Williams Hematology



Risk Factors and Infecting Organisms
Recognition and Diagnosis of Infection

Initial Treatment

Adjusting Therapy

Duration of Therapy

Fever Following Recovery from Chemotherapy

Catheter-Related Infections

Outpatient Therapy
Prevention of Infections

Prevention of Bacterial Infections

Prevention of Parasitic Infections

Prevention of Viral Infections

Prevention of Fungal Infections
Infections in Marrow Transplantation Recipients
Chapter References

Infection is a major cause of morbidity and mortality in patients receiving chemotherapy for treatment of hematologic neoplasms. Bacterial infections may result in rapid clinical deterioration and, if not treated appropriately, death. Fungal, viral, and parasitic infections may also result in potentially lethal complications during and after chemotherapy. Recognition and treatment of such infections in the context of different clinical situations is addressed. The introduction of home antibiotic therapy is noted and may be appropriate for certain patients. Since prevention of infection during periods of neutropenia should reduce morbidity and improve outcome, attention is also focused on various means of prophylaxis of bacterial, parasitic, viral, and fungal infections.

Acronyms and abbreviations that appear in this chapter include: CMV, cytomegalovirus; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; PCR, polymerase chain reaction; RSV, respiratory syncytial virus.

The profound pancytopenia that results from cytoreductive chemotherapy is a common and dramatic manifestation of stem cell failure. During the periods of neutropenia that follow such chemotherapy, infection will develop in most patients. Patients with neoplasms of the lymphoid system commonly manifest altered humoral and cellular immunity, resulting in an increased incidence of nonbacterial infection.
Bacterial, fungal, viral, and parasitic organisms may cause infection in neutropenic patients. Bacterial infections are the most frequent and usually the most serious. The risk for bacterial infection increases somewhat when the neutrophil count falls below 500/µl (0.5 × 109/liter) and becomes especially pronounced at neutrophil counts below 100 ml (0.1 × 109/liter; see Fig. 17-1).1 The duration of the neutropenia and rate of decline of the granulocyte count are also important in determining the risk of bacterial infection. Disruption of integumental barriers further favors the development of infection by providing portals of entry.

FIGURE 17-1 Relationship between the granulocyte count and the percentage of patient days with infection (

) and the episodes of severe infections per 1000 days (

). (Based on the data of Bodey et al.1)

