reviewed by deborah blamble, pharm.d., bcop; and h

Infections in Patients with Cancer147

INFECTIONS INPATIENTS WITHCANCER

Pharmacotherapy Self-Assessment Program, 5th Edition

Robert K. Sylvester, Pharm.D.Reviewed by Deborah Blamble, Pharm.D., BCOP; and H. William Kelly, Pharm.D., FCCP, BCPS

Learning Objectives 1. Assess the relative morbidity risk for patients with

cancer with febrile neutropenia. 2. Justify the use of prophylactic antimicrobial drug

regimens administered to patients with cancer.3. Evaluate the appropriateness of initial antimicrobial

drug therapy administered to patients with febrileneutropenia.

4. Design a plan for managing bacteremia or fungemia inpatients with an infected vascular access device (VAD).

5. Determine the therapeutic end point for antimicrobialdrug regimens administered to febrile patients withcancer.

6. Justify recommendations for modifying antimicrobialdrug therapy in patients with febrile neutropenia.

7. Justify the use of colony-stimulating factors (CSFs) forprophylactic and therapeutic indications in patientswith cancer.

Introduction In the middle of the 20th century, chemotherapy was

established as an effective antineoplastic treatment.Unfortunately, the effectiveness of many chemotherapydrugs is limited by chemotherapy-induced neutropenia,resulting in an increase in potentially life-threateninginfections. In the 1970s, gram-negative bacteria were theprevalent infecting microorganisms. Fifty percent to 80% ofpatients with febrile neutropenia who were diagnosed withPseudomonas aeruginosa bacteremia died within 2–3 daysof diagnosis. This high mortality rate led to administeringempiric antibiotic drug therapy to patients with febrileneutropenia. Empiric administration of gentamicin andcarbenicillin substantially decreased the fatality rate of

patients with P. aeruginosa bacteremia. As a result, thisapproach was quickly accepted as standard therapy.

The management of infectious complications in patientswith cancer has improved significantly since the 1970s. Thepattern of infecting pathogens and their antimicrobialsusceptibility has evolved. Potentially fatal infectionsremain a persistent risk and a challenge to treat. Currentestimates are that 30% of patients administeredchemotherapy for nonhematologic neoplasms and 85% ofpatients administered induction chemotherapy for acuteleukemias develop potentially life-threatening infections.Infectious complications caused death in up to 70% ofpatients treated for acute leukemia. A variety of effectiveempiric antibiotic drug regimens have been developed totreat patients with cancer with febrile neutropenia. Seventypercent to 80% of patients with febrile neutropenia respondto initial empiric antibiotic drug therapy and less than 10%of infections are fatal. This chapter provides pharmacistswith an understanding of evidence that can be applied inpractice settings to optimally manage infections in patientswith cancer.

Impaired Host Defenses inPatients With Cancer Impaired Neutrophil Function

Neutrophils are the primary phagocyte in the body.Neutropenia is defined as a neutrophil count of less than 500 cells/mm3 or a neutrophil count of less than 1000 cells/mm3 with a predicted decrease to less than 500 cells/mm3. The term absolute neutrophil count (ANC) isthe total number of mature segmented neutrophils and lessmature neutrophils identified as bands on a white blood cell(WBC) differential. An ANC is calculated by multiplyingthe WBC count by the percentage of segmented neutrophilsand bands reported on the WBC differential. For example,

TM

chemotherapy administered to patients with less aggressiveneoplasms is less myelosuppressive. These patientsinfrequently experience an ANC less than 100 cells/mm3. Ifsuch severe chemotherapy-induced neutropenia does occur,it rarely persists beyond several days. Underlying neoplasticdisease seldom causes neutropenia; however, it isoccasionally reported as a complication in patients withhematologic neoplasms or neoplasms that have replaced thenormal elements in bone marrow.

Impaired Cellular and Humoral Immunity Defects in cellular and humoral immunity are associated

with certain neoplasms and with many antineoplastictherapies. Impaired T-cell and B-cell function generallyresults in increased susceptibility to opportunisticinfections. The activation of varicella zoster virus (VZV) isa well-documented complication of Hodgkin’s diseaseattributed to disease-related defects in cellular immunity.Defects in humoral immunity, notably the decreasedproduction of immunoglobulins, are associated withincreased infections in patients with chronic lymphocyticleukemia and multiple myeloma.

Lymphopenia is a frequent complication ofchemotherapy and radiation. The incidence of infections,especially opportunistic infections, is a function of the depth

Abbreviations in thisChapterAmB Amphotericin B deoxycholateANC Absolute neutrophil countASCO American Society of Clinical

Oncology CSF Colony-stimulating factor CYP Cytochrome P450HSCT Hematopoietic stem cell

transplantationHSV Herpes simplex virusIDSA Infectious Diseases Society of

AmericaL-AmB Amphotericin B liposome for

injectionMASCC Multinational Association for

Supportive Care in Cancer PCP Pneumocystis jiroveci pneumoniaVRE Vancomycin-resistant enterococciVAD Vascular access deviceVZV Varicella zoster virusWBC White blood cell

148Infections in Patients with Cancer Pharmacotherapy Self-Assessment Program, 5th Edition

the ANC of a patient with a WBC of 8000 cells/mm3 with48% segmented neutrophils and 2% bands, is 4000cells/mm3 (8000 X 0.5 = 4000). Neutropenia is one of themost critical risk factors leading to infections in patientswith cancer. The severity of infectious complications iscorrelated to the grade and duration of chemotherapy andradiation-induced neutropenia. Research published in the1970s documented that infectious morbidity increases whena patient’s ANC is less than 500 cells/mm3, and theincidence of infectious morbidity rises more rapidly when apatient’s ANC falls below 100 cells/mm3. According to the2002 Infectious Diseases Society of America (IDSA)Guidelines for the Use of Antimicrobial Agents inNeutropenic Patients with Cancer, “[a]t least one-half ofneutropenic patients who become febrile have anestablished or occult infection and at least one-fifth ofpatients with neutrophil counts less than 100 cells/mm3

have bacteremia.” The resolution of fever and othersymptoms of infection typically do not occur until apatient’s neutropenia resolves.

Chemotherapy accounts for the majority of neutropeniain patients with cancer. Typically, the neutrophil nadiroccurs 7–14 days after completing myelosuppressivechemotherapy. The degree and duration of neutropenia arerelated to the intensity of the treatment regimen. The mostprofound neutropenia is commonly reported in patients whohave completed induction chemotherapy for acute leukemiaor myeloablative chemotherapy before hematopoietic stemcell transplantation (HSCT). Standard inductionchemotherapy for a patient with acute nonlymphocyticleukemia typically results in an ANC less than 100 cells/mm3, which persists for 2–3 weeks. In general, the

and duration of lymphopenia. Immunosuppressive effects ofolder drugs such as cyclophosphamide and corticosteroidsare well documented. Corticosteroids, which are extremelyeffective in treating malignant lymphomas and lymphocyticleukemias, suppress numerous aspects of lymphocytefunction (Table 1-1). Newer drugs, such as fludarabine,cladribine, rituximab, and alemtuzumab, are also associatedwith profound and persistent suppression of cellularimmune responses.

Disruption of Skin and Mucosal Barriers The first line of host defense against microbial invasion

is the physical barrier provided by epidermal and mucosaltissue. Normal flora, consisting of bacteria and yeast,colonize the skin and the mucosal surfaces of thegastrointestinal tract and assist in the normal protectivefunction of these tissues (e.g., colonization resistance). Skinand mucosal tissues are susceptible to damage fromchemotherapy, radiation therapy, and invasive procedures(e.g., needle punctures, surgical incisions, and insertion ofvascular access devices [VADs]).

Mucositis caused by chemotherapy and radiation therapyis a frequent source of infection in patients with cancer.Typically, the onset of treatment-induced mucositis isdiagnosed within 1 week of completing treatment andgradually resolves within a week of its onset. Patients withsevere mucositis may need parenteral nutrition andanalgesic support. The infection risk, length ofhospitalization, and mortality can increase with the severityof mucositis. Mucosal damage in the mouth has beenassociated with infections caused by normal flora in the oralcavity (e.g., gram-positive bacteria and herpes simplex virus[HSV]), whereas damage to mucosa in the lowergastrointestinal tract has been associated with infections

Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet 2003;362:1828–38. Review.

149

caused by resident normal flora (e.g., enteric gram-negativebacilli).

Breaks in the epidermal barrier can result in residentmicroflora causing local infections that become systemic.Vascular access devices are a frequent source of infection.The infection risk varies with the type of VAD surgicallyimplanted. The incidence of bacteremias ranges from 20.9%to 36.7% for external catheters and from 5.1% to 11.2% forsubcutaneous VADs. Similarly, subcutaneous devices areassociated with a lower risk of exit-site or tunnel pocketinfections. The mean incidence of localized infections is 7%for subcutaneous devices and 15.8% for external catheters.Skin microflora such as coagulase-negative staphylococci,Staphylococcus aureus, and Candida albicans are the mostcommon causes of catheter-related bacteremia.

Impaired Reticuloendothelial Function The reticuloendothelial system consists of all phagocytic

cells of the body except neutrophils. The reticuloendothelialsystem includes the cells lining the sinusoids of the spleen.Macrophages in the spleen function to remove non-opsonized microbes. In addition, the opsonization ofmicrobes that occurs in the spleen enhances thephagocytosis of encapsulated bacteria. Consequently,patients with cancer who are functionally asplenic afterundergoing HSCT or patients who have beensplenectomized because of refractory hypersplenism are atan increased risk of developing severe infections withencapsulated bacteria such as Haemophilus influenzae andStreptococcus pneumoniae.

Pathogens InfectingPatients with Cancer Etiology of Infections in Patients with Cancer

The multiple defects in immune function detailed in theprevious section often affect patients with cancersimultaneously. As a result, immunocompromised patientscommonly develop infections caused by indigenous

bacteria, fungi, and viruses. Immunocompromised patientswith cancer are also at risk for developing infections causedby exposure to exogenous pathogens. Protective isolationand routine hand washing are recommended procedures tolimit the exposure of immunocompromised patients withcancer to exogenous pathogens. The etiologies of infectionsin patients with cancer have evolved in response toantibiotic drug therapies and supportive interventions.

Pathogens Isolated From Infected Patients Bacterial Pathogens

Bacteria originating from a patients’ normal microfloraare the most common cause of infection inimmunocompromised patients with cancer. In the 1970s and1980s, the majority of microbiologically documentedinfections in patients with febrile neutropenia were causedby enteric gram-negative bacteria. Escherichia coli, P. aeruginosa, Klebsiella pneumoniae, and Enterobacterspecies represented 60%–70% of microbiologicallydocumented infections. Gram-positive bacteria typicallyfound on the skin (S. aureus, Staphylococcus epidermidis,Staphylococcus haemolyticus, and Staphylococcus hominis)and oral mucosa (e.g., Viridans group streptococci [mitisand oralis], Enterococci [faecalis and faecium]) accountedfor fewer than 40% of microbiologically documentedinfections.

