Infection Rx

2 Dec 2003 21:30 AR AR206-ME55-29.tex AR206-ME55-29.sgm LaTeX2e(2002/01/18)P1: GCE10.1146/annurev.med.55.091902.103826

Annu. Rev. Med. 2004. 55:519–26doi: 10.1146/annurev.med.55.091902.103826

Copyright c© 2004 by Annual Reviews. All rights reservedFirst published online as a Review in Advance on Oct. 15, 2003

MANAGEMENT OF INFECTIONS IN THE

NEUTROPENIC PATIENT

Kenneth V.I. RolstonDepartment of Infectious Diseases, Infection Control and Employee Health,The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030;email: [email protected]

Key Words risk assessment, bacterial/fungal infections, empiric therapy, infectionprevention

■ Abstract Neutropenic patients continue to be at increased risk for developing se-rious infections despite substantial advances in supportive care. Epidemiologic shiftsoccur periodically and need to be detected early because they influence prophylactic,empiric, and specific therapy strategies. Although effective in preventing bacterial andsome fungal infections, prophylaxis must be used with caution because it is associatedwith the emergence of resistance. The choices for empiric therapy include combinationregimens and monotherapy. Specific choices depend on local factors (epidemiology,susceptibility/resistance patterns, availability). Various treatment settings (hospital-based, early discharge, outpatient) are also available, and the choice depends on thepatient’s risk category. Early diagnosis and treatment of many fungal and viral infec-tions remains suboptimal. Infection control and prevention are important strategies,especially with the emergence of multidrug-resistant organisms.

INTRODUCTION

It has been four decades since Bodey et al. first described the relationship betweenneutropenia and infection (1). Although the risk of infection increases when theabsolute neutrophil count (ANC) falls below 1000/mm3, the currently accepteddefinition of neutropenia is an ANC of≤500/mm3 (2). The severity and duration ofneutropenia are both important and influence not only the frequency and severityof infection but also the response to therapy and overall outcome. It has beenestimated that all patients who have severe neutropenia (<100/mm3) for 3 weeksor more will develop a serious infection (3).

In addition to quantitative neutropenia, many patients with hematologic dis-orders (e.g., acute leukemias) have defects in neutrophil function as well, andare at increased risk of infection despite adequate or even increased numbers ofneutrophils.

0066-4219/04/0218-0519$14.00 519

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520 ROLSTON

Chemotherapy-induced neutropenia is often superimposed on other immuno-logical deficits (impaired humoral or cell-mediated immunity) that might be presentbecause of the underlying malignancy. In such patients, infections associated withthose immunologic deficits must be considered in addition to infections generallyassociated with neutropenia.

The spectrum of infection in neutropenic patients undergoes periodic changes,and geographic/institutional differences are also common. Knowledge of localepidemiology and of susceptibility/resistance patterns is vital to the appropriatemanagement of neutropenic patients. Standard management includes the promptadministration of broad-spectrum, empiric antibiotic therapy after hospitaliza-tion (2).

Recent understanding of the syndrome of “febrile neutropenia” has made itpossible to recognize low-risk subsets among neutropenic patients, and to consideroptions such as oral, outpatient therapy (4).

SPECIAL CONSIDERATIONS

Patients with neutropenia often fail to develop symptoms and signs of infectionbecause of a blunted inflammatory response. Only 8% of patients with severeneutropenia who develop pneumonia produce purulent sputum compared to 84%who are not neutropenic (5). Chest radiographs show that neutropenic patientswith pneumonia often do not develop pulmonary infiltrates; those with urinarytract infections may not have localized symptoms such as dysuria; and some mayhave meningitis without overt meningeal symptoms or signs.

Fever may be the initial and often the only sign of infection. Occasionally, an in-fection may develop in the absence of fever, as with organisms such asClostridiumsepticum, or if the patient is receiving corticosteroids. Approximately 50%–60%of febrile episodes in neutropenic patients never have clinical or microbiologicalevidence of infection, hence the designation “unexplained fever.” Most of thesepatients respond to antibiotic therapy, which suggests that these fevers are probablycaused by low-grade, undetected infections.

