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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Bacterial Infections

, MD, FACP and , MD.

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 15 to 20 years, gram-positive infections have been predominant.1,24–26 The incidence of gram-positive infections increased from approximately 20% in the mid-1970s to 50% in the mid-1990s (Table 160-4). Several factors are responsible for this epidemiologic shift. The most important is the increased use of catheters (ie, 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 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 gram-negative infections but have not had a significant impact on, or occasionally have led to an increase in, gram-positive infections.27

Table 160-4. Distribution of Bacterial Infection in 4,452 Febrile Episodes in Neutropenic Cancer Patients.

Table 160-4

Distribution of Bacterial Infection in 4,452 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. 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, 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 β-lactam antimicrobial agents as a result of the production of type 1 and extended-spectrum β-lactamases 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

Pseudomonas aeruginosa has been a leading cause of infection in cancer patients, especially among those with severe neutropenia. It is also a cause of catheter-related infections. Pneumonia and bacteremia are the most common infections, but the urinary tract, skin and gastrointestinal tract are also sites of infection. Prior to the introduction of the antipseudomonal penicillins, the fatality rate from Pseudomonas septicemia among persistently neutropenic patients exceeded 75%, whereas now it is less than 40%. In recent years, there has been a decline in gram-negative bacteremias including P. aeruginosa among neutropenic patients.1 However, the frequency of P. aeruginosa bacteremia among patients with acute leukemia has not changed.32 This organism accounts for approximately 15% to 20% of gram-negative infections.29

Several reviews of Pseudomonas bacteremia in cancer patients have been published.32,33 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 catheter entry sites. A recent review from the same institution found a major increase in the frequency of community-acquired infections and a substantial decrease in complications such as disseminated intravascular coagulation and ecthyma gangrenosum.32

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 ( Figure 160-2). 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 160-2. Multiple skin lesions (ecthyma gangrenosum) in a patient with Pseudomonas aeruginosa bacteremia.

Figure 160-2

Multiple skin lesions (ecthyma gangrenosum) in a patient with Pseudomonas aeruginosa bacteremia. (Four-color version of figure on CD-RM)

P. aeruginosa is widespread in the hospital environment, because 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. Approximately 25% of patients with acute leukemia are stool carriers of P. aeruginosa on admission to hospital.34 This figure rises to 50% at the end of the first month of hospitalization in patients who are not receiving antimicrobial prophylaxis. 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. The widespread use of antimicrobial prophylaxis probably reduces Pseudomonas carriage substantially.

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 β-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 80%. Improved cure rates have been observed in those patients with poor prognostic signs such as shock, pneumonia, and persistent neutropenia.

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.35 As in the case of P. aeruginosa, moist hospital environments, such as sink drains and water faucets, are potential sources of infection. Broadspectrum 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.36 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. Approximately 70% of strains are susceptible to trimethoprimsulfamethoxazole (TMP-SMX), although increasing resistance to this agent is being reported. Alternative agents include ticarcillin/clavulanate, minocycline, rifampin, the newer fluoroquinolones, and some 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.37 High-dose therapy with TMP/SMX as used for the treatment of Pneumocystis carinii pneumonia, might be beneficial in some patients.

Acinetobacter Species

Acinetobacter species are acknowledged to be opportunistic pathogens and usually cause disease in debilitated patients and in 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 (approximately 4% of all gram-negative infections in cancer patients), 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.38 Recent data indicate that this trend has been maintained, and using current nomenclature, A. baumannii remain the predominant species isolated from clinical specimens.39

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.38–40 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.39 Appropriate therapy includes the administration of antimicrobial agents to which the organisms are susceptible, and removal of the offending catheter in catheter-related infections. Multidrug resistance is common among these organisms and may complicate the treatment of serious infections. Recently, there were 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.39–42

Salmonella Species

There has been a substantial increase in the incidence of nontyphoidal Salmonella infections in the recent years. Fifteen percent 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 gastroenteritis, which is usually self-limited, does 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. 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. The most reliable agents against Salmonella spp are the fluoroquinolones, the extended-spectrum cephalosporins, and the carbapenems.43 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.44,45

Streptococcus Species

Many streptococcal species are important pathogens in cancer patients. S. 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.46 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.47 Defects in antibody formation and clearing of the organisms from the bloodstream are probably responsible for this clinical syndrome.23 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.48,49 Most penicillin-resistant strains are susceptible to the extended-spectrum cephalosporins (ceftriaxone, ceftazidime, cefepime) although pneumococcal strains resistant to these and other β-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 (gatifloxacin, moxifloxacin), 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 anti pneumococcal activity (eg, amoxicillin/clavulanic acid, Augmentin®, 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/clavulanate might be prudent, and occasionally lifesaving, 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. The new conjugate pneumococcal vaccine is due is likely to be an improvement on the polyvalent vaccine.

α-Hemolytic (viridans) streptococci are important pathogens in cancer patients, particularly in patients with acute leukemia undergoing intensive chemotherapy and in allogeneic bone marrow transplant recipients.50 α-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 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.51 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 (Figure 160-3). 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 160-3. Invasive infection caused by α-hemolytic (viridans) streptococci.