In the early 1980s, VADs became a standard of care forpatients with cancer who required reliable venous access.Although the benefits of VADs are well established, theassociated risk of developing infection is also welldocumented. The implantation of indwelling vascular accesscatheters has become a major contributing factor ofincreased infections caused by gram-positive microflora.The most common gram-positive bacteria isolated byculture are coagulase-negative staphylococci, S. aureus,Enterococci (faecalis and faecium) and Corynebacteriumspecies. Long-term use of VADs and their frequentmanipulation can provide an entry site for these microflora.

Quinolone prophylaxis and high-dose cytarabine alsohave been linked to an increased incidence of gram-positivestreptococcal infections. A prospective, multicenter study ofmore than 500 patients with febrile neutropenia analyzedrisk factors for developing infections with gram-positivecocci. Microorganisms were isolated in 32% of the patientswith febrile neutropenia. Gram-positive cocci accounted for64% (108/168) of microbiologically documented infectionswith staphylococcal infections the most prevalent (65% ofthe gram-positive isolates were staphylococcal and 35%streptococcal). Multivariate analysis identified theadministration of high-dose cytarabine, gut decontaminationwith colimycin, administration of nonabsorbableantifungals, and diarrhea with increased risk ofstreptococcal infections. Relative risks for streptococcalinfections were 2.9 for patients with one risk factor, 13.2 forthose with two risk factors, and 20.7 for patients with threeor more risk factors.

Infections in Patients with CancerPharmacotherapy Self-Assessment Program, 5th Edition

Table 1-1. Corticosteroid-Induced Effects onLymphocyte FunctionReversible lymphopenia, CD4 depletionDecreased lymphocyte-proliferation and migration Impaired delayed-hypersensitivityImpaired natural killer cell cytotoxicityDecreased lymphokine production (interleukin-2, TNF-alpha,

interferon gamma, interleukin-12)Dysregulation of T-helper cellsImpaired phagocyte effector cell function and cellular immune

responseTNF = tumor necrosis factor.Adapted with permission from Elsevier. Lionakis MS, Kontoyiannis DP.Glucocorticoids and invasive fungal infections. Lancet 2003;362:1828–38.

Donnelly JP, DePauw BE. Infections in the immunocompromised host: general principles. In: Mandell GL, Bennett JE, eds. Mandell, Douglas, and Bennett’sPrinciples and Practice of Infectious Diseases, 6th ed. Philadelphia: Elsevier, 2005:3421–32. Cordonnier C, Buzyn A, Leverger G, et al. Epidemiology and risk factors for gram-positive coccal infections in neutropenia: toward a more targeted antibioticstrategy. Clin Infect Dis 2003;36:149–58.


Prophylactic antibiotic drugs have influenced theetiology of bacterial infections in patients with febrileneutropenia. The ability of prophylactic administration ofquinolones, cotrimoxazole, penicillin, cefazolin, andmacrolides to decrease infections has been documented. Astudy of bone marrow transplant recipients who wereadministered penicillin, cefazolin, and macrolides asprophylaxis reported a 40% reduction of gram-positiveinfections (about 50%–10%). However, increases in theisolation of bacteria not inhibited by the prophylacticantibiotic drugs have occurred. In four studies publishedduring the past 5 years, gram-positive microflora accountedfor 44%–67% of microbiologically documented infectionsin 797 patients with febrile neutropenia. The reported ratesof gram-positive infections were 67.1%, 66.1%, 44.4%, and44.1%. In the two studies that reported the highest incidenceof gram-positive pathogens, the majority of patients wereadministered prophylactic antibiotic drugs withpredominately gram-negative coverage (i.e., colistin andquinolones).

In contrast to these data, in the two studies in whichprophylactic antibiotic drugs were not used or administeredto less than 25% of patients, enteric bacteria were isolated in55% of patients. Escherichia coli, P. aeruginosa, and K. pneumoniae continue to be the most commonly isolatedgram-negative pathogens in patients with febrileneutropenia.

Finally, patients with impaired humoral immunity are atincreased risk of severe complications from infectionscaused by encapsulated bacteria such as S. pneumoniae andH. influenzae.

Fungal Pathogens Opportunistic microorganisms cause significant

morbidity and mortality in patients with cancer, especiallyin those who have severe defects in cellular immunity.Fungal infections account for 2%–10% of initialmicrobiologically confirmed infections in patients withcancer who have febrile neutropenia. The incidence ofpositive fungal cultures in patients with persistent febrileneutropenia approaches 30%. Furthermore, the incidence ofinvasive fungal infections in autopsy studies of patients withprolonged febrile neutropenia has ranged from 40% to 69%.Among fungal pathogens, the Candida species are the mostcommon cause of documented infection. Candida albicansand Candida parapsilosis colonize the skin; C. albicans,Candida tropicalis, and Candida glabrata colonize the oralmucosa. These Candida species are potential pathogens thatcan result in local or systemic infections inimmunocompromised patients with cancer. Typically,Candida infections are diagnosed after neutropenic episodesthat exceed 7 days.

Aspergillus species are saprophytic molds widelydistributed in the environment in the form of spores.Inhalation of Aspergillus spores can lead to colonization ofthe airways, especially in patients with defective cellularimmunity. Patients with cancer who develop severe andprolonged immunosuppression are predisposed to develop

Aspergillus pneumonia and invasive disease. Most oftenAspergillus infections are diagnosed after neutropenicepisodes exceeding 2 weeks. Fatality rates for patients withprolonged neutropenia and documented Aspergillusinfections range from 60% to 80%.

Viral Pathogens Herpes viruses (HSV, VZV, and cytomegalovirus) are

ubiquitous. They seldom cause severe infections inindividuals who are immunocompetent. However, inpatients with defective cellular immunity, the herpes virusesare pathogenic. Patients developing chemotherapy-inducedmucositis are predisposed to HSV infections. Thecytomegalovirus has been a major cause of mortality inpatients treated with allogeneic HSCT complicated by graft-versus-host disease.

Pneumocystis jiroveciPneumocystis carinii was originally classified as a

protozoan parasite because of antimicrobial susceptibilities.Subsequent ribosomal RNA sequencing technologyrevealed that it is more similar to fungi than protozoa.Several strains have been identified. In the early 1900s, P. carinii isolated from rats and other animals was firstrecognized. In 1952, Otto Jirovec published an article thatdocumented a P. carinii epidemic in humans. Molecular andimmunologic studies published in 2002 led to theconclusion that the Pneumocystis isolated from animals isdistinct from the strain isolated from humans. Pneumocystisjiroveci was the nomenclature introduced to identify thePneumocystis strain that infects humans whereas P. cariniirefers to the strain isolated from animals. The merit of thischange in nomenclature has been a point of contention.Pneumonia caused by P. jiroveci in humans is commonlyreferred to by the acronym PCP. Patients with impairedcellular immunity are predisposed to potentially fatal PCP.Research performed in patients with acute lymphocyticleukemia discovered that cotrimoxazole is effective intreating and preventing PCP.

Clinical Presentation ofInfection in Patients withCancer Diagnosis—Signs and Symptoms

The diagnosis of infections in immunocompromisedpatients with cancer requires a high degree of suspicion.Common signs and symptoms of inflammation are less prominent in patients who are severelyimmunocompromised. Consequently, infections are lesslikely to cause erythema, induration, and pus formation;productive cough and infiltrates on chest radiographs maybe less prominent. Pyuria may be minimal or absent.However, inflammatory responses resulting in sepsis dooccur and can rapidly progress to multisystem failure. Fever

Ramphal R. Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of the currently isolated pathogens. Clin Infect Dis2004;39(suppl 1):S25–S31.

151

onset is often the first and only symptom of possibleinfection. The IDSA 2002 Guidelines for the use ofantimicrobial drugs in neutropenic patients with cancerdefine fever as a single oral temperature above 101°F or atemperature above l00.4°F for at least 1 hour. Patients withfebrile neutropenia should receive a thorough physicalexamination to identify potential infection sites. Commoninfection sites include the skin (especially incisions madefor VAD implantation), the alimentary tract, lungs, andperianal region.

The recommended diagnostic workup for infection inpatients with cancer includes bacterial, fungal, and viralcultures of the blood, urine, and any inflammation site foundon the skin and mucosa. Positive cultures confirm the causeof fever in only 30%–50% of patients with febrileneutropenia. The IDSA guidelines for managingintravascular catheter-related infections suggest that blooddrawn percutaneously and from the catheter can helpexclude catheter-related bacteremia. These guidelines citedata reporting positive predictive values of 73% for bloodcultures drawn percutaneously and of 63% for bloodcultures drawn from the catheter. The respective negativepredictive values are 98% and 99%, respectively. A chestradiograph or computed tomography scan can diagnosepulmonary infections. Bronchoscopy is warranted inpatients with pulmonary infiltrates. Specimens obtained bybronchoalveolar lavage should be submitted for theappropriate cultures (bacteria, fungi, and virus) and smears(acid-fast bacilli, P. jiroveci, Nocardia spp.). If diarrhea orabdominal pain is present, an assay for Clostridium difficiletoxin should be ordered.

Risk Assessment Characterization of a patient’s risk for developing severe

infectious complications is useful for making antibiotic drugmanagement decisions. The IDSA guidelines for usingantimicrobial drugs in neutropenic patients with cancercategorize febrile patients as being at either low or high riskfor developing infectious complications. Patients with low-risk features may be treated with oral antibiotic drugs andmay possibly be treated as outpatients. Patients with high-risk features should be hospitalized for close observationand administered parenteral antibiotic drugs.

Features known to be associated with a low risk forsevere infection include the following: • ANC greater than 100 cells/mm3• Absolute monocyte count greater than 100 cells/mm3• Normal findings on a chest radiograph • Duration of neutropenia less than 1 week• Expected resolution of neutropenia in fewer than 10 days• No infection at the site of a VAD • Early evidence of bone marrow recovery • No appearance of illness

Patients whose febrile illnesses do not meet the criteriafor low risk are considered at high risk for infectiouscomplications.

In 2000, the Study Section on Infections of theMultinational Association for Supportive Care in Cancer

(MASCC) published a risk index for identifying febrileneutropenic adult patients with cancer at low risk fordeveloping infectious complications (Table 1-2). The indexwas validated in a study of 1139 patients with febrileneutropenia. The range of MASCC scores was 0 to 26, withhigher scores indicating lower risk for infectiouscomplications. A score of 21 is the threshold for designatinga patient at low risk. This threshold score identified patientsat low risk for developing infectious complications with apositive predictive value of 91%, a specificity of 68%, anda sensitivity of 71%. In 2004, a comparison of the MASCCrisk index and an alternative model revealed that theMASCC score resulted in fewer low-risk patientsmisclassified as being at high risk for developing infectiouscomplications.

