Infections in Oncology Patients: Febrile Neutropenia and Beyond

Corey Casper, MD MPHVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center

Division of Infectious Disease, University of Washington

9 July 2010

Overview• Febrile Neutropenia

– Epidemiology– Microbiology– Evidence for Various Prophylactic Strategies– Controversies

• VRE• Prevention and treatment of invasive

fungal infections

Incidence of Infection in Neutropenic Patients with Cancer

• Prior to routine antibiotic prophylaxis, infection was a common complication of cancer therapy– Acute Leukemia

• 20-40 infections per 1000 patient-days• Bodey GP (1966), Ann Intern Med

– Transplant• 71-100 infections per 1000-patient days

• Engels EA (1999), Clin Infect Dis

• Infections frequently associated with high mortality– 75% of mortality in early era of chemotherapeutics was due to

infection• Schimpff SC (1971). N Engl J Med

Risk Factors for Infection in Patients with Neutropenia: Duration

Viscoli C (2005), Clin Infect Dis

Risk Factors for Infection in Patients with Neutropenia: Depth

Engels EA (1999). Clin Infect Dis

No Abx

IV Abx

PO Cipro IV Abx + PO Cirpo

Risk Factors for Infection in Patients with Neutropenia: Other

• Therapy– Type of chemotherapy– Corticosteroids

• Breach of Physical Barriers to Infection

• Skin / mucous membranes• Catheters

• Malignancy– Those which impair Ig function

• Multiple myeloma• CLL

– Those associated with splenectomy

Incidence of Febrile Neutropenia by Cancer Type

Etiology of Fever in Neutropenia• Only 50% of patients with fever during

neutropenia will have a documented infection– Of those 50%, only 20% have blood stream

infection– Not all are bacterial

Etiology of Bacteremia in Neutropenic Cancer Patients (1)

Viscoli C (2005) Clin Infect Dis

Etiology of Bacteremia in Neutropenic Cancer Patients (2)

Wisplinghoff H (2003), Clin Infect Dis

Sites of Infection in Cancer Patients

Yadegarynia D (2003), Clin Infect Dis, MD Anderson

Is Prophylaxis For Neutropenia Effective?

• Landmark 1988 study at FHCRC looking at approach to prophylaxis in 342 MRD transplant patients

– Control: standard care without antibiotics or rooms with laminar air flow (LAF)

– Prophylactic systemic antibiotics, no LAF

– LAF only, no antibiotics– LAF + Antibiotics

05

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Petersen F (1988), Infection

But which general oncology patients should receive prophylaxis?

Antibiotic Prophylaxis for General Oncology Patients with Short-Term Neutropenia (1)

Cullen, et. al. NEJM 2005

Antibiotic Prophylaxis for General Oncology Patients with Short-Term Neutropenia (2)

0

10

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Fever Infection Hospitalization

Levo

Placebo

P value for all comparisons <0.01, Cullen, et. al. NEJM 2005

Antibiotic Prophylaxis for General Oncology Patients with Short-Term Neutropenia (3)

Bucaneve NEJM 2005

Antibiotic Prophylaxis for General Oncology Patients with Short-Term Neutropenia (4)

…But Resistance to Fluoroquinolones is Increasing

• Among 823 hematology/oncology patients receiving FQ pphx, risk of FQ resistant bacteremia was 3 fold higher among those receiving prophylaxis– Cattaneo J Antimicrob Chemother. 2008

Prediction Model to Identify Neutropenic Patients Needing Pphx?

Cullen, JCO 2007

Predicting Risk of Infection During Neutropenia : Risk Groups

NCCN, “Prevention and Treatment of Cancer-Related Infections”

Principals of Antibiotics for Febrile Neutropenia

• Antibiotics are not antipyretics• Look for sources

– Risk factors– Exam– Studies

• Know antibiotic resistance patterns at UWMC / FHCRC and inherent susceptibilities of organisms to antibiotics

Evaluation of Patients with Febrile Neutropenia

Empiric Therapy for Febrile Neutropenia

Does Cefepime Kill People? The Story

Cefepime Meta-analysis• Lancet meta-analysis indicated that use of

Cefepime was associated with a 26% increased risk of death compared with other antibiotics– Not due to microbiologic failure

• NCCN hired biostatistician to review data, found methodology to be sound

Does Cefepime Kill People?The Data

Cefepime FDA Re-review• FDA asked for additional primary data from company

and found no increased risk for death– Quality / comprehensiveness of additional data provided?– Subgroup analysis found significantly increased risk of

death in solid tumor patients (but small numbers) and trend in hematologic malignancy patients

• My conclusion (only partially evidenced-based): use another agent in cancer patients when possible!