Historically, gram-negative bacilli have been the most commonly isolated pathogens. These organisms include Pseudomonas, Klebsiella, Escherichia coli, and Proteus and are responsible for a broad variety of infections, including pneumonia, soft tissue infections, perirectal infections, and primary bacteremia. Urinary tract infections are surprisingly infrequent unless a urinary catheter is present or urinary tract obstruction has developed. Meningitis is also uncommon.
During the past two decades, the incidence of gram-positive infection has increased.2 Staphylococcal species, enterococcus, and Corynebacterium are now the pathogens most frequently isolated from neutropenic patients. This may be due, in part, to the popularity of semipermanent venous catheters. Several recent reports document the increasing frequency of Streptococcus viridans as a major pathogen in neutropenic patients,3 especially in those receiving marrow transplant, perhaps because these patients have a higher incidence of mucositis. Septic shock may occur in these patients.4 Anaerobic infections are less common unless there is coexisting dental or gastrointestinal pathology.
Patients with Hodgkin’s disease, other lymphomas, or chronic lymphocytic leukemia primarily suffer from impaired cell-mediated immunity and diminished antibody production.5 Consequently, the spectrum of infections in these patients differs from that found in the neutropenic patient. Bacterial infections, when they occur, tend to be due to encapsulated organisms such as Pneumococcus or Haemophilus. Listeria and Nocardia infections are also seen more frequently in this group of patients.
Fungal infections are also common during periods of prolonged neutropenia as well as in patients with lymphomas or chronic lymphocytic leukemia. Candida species are most frequently isolated, but Aspergillus and Phycomycetes are also found. The gastrointestinal tract serves as a reservoir for Candida; thrush and erosive esophagitis may develop. Candida may also enter the bloodstream via indwelling catheters. Aspergillus and Phycomycetes tend to colonize and infect the sinuses and bronchopulmonary tree. Since cell-mediated immunity is required for defense against fungal infections, it is not surprising that infections with Cryptococcus, Aspergillus, Coccidioides, Histoplasma, and Candida are more common in patients with leukemia or lymphoma who have required glucocorticoid treatment.
Viral infections are especially frequent in patients with impaired cell-mediated immunity. Among viruses that cause infections in immunocompromised hosts, herpes simplex, varicella zoster, CMV, and adenoviruses are the most important. Cutaneous lesions and mucositis are often caused by herpes simplex. Herpes zoster infections may be especially severe and have a propensity for dissemination. Primary varicella infections are associated with a high mortality rate if not treated. CMV may cause febrile illnesses associated with pneumonia, hepatitis, and/or gastrointestinal tract ulcerations. This virus may be isolated by culture or demonstrated by the presence of viral antigens or viral DNA in clinical specimens.6 Respiratory infections caused by RSV have been documented in about 18 percent of marrow transplant recipients with pulmonary symptoms during the winter months.7 Influenza, picorna viruses, and others have also been isolated.
Pneumocystis carinii, a ubiquitous, endogenous parasite, may cause pneumonia in neutropenic patients as well as in those with defective cell-mediated immunity. It often becomes clinically evident after glucocorticoids have been tapered or discontinued. Toxoplasma gondii, another protozoan parasite, may be responsible for brain abscesses in patients with lymphoma or chronic lymphocytic leukemia, especially those treated with glucocorticoids. Glucocorticoid-treated patients are also at risk for Strongyloides hyperinfection.
The association between lymphoid malignancies and tubercu-losis has been recognized for over a century. With the resurgence of tuberculosis and the increased prevalence of drug-resistant strains, this threatens to become a more frequent, serious problem.8 Atypical mycobacterial infections, while very common in HIV-positive patients, are fairly rare in patients receiving chemotherapy.
The development of an infection in a neutropenic patient may be accompanied by dramatic clinical manifestations or by none at all. Fever, if it develops, is very suggestive of infection. However, hypothermia, declining mental status, myalgias, or lethargy may indicate infection in these patients. The usual local signs of infection may be absent or delayed because these are mediated by neutrophils.9