Empiric Antibiotic DrugTherapy—Initiation andMonitoring

The MASCC risk index for identifying febrileneutropenic adult cancer patients at low risk for developinginfectious complications (Table 1-2) can help determinewhich patients can be effectively treated with oral antibioticdrugs. A study is currently under way to determine whetherthe index can be used to identify patients at low risk forinfectious complications who can be effectively treatedexclusively as outpatients with empiric oral antibiotic drugs.If the hospitalization of low-risk patients with febrile


Table 1-2. The MASCC Predictive Model for Risk ofComplications in Patients With Febrile NeutropeniaCharacteristic ScoreBurden of illnessa

No or mild symptoms 5Moderate symptoms 3

No hypotension 5No chronic obstructive pulmonary disease 4Solid tumor or no previous fungal infection

in hematologic tumor 4Outpatient status 3No dehydration 3Age younger than 60 yearsb 2NOTE: Highest theoretical score is 26. A risk

index score of ≥ 21 indicates that the patient is likely to be at low risk for complications and morbidity.

aChoose 1 item only.bDoes not apply to patients 16 years of age or younger. Initial monocytecount of ≥ 100 cells/mm3, no comorbidity, and normal chest radiographfindings indicate children at low risk for significant infections.MASCC = Multinational Association for Supportive Care in Cancer.Adapted with permission from Elsevier. Klastersky J. Management offever in neutropenic patients with different risks of complications. Clin Infect Dis 2004:39(suppl 1):32–7.

Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system foridentifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038–51.

neutropenia for administration of intravenous antibioticdrugs can be avoided, a substantial cost savings can beachieved.

The infection pattern in immunocompromised patientswith cancer is determined by the immune defects unique topatients’ treatment regimens and underlying cancer. Bacteriaare the most common pathogens identified during the initial days of febrile episodes. Chemotherapy-inducedneutropenia and mucositis are the principal predisposingfactors that result in normal microflora causing infection atthis point. Consequently, empiric administration of broad-spectrum antibiotic drug regimens with establishedcoverage of the most prevalent bacteria is standard practice.If patients’ chemotherapy-induced neutropenia exceeds 3–7days and does not respond to initial antibiotic drug therapy,the incidence of microbiologically documentedopportunistic infections (e.g., fungi, P. jiroveci, and herpesviruses) increases. Patients treated with allogeneic HSCTand aggressive myelosuppressive chemotherapy for acuteleukemias and lymphomas are at the greatest risk foropportunistic infections.

In 2002, the IDSA published its most recent revision ofGuidelines for the Use of Antimicrobial Agents inNeutropenic Patients with Cancer. These comprehensiveguidelines remain the standard of care for treating febrileneutropenia. The guidelines provide four algorithms toassist clinicians with selecting and managing appropriateantimicrobial drug therapy.

Figure 1-1 addresses the initial selection of antibioticdrug therapy. Two critical assessments in guiding antibiotictherapy are a patient’s risk status and need for vancomycin.Patients who are febrile who meet low-risk criteria and

without clinical findings to justify empiric vancomycintherapy (Table 1-3) can be treated safely with oral antibioticdrug combinations. The combination of amoxicillin-clavulanic acid 750 mg every 8 hours and ciprofloxacin 750 mg every 12 hours has been the most widely studied.Initial studies evaluating the effectiveness of oral regimensin hospitalized patients at low risk for infectiouscomplications established the effectiveness of this strategy.More recently, oral regimens are being administered tocarefully selected outpatients (e.g., low-risk patients whocan be monitored and who can access medical care withoutdelay). The cost-effectiveness of this approach has resultedin its acceptance for adult patients at low risk for infectiouscomplications.

Fewer studies of initial oral antibiotic drug therapy infebrile neutropenic pediatric patients have been publishedbecause FDA labeling limits the use of quinolones inpatients under age 18. Oral cefixime has been evaluated inseveral pediatric studies. Pediatric patients at low risk forinfectious complications have been discharged from thehospital on oral cefixime after completing a minimum of 48 hours of intravenous therapy. The IDSA guidelinesconclude that more data are needed to establish the efficacyof oral antibiotic drugs as initial therapy for children withfebrile neutropenia.

Empiric Vancomycin Intravenous vancomycin is recommended as initial

empiric treatment for any patient if a catheter-relatedinfection is suspected (e.g. localized inflammation), if


Fever (temperature ≥ 38.3°C) + Neutropenia (< 500 neutrophils/mm3)

Low risk High risk

Oral iv Vancomycinnot needed

Vancomycinneeded

Ciprofloxacin+

Amoxicillin-clavulanate(adults only)

Monotherapy

• Cefepime,• Ceftazidime, or• Carbapenem

Two Drugs

Aminoglycoside +• Antipseudomonal penicillin,• Cefepime,• Ceftazidime, or• Carbapenem

Vancomycin +

Vancomycin+

Cefepime, ceftazidime,or

carbapenem

± aminoglycoside

Reassess after 3–5 days

Figure 1-1. Algorithm for initial management of febrile neutropenic patients.iv = intravenous.Reprinted with permission from the University of Chicago Press. Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use of antimicrobialagents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730–51.

Vidal L, Paul M, Ben dor I, Soares-Weiser K, Leibovici L. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients: a systematicreview and meta-analysis of randomized trials. J Antimicro Chemother 2004;54:29–37. Review.

colonization with resistant gram-positive bacteria has beendocumented, if blood cultures are positive for gram-positivebacteria prior to final identification and sensitivity testing,or if symptoms consistent with cardiovascularcomplications are present (Table 1-3). Two additionalfactors that can increase a patient’s risk of developinginfections warranting vancomycin are prophylacticadministration of quinolone antibiotic drugs and treatmentwith high-dose cytarabine. Additional evidence is needed tovalidate their predictive values.

Management of VAD Infections Surgically implanted central venous catheters or

subcutaneous ports contribute to the increased incidence ofbacteremias caused by microflora. Data gathered from 1992to 1999 reported that coagulase-negative staphylococci(37%), S. aureus (13%), Enterococcus (13%), Candidaspecies (8%), and E. coli (5%) were the most commoncauses of bacteremia in hospitalized patients. The rise inincidence of vancomycin-resistant enterococci (VRE)during the 1990s was alarming. The National NosocomialInfections Surveillance System reported that from 1990 to1999 the incidence of VRE increased from 0.5% to 25.9%.

A critical determination in managing VAD-relatedinfections is the need to remove the VAD. Guidelines formanaging intravascular catheter-related infections publishedby the IDSA, the American College of Critical CareMedicine, and the Society for Healthcare Epidemiology ofAmerica recommend not removing a VAD unless symptomsconsistent with a catheter infection accompany fever.Removal of a VAD and initiation of antibiotic drug therapyare recommended when focal findings indicate a tunnel,pocket, or exit-site infection or when endocarditis, septicthrombosis, osteomyelitis, or catheter-related fungemia isdiagnosed. The suggested duration of antimicrobial drugtherapy is 1–2 weeks for localized infections, 4–6 weeks forendocarditis and septic thrombosis, 6–8 weeks forosteomyelitis, and 14 days beyond resolution of signs andsymptoms of fungal infections.

The guidelines state that it is appropriate to considersalvage therapy for infections associated with colonizationof VADs by coagulase-negative staphylococci, S. aureus,

and gram-negative bacilli. Salvage therapy eradicates theinfection with the infusion of systemic antibiotic drugsthrough the VAD and antibiotic-lock therapy. Antibiotic-lock therapy fills the lumen of the VAD with highconcentrations of an antibiotic solution active against theisolated bacteria and leaves the antibiotic drug in placebetween intermittent infusions. Vancomycin concentrationsof 1–5 mg/mL and ciprofloxacin, gentamicin, and amikacinconcentrations of 1–2 mg/mL have eradicated bacteria in upto 80% of cases in published trials. The recommendedduration of salvage therapy is 1–2 weeks of systemicantibiotic drug therapy and 2 weeks of antibiotic-locktherapy.

A persistent source of controversy is the safety ofdelaying the administration of glycopeptides until cultureresults document resistant gram-positive infections. Ameta-analysis that evaluated data on nearly 2400 patients toaddress this question concluded that is safe to defertreatment with glycopeptides until infection with resistantgram-positive microorganisms is documented. These dataprovide additional support for the IDSA recommendationthat empiric vancomycin be restricted to patients presentingwith one of the variables associated with a high likelihoodof a gram-positive infection (Table 1-3). Broad supportexists for restricting vancomycin’s use to treat infectionscaused by methicillin-resistant S. aureus to limit thedevelopment of VRE. In general, most infections caused bygram-positive bacteria do not progress rapidly. Therefore, itis not necessary to start vancomycin until culture andsensitivity results indicate it is needed. An exception to thisapproach has been infections caused by viridansstreptococci. An increased incidence of fatal gram-positiveinfections caused by strains of viridans streptococci hasbeen reported in patients not receiving vancomycin.Consequently, in settings where potentially life-threateninggram-positive infections have been documented, the empiricadministration of vancomycin is warranted for patients athigh risk for infectious complications. If vancomycin isincluded in the initial empiric therapy, it is important tomonitor culture and sensitivity reports and to discontinuevancomycin if culture results are negative.

Treatment of VRE Linezolid, quinupristin/dalfopristin, and daptomycin are

effective alternatives for patients with infections caused byVRE or who cannot tolerate vancomycin (Table 1-4). Allthree drugs represent new chemical entities that haveactivity against gram-positive pathogens, including VRE.Linezolid is an oxazolidinone derivative available forintravenous and oral administration. It is a bacteriostaticdrug with the exception of being bacteriocidal for penicillin-susceptible S. pneumoniae. One adverse effect that maylimit its use in patients with cancer is thrombocytopenia,which appears to be dose and duration dependent.Thrombocytopenia has occurred in up to 10% of patientsreceiving linezolid for periods exceeding 2 weeks.Quinupristin/dalfopristin is a streptogramin antibioticcombination that is bactericidal against most susceptible

153 Infections in Patients with CancerPharmacotherapy Self-Assessment Program, 5th Edition

Table 1-3. Clinical Findings that Warrant EmpiricVancomycin Therapy in Patients Regardless of RiskStatus1. Clinically suspected serious catheter-related infection, 2. Known colonization with penicillin- and cephalosporin-

resistant pneumococci or methicillin-resistant pneumococci or methicillin-resistant Staphylococcus aureus,

3. Positive blood culture for gram-positive bacteria before final identification and susceptibility testing, or

4. Hypotension or other evidence of cardiovascular impairment Adapted with permission from the University of Chicago Press. HughesWT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use ofantimicrobial agents in neutropenic patients with cancer. Clin Infect Dis2002;34:730–51.

