Infectious Complications
W. Lance George
I. BACKGROUND.
The development of infection in patients undergoing treatment for malignancies is a complex interplay of a number of factors. These include alterations in the host’s natural mechanical barriers to infection, reduction in the number and function of “professional” phagocytes (particularly neutrophils), and alterations in both humoral and cell-mediated immunity. These various alterations may be a consequence of the malignancy itself or of the treatment (chemotherapy and radiation therapy).
Certain patterns of infection have been recognized and form the basis for empirical management. For example, neutropenia is a major predisposition to bacterial infection, yet it is clear that chemotherapy-induced neutropenia typically occurs in association with alterations in the host’s mechanical barriers to infection and alterations in both humoral and cell-mediated immunity. These interactions likely account both for the different infectious complications that occur during therapy of malignancies and for the types of infections that may be seen with different malignancies.
II. NEUTROPENIA AND FEVER
A. Principles. Development of fever in neutropenic patients should always be regarded as a medical emergency caused by infection. The patient who has signs or symptoms of infection, in the absence of fever, should still be treated in a manner similar to that of the febrile patient.
Early in the period of neutropenia, bacterial infections predominate; hence, management of suspected infection is usually directed initially toward bacterial processes. Diagnosis of a specific infectious process is not possible, however, in a significant proportion of febrile neutropenic patients; much of the clinical uncertainty in treating patients with neutropenia is related to the lack of a specific diagnosis. This should not, however, deter the physician from performing a thorough evaluation and continuing to reassess the patient. Management of infection in the neutropenic patient continues to evolve as new diagnostic tests and antimicrobial therapies (particularly antifungal) are developed.
1. Definitions
a. Fever. A single oral temperature measurement of ≥101°F (38.3°C) or a temperature of ≥100.4°F (38.0°C) for >1 hour constitutes fever.
b. Neutropenia. Although an absolute neutrophil count (ANC) of ≤1,000 cells/µL has long been the cutoff for the term “neutropenia,” the increased risk of infection with ANC > 500 cells/µL is minimal. The risk of infection increases substantially when the ANC is ≤500 cells/µL, and it is quite high when the ANC is ≤100 cells/µL; “profound neutropenia” is frequently used to refer to ANC ≤ 100 cells/µL. “Functional neutropenia” refers to impaired function (e.g., phagocytosis) of circulating neutrophils that can occur with certain hematologic malignancies.
2. Prevention of infection in neutropenic patients
a. General measures
(1) Skin care is important in preventing infections with Staphylococcus aureus and other pathogens. Occlusive antiperspirants should be avoided. Electric shavers are preferred; not shaving at all may be best.
(2) Procedures involving the use of tubes, tapes, and instruments should be minimized because they may be sources of infection.
(3) Fresh flowers, dried flowers, and plants should not be present in the rooms of neutropenic patients because they may carry molds such as Aspergillus.
(4) Avoidance of foods with high bacterial contents (e.g., fresh fruits, uncooked foods, and tap water) is commonly practiced but has no established value.
(5) Pet therapy, the use of household pets at the bedside, should be avoided.
b. Isolation methods
(1) Appropriate hand hygiene is the single most important means to prevent infection in hospitalized patients.
(2) Standard barrier precautions should be employed for all patients; infection-specific isolation should be employed as indicated by the hospital infection control policy.
(3) Reverse or neutropenic isolation (caps, masks, gloves, and gowns) has no established benefit. In addition, it deters good patient care by limiting patient contact with the hospital staff and family.
(4) High-efficiency particulate air filters and laminar airflow rooms, which are expensive, are of questionable benefit.
c. Prophylactic antibiotics. Using absorbable, orally administered antibiotics in neutropenic patients alters the indigenous microbial flora, particularly of the gastrointestinal (GI) tract. Many have advocated this as a form of prophylaxis in the neutropenic patient. The disadvantage of routine oral prophylaxis is the risk of inducing significant resistance of the bacterial and fungal flora to the agents being used for prophylaxis and perhaps other agents; this, in turn, would limit the availability of effective agents to treat infection.