A careful physical examination should be performed when such a change in condition is observed. Special attention should be paid to the mouth and teeth for evidence of thrush or periodontal disease. The skin should be examined in detail. Innocuous-appearing skin lesions may actually be septic emboli, and trivial injuries inflicted by venipuncture or intravenous catheters may become infected and result in septicemia. There is an increased incidence of perianal and perirectal infection in the neutropenic patient10; examination of the rectum may provide a clue to the source of fever in patients without other clinical findings. While such examinations should not be performed unnecessarily on an immunocompromised patient, rectal or pelvic examination should not be deferred when searching for a cause of fever.
Chest x-rays should be obtained initially and may need to be repeated, although this practice has been questioned in patients without respiratory complaints.11 Chest computed tomography may reveal lesions not detected on routine radiograms.12 Sinus x-rays may be helpful if symptoms are present.
Blood cultures should be collected prior to the institution of antibiotic therapy and periodically thereafter if fever persists. If an indwelling venous catheter is present, some of the cultures should be obtained from the catheter. There does not seem to be a physiologic or experimental basis for the common practice of separating blood cultures by 10 to 15 min. However, obtaining two to three cultures improves the likelihood of recovering fastidious organisms. To improve the likelihood of isolating fungal pathogens, the specimens should be retained by the laboratory for at least 10 days. Urine cultures and sputum cultures may be helpful. Results of the latter, however, must be interpreted with caution, since they may reflect the flora colonizing the oropharynx rather than the pathogens infecting the lung. Skin lesions of a suspicious nature should be biopsied and cultured. Stools should be examined for Clostridium difficile toxin in patients with diarrhea. Potentially infected intravenous lines should be cultured upon removal. Nasal cultures may be useful in predicting pulmonary aspergillosis.13 Fungal infections, which may be difficult to document using conventional culture techniques, may be diagnosed by PCR and by antigen detection.14,15 However, there are currently only limited data available validating these assays, and they are not routinely available at the present time.
Open lung biopsies were once advocated for further evaluation of the neutropenic patient with pulmonary infiltrates.16 However, since this procedure rarely establishes a treatable diagnosis, it should not be routinely performed in immunocompromised patients with pneumonia. It may be useful under certain limited circumstances, for example, when further empiric therapy would be unacceptably toxic in a patient whose clinical condition is deteriorating.
Transbronchial lung biopsies are generally considered to be unsafe in patients with thrombocytopenia because the risk of uncontrolled bleeding is high. Obtaining material via bronchial brushing or lavage carries a lower risk and may yield useful information.17
The need for prompt, effective therapy is dramatized by the finding that mortality rates approach 100 percent in bacteremic neutropenic patients treated with regimens lacking activity against the organisms subsequently isolated.18 In contrast, patients receiving appropriate therapy have mortality rates that are much lower.19 Therefore, it is critical to select potent, broad-spectrum agents when initiating empiric antimicrobial therapy in the neutropenic patient. It is particularly important that therapy effective against gram-negative organisms be given; gram-positive organisms tend to be less virulent, and brief delays in treating these organisms may not be attended by increased mortality,20 at least in institutions where methicillin-resistant Staphylococcus aureus or fulminant gram-positive infections are uncommon.21
In general, antibiotics should be given at the maximum recommended doses (see Table 17-1). Aminoglycoside and vancomycin levels should be measured to establish proper doses. High peak levels of aminoglycosides are desirable. The increasingly common practice of administering aminoglycosides as a single, daily dose seems to be effective in neutropenic patients.22,23 Aminoglycoside selection will depend on institutional sensitivity patterns. In the case of b-lactam drugs, frequent or continuous administration following a loading dose ensures constant therapeutic levels24 and may be advantageous.