Cometta A, Kern WV, De Bock R, et al. Vancomycin versus placebo for treating persistent fever in patients with neutropenic cancer receiving piperacillin-tazobactam monotherapy. Clin Infect Dis 2003;37:382–9.


bacteria; it is bacteriostatic against enterococci. It iseffective in treating E. faecium, but not E. faecalis.Consequently, quinupristin/dalfopristin is not consideredappropriate for empiric therapy of suspected enterococcalinfections. Its toxicity profile is notable for inflammation atthe infusion site and myalgia that have been reported in upto 40% and 10% of patients, respectively. Daptomycin is acyclic lipopeptide antibiotic drug that is bactericidal for allsusceptible bacteria. It is active against both E. faecium andE. faecalis. Daptomycin is generally well tolerated, withadverse effects being reported in fewer than 10% of patients.Product labeling for linezolid includes administration tochildren. The safety and efficacy of quinupristin/dalfopristinand daptomycin have not been established for patients underages 16 and 18, respectively.

Broad-Spectrum Monotherapy It is critical that patients at high risk for infectious

complications with febrile neutropenia be promptly startedon intravenous antibiotic drugs that are active against themost common pathogens. The IDSA guidelines recommendthat in patients at high risk for infectious complications whodo not require empiric vancomycin, monotherapy with acarbapenem (imipenem-cilastatin or meropenem) or a third-generation or fourth-generation cephalosporin(ceftazidime or cefepime) is an appropriate option. Ingeneral, all of these monotherapy options provide adequategram-negative antibacterial coverage. However, cefepimeand the carbapenems are the preferred alternatives becauseof their superior activity against viridans streptococci,pneumococci, and Enterobacter species. Piperacillin-tazobactam also has been effective as empiric monotherapyin limited studies. Further evaluation of the effectiveness ofpiperacillin-tazobactam monotherapy in well-designedcomparative trials is needed to determine whether it is areasonable alternative to cefepime, ceftazidime, and thecarbapenems.

Although the effectiveness of initiating empiric antibioticdrug therapy with a single broad-spectrum antibiotic drughas been effective, monotherapy is not standard care. A

meta-analysis of 47 randomized trials compared theeffectiveness of β-lactam monotherapy and β-lactam plus anaminoglycoside combination therapy. Although there weresome limitations, no difference was found betweenmonotherapy and combination therapy for all-cause fatality.These data supported the conclusion that β-lactammonotherapy “should be regarded as the standard of care”for patients with febrile neutropenia.

Table 1-5 lists the costs of antibiotic drugs proveneffective as monotherapy based on the dosage regimen ineach product’s Food and Drug Administration-approvedlabeling. These are the dosage regimens most commonlystudied in clinical trials. Whether these dosage schedules arethe most cost-effective for each antibiotic drug has not beenadequately studied. Data from a limited number of studiesinvolving smaller numbers of patients suggest that lowerdose regimens are equally effective. Specifically, cefepime2 g administered every 12 hours and ceftazidime 1 gadministered every 8 hours have been evaluated. The IDSAguidelines state that more outcome data are needed todetermine whether the lower cost of low-dose regimenswarrants their acceptance as standard treatment.

Table 1-4. Summary of Antimicrobial Drugs Used to Treat Vancomycin-resistant EnterococcusDrug Linezolid Quinupristin-Dalfopristin Daptomycin

Dosagea 400–600 mg every 12 hours 7.5 mg/kg every 8–12 hours 4 mg/kg every 12 hoursRoute of Administration IV or PO IV IVDaily acquisition costb $134 $440 $182FDA labeling (pediatrics) Yes No NoDosage adjustments No No Creatinine clearance ≤ 30 mL/minute

for renal impairment increase interval to 48 hoursaAs recommended in the Food and Drug Administration-approved package labeling.bEstimate based on maximum IV dosage regimen for an 80-kg patient with normal renal function. Comparable cost for vancomycin is $10.00.FDA = Food and Drug Administration; IV = intravenous; PO = oral.

Table 1-5. Comparative Acquisition Costs of EmpiricBroad-Spectrum Antibiotic Drugs Appropriate forEmpiric MonotherapyDrug Dosagea Daily

Acquisition Costb

Cefepime 2 g every 8 hours $96

Ceftazidime 2 g every 8 hours $38Imipenem-cilastatin 500 mg every 6 hours $104Meropenem 1 g every 8 hours $93 Pipercillin-tazobactamc 3.375 g every 6 hours $56aAs recommended in the Food and Drug Administration-approved packagelabeling for the treatment of serious infections including febrileneutropenia. bEstimate based on a daily dose calculated for an 80-kg patient withnormal renal function.cEffectiveness as monotherapy based on limited data.

Cherif H, Bjorkholm M, Engervall P, et al. A prospective, randomized study comparing cefepime and imipenem-cilastatin in the empirical treatment of febrileneutropenia in patients treated for haematological malignancies. Scand J Infect Dis 2004;36:593–600.Klastersky JA. Use of imipenem as empirical treatment of febrile neutropenia. Int J Antimicrob Agents 2003;21:393–402. Review.Raad II, Escalante C, Hachem RY, et al. Treatment of febrile neutropenic patients with cancer who require hospitalization: a prospective randomized studycomparing imipenem and cefepime. Cancer 2003;98:1039–47.Tamura K, Imajo K, Akiyama N, et al. Randomized trial of cefepime monotherapy or cefepime in combination with amikacin as empirical therapy for febrileneutropenia. Clin Infect Dis 2004;39(suppl 1):15–24.

Broad-Spectrum Combination Therapy Two-drug combinations consisting of an aminoglycoside

plus an extended-spectrum penicillin, cefepime,ceftazidime, or a carbapenem are alternative options forpatients with febrile neutropenia at high risk for infectiouscomplications. If vancomycin is indicated, the IDSAguidelines recommend combining vancomycin withcefepime, ceftazidime, or a carbapenem with the option ofadding an aminoglycoside as a third antibiotic (Figure 1-1).

Close monitoring of a patient’s response to the initialempiric therapy is vital for determining what, if any,changes in antibiotic coverage are indicated. As indicated inFigure 1-1, IDSA guidelines recommend that the initialregimen be continued for 3–5 days with the caveat thatclinical deterioration and culture results may warrant earliermodification of the initial regimen. Reported median timesto defervescence are 2 days for patients at low risk forinfectious complications and 5–7 days for patients at highrisk for infectious complications.

Figure 1-2 is the IDSA algorithm for patients whobecome afebrile within 3–5 days of empiric treatment. If apathogen is isolated, susceptibility and cost data can be usedto modify broad-spectrum therapy. The appropriate regimenshould be administered for at least 1 week or until thepatient’s symptoms have resolved and repeat cultures arenegative. Ideally, the patient’s ANC should be greater than500 cells/mm3. However, if a clinical response has beenachieved, the IDSA guidelines suggest that stoppingantibiotic drugs may be considered in a patient with an ANCless than 500 cells/mm3 if the patient has no apparent focusof infection (e.g., infection related to vascular access ormucositis) and will be closely observed. If no pathogen isisolated, patients at high risk of infectious complications aremaintained on the initial intravenous antibiotic drugregimen until resolution of factors that increase the risk forinfectious complications. If no pathogen is isolated, patientsat low risk of infectious complications (e.g., ANC greaterthan 500 cells/mm3, no identified focus of infection) can beswitched to an oral regimen after a minimum of 2 days ofintravenous therapy. A combination of a quinolone plusamoxicillin-clavulanic acid is recommended for adultpatients and cefixime for pediatric patients.

Patients whose fever persists 3–5 days after theadministration of appropriate empiric antibacterial treatmentand for whom no etiology has been identified requirethorough reassessment of a diagnostic workup to rule outpossible causes of the fever. Possible causes include aninfection that is slow to respond to the initial regimen (e.g.,an abscess), an infection caused by resistant bacteria, or aninfection caused by nonbacterial pathogens. The IDSAguidelines propose three options for patients with persistentfever (Figure 1-3). Continuation of the initial broad-spectrum regimen is acceptable for patients who remainstable, whose anticipated duration of chemotherapy-inducedneutropenia is less than 5 days, and whose diagnostic resultsdo not support a change in broad-spectrum antibiotic drugs.If patients remain stable and vancomycin was in the initialregimen, IDSA guidelines propose discontinuing it unlesssupported by initial culture and sensitivity results. Thesecond option proposes adding or changing antibiotic drugs

if patients’ infectious symptoms worsen. If the initialregimen did not include vancomycin, it should be added ifpreviously identified factors associated with a highprobability of gram-positive etiology exist. Replacingcefepime or ceftazidime with a carbapenem and adding anaminoglycoside, if not included in the initial regimen, arealso feasible options. The third option is to initiateantifungal therapy. This alternative is recommended forpatients whose neutropenia is expected to persist for anadditional week or more. Fungal infections account for2%–10% of initial microbiologically documented infectionsin patients with cancer who have febrile neutropenia.

155 Infections in Patients with CancerPharmacotherapy Self-Assessment Program, 5th Edition

Afebrile within first 3–5 days of treatment

No etiology identified Etiology identified

Lowrisk

Highrisk

Change to:ciprofloxacin

+amoxicillin-clavulante(adults) or

cefixime (child)

Continuesame

antibiotics

Discharge

Adjust to mostappropriate treatment

Figure 1-2. Guide for the management of patients who become afebrile inthe first 3–5 days of initial antibiotic therapy.Reprinted with permission from the University of Chicago Press. Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use ofantimicrobial agents in neutropenic patients with cancer. Clin Infect Dis2002;34:730–51.

Persistent fever during first 3–5 daysof treatment: no etiology

Reassess patient on days 3–5

Continueinitial

antibiotics

Change antibiotics

Antifungal drug,with or without

antibiotic change

If no change inpatient’s condition

(considerstopping

vancomycin)

-If progressivedisease,

-if criteria forvancomycin

are met

If febrile throughdays 5–7 andresolution of

neutropenia isnot imminent

Figure 1-3. Guide to treatment of patients with persistent fever after 3–5 days of treatment.Reprinted with permission from the University of Chicago Press. Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use ofantimicrobial agents in neutropenic patients with cancer. Clin Infect Dis2002;34:730–51.

Candida and Aspergillus species have been identified as theetiology of persistent fever in nearly one-third ofneutropenic patients who do not respond to 1 week ofempiric broad-spectrum antibacterial therapy.

Empiric Antifungal Therapy Amphotericin B Products

The IDSA guidelines recommend that empiric antifungaltherapy directed against Candida and Aspergillus species beconsidered for patients with febrile neutropenia who do notrespond after 5 days of appropriate broad-spectrumantibiotic drugs. Amphotericin B deoxycholate (AmB) hasbeen considered the antifungal of choice for empirictherapy. However, recent data suggest that less toxic andperhaps more effective antifungal options exist.Comparative studies of AmB and lipid formulations ofamphotericin (amphotericin B liposome for injection,amphotericin B lipid complex for injection, and AmBcholesteryl sulfate complex for injection) have establishedthat these lipid products are equally effective to AmB andcause less renal toxicity. The high cost of the lipidformulations limits their use to patients intolerant to AmB(e.g., increase in serum creatinine to 2 mg/dL, a decrease increatinine clearance of 50%, or severe infusion-relatedfever, rigors, or wheezing unresponsive to appropriatepremedication).

