial infection in neutropenic hosts (Fig. 11-2).


Treatment: INFECTIONS IN CANCER PATIENTS ANTIBACTERIAL THERAPY

Hundreds of antibacterial regimens have been tested for use in patients with cancer. The major risk of infection is related to the degree of neutropenia seen as a consequence of either the disease or the therapy. Many of the relevant studies involved small populations in which the outcomes were generally good, and most lacked the statistical power to detect differences among the regimens studied. Each febrile neutropenic patient should be approached as a unique problem, with particular attention given to previous infections and recent antibiotic exposures. Several general guidelines are useful in the initial treatment of neutropenic patients with fever (Fig. 11-2):


1. In the initial regimen, it is necessary to use antibiotics active against both gram-negative and gram-positive bacteria (Table 11-4).

2. An aminoglycoside or an antibiotic without good activity against gram-positive organisms (e.g., ciprofloxacin or aztreonam) alone is not adequate in this setting.

3. The agents used should reflect both the epidemiology and the antibiotic resistance pattern of the hospital.  

4. If the pattern of resistance justifies its use, a single third-generation cephalosporin constitutes an appropriate initial regimen in many hospitals.

5. Most standard regimens are designed for patients who have not previously received prophylactic antibiotics. The development of fever in a patient who has received antibiotics affects the choice of subsequent therapy, which should target resistant organisms and organisms known to cause infections in patients being treated with the antibiotics already administered.

6. Randomized trials have indicated the safety of oral antibiotic regimens in the treatment of “low-risk” patients with fever and neutropenia. Outpatients who are expected to remain neutropenic for <10 days and who have no concurrent medical problems (such as hypotension, pulmonary compromise, or abdominal pain) can be classified as low risk and treated with a broad-spectrum oral regimen.

7. Several large-scale studies indicate that prophylaxis with a fluoroquinolone (ciprofloxacin or levofloxacin) decreases morbidity and mortality rates among afebrile patients who are anticipated to have neutropenia of long duration. The initial antibacterial regimen should be refined on the basis of culture results (Fig. 11-2).


Blood cultures are the most relevant on which to base therapy; surface cultures of skin and mucous membranes may be misleading. In the case of gram-positive bacteremia or another gram-positive infection, it is important that the antibiotic be optimal for the organism isolated. Although it is not desirable to leave the patient unprotected, the addition of more and more antibacterial agents to the regimen is not appropriate unless there is a clinical or microbiologic reason to do so. Planned progressive therapy (the serial, empirical addition of one drug after another without culture data) is not efficacious in most settings and may have unfortunate consequences. Simply adding another antibiotic for fear that a gram-negative infection is present is a dubious practice. The synergy exhibited by â-lactams and aminoglycosides against certain gram-negative organisms (especially P. aeruginosa) provides the rationale for using two antibiotics in this setting, but recent analyses suggest that efficacy is not enhanced by the addition of aminoglycosides, whereas toxicity may be increased. Mere “double coverage,” with the addition of a quinolone or another antibiotic that is not likely to exhibit synergy, has not been shown to be of benefit and may cause additional toxicities and side effects. Cephalosporins can cause bone marrow suppression, and vancomycin is associated with neutropenia in some healthy individuals (Chap. 33). Furthermore, the addition of multiple cephalosporins may induce â-lactamase production by some organisms; cephalosporins and double â-lactam combinations should probably be avoided altogether in Enterobacter infections.


ANTIFUNGAL THERAPY

Fungal infections in cancer patients are most often associated with neutropenia. Neutropenic patients are predisposed to the development of invasive fungal infections, most commonly those due to Candida and Aspergillus species and occasionally those caused by Fusarium, Trichosporon, and Bipolaris. Cryptococcal infection, which is common among patients taking immunosuppressive agents, is uncommon among neutropenic patients receiving chemotherapy for AML. Invasive candidal disease is usually caused by C. albicans or C. tropicalis but can be caused by C. krusei, C. parapsilosis, and C. glabrata. For decades it has been common clinical practice to add amphotericin B to antibacterial regimens if a neutropenic patient remains febrile despite 4–7 days of treatment with antibacterial agents. The rationale for the empirical addition of amphotericin B is that it is difficult to culture fungi before they cause disseminated disease and that mortality rates from disseminated fungal infections in granulocytopenic patients are high. Before the introduction of newer azoles into clinical practice, amphotericin B was the mainstay of antifungal therapy. The insolubility of amphotericin B has resulted in the marketing of several lipid formulations that are less toxic than the amphotericin B deoxycholate complex.