Figure 160-3

Invasive infection caused by α-hemolytic (viridans) streptococci. Note the hemorrhagic nature of the lesions in this patient with thrombocytopenia. (Four-color version of figure on CD-RM)

Of increasing concern are reports that 20% to 60% of α-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.50 These organisms are also susceptible to the newer generation quinolones (gatifloxacin, moxifloxacin) and linezolid, but clinical experience is limited. Clearly, viridans streptococci have become formidable pathogens in neutropenic patients with hematologic malignancies, and newer strategies for infection prevention and therapy are needed.

β-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/tolerance to the penicillins is being described. Bactericidal combinations are recommended for the treatment of tolerant isolates.52

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 Staphylococcus aureus but a considerable increase in the incidence of infections caused by coagulase-negative staphylococci.1,24,26 The predominant species is Staphylococcus epidermidis, although Staphylococcus hominis and Staphylococcus 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, because they commonly inhabit normal skin. The gastrointestinal tract, however, also serves as an important source for coagulase-negative 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, and surgical wound infections, are also common. Although frequently regarded as contaminants or organisms associated with low virulence, coagulase-negative staphylococci are 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 treatment of staphylococcal infection should be guided by antimicrobial susceptibility. S. aureus isolates are susceptible to methicillin more often (60% to 80%) than coagulase-negative staphylococci (5% to 15%). Methicillinsusceptible strains can be treated with a semisynthetic penicillin (nafcillin, oxacillin). Most broad-spectrum agents used for empiric therapy in febrile neutropenic patients (cefepime, imipenem, meropenem, piperacillin-tazobactam) are also active against these isolates. Vancomycin is a suitable alternative in patients with serious β-lactam allergy and for methicillin-resistant strains. Older agents (tetracyclines, TMP-SMX, rifampin) and newer agents (linezolid, quinupristin-dalfopristin) are also useful for the treatment of staphylococcal infections. 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.53

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 coagulase-negative 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 to which these organisms are intrinsically resistant.54,55 The most common infections caused by enterococci are those of the bloodstream, urinary tract, wounds, and intraabdominal 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 Enterococcus faecium are rising, particularly in neutropenic and other immunosuppressed patients.56 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 25% of enterococcal isolates from high-risk populations.57 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).56 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.58

For strains of VRE that are moderately susceptible to ampicillin (minimal inhibitory concentration [MIC] ≤ 32 μg/mL), the administration of high doses of ampicillin (20 to 24 g/d) in combination with gentamicin might be worthwhile. When faced with an infection caused by a strain with high-level resistance to the aminoglycosides and ampicillin, there are two established therapeutic options: linezolid and quinupristin-dalfopristin (Synercid). Neither agent is bactericidal against VRE and response rates range from 55% to 65%, well below the 80% to 85% response rates seen with bactericidal combinations against susceptible enterococci.59 Newer agents (daptomycin, oritavancin) may have better bactericidal activity.60

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 160-5) and strict compliance by hospital personnel is a prerequisite for their success.61–63

Table 160-5. Infection Control Measures Designed to Limit Nosocomial Spread of Vancomycin-Resistant Enterococci in High-Risk Areas (Oncology Units).

Table 160-5

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

Listeria monocytogenes

Listeria 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. Although the majority of Listeria infections arise in previously healthy individuals, they are frequently seen in immunocompromised patients, including those with lymphoma.64 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.65 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 more than 60% of cases in cancer patients and septicemia without meningitis accounts for approximately 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. Although 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, because 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. Several newer quinolones (gatifloxacin, moxifloxacin) are active against L. monocytogenes, but clinical experience with these agents is lacking.66,67

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 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 a result of Hodgkin 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 acquired immunodeficiency syndrome (AIDS).68 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 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 healthcare 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.69–71

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 multidrug-resistant (MDR) isolates.72 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.68 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 to 3 weeks) by the use of radiometric culture methods followed by a deoxyribonucleic acid (DNA)-probe for an M. tuberculosis-specific ribosomal ribonucleic acid (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 h.

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.73 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.74 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.73,75 Directly observed therapy 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).76,77 Recent data indicate that MAC infections are not uncommon in patients with solid tumor as well.78 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 (four to six 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.79,80 Refractory cases may respond to therapy with interferon-gamma (INF-γ) in combination with drug therapy.81

Mycobacterium kansasii also causes infection both in patients with hematologic malignancies and in patients with solid tumors.82 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 (Mycobacterium chelonei and Mycobacterium 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.83,84 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.85,86 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.87 In addition, severe pneumonia, pleural effusion, empyema, and lung abscess formation, are recognized complications of L. pneumophila infection and occur more often in the immunosuppressed host.88 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 in 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 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 indicates that azithromycin is more active than erythromycin and clarithromycin against both intracellular and extracellular L. pneumophila and should be used as a frontline agent for legionellosis.89 The fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin) are also very active against L. pneumophila and are now the drugs of choice for the treatment of this infection.89 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.

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Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK13792

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