Amphotericin B liposome for injection (L-AmB) is thelipid formulation that has been most rigorously evaluated incomparative studies evaluating empiric antifungal therapyin patients with febrile neutropenia. In a comparative studyof AmB and L-AmB, initial dosage regimens were 0.6 mg/kg/day intravenously and 3 mg/kg/day intravenously,

respectively. This study included guidelines for titration ofdoses based on a patient’s clinical status. All of the recentlypublished studies recommend that patients with documentedsystemic fungal infections receive the maximum tolerateddosages of antifungal therapy.

The following composite scoring system has becomestandard methodology for determining the efficacy ofempiric antifungal therapy in patients with febrileneutropenia. The overall success of a therapy is determinedby the evaluation of five outcomes: 1) resolution of fever, 2) no breakthrough fungal infection within 7 days of the endof therapy, 3) resolution of baseline fungal infection, 4) survival 7 days after therapy has been discontinued, 5) nodiscontinuation of therapy as a result of toxicity or lack ofefficacy.

The difference in overall success rates for AmB and L-AmB was not statistically significant. The L-AmBresulted in fewer breakthrough fungal infections. Toxicitydata revealed that L-AmB was better tolerated than AmB.The incidence of infusion-related adverse effects (e.g., feverand rigors) and of renal impairment was substantially lowerin the group randomized to L-AmB.

Recommended doses for the L-AmB products aresubstantially higher than the recommended dose for AmB(e.g., 3–6 mg/kg/day and 1–1.5 mg/kg/day, respectively).Special caution is needed when processing AmB orders.Confusion regarding the 3-fold difference in dosages hasresulted in patients developing severe renal toxicity afterreceiving AmB daily doses of 3 mg/kg. Antifungal dosageregimens are summarized in Table 1-6.

Itraconazole Itraconazole is an extended-spectrum triazole antifungal

agent that is active against Aspergillus species. It is


Table 1-6. Antifungal Therapies: Dosage Regimens and Monitoring Parameters Drug Dosage Regimena Adverse Effects/MonitoringAmphotericin B 0.6 to 1 mg/kg/day IV; increase up to Infusion-related reactions (fever, chills, rigors, flushing, dyspnea, Deoxycholate 1.5 mg/kg/day IV for documented infections hypotension, hypertension, flushing, and tachycardia), nausea,

vomiting, headache, renal impairment, hypokalemia, hypomagnesemia,and hyperbilirubinemia

Amphotericin B 3 mg/kg/day; increase up to 4.5–6 mg/kg/day Infusion-related reactions (fever, chills, rigors, flushing, dyspnea, liposome for for documented infections hypotension, hypertension, flushing, and tachycardia), nausea, injection vomiting, headache, renal impairment, hypokalemia, hypomagnesemia,

and hyperbilirubinemiaItraconazole 200 mg every 12 hours IV for first 48 hours, Nausea, vomiting, diarrhea, rash, elevation of hepatic enzymes and

then 200 mg/day IV; switch to oral solution bilirubin; taste disturbance after oral solutionas indicatedb

Voriconazole 6 mg/kg IV every 12 hours for two doses, Transient alteration of light perception, visual hallucinations, then 3–4 mg/kg IV every 12 hours; transient elevation in hepatic enzymes; monitor for multipleswitch to 200–300 mg by mouth every potential drug interactions because voriconazole is metabolized by12 hours as indicatedb and inhibits cytochrome P450 enzymes

Caspofungin 70 mg IV on day 1, then 50 mg/day IV Infusion-related adverse events (fever, chills, and phlebitis), andnephrotoxicity

aCurrent standard of practice is to administer the maximum tolerated dosages of antifungal therapy to patients with documented systemic fungal infections.bIntravenous itraconazole and voriconazole were switched to oral formulations for patients showing clinical improvement after a minimum of 3–7 days ofintravenous therapy.IV = intravenously.

Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute ofAllergy and Infectious Diseases Mycoses Study Group. N Engl J Med 1999;340:764–71.

157

available as a solution for intravenous administration and asa suspension and capsule for oral administration.Itraconazole bioavailability is significantly higher afteradministration of the oral suspension. Patients should beinstructed to take itraconazole suspension on an emptystomach to enhance absorption. Itraconazole was proven aseffective as AmB in patients with febrile neutropenia.Patients treated with itraconazole had lower rates ofinfusion-related reactions and nephrotoxicity. Itraconazolewas administered by intravenous infusion initially, but waschanged to the oral suspension in selected patients after theyshowed clinical improvement. A minimum of 7 days ofintravenous itraconazole was required before switching tothe oral solution was permitted. See Table 1-6 for dosageand monitoring recommendations.

Voriconazole Voriconazole and caspofungin have been compared to

L-AmB for efficacy as empiric antifungal therapy forpatients with persistent febrile neutropenia. Voriconazole isa broad-spectrum second-generation triazole antifungal drugthat is well-absorbed after oral administration. The NationalInstitute of Allergy and Infectious Diseases Mycoses StudyGroup compared voriconazole and L-AmB in a study of 837 patients. Patients received antifungal therapy for up to 3days after their ANC exceeded 250 cells/mm3, up to amaximum of 3 months. The recommended dosage regimenand monitoring parameters are provided in Table 1-6.Voriconazole was administered intravenously for aminimum of 3 days before switching to oral administrationwas allowed.

Comparison of the five composite measures of successrevealed similar efficacy for all outcomes, except forbreakthrough fungal infections within 7 days aftercompletion of therapy. The incidence of breakthroughinfections was lower in the voriconazole group. Comparisonof adverse effects revealed several statistically significantdifferences. Voriconazole was associated with a lower rateof chills, flushing, dyspnea, and renal impairment. The mostcommon adverse events associated with voriconazole werevisual disturbances. Twenty-two percent of patients in thevoriconazole group reported transient alteration of lightperception compared with 1% in the L-AmB group. Thiseffect was reported most often during the first infusion anddecreased with subsequent infusions. Voriconazole alsoresulted in a higher incidence of visual hallucinations thatwas statistically significant (4.3% vs. 0.5%). Typically, thehallucinations were described as unrelated to the infusion-related changes in light perception. There was no differencebetween voriconazole and L-AmB in the number of patientswho discontinued the assigned treatment because of toxicity.However, more patients discontinued voriconazole than L-AmB due to apparent lack of efficacy.

Because voriconazole is metabolized by cytochromeP450 (CYP) enzymes CYP2C19, CYP2C9, and CYP3A4,and it also inhibits the activity of these enzymes, thepotential for significant drug interactions warrantsdiligence. Concurrent administration of voriconazole withrifampin, ritonavir, carbamazepine, and long-actingbarbiturates is contraindicated to avoid substantialreductions in voriconazole blood concentrations.Concurrent administration of voriconazole with CYP3A4substrates sirolimus, ergot alkaloids, cisapride, pimozide,and quinidine is contraindicated to avoid significantincreases in the systemic exposure and potential forincreased toxicity of these drugs. Concurrent administrationof voriconazole with efavirenz and rifabutin also iscontraindicated because it results in substantial decreases invoriconazole blood concentrations and substantial increasesin efavirenz and rifabutin blood concentrations. In addition,voriconazole has resulted in significant increases insystemic exposure of methadone, cyclosporine, tacrolimus,and warfarin. Furthermore, in vitro data suggest that plasmaconcentrations of statins, benzodiazepines, calcium channelblockers, vinca alkaloids (CYP3A4 substrates), as well asglipizide and glyburide (CYP2C9 substrates) may beincreased when administered with voriconazole.Consequently, vigilant monitoring for toxicity andconsideration of dosage reduction are indicated whenpatients receive these drugs at the same time asvoriconazole.

Caspofungin Caspofungin is the first echinocandin antifungal agent

approved for the treatment of infections caused by Candidaspecies and refractory invasive aspergillosis. It wascompared to L-AmB as empiric antifungal therapy in a well-designed multicenter study of 1095 patients with persistentfebrile neutropenia. The composite overall success rates anddurations of treatment were similar for both antifungaldrugs. Caspofungin resulted in statistically significantdifferences in resolution of baseline fungal infections, insurvival for at least 7 days after discontinuation of therapy,and in early discontinuation of therapy. Caspofungin wasassociated with lower rates of infusion-related adverseevents and nephrotoxicity. Fewer patients discontinuedcaspofungin because of drug-induced adverse effects. Referto Table 1-6 for the recommended dosage regimen andmonitoring parameters.

In summary, data from well-designed, large-scale,multicenter trials evaluating empiric antifungal therapyestablished that itraconazole and L-AmB are as effective as,and better tolerated than, AmB. Within the past 3 years, datafrom two well-designed, multicenter trials established thatvoriconazole and caspofungin were as effective as, andbetter tolerated than, L-AmB. Appropriately designed trials


Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapyfor persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial. Ann Intern Med2001;135:412–22. Walsh TJ, Pappas P, Winston DJ, et al; National Institute of Allergy and Infectious Diseases Mycoses Study Group. Voriconazole compared with liposomalamphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346:225–34.Walsh TJ, Teppler H, Conowita GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever andneutropenia. N Engl J Med 2004;351:1391–402.

are needed to determine the comparative cost-effectivenessof itraconazole, voriconazole, and caspofungin as empiricand primary therapy for fungal infections.

An international committee with representatives fromThe Invasive Fungal Infections Cooperative Group of theEuropean Organization for Research and Treatment ofCancer and from the Mycoses Study Group of the NationalInstitute of Allergy and Infectious Diseases developedstandard definitions to facilitate clinical andepidemiological research addressing invasive fungalinfections. The committee proposed the terms “proven,”“probable,” and “possible” to describe three levels ofprobability of patients having an invasive fungal infection.Patients with a probable fungal infection meet bothmicrobiological and clinical criteria, whereas patients with apossible fungal infection meet microbiological or clinicalcriteria. The term preemptive antifungal therapy has beenintroduced to describe treating patients with febrileneutropenia with probable fungal infections in contrast toempiric antifungal therapy that defines treating patients withpossible fungal infections. An assay to detectgalactomannan, an antigenic polysaccharide associated withAspergillus, has become useful in diagnosing invasiveaspergillosis. The international committee included positiveAspergillus galactomannan assays in their criteria forestablishing microbiological fungal infections. Specifically,two or more positive blood assays or a single positivecerebral spinal fluid or bronchoalveolar lavage fluid assay isconsidered diagnostic. The Food and Drug Administrationapproved the enzyme-linked immunosorbent assay in 2003

based on a 81% sensitivity and 89% specificity. Piperacillin-tazobactam has resulted in false-positive tests.Consequently, when interpreting positive tests in patientsreceiving piperacillin-tazobactam, it is recommended thatthe diagnosis be confirmed with other diagnostic tests.