Many different regimens have been evaluated and found to be acceptable for empiric therapy in neutropenic patients.21 Several are listed in Table 17-2. Generally, combinations of two or three drugs have been favored for initial empiric therapy, but single-drug therapy may also be efficacious. Imipenem,25 meropenem,26,27 cefipime,25,28 and ceftazidime27 have each been studied as single agents. These drugs are active against most of the virulent pathogens infecting neutropenic patients, and subsequent modification of therapy can serve to optimize treatment. Antibiotic toxicity is reduced by omitting the aminoglycoside from the regimen. However, development of resistant organisms during single-drug therapy is of concern. Aminoglycosides may provide synergy against gram-negative bacilli and further broaden the spectrum of antimicrobial activity. It is also important to note that none of these agents is active against methicillin-resistant staphylococcus or against Corynebacterium. Cefipime and ceftazidime lack activity against enterococcus.


Therapy with two b-lactam drugs has been advocated by some, but development of resistant organisms has been a problem, and the second b-lactam drug may increase the frequency of toxicity without improving efficacy. Quinolones, usually in conjunction with another antibiotic, are effective in patients who have not received quinolone prophylaxis.29
The use of single-drug therapy cannot be recommended for all patients with stem cell failure. Single-drug therapy may be appropriate for patients with less profound neutropenia, those who are not frankly septic, and those who may have problems tolerating aminoglycosides. Differences in institutional sensitivity patterns will also influence antibiotic selection.
Vancomycin-resistant enterococcus is being isolated with increasing frequency and presents a major challenge.30 Several regimens have been employed, including chloramphenicol as a single agent or combination therapy with penicillin, vancomycin, and one or two other agents (rifampin and/or a quinolone.) None of these strategies has met with consistent success. Synercid (quinupristin/dalfopristin), is active against about 86 percent of vancomycin-resistant enterococci.31 There is limited clinical experience with this drug in neutropenic patients.
Therapeutic use of granulocytes is rarely necessary (see Chap. 141), may result in the transmission of CMV disease, and may cause severe reactions.
Amphotericin B is the drug of choice for the majority of fungal infections that develop in the neutropenic host. The dose should be advanced rapidly so that the full therapeutic dose is given by the first or second day. Serum creatinine, potassium, and magnesium levels should be monitored. Fever and chills associated with administration of this drug may be treated or prevented with meperidine (Demerol) or diphenhydramine hydrochloride (Benadryl) and acetaminophen. This will not be necessary in all patients, and systemic reactions tend to decrease after several doses. Twenty-five to 100 mg hydrocortisone added to the infusion may attenuate the reactions. Infusions should be given over 2 to 6 h. More rapid infusions have been studied but are not recommended for routine use.32
Flucytosine provides synergy against Cryptococcus neoformans and some strains of Candida but not against Aspergillus. This drug is myelotoxic and may cause hepatitis and colitis; therefore, it should not be used routinely in the treatment of fungal infections in this group of patients.
Several preparations of liposomal amphotericin B have recently become available.33 They are more likely than nonliposomal amphotericin B to cause infusion-related symptoms34 but are less nephrotoxic.35,36 Higher doses are required to achieve a clinical response, and the cost is considerably higher than that of amphotericin B. Therefore, those formulations should be reserved for patients who have underlying renal insufficiency or who have experienced nephrotoxicity with amphotericin B.33
Fluconazole, an azole drug that may be administered orally or intravenously, is approved for treatment of Candida albicans, Cryptococcus neoformans, and Coccidioides immitis. It is less active against non-albicans Candida species and is completely inactive against Candida krusei. It can be used to treat patients with sensitive strains of fungus who are unable to tolerate amphotericin B or who fail treatment with it. It has been used as first-line therapy in hepatosplenic candidiasis (see below) and may be appropriate for patients with nonsystemic fungal infections.
Itraconazole is not approved for the treatment of candidiasis. It can be used in the treatment of Aspergillus infection, although amphotericin is more potent and reliable. Currently it is only available orally; an intravenous preparation is expected to be released in the near future. Ketoconazole and miconazole have no role in the treatment of seriously ill patients with fungal infections.
There are a limited number of options for the treatment of viral infections. Acyclovir is active against herpes simplex and, at higher doses, against varicella zoster. It is not useful against CMV or Epstein-Barr virus. Newer agents (e.g., famciclovir and valacyclovir) may be administered less frequently but are not available for intravenous administration. Valacyclovir has been shown to be efficacious in the prevention of CMV in renal transplant patients,37 but otherwise these agents have not been well studied in immunosuppressed patients.
Ganciclovir and foscarnet have documented efficacy in the treatment of CMV disease and are also active against herpes simplex. They are most effective when used early in the course of the infection. Hence, frequent screening for antigenemia in high-risk (e.g., marrow transplant) patients may allow for improved outcomes.38 Both agents have been used successfully in conjunction with CMV immunoglobulin to treat CMV pneumonia in marrow transplant patients.39 Ganciclovir results in neutropenia in a significant percentage of patients who receive it. Foscarnet therapy may be complicated by azotemia and electrolyte abnormalities. Ribavirin can be used to treat RSV. Rimantadine should be used if influenza A is suspected.