(1) Prophylaxis with fluoroquinolones (e.g., ciprofloxacin or levofloxacin) can be considered in patients who are high risk (see Section II.C.1 for definition of high and low risk) for infection and are expected to be profoundly neutropenic for more than 7 days. The greater gram-positive activity of levofloxacin over ciprofloxacin is potentially an advantage for patients with mucositis. Fluoroquinolone prophylaxis reduces the incidence of fever, “probable” infection, and hospitalization but does not reduce overall mortality. Subsequent infections are more likely to be the result of resistant organisms. Significant concern exists regarding the rising incidence of resistance to fluoroquinolones and the relationship of this resistance to Clostridium difficile diarrhea and colitis. If routine prophylactic antimicrobial therapy is adopted at a cancer center, it should be done in association with rigorous infection control practices and monitoring for emergence of resistant microorganisms.
(2) The routine use of sulfamethoxazole-trimethoprim (Bactrim or Septra) for bacterial prophylaxis in neutropenic patients is of limited benefit and possesses some of the same risks associated with fluoroquinolone prophylaxis. Patients at appreciable risk for Pneumocystis carinii or PCP (renamed P. jiroveci) infection, such as those with acquired immunodeficiency
syndrome (AIDS) and CD4 lymphocyte counts <200 cells/µL, should, however, receive prophylaxis in the form of one double-strength tablet (800 mg of sulfamethoxazole plus 160 mg of trimethoprim) once daily. Data documenting the benefit of PCP prophylaxis in patients with leukemia, lymphoma, and certain solid tumors receiving chemotherapy are much less robust than for HIV infection. Sulfamethoxazole-trimethoprim is not recommended for bacterial prophylaxis.
syndrome (AIDS) and CD4 lymphocyte counts <200 cells/µL, should, however, receive prophylaxis in the form of one double-strength tablet (800 mg of sulfamethoxazole plus 160 mg of trimethoprim) once daily. Data documenting the benefit of PCP prophylaxis in patients with leukemia, lymphoma, and certain solid tumors receiving chemotherapy are much less robust than for HIV infection. Sulfamethoxazole-trimethoprim is not recommended for bacterial prophylaxis.
(3) Intravenous vancomycin prophylaxis has been used to prevent catheter-associated gram-positive infections; it has sometimes been given as combination prophylaxis with quinolones. This practice is strongly discouraged.
(4) Linezolid, daptomycin, and quinupristin-dalfopristin (Zyvox, Cubicin, and Synercid, respectively) are newer agents with activity against some resistant gram-positive organisms; they should not be used as prophylactic agents.
(5) Antifungal agents. Posaconazole prophylaxis was recently shown to improve survival when compared with fluconazole and itraconazole in patients with certain types of immunosuppression. Patients studied were those who received chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome and those undergoing allogeneic hematopoietic stem cell transplantation with graft versus host disease (GVHD). The benefit was largely a lower incidence of invasive Aspergillus infection; serious side effects of prophylaxis were noted. Although there is debate regarding the overall benefit of antifungal prophylaxis in severely immunosuppressed patients, antifungal prophylaxis in patients with lesser degrees of immunosuppression is not recommended.
3. Predisposition to infection
a. The degree and the duration of neutropenia are the most important and easily measured risk factors that predispose to the development of infection. Infection that develops in the setting of neutropenia of relatively brief duration (5 to 7 days) is most likely to be associated with bacterial infection, reflecting the important role of granulocytes in the prevention or control of bacterial infection. Defects in granulocyte function, humoral immunity, and cell-mediated immunity are likely contributing factors, particularly when neutropenia is of longer duration, but these defects are difficult to assess clinically; in patients with profound neutropenia lasting longer than 7 days, fungal infections become a major concern.
b. Defects in the normal mechanical barriers of the host to infection are important predispositions to infection.