A prompt diagnosis of fungal infections in patients withfebrile neutropenia remains elusive. In three recent trialsevaluating empiric antifungal therapy in 2616 patients,resolution of fever occurred in about 50% of patients.However, fewer than 10% of these patients had fungalinfections confirmed microbiologically. This gap impliesthat defervescence may not be reliable evidence ofsuccessful antifungal therapy. Further studies need todetermine whether preemptive or empiric antifungal therapyprovides more cost-effective outcomes.

Duration of AntimicrobialTherapy

Figure 1-4 summarizes the IDSA guidelines fordetermining the duration of empiric antimicrobial drugtherapy. A patient’s ANC and response to the initial empiricantimicrobial drug are critical variables in determiningwhen it is appropriate to discontinue antibiotic drugs.Patients who respond within 3–5 days of empiric therapymay have antibiotic drugs stopped when their ANCs exceed500 cells/mm3 for 2 consecutive days and when they remainafebrile for 48 hours.


Duration of antibiotic therapy

Afebrile by days 3–5 Persistent fever

ANC ≥ 500 cells/mm3

for 2 consecutive daysANC < 500 cells/mm3

by day 7ANC ≥ 500 cells/mm3 ANC < 500 cells/mm3

Stop antibiotics48 hours after

afebrile +ANC ≥ 500 cells/mm3

Initial low risk

Clinically well

Stopwhen

afebrile for5–7 days

Initial high risk• ANC < 100 cells/mm3

• Mucositis• Unstable signs

Stop 4–5days after

ANC > 500 cells/mm3

Reassess

Continue for2 weeks

Stop if nodisease

and conditionis stable

Continueantibiotics

Reassess

Figure 1-4. Suggested scheme for estimating the duration of antibiotic administration under various conditions.ANC = absolute neutrophil count.Reprinted with permission from the University of Chicago Press. Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelines for the use of antimicrobialagents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730–51.

Ascioglu S, Rex JH, de Pauw B, et al; Invasive Fungal Infections Cooperative Group of the European Organization of Research and Treatment of Cancer;Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromisedpatients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002;34:7–14.

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The duration of antibiotic drugs is longer for patientswho become afebrile within 3–5 days of empiric therapy butwhose ANC is less than 500 cells/mm3. The IDSAguidelines propose that patients at low risk for infectiouscomplications who remain asymptomatic can haveantibiotic drugs discontinued after 5–7 days. However, forpatients who initially present with findings associated witha high risk for infectious complications (an ANC less than100 cells/mm3, mucositis, or unstable vital signs), it isrecommended that administration of antibiotic drugs becontinued until the ANC exceeds 500 cells/mm3. In cases ofprofound neutropenia without signs of imminent recovery,stopping the antibiotic drugs can be considered after 14 days, provided that a patient has no confirmed focus ofinfection and will be carefully monitored. If antibiotic drugsare discontinued in an afebrile neutropenic patient, carefulmonitoring and prompt administration of intravenousantibiotic drugs are mandatory if symptoms of infectionrecur.

The IDSA guidelines recommend starting patients whohave a persistent fever after 5 days of empiric antibioticdrugs on empiric antifungal therapy. Reevaluation for occultbacterial, fungal, viral, or mycobacterial infections isindicated. The ANC is used to determine the duration of afebrile patient’s antimicrobial drug therapy. If no infection isdocumented and a patient remains clinically stable, stoppingthe antibiotic drugs can be considered after an ANCrecovery to greater than 500 cells/mm3 for 4–5 days. If apatient’s ANC remains below 500 cells/mm3, clinical statusdetermines the therapy duration. If a patient’s only symptomof infection is persistent fever, stopping antimicrobial drugtherapy can be considered after 2 weeks. A patient who isfebrile with symptoms consistent with significant infectionshould have his or her antimicrobial drug therapy continueduntil ANC recovery occurs.

The optimum duration of antifungal therapy for patientswith confirmed systemic fungal infections has not beenclearly established. In a well-designed trial comparing AmBand voriconazole for the treatment of patients with invasiveaspergillosis, the planned therapy was 12 weeks. In thisstudy, voriconazole resulted in superior response rates,survival, and safety. However, in recently completed well-designed trials evaluating empiric antifungal therapy, thetherapy duration for patients who were eventually diagnosedwith invasive fungal infections was determined by patients’response to therapy and the ANC. In the most recent of thesestudies, caspofungin and L-AmB were continued for aminimum of 14 days with at least 7 days of therapyfollowing resolution of symptoms and neutropenia.

The duration of antifungal therapy for a patient who doesnot have a proven or probable systemic fungal infection isdetermined by the patient’s clinical status. In recent clinicaltrials, empiric antifungal therapies were stopped when apatient was clinically well with an ANC exceeding 500 cells/mm3 for 2–3 days and normal imaging studies. Fora patient who remains neutropenic, but is clinically wellwith normal imaging studies, empiric antifungal therapy canbe stopped after 14 days of therapy. For a patient with

persistent febrile neutropenia, antifungal therapy iscontinued for the duration of neutropenia.

Treatment of Pneumocystisjiroveci Pneumonia

A 1973 landmark study authored by researchers from theSt. Jude Children’s Research Hospital described PCP in 17pediatric patients with cancer. This research established thatcorticosteroid therapy and hematologic malignancies wereassociated with an increased risk for PCP. In the 1980s, PCPwas identified as a prevalent opportunistic infection inpatients with acquired immune deficiency syndrome. Beforethe development of effective PCP prophylaxis, the incidenceof PCP in patients undergoing allogeneic HSCT rangedfrom 5% to 16%. The infection in patients who werenegative for human immunodeficiency virus has had a morerapid onset than in patients who are positive for humanimmunodeficiency virus. Severe hypoxia is the classicpresenting symptom in patients with PCP. Preferreddiagnostic techniques are bronchoalveolar lavage withtransbronchial biopsy and open-lung biopsy. Animmunofluorescent assay that detects epitopes fromPneumocystis cysts and trophozoites has become thepreferred diagnostic test.

Cotrimoxazole, the drug of choice for PCP, is given at15–20 mg/kg/day of trimethoprim, which is administeredintravenously in four divided dosages. The regimen can beswitched to an oral regimen in patients whose symptomsimprove after several days of intravenous therapy and whodo not have any conditions that preclude oral administration.Pentamidine and atovaquone are alternative therapies forpatients who do not tolerate or respond to cotrimoxazole.Pentamidine is administered by intravenous injection at 4 mg/kg/day. Atovaquone is administered orally at 750 mg3 times/day with meals. These treatments are generallycontinued for 21 days.

Treatment of Viral InfectionsThe IDSA guidelines recommend antiviral drugs be

administered only to patients with febrile neutropenia withdocumented viral infections. If severe infections caused byHSV and VZV are documented in patients who areimmunocompromised, intravenous acyclovir is indicated.Oral acyclovir, famciclovir, and valacyclovir can be used totreat less severe infections. The recommended dosageregimens are shown in Table 1-7. Higher dosages arerequired for treating VZV because it is less susceptible thanHSV to these drugs. Famciclovir and valacyclovir can beadministered less frequently than acyclovir because theseacyclovir prodrugs are more readily absorbed. The durationof treatment of HSV and VZV infections is a minimum of 7 days and often longer due to delayed resolution ofsymptoms in patients who are immunocompromised.


Herbrecht R, Denning DW, Patterson TE, et al; Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer andthe Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–15.

Systemic cytomegalovirus infections are infrequentlydiagnosed in patients with chemotherapy-inducedneutropenia but remain a common cause of infection inpatients with cancer following HSCT. Ganciclovir andfoscarnet are the antiviral drugs recommended for treatingsystemic cytomegalovirus infections.

Prophylactic AntimicrobialTherapy Bacterial Prophylaxis

The IDSA guidelines provide an objective overview ofthe benefits and risks of antimicrobial drug prophylaxis.There is ample evidence that prophylactic administration ofantimicrobial drugs reduces the incidence of infections.However, the ability of prophylactic antibiotic drugs toreduce infection-related mortality has not been reliablydocumented. The increase in antibiotic-resistant bacteriathat is associated with prophylactic administration has beena concern. Routine use of quinolone antibiotic drugs asprophylaxis in neutropenic cancer patients has resulted inquinolone-resistant gram-negative pathogens. The IDSAguidelines do not recommend routine antibacterialprophylaxis in managing patients with febrile neutropenia.

PCP Prophylaxis The 2002 IDSA guidelines recommend that all patients at

risk for PCP receive prophylaxis with cotrimoxazole. Ingeneral, the critical risk factor associated with increased riskof PCP is impaired function of T-lymphocytes. Neutropeniaby itself has not been established as a significant risk factorfor P. jiroveci infection. Patients at greatest risk for PCPinclude those receiving intensive chemotherapy for acutelymphoblastic leukemia and aggressive lymphomas, allrecipients of allogeneic HSCT, and recipients of autologousHSCT who have underlying hematologic malignancies. TheIDSA, along with the Centers for Disease Control andPrevention and the American Society of Blood and MarrowTransplantation, have published Guidelines for PreventingOpportunistic Infections Among Hematopoietic Stem CellTransplant Recipients. These guidelines recommend PCPprophylaxis for recipients of allogeneic HSCT and forrecipients of autologous HSCT with underlying hematologicneoplasms.

The incidence of PCP increases with increased durationand dosage of corticosteroid therapy. An increased incidenceof PCP has been reported with prednisone doses as low as16 mg/day. In one study, 25% of infected patients received

corticosteroids for 2 months or less. In another study ofpatients with cancer who have solid tumors, 5% developedPCP after just 1 month of corticosteroid therapy, and 70% ofthose infections were diagnosed when corticosteroids werebeing tapered.

Cotrimoxazole is the drug of choice for preventing PCP.The cotrimoxazole dose initially recommended for PCPprophylaxis was trimethoprim 5 mg/kg/day andsulfamethoxazole 25 mg/kg/day. Subsequently, lower doseswere studied to evaluate whether efficacy could bemaintained while decreasing the incidence of adverseeffects, primarily skin rashes and myelosuppression.Currently, three lower dose cotrimoxazole regimens areincluded in the Guidelines for Preventing OpportunisticInfections Among Hematopoietic Stem Cell TransplantRecipients: one double-strength tablet daily (trimethoprim160 mg/sulfamethoxazole 800 mg), one single-strengthtablet daily (trimethoprim 80 mg/sulfamethoxazole 400 mg), or one double-strength tablet by mouth 3 times/week.Alternatives for patients who cannot tolerate cotrimoxazoleare dapsone given 100 mg/day orally or 50 mg orally 2 times/day, or pentamidine 300 mg every 3–4 weeks byinhalation. Additional comparative studies are needed toestablish the efficacy of atovaquone for PCP prophylaxis.

Prophylaxis should be administered to recipients ofHSCT from the time of engraftment until 6 months post-HSCT. Patients with HSCT who have chronic graft-versus-host disease or those on chronicimmunosuppressive therapy require prophylaxis beyond 6 months. Likewise, for non-HSCT patients at risk for PCP,prophylaxis should be continued until immunosuppressivetherapy is discontinued.