Patients with neutropenia can develop infections at unusual sites, with uncom-mon manifestations, and by opportunistic pathogens that seldom cause infection inimmunocompetent hosts. Typhilitis, an inflammatory process most commonly in-volving the caecum, occurs almost exclusively in patients with acute leukemia (6).Perirectal infections with extensive tissue necrosis extending into the rectum alsooccur predominantly in patients with acute leukemia (7). Endocarditis is a rareinfection in neutropenic patients, presumably because most of these patients arealso thrombocytopenic and fail to make the fibrin/platelet mesh that is criticalfor the formation of bacterial vegetations. Infections can disseminate rapidly inmany patients with severe neutropenia, underscoring the importance of early,broad-spectrum antibiotic therapy. However, a low-risk subset also exists, partic-ularly among patients with solid tumors and short-lived neutropenia. Clinical and

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INFECTIONS IN NEUTROPENIC PATIENTS 521

statistically derived risk-prediction rules have been developed in order to iden-tify such patients (8–10). Finally, it is important to consider noninfectious causesof fever such as transfusion reactions, chemotherapy or other drug-related fever,allergic reactions, and occasionally tumor fever.

SPECTRUM OF INFECTION

Infections that occur during the early phases of a neutropenic episode are predom-inantly bacterial. Fungal infections are generally seen in patients with severe andprolonged neutropenia and in those receiving multiple courses of broad-spectrumantibiotics. Most large cancer treatment centers have reported a predominance ofGram-positive pathogens as a cause of bacteremia in neutropenic patients (11).However, institutional differences do exist; many centers often encounter Gram-negative bacilli instead. Additionally, most tissue-based infections (pneumonia,typhilis/enterocolitis, perirectal infections) and polymicrobial infections are fre-quently Gram-negative (12). Yeasts such asCandidaspp. andTrichosporonspp.and molds such asAspergillusspp., theZygomycetes, andFusariumspp. are theusual causes of fungal infections. Viral infections are uncommon, but herpesviruses(HSV, VZV, CMV, HHV6) and community respiratory viruses are the most fre-quent pathogens. Table 1 lists the common pathogens encountered in neutropenicpatients.

EMPIRIC THERAPY

The administration of empiric, broad-spectrum antibiotic therapy is consideredthe standard of care for febrile episodes in neutropenic patients (2). Several ther-apeutic choices are available (Table 2). Individual institutions must tailor the useof specific agents based on local epidemiology and local susceptibility/resistancepatterns. Some experts favor combination regimens that are potentially bacteri-cidal over single-agent regimens (monotherapy), especially in high-risk patientswith documented Gram-negative infections. However, most head-to-head clinicaltrials have not demonstrated the superiority of combination therapy over monother-apy (2). Combination regimens may reduce the overall emergence of resistance,but may be associated with increased toxicity and cost.

Combinations that do not include a glycopeptide (e.g., vancomycin) consist ofan aminoglycoside (e.g., amikacin, tobramycin, gentamicin) along with a cephalo-sporin (e.g., cefepime, ceftazidime), carbapenem (e.g., imipenem, meropenem),quinolone (e.g., ciprofloxacin), or an antipseudomonal penicillin/beta-lactamaseinhibitor (e.g., piperacillin/tazobactam). When more potent Gram-positive cover-age is indicated, combining vancomycin with ceftazidime, imipenem, meropenem,or a quinolone might be indicated. Other specific Gram-positive agents (e.g., line-zolid, quinupristin/dalfopristin) are not yet indicated for use in empiric regimens.

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TABLE 1 Common causes of documentedinfections in neutropenic patients

BacteriaGram-positive

Staphylococcusspp.Viridans streptococciEnterococcusspp.Corynebacteriumspp.Bacillusspp.

Gram-negativeEscherichia coliPseudomonas aeruginosaKlebsiellaspp.Enterobacterspp.Proteusspp.Stenotrophomonas maltophilia

FungiCandida albicansand otherCandidaspp.Trichosporon beigelliAspergillus fumigatusand otherAspergillusspp.ZygomycetesFusariumspp.

VirusesHerpesvirusesRespiratory syncytial virusInfluenza virusParainfluenza virusAdenovirus

Based on current susceptibility patterns, cefepime, meropenem, and imipenem arethe most appropriate agents for monotherapy (13, 14).

The response rates of most empiric regimens range from 55% to 85% (2). Itis customary to treat for 72–96 h before making alterations, in order to allow theinitial regimen to produce a response. These alterations depend on the clinical set-ting (e.g., suspected catheter-related infection, abdominal or pelvic focus, centralnervous system infection) and microbiologic data. The most common modifica-tions are the addition of a glycopeptide, if not used initially, or the addition ofan antifungal agent. Strengthening Gram-negative or anaerobic coverage whenindicated is also commonplace. The choice of antifungal agents depends on theuse of antifungal prophylaxis and the nature of the fungal infections (yeast ver-sus mold). In general, amphotericin B or one of its lipid preparations is usedin this setting. Newer agents such as voriconazole and caspofungin are also be-ing evaluated for empiric antifungal therapy in persistently febrile neutropenicpatients (15).