(1) Defects in mechanical barriers related to treatment of malignancy are major predisposing factors. The most common sites of such breaches are the skin, the paranasal sinuses, and the alimentary tract; breaches of these barriers allow for local and disseminated infection by the indigenous (normal) and colonizing (environmental) flora of the skin and alimentary tract. Placement of vascular access devices creates a portal for infection of the surrounding soft tissues and bloodstream by microorganisms. Other invasive procedures pose risks for infection that relate to the site of the procedure.
(2) Other types of impairment of the host’s normal barriers to infection include tumor invasion of mucosal surfaces and of the integument; loss of protective reflexes, such as cough; and obstruction to drainage of hollow organs, such as the urinary bladder and the gall bladder.
c. Hospitalization, per se, does not increase the risk of infection, but it does influence the types of infecting organisms and their antimicrobial susceptibility.
4. Infecting organisms
a. Early in the course of neutropenia, bacteria predominate as the microbiologically documented pathogens. Gram-positive bacteria now account for approximately two-thirds of isolates, gram-negative bacilli account for approximately one-fourth, and Candida species and other fungi are occasional pathogens; fungi other than Candida (molds) are usually not of major concern early in neutropenia. Gram-negative bacilli that are encountered frequently include Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and, more recently, Acinetobacter baumannii.
Increasing antimicrobial resistance among gram-positive bacteria has made management difficult. Approximately 50% of Staphylococcus aureus are resistant to traditional antimicrobial agents (penicillins and cephalosporins) and can produce rapidly fatal infection. Other gram- positive organisms may also display significant antimicrobial resistance but typically have a more indolent course; these include coagulase-negative staphylococci, enterococci, including vancomycin-resistant enterococci, and Corynebacterium jeikeium.
b. Later in the course of neutropenia, fungi, particularly yeast (Candida species) and molds (particularly Aspergillus species), must be considered as potential pathogens. In addition, multiply drug-resistant bacteria must be considered.
c. Clostridium difficile-associated diarrhea or colitis is now frequently hospital acquired; it is often associated with fever and almost invariably follows antimicrobial therapy. Of note, onset of symptoms may occur during antimicrobial treatment or as many as 6 weeks after cessation of antimicrobial therapy.
B. Diagnosis
1. History and physical examination. A careful history should be taken, with a focus on new symptoms and on sites that are most commonly infected. Classic signs of inflammation may not be present because of the absence of neutrophilic exudates in infected tissues, although the presence of localized pain may be an important clue. A detailed examination should be performed of the ocular fundus; oropharynx, including teeth and supporting structures; lungs; perineum and perianal areas; and the skin, including vascular access catheter sites and other breaks in the integument related to diagnostic procedures. Digital rectal examination and pelvic examination are usually not performed because trauma to the mucosa during the examination may cause bacteremia.
2. Laboratory evaluation. In addition to routine laboratory tests, at least two samples of blood for bacterial and fungal culture should be obtained promptly by percutaneous collection. The benefit of obtaining blood cultures via a central venous catheter (CVC) is debated; if microorganisms are present in blood, they will be detected by percutaneously collected cultures. Recovery of organisms from cultures collected from a CVC may reflect true infection but frequently reflects contamination of the external port or connection hardware of the CVC; this often leads to much confusion, unnecessary use of antimicrobial agents, with the attendant risks of adverse side effects and colonization of the patient by increasingly resistant microorganisms.
If a CVC is present, the skin exit site should be carefully inspected. If there is drainage from the CVC exit site, the exudate should be submitted
to the laboratory for Gram stain, bacterial culture, and fungal culture and microscopic examination.
to the laboratory for Gram stain, bacterial culture, and fungal culture and microscopic examination.