Pneumocystis carinii may be treated with trimethoprim-sulfamethoxazole or with pentamidine. Doses are listed in Table 17-1. A number of other regimens, including dapsone-trimethoprim, primaquine-clindamycin, and atovaquone, have proven efficacious in patients with AIDS but are largely untested in patients with chemotherapy-related immunosuppression.
For several reasons, it may prove necessary to adjust or modify the initial antimicrobial regimen. Results of cultures may suggest that another regimen would be more active or less toxic. All cultures may remain negative while the patient fails to respond to the regimen employed. Fever may recur following an initial response to therapy, raising the possibility of a superinfection.
Adjusting therapy based on a culture report is usually straightforward, but the other two situations may pose dilemmas. In these circumstances, resistant organisms or noninfectious causes of fever need to be considered. Repeat cultures and careful clinical reappraisal may prove to be helpful. Empiric modification of the antibiotic regimen to enhance the effect on gram-positive or fungal pathogens may be successful. Vancomycin is active against gram-positive organisms; antifungal therapy should be strongly considered if a combination of antibacterial agents proves ineffective after 5 to 7 days of treatment.21 Addition of a nonsteroidal anti-inflammatory agent may eliminate fever caused by tumor or tumor lysis.
Antibiotics should usually be discontinued when the neutropenia has resolved if there is no clinical evidence of infection. Often, however, the fever may resolve, while neutropenia is expected to continue for a prolonged period of time. Antibiotic therapy is commonly continued until the granulocyte count reaches 500 µl (0.5 × 109/liter). While this reduces the number of relapsing infections, it is likely to increase the risk of superinfection and the risk of antibiotic toxicity. Marrow recovery may be delayed by cephalosporins and sulfa drugs. Therefore, it is reasonable to discontinue antibiotics after an appropriate course in patients who have responded promptly and completely to therapy.21,40,41 If antibiotics are discontinued, close observation is required and therapy should be reinstituted at any suggestion of recurrent infection.
The duration of antifungal therapy will vary considerably. Parasitic infection with Pneumocystis requires 2 to 3 weeks of therapy. Herpetic infections are generally treated for 7 days.
Occasionally fevers will persist after the granulocyte count has returned to normal levels. Drug fever is a consideration in this setting, but more commonly a deep-seated infection is present.42 Pulmonary and hepatic43 fungal infections must be considered. Elevations of serum alkaline phosphatase levels and a characteristic image on computed tomography are common with hepatic involvement.44 Hepatic ultrasound45 and magnetic resonance imaging46 have also been reported to be diagnostically useful, but biopsy may be required to establish this diagnosis. Hepatosplenic candidiasis requires prolonged therapy. Several regimens have been proposed, including fluconazole47 and liposomal amphotericin B.48 Cure is difficult to achieve regardless of the regimen employed.
Indwelling catheter infection should also be considered when fevers continue after marrow recovery.
Minor exit site infections generally respond promptly to therapy. Infection of indwelling catheters with Staphylococcus epidermidis and other avirulent pathogens can often be cured with a prolonged course (at least 2 weeks) of an appropriate antibiotic. If a tunnel infection is present, successful therapy is less likely. Gram-negative infections or fungal infections49 of the catheter usually necessitate its removal. This may be followed, if necessary, by insertion of a new catheter at a different site. Catheters impregnated with antibiotics may resist infection but have not been widely studied in neutropenic patients or with tunneled catheters. Chlorhexidine and silver-impregnated central venous catheters do not appear to prevent bloodstream infections in neutropenic patients.50 Catheter infections and their management are considered in greater detail in Chap. 21 and have been reviewed elsewhere.51
Ten years ago, treatment of the febrile neutropenic patient outside of the hospital would have been unthinkable. More recently, economic pressures, coupled with the widespread availability of home intravenous antibiotic services and more potent oral antibiotics, have made outpatient therapy an option for some of these patients.52,53 Outcomes seem to be comparable to those observed in hospitalized patients, provided that the patients are selected properly and that appropriate monitoring can be ensured. Suitable candidates for home intravenous therapy include those patients who are expected to have a short duration of neutropenia. Individuals who remain febrile, who require multiple antibiotics, or who are unreliable are not candidates for home intravenous therapy. Nurses must be experienced in the evaluation of chemotherapy patients and familiar with catheter care and maintenance. Rigorous family education is a crucial ingredient for a successful outcome.
In view of the high mortality rate associated with infections in neutropenic patients, preventive measures remain a priority. Instrumentation should be avoided whenever possible. Intravenous access sites should be carefully maintained. The earliest strategies included administration of nonabsorbable oral antibiotics usually consisting of gentamicin, vancomycin, and nystatin.54 Unfortunately, this combination is poorly tolerated. Therefore, this practice has been abandoned in favor of systemic antibiotics. Trimethoprim-sulfamethoxazole has been especially well studied and is of benefit in some patients, particularly those with severe neutropenia expected to last over 2 weeks.21 It has the advantage of also preventing Pneumocystis, but it will cause a rash in 5 to 10 percent of individuals. Its use may be associated with infections with resistant organisms, and it may result in a delay of marrow recovery.55