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TABLE 2 Traditional choices for empiric therapy in febrile neutropenic patients

Combination Regimens (without glycopeptide)Aminoglycoside +antipseudomonal penicillin

± beta/lactamase inhibitor+extended spectrum cephalosporin+carbapenem or quinolone

Combination Regimens (with a glycopeptide)a

Vancomycin +antipseudomonal penicillin± beta/lactamase inhibitor

+extended spectrum cephalosporin+carbapenem+quinolone or monobactam

Single-Agent Regimens (monotherapy)Carbapenemb

Extended spectrum cephalosporinAntipseudomonal penicillin+ beta/lactamase inhibitorc

aLinezolid and quinoprinstin/dalfopristin not recommended for empiric therapy.bImipenem and meropenem (but not ertapenem).cMay need additional clinical data.

SPECIFIC THERAPY

When a specific pathogen is isolated, therapy can be adjusted to the organismisolated, based on local susceptibility patterns. Table 3 lists the agents used mostoften, including some newer options. The isolation of a specific pathogen, espe-cially if it is a Gram-positive organism, does not necessarily permit the use ofnarrow-spectrum agents in patients with severe neutropenia (particularly thosewith significant mucositis), since these patients may have occult Gram-negativeor polymicrobial infections. Our antifungal armamentarium is expanding; severalnewer triazoles (voriconazole, posaconazole, ravuconazole) and echinocandins(caspofungin, anidulafungin, micafungin) have either recently become availableor are nearing approval by the US Food and Drug Administration. Our ability totreat most viral infections is still quite limited; new antiviral agents are needed.

LENGTH OF THERAPY

The length of therapy depends on the type of infection (bacteremia, urinary tractinfection, pneumonia, etc.), the organism isolated (S. aureus, coagulase-negativestaphylococci,P. aeruginosa, Candidaspp., etc.), and the persistence of or recov-ery from neutropenia. Most experts continue therapy until (a) all signs and symp-toms of infection have resolved, (b) the patient has been afebrile for 3–4 days,(c) cultures, if initially positive, have been rendered negative, and (d) radiographicevidence of infection, if initially present, shows signs of resolution. Some experts

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TABLE 3 Therapeutic agents for the treatment of documentedinfections in febrile neutropenic patients

Antibacterial AgentsNarrow-spectrum (Gram-positive)

Nafcillin, oxacillinVancomycin (teicoplanin, where available)LinezolidQuinupristin/dalfopristin

Narrow-spectrum (Gram-negative)AminoglycosidesMonobactams (aztreonam)Quinolones (ciprofloxacin)Narrow-spectrum (anaerobic)MetronidazoleClindamycin

Broad-spectrumMeropenem, imipenemCefepime, ceftazidimePiperacillin/tazobactamMoxifloxacin, gatifloxacin (additional clinical data needed)Trimethoprim/sulfamethoxazole

Antifungal AgentsAmphotericin B (including lipid preparations)Fluconazole, itraconazole, voriconazoleCaspofungin

Antiviral AgentsAcyclovirValacyclovircGanciclovirFoscarnetCidofovirRibavirin

recommend continuing therapy until resolution of neutropenia (ANC≥ 500/mm3

for 2 consecutive days) (2).

RISK ASSESSMENT AND RISK-BASED THERAPY

It has long been recognized that not all febrile neutropenic patients have the samerisk of developing serious infection-related or other complications. However, ithas only recently become possible to identify low-risk patients accurately and ina timely manner, using clinical criteria and/or statistically derived prediction rules(8–10, 16, 17). Low-risk patients can be discharged early after initial stabilizationin the hospital or can be treated for the febrile episode without any hospitalization(8, 18, 19). Most outpatient regimens are quinolone-based (e.g., ciprofloxacin+

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amoxicillin/clavulanate or clindamycin) and can be administered orally, althoughparenteral outpatient therapy is also feasible in low-risk patients who are unable totolerate oral therapy. An experienced team and the appropriate infrastructure areessential for a risk-based program to be successful.

INFECTION PREVENTION

Antibacterial prophylaxis (generally with a quinolone such as ciprofloxacin) hasbeen found to reduce the frequency of documented Gram-negative infections,but it may have no impact, or occasionally may lead to an increase in Gram-positive infections (20). Increased survival as a result of antibacterial prophylaxishas not been demonstrated. The emergence of resistant organisms is a significantdrawback of chemoprophylaxis (21). Consequently, it is recommended only forpatients anticipated to have severe and prolonged neutropenia (ANC≤ 100/mm3

for>10–14 days). Antifungal prophylaxis (e.g., fluconazole/itraconazole) has beenshown to reduce the frequency of infections caused byCandidaspp. (22, 23). Moldinfections are much more difficult to prevent, and effective strategies are yet to bedeveloped. Some of the newer antifungal agents with activity against filamentousfungi (e.g., voriconazole, posaconazole) are being evaluated for the prevention offungal infections.