However, because of the high cost of the lipid preparations, their use at many centers is reserved for patients who fail to respond to standard amphotericin B. Since the side effects of the formulations differ, unnecessary switching from one to another is not recommended. Although fluconazole is efficacious in the treatment of infections due to many Candida spp., its use against serious fungal infections in immunocompromised patients is limited by its narrow spectrum: it has no activity against Aspergillus or against several non-albicans Candida spp.The release of newer broad-spectrum azoles (such as voriconazole and posaconazole) has provided another option for the treatment of Aspergillus infection (including CNS infection, in which amphotericin B has usually failed). In fact, experience indicates that these drugs may well supplant amphotericin B as the mainstay of treatment because of their lesser toxicity and better penetration into cerebrospinal fluid and other sites. Clinicians should be aware that the spectrum of each azole is somewhat different and that no drug can be assumed to be efficacious against all fungi. For example, although voriconazole is active against Pseudallescheria boydii, amphotericin B is not; however, voriconazole has no activity against Mucor. Recent studies suggest a role for posaconazole as a prophylactic agent in patients with prolonged neutropenia. For a full discussion of antifungal therapy, see Chap. 102. Echinocandins (such as caspofungin) are useful in the treatment of infections caused by azole-resistant Candida. Studies in progress are assessing the use of these agents in combinations to determine whether treatment with multiple antifungal agents leads to better outcomes.


ANTIVIRAL THERAPY

The availability of a variety of agents active against herpes-group viruses, including some new agents with a broader spectrum of activity, has heightened focus on the treatment of viral infections, which pose a major problem in cancer patients.Viral diseases caused by the herpes group are prominent. Serious (and sometimes fatal) infections due to HSV and CMV are well documented, and VZV infections may be fatal to patients receiving chemotherapy. The roles of human herpesvirus (HHV) 6, HHV-7, and HHV-8 (Kaposi’s sarcoma herpesvirus) in cancer patients are being defined (Chap. 83). Although clinical experience is most extensive with acyclovir, which can be used therapeutically or prophylactically, a number of derivative drugs offer advantages over this agent (Table 11-8). In addition to the herpes group, several respiratory viruses (especially RSV) may cause serious disease in cancer patients. Although vaccination with influenza vaccine is recommended (see below), it may be ineffective in this patient population. The availability of antiviral drugs with activity against influenza viruses gives the clinician additional options for the treatment of these patients (Table 11-9).


OTHER THERAPEUTIC MODALITIES

Another way to address the problems of the febrile neutropenic patient is to replenish the neutrophil population. Although granulocyte transfusions are efficacious in the treatment of refractory gram-negative bacteremia, they do not have a documented role in prophylaxis. Because of the expense, the risk of leukoagglutinin reactions (which has probably been decreased by improved cell-separation procedures), and the risk of transmission of CMV from unscreened donors (which has been reduced by the use of filters), granulocyte transfusion is reserved for patients unresponsive to antibiotics. This modality is efficacious for documented gram-negative bacteremia refractory to antibiotics, particularly in situations where granulocyte numbers will be depressed for only a short period. The demonstrated usefulness of granulocyte colonystimulating factor (G-CSF) in mobilizing neutrophils and advances in preservation techniques may make this option more useful than in the past. A variety of cytokines, including G-CSF and granulocytemacrophage colony-stimulating factor, enhance granulocyte recovery after chemotherapy and consequently shorten the period of maximal vulnerability to fatal infections.


The role of these cytokines in routine practice is still a matter of some debate.Most authorities recommend their use only when neutropenia is both severe and prolonged. The cytokines themselves may have adverse effects, including fever, hypoxemia, and pleural effusions or serositis in other areas. Since there is little evidence that their routine administration lessens the risk of death and since they are still expensive, the use of these cytokines has not become the standard of care in all centers. The role of other cytokines (such as macrophage colony-stimulating factor for monocytes or interferon-ã) in preventing or treating infections in granulocytopenic patients is under investigation. Once neutropenia has resolved, patients are not at increased risk of infection. However, depending on what drugs they receive, patients who continue on chemotherapeutic protocols remain at high risk for certain diseases. Any patient receiving more than a maintenance dose of glucocorticoids (including many treatment regimens for diffuse lymphoma) should also receive prophylactic TMP-SMX because of the risk of Pneumocystis infection; those with ALL should receive such prophylaxis for the duration of chemotherapy.