Cutaneous lesions should be either aspirated or biopsied for bacterial and fungal cultures and histopathologic examination. Sputum for bacterial culture should be obtained if pulmonary symptoms are present or radiographic abnormalities are seen. Urine culture is indicated if there are symptoms, a bladder catheter is present, or the urinalysis is abnormal. If diarrhea is present, then samples should be submitted for C. difficile toxin test and routine bacterial cultures; if diarrhea has been present for >7 days, tests for Giardia, Cryptosporidium, Cyclospora, and Isospora should be submitted.
3. Surveillance cultures. No clinical value is seen in obtaining surveillance cultures from sites such as the anterior nares, pharynx, urine, and rectum or perianal area.
4. Imaging studies. A baseline chest radiograph (posteroanterior and lateral views) should always be done as part of the initial evaluation. In the case of persistent fever and neutropenia, CT, MRI,67Ga scanning, and other isotopic scans and imaging studies may occasionally be of diagnostic value, depending on the particular clinical circumstances. CT scanning of the lungs and paranasal sinuses may be particularly useful.
C. Empiric therapy
1. Initial empiric antimicrobial therapy: high- and low-risk patients. Subject to the definitions of fever and neutropenia given above, febrile neutropenic patients should be rapidly assessed for evidence of infection. Even if there is no evidence of infection other than fever, prompt institution of empiric antimicrobial therapy is essentially always indicated.
In order to facilitate management, febrile neutropenic patients can be subdivided in those who are at low risk and those who are at high risk for serious infection. Low-risk patients are individuals whose period of neutropenia is expected to be brief (<7 days) and who lack significant medical comorbidities; they can be safely treated with either oral or intravenous antimicrobial therapy as outpatients. High-risk patients are those who are anticipated to have prolonged (>7 days) and profound neutropenia (ANC ≤ 100 cells/µL). The presence of significant medical comorbidities such as hypotension, pneumonia, abdominal pain, and change in neurologic status would obviously warrant hospitalization and intravenous antibiotic treatment, regardless of the anticipated duration and severity of neutropenia.
Useful antibacterial and antifungal agents for the treatment of neutropenic fever are shown in Table 35.1.
2. Intravenous antimicrobial therapy. Most patients will likely fall into the so-called “high risk” category. In the past, several different antibiotic combinations were employed for empirical treatment. Empirical treatment has been greatly simplified but requires knowledge of the antimicrobial susceptibility patterns of bacteria isolates at the facility where the patient has been receiving care as well as consideration of the particular infection. Information regarding antimicrobial susceptibility, often termed the hospital “antibiogram,” can usually be obtained from the microbiology laboratory.
The goal of empiric therapy is to provide coverage against likely pathogens pending receipt of culture results. Information from the antibiogram can be used to tailor empiric treatment based on local resistance patterns. In the past decade, initial empiric treatment has been simplified to the use of one of several broad-spectrum agents; this approach has been highly effective.
Table 35.1 Useful Antibiotics for Neutropenic Fever | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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a. A main goal of initial empiric therapy is coverage of gram-negative bacilli, including Pseudomonas aeruginosa; this coverage can usually be accomplished by monotherapy with a beta-lactam antimicrobial. Agents appropriate for this goal include piperacillin-tazobactam, cefepime, and selected carbapenems (either meropenem or imipenem-cilastatin). These antimicrobial agents also provide moderate to excellent coverage for many (but not all) gram-positive organisms and anaerobic bacteria and are often used as monotherapy for fever in the setting of neutropenia.
Generally, these agents are appropriate when the patient has not been exposed repeatedly to antimicrobial therapy, and the microbiology laboratory at the treatment facility has not recorded appreciable resistance to these agents. If the patient is not clinically stable or there is concern about infection with more resistant bacteria, addition of other agents to the regimen may be warranted; these agents would include vancomycin, daptomycin, linezolid, fluoroquinolones (ciprofloxacin and levofloxacin), aminoglycosides (particularly amikacin), colistin, and tigecycline (see below).