SUMMARY

The management of febrile neutropenic patients has evolved considerably. Al-though hospital-based, empiric therapy remains the standard for high-risk patients,newer strategies such as early discharge or oral, out-patient therapy are becom-ing the norm for low-risk patients. The most important factors for the selectionof antimicrobial agents for empiric use are local microbiology and susceptibility/resistance patterns. Better strategies for infection prevention are needed, partic-ularly for fungal and viral infections. These issues will continue to challengeclinicians caring for febrile neutropenic patients for the foreseeable future.

The Annual Review of Medicineis online at http://med.annualreviews.org

LITERATURE CITED

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timicrobial agents in neutropenic patientswith cancer.Clin. Infect. Dis.34:730–51

3. Rolston KVI, Bodey GP. 2003. Infectionsin patients with cancer. InCancer Medi-cine, ed. JF Holland, E Frei, pp. 2633–58.Ontario: BC Decker. 6th ed.

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for risk-based therapy in febrile neutrope-nia.Diagn. Microbiol. Infect. Dis.31:411–16

5. Sickles EA, Greene WH, Wiernik PH.1975. Clinical presentation of infectionin granulocytopenic patients.Arch. Intern.Med.135:715–19

6. Gomez L, Martino R, Rolston KV. 1998.Neutropenic enterocolitis: spectrum of thedisease and comparison of definite andpossible cases.Clin. Infect. Dis.27:695–99

7. Rolston KVI, Bodey GP. 1993. Diagnosisand management of perianal and perirectalinfection in the granulocytopenic patient.In Current Clinical Topics in InfectiousDiseases, ed. J Remington, MN Swartz,pp. 164–71. Boston: Blackwell Sci.

8. Rolston K. 1999. New trends in patientmanagement: risk-based therapy for febrilepatients with neutropenia.Clin. Infect. Dis.29:515–21

9. Talcott JA, Siegel RD, Finberg R, et al.1992. Risk assessment in cancer patientswith fever and neutropenia: a prospective,two-center validation of a prediction rule.J. Clin. Oncol.10:316–22

10. Klastersky J, Paesmans M, Rubenstein E,et al. 2000. The MASCC Risk Index: amultinational scoring system to predictlow-risk febrile neutropenic cancer pa-tients.J. Clin. Oncol.18:3038–51

11. Zinner SH. 1999. Changing epidemiologyof infections in patients with neutropeniaand cancer: emphasis on gram-positive andresistant bacteria.Clin. Infect. Dis.29:490–94

12. Elting LS, Bodey GP, Fainstein V. 1986.Polymicrobial septicemia in the cancer pa-tient.Medicine65:2l8–25

13. Jones RN. 1999. Contemporary antimi-crobial susceptibility patterns of bacte-rial pathogens commonly associated withfebrile patients with neutropenia.Clin. In-fect. Dis.29:495–502

14. Rolston KVI, Kontoyiannis DP, Raad II,et al. 2003. Susceptibility surveillanceamong gram-negative bacilli at a compre-

hensive cancer center.Presented at Gen.Meet. Am. Soc. Microbiol., 103rd, Wash-ington, DC, May 18–22 (Abstr. #2362)

15. Walsh TJ, Pappas P, Winston DJ, et al.2002. Voriconazole compared with liposo-mal amphotericin B for empirical antifun-gal therapy in patients with neutropenia andpersistent fever.N. Engl. J. Med.346:225–34

16. Freifeld A, Marchigiani D, Walsh T, et al.1999. A double-blind comparison of empir-ical oral and intravenous antibiotic therapyfor low-risk febrile patients with neutrope-nia during cancer chemotherapy.N. Engl.J. Med.341:305–11

17. Kern WV, Cometta A, DeBock R, et al.1999. Oral versus intravenous empiricalantimicrobial therapy for fever in patientswith granulocytopenia who are receivingcancer chemotherapy.N. Engl. J. Med.341:312–18

18. Rubenstein EB, Rolston K, Benjamin RS,et al. 1993. Outpatient treatment of febrileepisodes in low risk neutropenic cancer pa-tients.Cancer71:3640–46

19. Mullen CA, Petropoulos D, Roberts WM,et al. 1999. Outpatient treatment of febrileneutropenia in low risk pediatric cancer pa-tients.Cancer86:126–34