PREVENTION OF INFECTION IN CANCER PATIENTS EFFECT OF THE ENVIRONMENT

Outbreaks of fatal Aspergillus infection have been associated with construction projects and materials in several hospitals. The association between spore counts and risk of infection suggests the need for a high-efficiency airhandling system in hospitals that care for large numbers of neutropenic patients. The use of laminar-flow rooms and prophylactic antibiotics has decreased the number of infectious episodes in severely neutropenic patients. However, because of the expense of such a program and the failure to show that it dramatically affects mortality rates, most centers do not routinely use laminar flow to care for neutropenic patients. Some centers use “reverse isolation,” in which health care providers and visitors to a patient who is neutropenic wear gowns and gloves. Since most of the infections these patients develop are due to organisms that colonize the patients’ own skin and bowel, the validity of such schemes is dubious, and limited clinical data do not support their use. Hand washing by all staff caring for neutropenic patients should be required to prevent the spread of resistant organisms. The presence of large numbers of bacteria (particularly P. aeruginosa) in certain foods, especially fresh vegetables, has led some authorities to recommend a special “low-bacteria” diet. A diet consisting of cooked and canned food is satisfactory to most neutropenic patients and does not involve elaborate disinfection or sterilization protocols. However, there are no studies to support even this type of dietary restriction. Counseling of patients to avoid leftovers, deli foods, and unpasteurized dairy products is recommended.


PHYSICAL MEASURES

Although few studies address this issue, patients with cancer are predisposed to infections resulting from anatomic compromise (e.g., lymphedema resulting from node dissections after radical mastectomy). Surgeons who specialize in cancer surgery can provide specific guidelines for the care of such patients, and patients benefit from commonsense advice about how to prevent infections in vulnerable areas.


IMMUNOGLOBULIN REPLACEMENT

Many patients with multiple myeloma or CLL have immunoglobulin deficiencies as a result of their disease, and all allogeneic bone marrow transplant recipients are hypogammaglobinemic for a period after transplantation. However, current recommendations reserve intravenous immunoglobulin (IVIg) replacement therapy for those patients with severe (<400 mg/dL), prolonged hypogammaglobulinemia. Antibiotic prophylaxis has been shown to be cheaper and efficacious in preventing infections in most CLL patients with hypogammaglobulinemia. Routine use of IVIg replacement is not recommended.


SEXUAL PRACTICES

The use of condoms is recommended for severely immunocompromised patients.Any sexual practice that results in oral exposure to feces is not recommended. Neutropenic patients should be advised to avoid any practice that results in trauma, as even microscopic cuts may result in bacterial invasion and fatal sepsis.


ANTIBIOTIC PROPHYLAXIS

Several studies indicate that the use of oral fluoroquinolones prevents infection and decreases mortality rates among severely neutropenic patients. Fluconazole prevents Candida infections when given prophylactically to patients receiving bone marrow transplants. The use of broader-spectrum antifungal agents (e.g., posaconazole) appears to be more efficacious. Prophylaxis for Pneumocystis is mandatory for patients with ALL and for all cancer patients receiving glucocorticoid-containing chemotherapy regimens.


VACCINATION OF CANCER PATIENTS

In general, patients undergoing chemotherapy respond less well to vaccines than do normal hosts.Their greater need for vaccines thus leads to a dilemma in their management. Purified proteins and inactivated vaccines are almost never contraindicated and should be given to patients even during chemotherapy. For example, all adults should receive diphtheria-tetanus toxoid boosters at the indicated times as well as seasonal influenza vaccine. However, if possible, vaccination should not be undertaken concurrent with cytotoxic chemotherapy. If patients are expected to be receiving chemotherapy for several months and vaccination is indicated (for example, influenza vaccination in the fall), the vaccine should be given midcycle—as far apart in time as possible from the antimetabolic agents that will prevent an immune response. The meningococcal and pneumococcal polysaccharide vaccines should be given to patients before splenectomy, if possible. The H. influenzae type b conjugate vaccine should be administered to all splenectomized patients. In general, live virus (or live bacterial) vaccines should not be given to patients during intensive chemotherapy because of the risk of disseminated infection. Recommendations on vaccination are summarized in Table 11-2.  ​