Fungal Prophylaxis The 2002 IDSA guidelines recommend that fluconazole

be administered to all patients receiving allogeneictransplants, patients with hematologic neoplasms receivingautologous transplants, and recipients of HSCT who wererecently treated with fludarabine or cladribine. Therecommended regimen is fluconazole 400 mg/daybeginning the day of transplantation until bone marrowrecovery (e.g., 7 days of ANC exceeding 1000 cells/mm3).This recommendation is supported by data from severalstudies that documented a significant decrease in theincidence of superficial and, more importantly, invasiveinfections caused by the Candida species. Most often, C. krusei and occasionally C. glabrata are resistant tofluconazole. Itraconazole is also effective in preventingsystemic fungal infections caused by the Candida species.Several trials compared fluconazole and itraconazole for


Table 1-7. Dosage Regimens for Drugs Used to Treat Common Herpes VirusesDrug Acyclovir Famciclovir Valacyclovir

Dosagea

Herpes simplex 5 mg/kg IV every 8 hours; 400 mg PO 5 times/day 500 mg BID PO 500 mg BID POHerpes zoster 10–12 mg/kg IV every 8 hours; 800 mg PO 5 times/day 500 mg TID PO 1 g TID POaAs recommended in the Food and Drug Administration-approved package labeling for patients with normal renal function; dose adjustment for patients withrenal impairment is required. BID = 2 times/day; IV = intravenously; PO = orally; TID = 3 times/day.

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prophylaxis in HSCT and in acute leukemia patients andyielded conflicting results. However, the Guidelines forPreventing Opportunistic Infections Among HematopoieticStem Cell Transplant Recipients recommend thatitraconazole capsules not be used in HSCT recipients forthree reasons: itraconazole’s bioavailability afteradministration of capsules is unreliable; steady-state serumconcentrations are not achieved until the second week oftherapy; and numerous potentially significant druginteractions have been documented with itraconazole.

Viral Prophylaxis The IDSA, the Centers for Disease Control and

Prevention, and the American Society of Blood and MarrowTransplantation Guidelines for Preventing OpportunisticInfections Among Hematopoietic Stem Cell TransplantRecipients recommend acyclovir prophylaxis for patientswho are HSV-seropositive and receiving an allogeneictransplantation. The recommended regimen is acyclovir 200mg by mouth 3 times/day or 250 mg/m2 intravenously every12 hours. Prophylaxis should continue until engraftment oruntil mucositis resolves. This regimen significantly reducesthe reactivation rate of HSV. Well-designed, clinical trialsneed to determine the comparative efficacy of acyclovir,valacyclovir, and famciclovir for HSV prophylaxis. None ofthese antiviral drugs has reduced the reactivation of VZV.

Use of Colony-StimulatingFactors

Three colony-stimulating factors (CSFs) have beenapproved for use in the United States (filgrastim,pegfilgrastim [a covalent conjugate of filgrastim andmonomethoxypolyethylene glycol], and sargramostim).These products shorten the duration of neutropeniafollowing administration of myelosuppressivechemotherapy. Pegfilgrastim was approved for use in theUnited States in 2002 with the labeled indication “todecrease the incidence of infection, as manifested by febrileneutropenia, in patients with nonmyeloid malignanciesreceiving myelosuppressive anti-cancer drugs associatedwith a clinically significant incidence of febrileneutropenia.” The conjugation of filgrastim withmonomethoxypolyethylene glycol effectively extends theserum half-life of filgrastim from 2–7 hours to 15–80 hoursfor pegfilgrastim. Studies conducted in patients with breastcancer receiving myelosuppressive chemotherapy foundthat one subcutaneous injection of pegfilgrastim 6 mg wasequivalent to daily subcutaneous injections of filgrastim 5 mcg/kg/day. The incidence of febrile neutropenia andgrade 4 neutropenia was similar between treatment groups.The pegfilgrastim package labeling states that the 6-mgfixed dose should not be administered to pediatric patientsweighing less than 45 kg. A study comparing filgrastim 5 mcg/kg/day and pegfilgrastim 100 mcg/kg once aftermyelosuppressive chemotherapy was administered to

children with sarcomas concluded that the two formulationswere equally effective in shortening chemotherapy-inducedneutropenia. Pegfilgrastim offers patients and clinics theadvantage of avoiding multiple daily office visits foradministration of subcutaneous injections of filgrastim orsargramostim.

The American Society of Clinical Oncology (ASCO)evidence-based clinical practice guidelines first published in1994 were most recently updated in 2000. An expert paneldeveloped 11 specific guidelines that focus on the optimaluse of CSFs. This discussion summarizes five of theguidelines considered most important to pharmacistsmanaging CSF therapy in patients with cancer. Theguidelines selected for discussion address indications foruse and dosage regimens.

The first involves the administration of CSFs to preventfebrile neutropenia in patients receiving myelosuppressivechemotherapy for the first time (defined primaryprophylaxis). The potential benefit of primary CSFprophylaxis is related to the incidence of febrile neutropeniaassociated with the chemotherapy regimen. Three studiesreported that primary CSF prophylaxis significantly reducedfebrile neutropenia (about 50% decrease). In these studies,the incidence of febrile neutropenia was at least 40% in thegroups administered a placebo. The effectiveness of primaryCSF prophylaxis to significantly reduce the incidence offebrile neutropenia in patients receiving lessmyelosuppressive therapy has not been consistentlydocumented. As a result, the ASCO guidelines recommendthat primary CSF prophylaxis be restricted to patientsreceiving chemotherapy regimens that result in an incidenceof febrile neutropenia reported in the control arms of thesetrials (40% or higher). The National Comprehensive CancerNetwork has also published clinical practice guidelinesaddressing myeloid growth factors in cancer treatment. Itsmost recently published guidelines state that CSFprophylaxis is an appropriate consideration for patientsreceiving chemotherapy associated with an incidence offebrile neutropenia of 20% or higher. This recommendationis based on increased costs of hospitalization and recentlypublished trials suggesting that the prophylacticadministration of CSF yields clinical benefit in patientsreceiving chemotherapy with lower rates of febrileneutropenia. Furthermore, the guiding principle of the panelthat authored these guidelines is that cost-effectiveness wassecondary to clinical outcome.

The second guideline of interest addresses secondaryprophylactic CSF administration. Secondary prophylaxis isthe administration of a CSF as prophylaxis for febrileneutropenia only if a patient experienced febrile neutropeniaafter the previous chemotherapy cycle. The 2000 ASCOguidelines recommend that secondary prophylaxis is areasonable consideration in patients receiving potentiallycurative chemotherapy or chemotherapy regimens for whichmaintaining dose-intensity is important for achievingdisease-free or overall survival benefits. In patientsreceiving myelosuppressive chemotherapy that does not


NCCN. Clinical Practice Guidelines in Oncology: Myeloid Growth Factors in Cancer Treatment, v.2.2.2005. Available athttp://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf. Accessed January 31, 2006.

result in these outcomes, dose reduction rather thansecondary CSF prophylaxis is recommended.

The third guideline pertinent to the topic of infections inpatients with cancer addresses the use of a CSF as an adjuncttreatment to antibiotic drugs in patients with febrileneutropenia. The updated ASCO guidelines analyzed datafrom eight prospective, randomized, controlled studiesdesigned to determine if CSFs added to empiric antibioticdrugs in patients with febrile neutropenia improved patientoutcomes. The guidelines acknowledge that CSFs shortenthe duration of chemotherapy-induced neutropenia, butconclude that no consistent clinical benefit has beendocumented for patients with “uncomplicated febrileneutropenia.” Adding a CSF to antibiotic drugs in thesestudies has not consistently resulted in decreased mortality,shorter length of hospitalization, or shorter duration ofantibiotic drug therapy. Uncomplicated febrile neutropeniais described as an episode that is less than 10 days induration and without symptoms of a documented infection(e.g., pneumonia, cellulitis, hypotension, abscess, andsinusitis) or systemic fungal infection.

The 2000 ASCO guidelines acknowledge that publisheddata do not support routine CSF administration asadjunctive therapy for patients with febrile neutropenia. Ameta-analysis of eight trials that evaluated the effectivenessof CSFs as adjunctive treatment of chemotherapy-inducedfebrile neutropenia reached the same conclusion.Furthermore, due to the high cost of CSFs,pharmacoeconomic studies are needed to determine theeconomic impact of CSF therapy.

However, the 2000 ASCO guidelines state that in patientsat high risk of developing infectious complications adding aCSF to antibiotic drugs is an appropriate consideration.Factors used to identify a patient at high risk of infectiouscomplications include an ANC less than 100 cells/mm3,sepsis syndrome and associated symptoms, pneumonia, andsystemic fungal infection. Since the publication of the 2000ASCO guidelines, a prospective, multicenter, randomizedtrial evaluated the effectiveness of adjuvant filgrastim inpatients with “high risk febrile neutropenia.” The study wasconducted in patients with solid tumors who presented withfebrile neutropenia and at least one of the following high-risk characteristics: an ANC less than 100 cells/mm3,administration of chemotherapy within the last 10 days,sepsis or clinically documented infections, severecomorbidity, Eastern Cooperative Performance Status of 3or 4, prior hospitalization, or the lack of response after 3 ormore days of outpatient quinolone therapy. Filgrastim wasassociated with improved clinical and economic outcomes,supporting the use of a CSF as an adjuvant to antibioticdrugs in patients with febrile neutropenia at high risk forinfectious complications.

Data from the trials that led to Food and DrugAdministration labeling for use of filgrastim andsargramostim after induction and consolidationchemotherapy for acute nonlymphocytic leukemia suggestthat these CSFs are well tolerated and have similarbeneficial effects on neutrophil recovery. Filgrastim and

sargramostim resulted in significantly shortened times torecovery of ANC to greater than 500 cells/mm3 (e.g., by 4–5 days). However, differences in median survival wereachieved for sargramostim but not for filgrastim.Sargramostim therapy was associated with fewer deathsfrom pneumonia. Whether the differences in survivalbetween a CSF and placebo in these studies resulted fromdifferences in patient characteristics, inductionchemotherapy, supportive therapies, or the CSF regimenwill remain unanswered until well-designed, prospective,comparative studies are completed.

Dosage guidelines specify that filgrastim andsargramostim can be administered subcutaneously orintravenously. In clinical practice, the subcutaneous route ispreferred for both drugs. The recommended doses forfilgrastim and sargramostim are 5 mcg/kg/day and 250 mcg/m2/day, respectively. Higher doses of either CSFhave not improved prophylactic or therapeutic outcomes.Filgrastim is available in single-use 300-mcg and 480-mcgvials, and sargramostim is available as multiple-use 250-mcg and 500-mcg vials. Rounding of doses to theappropriate vial size is suggested as a practical approach toimprove the cost-effectiveness of these CSFs. The multiusesargramostim vials have a 28-day shelf life that may provideadditional cost advantages.