20. Cruciani M, Rampazzo R, Malena M, et al.1996. Prophylaxis with fluoroquinolonesfor bacterial infections in neutropenic pa-tients: a meta-analysis.Clin. Infect. Dis.23:795–805

21. Rolston KVI. 1998. Commentary: chemo-prophylaxis and bacterial resistance in neu-tropenic patients.Infect. Dis. Clin. Pract.7:202–4

22. Goodman JL, Winston DJ, Greenfield A,et al. 1992. A controlled trial of flucona-zole to prevent fungal infections in patientsundergoing bone marrow transplantation.N. Engl. J. Med.326:845–51

23. Marr KA, Seidel K, White TC, et al. 2000.Candidemia in allogeneic blood and mar-row transplant recipients: evolution of riskfactors after the adoption of prophylacticfluconazole.J. Infect. Dis.181:309–16

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Annual Review of Medicine Volume 55, 2004

CONTENTSEffect of Completed Human Genome Sequence on Development of Novel Therapeutics for Human Disease, Christopher P. Austin 1

Toward Alzheimer Therapies Based on Genetic Knowledge, John Hardy 15Inherited Diseases Involving G Proteins and G Protein--Coupled Receptors, Allen M. Spiegel, Lee S. Weinstein 27The Scientific Basis for the Current Treatment of Parkinson's Disease, C. Warren Olanow 41Progress in Antisense Technology, Stanley T. Crooke 61

Serum Proteomics in the Early Diagnosis of Cancer, Kevin P. Rosenblatt, Peter Bryant-Greenwood, J. Keith Killian, Arpita Mehta, David Geho, Virginia Espina, Emanuel F. Petricoin, Lance A. Liotta 97Molecular Neurobiology of Drug Addiction, Jennifer Chao, Eric J. Nestler 113Beta Cell Replacement for Type 1 Diabetes, Peter G. Stock, Jeffrey A. Bluestone 133Cochlear Implantation for the Treatment of Deafness, Benjamin J. Copeland, Harold C. Pillsbury 157Drug-Eluting Stents, T. Cooper Woods, Andrew R. Marks 169New Approaches to Hemodialysis, Andreas Pierratos 179Emerging Infectious Threats to the Blood Supply, Roger Y. Dodd, David A. Leiby 191Lead Poisoning, Herbert Needleman 209The Impact of Minimally Invasive Surgical Techniques, Sir Ara Darzi, Yaron Munz 223Implementing a Research Agenda for Complementary and Alternative Medicine, Jonathan D. Berman, Stephen E. Straus 239Basic Advances and New Avenues in Therapy of Spinal Cord Injury, Bruce H. Dobkin, Leif A. Havton 255

Clinical Management of Tuberculosis in the Context of HIV, Bouke C. de Jong, Dennis M. Israelski, Elizabeth L. Corbett, Peter M. Small 283

HIV-Associated Lipodystrophy: Pathogenesis, Prognosis, Treatment, and Controversies, Polyxeni Koutkia, Steven Grinspoon 303Human Papillomavirus Vaccines and Prevention of Cervical Cancer, Kathrin U. Jansen, Alan R. Shaw 319

Opportunities for Control of Meningococcal Disease in the United States, Pratima L. Raghunathan, Scott A. Bernhardt, Nancy E. Rosenstein 333Recent Advances in the Development of HIV-1 Vaccines Using Replication-Incompetent Adenovirus Vectors, John W. Shiver, Emilio A. Emini 355Left Ventricular Diastolic Dysfunction and Diastolic Heart Failure, William H. Gaasch, Michael R. Zile 373Mechanisms of Pulmonary Fibrosis, Victor J. Thannickal, Galen B. Toews, Eric S. White, Joseph P. Lynch III, Fernando J. Martinez 395Systemic Mastocytosis, Cem Akin, Dean D. Metcalfe 419

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The erbB Family: Targets for Therapeutic Development Against Cancer and Therapeutic Strategies Using Monoclonal Antibodies and Tyrosine Kinase Inhibitors, Eric K. Rowinsky 433Nonmyeoablative Immunotherapy for Solid Tumors, Richard W. Childs, John Barrett 459

Rituximab: Expanding Role in Therapy for Lymphomas and Autoimmune Diseases, William Rastetter, Arturo Molina, Christine A. White 477Botulinum Toxin and Other New Approaches to Migraine Therapy, Avi Ashkenazi, Stephen D. Silberstein 505Management of Infections in the Neutropenic Patient, Kenneth V.I. Rolston 519

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