b. A history of uncomplicated penicillin-induced skin rash is not a contraindication to the use of these beta-lactam agents (penicillins, cephalosporins, and carbapenems). However, these drugs should be avoided in patients with a history of immediate hypersensitivity to penicillins (or other beta-lactam agents) or history of penicillin-associated Stevens-Johnson syndrome or toxic epidermal necrolysis. In the occasional situation in which a beta-lactam agent is clearly contraindicated because of risk of serious allergic reaction, alternative empiric regimens include cipro-floxacin-clindamycin or aztreonam-vancomycin; data regarding efficacy of these alternative regimens are limited.
c. The initial empiric use of vancomycin is indicated in patients who are suspected of having CVC-related infection, bacterial pneumonia, skin and soft tissues infection, or who are hemodynamically unstable, in addition to the gram-negative coverage listed above.
d. Modifications to the initial empiric antibiotic regimen are appropriate for patients who are at risk for infection with resistant organisms or who are bacteremic or are clinically unstable. A significant degree of expertise with regard to local hospital bacterial resistance patterns is often needed to address these issues; infectious diseases consultation should be considered.
3. Modifications (additions) to the recommended initial empiric antibiotic regimen is warranted whenever there is concern regarding the following: Staphylococcus aureus, vancomycin-resistant Enterococcus, or extended-spectrum beta-lactamase production.
a. Staphylococcus aureus. Effective treatment of infection due to Staphylococcus aureus has changed substantially in the past decade and likely will continue to change.
(1) Methicillin-resistant Staphylococcus aureus (MRSA) now accounts for an appreciable portion (>50%) of all infections due to S. aureus. Agents to be considered for treatment of suspected or documented infections due to S. aureus include vancomycin, daptomycin, and linezolid. The greatest clinical experience for treatment of MRSA is with vancomycin; it is considered by most experts to be the drug of choice. However, progressively rising concentrations of vancomycin (“MIC creep”) that are now required to treat MRSA infection have many experts concerned that this drug may eventually be lost as a first-line agent. Recommendations for treatment of serious MRSA infections
include a target serum trough level of 15 to 20 mg of vancomycin/mL of blood.
include a target serum trough level of 15 to 20 mg of vancomycin/mL of blood.
(2) Daptomycin also has good activity against MRSA and has been used with success. Potential concerns regarding daptomycin are several, however. The drug is significantly bound by pulmonary surfactant; daptomycin is not indicated for treatment of pneumonia. In addition, the vancomycin “MIC creep” noted above appears often to also be associated with a daptomycin MIC creep as well; the clinical significance of this finding is unclear but definitely concerning.
(3) Linezolid is a bacteriostatic agent with good activity against most gram-positive organisms, including MRSA. The major concerns about linezolid are its bacteriostatic nature and potential hematologic toxicity. The latter includes thrombocytopenia, anemia, and myelosuppression. Thrombocytopenia, the most concerning hematologic adverse effect, is thought to be an immune-mediated process that is particularly associated with linezolid therapy of >2 weeks duration.
(4) Ceftaroline is a new agent with activity against a variety of microorganisms, including MRSA. It was recently approved by the FDA for treatment of acute skin and soft tissue infections and communityacquired pneumonia due to susceptible organisms. Data to support ceftaroline’s efficacy for infections in immunosuppressed patients are lacking. In addition, it is unclear whether it will become another useful agent to treat most infections caused by MRSA (aside from skin/soft tissue infection).
b. Vancomycin/ampicillin-resistant Enterococcus (VRE) has become an important pathogen in many centers. The recommended empiric therapy for suspected VRE is either linezolid or daptomycin.
c. Multidrug-resistant gram-negative bacilli (GNB) are becoming increasingly common isolates and present major clinical challenges. They are extended spectrum beta-lactamase (ESBL) producing organisms (the most common form of multidrug resistant GNB) and carbapenemase-producing organisms (a relatively uncommon form).