The final guideline describes optimal “initiation andduration” of filgrastim and sargramostim administration.When prescribed as primary or secondary prophylaxis or asan adjunct to antibiotic drugs in high-risk patients withfebrile neutropenia, these drugs are scheduled to begin nosooner than 24 hours after completion of chemotherapy andto be continued until an adequate ANC is achieved. Theguidelines do not specify what ANC is adequate. However,the guideline does acknowledge that continuing a CSF untila patient’s ANC exceeds 10,000 cells/mm3 is not critical.The ANC target of 10,000 cells/mm3 was included in thefilgrastim package insert labeling approved by the Food andDrug Administration in 1991. Subsequent clinicalexperience established that it is safe to discontinue CSFsafter post-nadir ANCs exceed 1000–1500 cells/mm3 for 2–3 successive days. Further research is needed to addressthis issue. The recommended duration of administration forpegfilgrastim is more straightforward. Pegfilgrastim isapproved to be administered as a single dose followingadministration of myelosuppressive chemotherapy. The 6-mg dose was selected because its effects on neutrophilrecovery are similar to those achieved with dailyadministration of filgrastim for 14 days. No data have beenpublished to support the administration of more than asingle dose of pegfilgrastim for prophylaxis of febrileneutropenia.

In conclusion, CSFs are effective in shortening periods ofneutropenia and in preventing febrile neutropenia inselected cases. However, data proving CSFs decreaseinfection-related mortality are extremely limited. Well-designed, comparative trials are needed to more adequatelyestablish the cost-effectiveness of CSFs in managinginfections in patients with cancer.


Garcia-Carbonero R, Mayordomo JI, Tomnamira MV, et al. Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: amulticenter randomized trial. J Natl Cancer Inst 2001;93:31–8.

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Conclusion The continuing development of effective chemotherapy

for patients with cancer has resulted in substantialimprovement of patient outcomes. However, chemotherapy-related suppression of a patient’s immune system results inconsiderable risk for infectious morbidity and mortality.Immunocompromised patients with cancer represent aheterogeneous population at risk for a diverse and evolvingvariety of potentially fatal infections. The publication ofIDSA and ASCO evidence-based practice guidelines hasadvanced the management of infections in patients withcancer. Pharmacists with a working knowledge of theseguidelines and a commitment to following current literaturecan serve a critical role in optimizing cost-effectiveoutcomes for these patients.

Annotated Bibliography 1. Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the

management of febrile neutropenic patients with cancer in the21st Century. Cancer 2005;103:1103–13.

The management of patients with febrile neutropenia hasimproved substantially over the past 30 years. This articleprovides pharmacists a concise review of the InfectiousDiseases Society of America’s (IDSA) 2002 guidelines andmore recently published articles germane to the topic. Inaddition, it provides insight on remaining challenges dealingwith improving antifungal therapy (e.g., optimal duration ofempirical antifungal treatment, the need for further research tocompare the effectiveness of azole and echinocandinantifungals, and diagnostic progress that may lead topreemptive antifungal therapy replacing empirical antifungaltherapy).

2. Hughes WT, Armstrong D, Bodey GP, et al. 2002 Guidelinesfor the use of antimicrobial agents in neutropenic patientswith cancer. Clin Infect Dis 2002;34:730–51.

A panel of experts in infectious diseases and oncologywrote the IDSA’s 2002 guidelines. The panel used acceptedevidence-based criteria to provide clinicians comprehensiveand practical recommendations on managing infections inpatients with febrile neutropenic cancer. These guidelinesprovide useful algorithms that incorporate known patientcharacteristics and risk factors that are vital to selectingappropriate antimicrobial drug therapy for patients withchemotherapy-induced febrile neutropenia. The final sectionaddresses economic issues such as reducing costs byindividualizing antibiotic regimens to a patient’s risk statusand to considering cost when determining the dose andduration of antimicrobial regimens. These guidelines setstandards for managing patients with chemotherapy-inducedfebrile neutropenia. Recommendations for empiric use ofantifungal agents will need to be revised to address emergingdata that suggest that newer antifungal drugs may be superiorto amphotericin B deoxycholate (AmB).

3. Ozer H, Armitage JO, Bennett DL, et al. 2000 update ofrecommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practiceguidelines. J Clin Oncol 2000;18:3558–85.

Published by American Society of Clinical Oncology, thisdocument is the second and most recent revision of itscomprehensive, evidence-based practice guidelines for theuse of CSFs. An expert panel reviewed and analyzed datapublished since 1994 in the context of the 11recommendations published in the 1996 update. The 11recommendations address practical aspects of clinicallyrelevant uses of the colony-stimulating factors (CSFs) insupport of patients receiving care from hematology andoncology specialists. Pharmacists responsible for ensuringappropriate use of CSFs will find this reference valuable.

4. DePauw BE, Verweij PE. Infections in patients withhematologic malignancies. In: Mandell GL, Bennett JE, eds.Mandell, Douglas, and Bennett’s Principles and Practice ofInfectious Diseases, 6th ed. Philadelphia: Elsevier,2005:34320–41.

Patients with hematologic malignancies are treated muchmore aggressively than patients with solid tumors. Thischapter effectively contrasts differences in the severity andincidence of infectious complications between these disparatepopulations. The authors provide a current and thoroughoverview of the clinical presentations of infections in patientsat high risk of infectious complications and essentialdiagnostic considerations that are required to initiateappropriate antimicrobial drug therapy. Bacteremia andpneumonia are the primary focus of the chapter. Algorithmsfor managing intravascular catheter-acquired bacteremia andfor diagnosing fungal pneumonia are provided. Additionaltopics include diagnosing and managing infections of theoropharynx, the central nervous system, and thegastrointestinal tract.

5. Klastersky J. Management of fever in neutropenic patientswith different risks of complications. Clin Infect Dis2004;39(suppl 1):32–7.

In 2000, the Study Section on Infections of theMultinational Association for Supportive Care in Cancer(MASCC) published a risk index for identifying febrileneutropenic cancer patients at low risk of developinginfectious complications. This article provides an overview oftwo risk assessment tools that were developed and validatedto identify patients with febrile neutropenia at low risk ofdeveloping infectious complications who can be effectivelytreated with oral antibiotic drugs. A comparison of the tworisk assessment tools demonstrated that the MASCC indexresults in fewer patients at low risk of developing infectiouscomplications being categorized as at high risk of developinginfectious complications. Although patients at high risk ofdeveloping infectious complications should continue toreceive appropriate intravenous antibiotic drug therapy, theauthor proposes that patients at low risk for developinginfectious complications can be safely treated with oralcombination therapy when appropriate observation isprovided.

6. Paul M, Borok S, Fraser A, Vidal L, Leibovici L. Empiricalantibiotics against gram-positive infections for febrileneutropenia: systematic review and meta-analysis ofrandomized controlled trials. J Antimicrob Chemother2005;55:436–44.

The safety of delaying administration of glycopeptides(vancomycin, teicoplanin) until culture results confirm aninfection caused by resistant gram-positive bacteria has beena persistent source of controversy. This rather complex


meta-analysis of 13 studies evaluated data on nearly 2400patients to address this controversy. Empiric glycopeptidetreatment was evaluated for initial treatment in nine trials andfor persistent fever in two trials. All-cause mortality wassimilar in seven studies (relative risk = 0.86 [0.58–1.26]).Overall failure, failure associated with treatmentmodifications, development of superinfections, and adverseevents also were analyzed. Results support the safety ofdeferring treatment with glycopeptides until a resistant gram-positive bacterial infection is confirmed. This article providesvaluable evidence to pharmacists attempting to decrease theindiscriminate use of vancomycin.

7. Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. β lactam monotherapy versus β lactam-aminoglycosidecombination therapy for fever with neutropenia: systemicreview and meta-analysis. BMJ 2004;328:668–72.

This meta-analysis of 47 randomized trials compared theeffectiveness of β-lactam monotherapy and β-lactam plusaminoglycoside combination therapy. The data set included7807 patients and 8803 febrile episodes. The primaryoutcome was all-cause fatality at the completion of and up to30 days following therapy completion. The mean value was6.2%. There was no significant difference in all-cause fatality(relative risk = 0.85; 95% confidence interval = 0.72–1.02).Monotherapy resulted in fewer treatment failures and adverseevents. Limitations of the study were acknowledged;sensitivity analyses indicated that the shortcomings did notaffect results. The major caveat is the lack of fatality data insome of the trials. The authors conclude that β-lactammonotherapy “should be regarded as the standard of care” forpatients with febrile neutropenia.

8. Rodriguez M, Fishman, JA. Prevention of infection due toPneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients. Clin Microbiol Rev2004;17:770–82.

Pneumocystis jiroveci continues to be a persistent pathogenfor patients who are immunocompromised, including selectedpatients with cancer who are human immunodeficiency virus-negative. The authors address the relatively recent change innomenclature that differentiates the Pneumocystis species thatinfect animals and humans. This review provides a clinicallyrelevant discussion of the epidemiology, diagnosis,pathophysiology, and current prophylactic options for patientswith cancer at risk for P. jiroveci pneumonia.

9. Mermel LA, Varr BM, Sherertz RJ, et al. Guidelines for themanagement of intravascular catheter-related infections. ClinInfect Dis 2001;32:1249–72.

The IDSA, the American College of Critical CareMedicine, and the Society for Healthcare Epidemiology ofAmerica jointly published these evidence-based guidelinesfor managing vascular access device-related infections.Strengths of the guidelines include specific recommendationsfor diagnosing and managing catheter-related infections. Thenotable weakness of the guidelines, acknowledged by theauthors, is that none of the evidence to support therecommendations was generated from randomized, double-blind, clinical trials. Rather, these guidelines are based onpublished data generated from small nonrandomized, clinicaltrials. However, until data from more rigorously designedtrials prove alternative approaches are superior to theseguidelines, they provide a rational standard approach todiagnosing and managing catheter-related infections. This

reference provides specific recommendations on theappropriate use of antibiotic lock therapy. The use of salvageantibiotic drug therapy is incorporated into a well-designedalgorithm for managing a patient with catheter-relatedbacteremia.

10. Guidelines for preventing opportunistic infections amonghematopoietic stem cell transplant recipients.Recommendations of the CDC, the Infectious Disease Societyof America, and the American Society of Blood and Marrow Transplantation. MMWR Recomm Rep 2000;49(RR-10):1–128. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm. Accessed January 31, 2006.

These guidelines review current data and provide evidence-based recommendations for preventing bacterial, viral,fungal, and protozoal infections among patients whounderwent hematopoietic stem cell transplantation (HSCT).Recommendations for prophylaxis of opportunistic infectionsare specific for allogeneic, autologous, pediatric, and adultHSCT recipients. Recommendations for prevention are ratedby the strength of the recommendation and the quality of theevidence supporting the recommendation. In addition torecommendations for hospital infection control, theguidelines include strategies for vaccination and HSC safety.


reviewed by deborah blamble, pharm.d., bcop; and h

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