The fluorinated quinolones have received considerable attention for their ability to prevent gram-negative infections in neutropenic patients.56,57 and 58 Unfortunately, indiscriminate use of these agents in the community have diminished their value as resistant bacteria have developed. Infection with gram-positive organisms is more common in patients receiving quinolones prophylactically.59,60 Prophylactic use would also eliminate these agents for therapeutic use in the same patient.
Prophylactic antibiotics are of benefit in some patients with acute leukemia receiving induction chemotherapy. The best regimen remains to be determined and may vary from institution to institution. Perhaps equally important for preventing infection is careful attention to sterile technique and personal hygiene.61 Isoniazid hydrazide therapy is recommended for all tuberculin-positive patients who require chemotherapy unless they have previously been treated.
The ability of GM-CSF and G-CSF to raise the granulocyte count in neutropenic patients may serve as another means of preventing bacterial infections in this group of patients (see Chap. 15). While some series show a small reduction in the infection rate in patients receiving these agents,62 others do not.63,64 and 65 Although it is likely that a subset of patients will benefit from this therapy, definitive data are lacking.
Immunotherapy of various forms has been reviewed.66 Intravenous immunoglobulin has been advocated for prevention of bacterial infection in some patients with chronic severe hypogammaglobulinemia, such as may occur in chronic lymphocytic leukemia and multiple myeloma, but its value has not been proven. The value of special diets and reverse isolation has not been established. Granulocyte transfusions have no role in the prevention of infection.
Pneumocystis carinii pneumonia can be prevented with trimethoprim-sulfamethoxazole. Pentamidine administered monthly in aerosolized form also appears to be effective.67 Although P. carinii is a ubiquitous organism, it appears that there is institutional variability in the incidence of infection. Therefore, the need for prophylaxis will vary.
Acyclovir has proven useful for the prevention of recurrent herpes simplex infections in patients receiving chemotherapy and marrow transplantation.68,69 Such prophylaxis is probably unnecessary in patients who lack antibodies to herpes simplex virus. Varicella zoster immunoglobulin given to susceptible individuals reduces the incidence of varicella following exposure.
The incidence of CMV infection can be reduced by the avoidance of blood products from CMV-seropositive individuals.70 Passive immunization has provided benefit in some studies. Acyclovir, while ineffective in treating CMV infections, may reduce their incidence.71 Ganciclovir72 and foscarnet73 have been used successfully to prevent CMV infections in marrow recipients, but these strategies have not been applied to patients receiving conventional chemotherapy.
Active immunizations with killed vaccines (e.g., influenza) are of some benefit. Attenuated vaccines (e.g., measles) should be avoided.
Studies on prevention of fungal infections in neutropenic patients are difficult to evaluate. Results of the various studies have been conflicting, partly because different definitions have been applied and different doses of antifungal agents have been administered and partly because of the small numbers of patients.
Nystatin,74 amphotericin B,75 clotrimazole,76 and ketoconazole77 have been studied. Each has been effective in reducing colonization and mucositis, but none has been consistently effective in preventing systemic fungal infections and improving survival.
Several studies have documented a statistically significant reduction in superficial and invasive fungal infections when fluconazole is used prophylactically.78,79 However, many failures have also been reported, including breakthrough fungemia.80 Not all studies have documented a benefit of using fluconazole prophylactically.81,82 Superinfection with Aspergillus, Torulopsis glabrata, and Candida krusei have been seen when fluconazole has been used prophylactically.83 Itraconazole may be effective in preventing infection with Aspergillus.84
Thus, while antifungal prophylaxis appears to diminish the incidence of mucositis, close observation and early treatment of mucositis would also be a reasonable approach to this problem. The ability of antifungal agents to prevent systemic infection is not consistent. Prophylactic use of these agents may prove to select more resistant strains of fungus and may not reduce mortality. Therefore, pending the results of additional studies, earlier and more aggressive empiric antifungal therapy may be preferable to prophylaxis. Exceptions to this approach would include patients undergoing marrow transplantation and patients in facilities where there is a high incidence of invasive infections with C. albicans.
Patients receiving marrow transplants are at risk for the same infections occurring in patients rendered neutropenic by chemotherapy. Graft-versus-host disease and the immunosuppressive agents used to treat it result in a particularly high incidence of infection in this group of patients. Viral infections, especially CMV and varicella zoster virus, are especially troublesome. Infection in marrow transplant patients has been reviewed85,86 and is discussed in Chap. 18.

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Thomas ED, Blume KG, Forman SJ (eds): Hematopoietic Cell Transplantation, 2d ed. Blackwell Science, Boston, 1999.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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