(1) ESBL-producing GNB are relatively commonly isolated from hospitalized patients, whereas carbapenemase-producing GNB are uncommon. ESBL-producing GNB are considered to be resistant to penicillins (including piperacillin-tazobactam) and cephalosporins (including cefepime). Because there is not a single standardized clinical laboratory test for ESBL production, microbiology experts and the FDA have proposed a revision of laboratory susceptibility interpretation. This should eliminate testing for ESBL and provide a more uniform interpretation of antimicrobial activity.
At present, this field is in a state of flux. In general, GNB that produce ESBLs are often resistant to other classes of antibiotics, such as aminoglycosides and fluoroquinolones. Most experts recommend use of a carbapenem (imipenem or meropenem) if the patient is clinically unstable or has cultures that are suspicious for resistant GNB because of the high incidence of ESBL production.
(2) Carbapenemase-producing GNB are uncommon, but there is significant concern regarding widespread dissemination of these organisms. In general, most experts would consider adding either colistin or tigecycline to the regimen if the patient is clinically unstable or if culture results are suspicious for a carbapenemase-producing GNB.
Clinical data regarding the efficacy of these agents for treatment of infection in neutropenic patients are extremely sparse. Infectious diseases consultation would be prudent in such situations.
Clinical data regarding the efficacy of these agents for treatment of infection in neutropenic patients are extremely sparse. Infectious diseases consultation would be prudent in such situations.
4. Oral antimicrobial therapy. Oral antimicrobial therapy with ciprofloxacin (Cipro), 750 mg q12h, plus amoxicillin/clavulanate (Augmentin), 875 mg/125 mg q12h, has been shown to be safe and appropriate, when limited to adult patients who are at low risk for infectious complications of neutropenia. Such patients do not have an identifiable focus of infection and lack clinical findings of systemic infection other than fever.
A number of factors that favor a low risk for severe infection have been identified and a scoring index has been developed to identify low-risk subjects who would be suitable for oral therapy (see Hughes, et al. 2002 and Freifeld, 2010 in Suggested Reading). These patients, however, still require careful observation and immediate access to medical care. Outpatient oral antibiotic therapy may not be suitable for many patients and health care facilities, but likely greater use will be seen in the future as additional experience is gained with this form of management.
Other options available to the clinician are initial hospitalization for administration of intravenous antibiotics, followed by switch to oral therapy and discharge, or discharge home on IV antibiotic therapy. Patients with febrile neutropenia, regardless of route of antimicrobial therapy, should be seen and evaluated on a daily basis.
D. Empiric therapy. Management of antimicrobial therapy during the first 7 days. Response of fever to initiation of empiric antimicrobial therapy, if it is to occur, sometimes requires 3 to 5 days. After initiation of antimicrobial therapy, several possible outcomes exist: deterioration during the ensuing 1 to 3 days, resolution of fever during the first 3 to 5 days, or persistence of fever during the first 3 to 5 days. In the event of clinical instability, immediate reassessment of the patient and the treatment regimen is essential.
In many studies, the median time to defervescence after initiation of therapy is approximately 5 days. Therefore, in a patient who is clinically stable, except for persistent fever, the physician should consider waiting approximately 5 days before entertaining changes in the antimicrobial regimen, unless initial cultures yield an organism resistant to the treatment regimen. Changes in antimicrobial therapy should generally be made for specific reasons; an unintended consequence of aggressive, unjustifiably escalating antimicrobial therapy is the promotion of subsequent infection by more highly resistant microorganisms.
1. In patients who become afebrile within 3 days, broad-spectrum therapy should be maintained throughout the period of neutropenia, with appropriate modifications to the regimen based on results of cultures and other diagnostic tests. Cessation of therapy is appropriate when cultures and clinical assessment indicate eradication of infection and the ANC is >500 cells/µL. A switch from IV to oral antibiotic therapy is reasonable if the patient is clinically stable and impaired absorption of antibiotics from the gastrointestinal tract is not a concern. Clinically documented infection should be treated in a manner that is appropriate for the type of infection, irrespective of the rapidity with which neutropenia resolves.
2. In patients whose fever persists during the first 4 to 7 days of empiric therapy and in whom a specific infectious process has not been identified, a number of possibilities exist. In the event of persistent fever of unknown cause for more than 4 days, the most appropriate actions are (1) continue
treatment with the initial regimen, (2) change or add antibacterial agents to the original regimen, or (3) add an antifungal agent to the regimen (with or without making changes to the antibacterial regimen).
treatment with the initial regimen, (2) change or add antibacterial agents to the original regimen, or (3) add an antifungal agent to the regimen (with or without making changes to the antibacterial regimen).
a. Causes of persistent fever include
(1) Slow response to the treatment regimen
(2) Bacterial infection resistant to the treatment regimen
(3) Development of a second infection
(4) Inadequate antibiotic levels owing to suboptimal dosing
(5) Inadequate penetration of drugs into an infected site, such as infected necrotic tissue, an abscess, or a CVC site
(6) A nonbacterial infection
(7) Fever not of infectious origin, such as drug fever or pulmonary emboli
b. Reevaluation. In reevaluating the patient’s status after 3 to 4 days of therapy, the physician should repeat the initial diagnostic evaluation, review results of culture, obtain additional cultures, and consider obtaining radiographic imaging studies, if new localizing symptoms or signs are present. Any changes in therapy should be dictated by findings on reevaluation.
c. If the patient has remained clinically stable and the reevaluation was unrevealing, continuation of the initial regimen is reasonable. If neutropenia is expected to resolve within 5 days, this approach is quite appropriate.
d. With evidence of progressive disease, consideration should be given to changes in the antimicrobial regimen. The nature of these changes should be dictated by findings made during clinical reassessment and the components of the initial antimicrobial regimen. Examples of new findings include development of abdominal pain (suggesting cecitis, enterocolitis, or other intra-abdominal processes), development of diarrhea (suggesting C. difficile disease), detection of pulmonary infiltrates, drainage or inflammation at catheter entry sites, worsening stomatitis, and detection of sinus opacities on CT scanning.
e. Addition of antifungal therapy to the treatment regimens of patients who are febrile after initial antimicrobial therapy has been controversial, particularly with regard to the timing of such therapy and the particular antifungal agent to be used. The availability of newer, less toxic antifungal agents have facilitated a more uniform approach. Most experts believe that a patient with persistent fever and profound neutropenia after 4 days of empiric antimicrobial therapy should be considered for antifungal therapy. A thorough evaluation to detect systemic fungal infection should be done; this should include consideration of biopsy of suspicious lesions, chest radiographs, sinus radiographs or CT, and CT of the chest and abdomen. If a focus of bacterial infection is not found, fungal infection should strongly be considered. The fungi most likely to cause fever relatively early in the course of neutropenia are Candida species.
Detailed discussion of treatment of fungal infections is provided in Section VII. The use of antifungal agents in patients with prolonged neutropenic fever is discussed in Section VII.B.
E. Empiric therapy: Duration of therapy
1. Antibacterial therapy
a. The most important indicator in deciding to discontinue antibacterial therapy is the neutrophil count. If the ANC is ≥500 cells/µL and the patient has been afebrile for 2 consecutive days, therapy may be stopped
unless more prolonged therapy is indicated for treatment of a specific, documented infection (e.g., pneumonia or bacteremia).
unless more prolonged therapy is indicated for treatment of a specific, documented infection (e.g., pneumonia or bacteremia).
b. For the patient who becomes afebrile but is persistently neutropenic, most experts recommend continuation of therapy until the ANC is ≥500 cells/µL. Some experts would change to oral therapy if the patient were at low risk. In the completely healthy-appearing patient, some would discontinue antimicrobial therapy and engage in close monitoring, particularly with early evidence of bone marrow recovery.
c. For the patient who remains profoundly neutropenic (ANC ≤ 100 cells/µL), IV antimicrobial treatment should be continued.
2. Antifungal therapy
a. If a specific fungal infection has been documented,
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