GNR Resistance at UWMC (2009)

http://healthlinks.washington.edu/primeanswers/documents/antibiogram2009.pdf

SCCA Febrile Neutropenia Empiric Treatment Algorithm

Tally of Infection-Related Deaths in Transplant, Q1 2008

Infection Count

VRE 8

Aspergillus 4

CMV 4

RSV 3

BK 2

Influenza A 1

Adenovirus 1

Non-infectious 8

VRE Among SCCA PatientsInfectious Disease Surveillance Trends: Vancomycin Resistant Enterococcus

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Prevalence / Significance of VRE Among SCCA Transplant Patients

• All transplant patients receive “welcome” culture to survey for VRE– 25% of transplant patients arrive at SCCA colonized with VRE– Additional 25% of susceptible patients develop VRE over course

of treatment at SCCA• Presence of VRE colonization predicts the development

of bacteremia in up to 1/3rd of cancer patients. – Matar MJ, et. al.. Am J Infect Control 2006; Zaas AK, et. al. Clin Infect Dis 2002

• VRE bacteremia portends a poor prognosis in persons undergoing treatment of malignancies with a high mortality rate

– Avery R, et. al.. Bone Marrow Transplant 2005; Bach PB, et. al.. Infect Control Hosp Epidemiol 2002

Antimicrobials for VRE: No Magic Bullet

Antibiotic Limitation (s)

Linezolid •Bacteriostatic•Bone marrow suppression

Quinupristin/Dalfopristin (Synercid)

•Bacteriostatic•Only active against E. faecium•Relatively poor penetration to urine•Infusional Toxicity

Daptomycin •Poor alveolar penetration•Resistance relatively easy to engender

Tigecycline •Questionable efficacy in bacteremia•Significant toxicities / drug-drug interactions

New SCCA Strategy for VRE• Empiric use of daptomycin in all patients

with known VRE colonization prior to or subsequent to transplant when vancomycin would ordinarily be used

Sepsis Stat Pack - Rationale• Anecdotal observations found opportunities for

improvement in providing antibiotics to septic patients with febrile neutropenia presenting to SCCA outpatient clinic– No antibiotics given in clinic because they would slow

transfer to acute setting– Inappropriate antibiotics given in clinic

• Convenience• Failure to appreciate spectrum of resistant organisms

Sepsis Stat Pack - Implementation[ ] Adult Sepsis

Protocol Standard Imipenem 500 mg

IVPB STAT over 20 minutes

Tobramycin 80 mg IVPB STAT over 20 minutes

Linezolid 600 mg IVPB STAT over 30 minutes

[ ] Adult Sepsis Protocol PENICILLIN ALLERGIC

Aztreonam 2 gm IVPB STAT over 20 minutes

Tobramycin 80 mg IVPB STAT over 20 minutes

Linezolid 600 mg IVPB STAT over 30 minutes

Improved Survival of Cancer Patients with Sepsis with Use of “Stat Pack”

• Among patients meeting criteria for severe sepsis, 90% thirty-day survival– More than double

compared with other published studies

• No toxicities noted• 81% had follow-up ID

consultation and tailoring of antibiotics

Larche J, Intensive Care Med 2003Pene F, Crit Care Med 2008

Invasive Fungal Infections (IFI)Infection Count

VRE 8

Aspergillus 4

CMV 4

RSV 3

BK 2

Influenza A 1

Adenovirus 1

Non-infectious 8

IFI Prevention:New Triazole on the Block

• Fluconazole– Cheap (<$1 per generic dose)– Effective against yeast– Safe

• Voriconazole– Expensive ($68 per dose)– Increased toxicities / drug interactions– Effective against yeast and mould

• Posaconazole– Expensive ($88 per dose)– Equally safe as fluconazole– Proven efficacy against IFI (and in vitro activity against

Zygomycetes)

Posaconazole:Acute Leukemia and MDS with Prolonged

Neutropenia

Cornely, NEJM 2007

SCCA IFI ProphylaxisPre-transplant voriconazole (begin at presentation if not already on) for:1. Known invasive aspergillosis or colonization with aspergillus species2. Pulmonary nodules of uncertain etiologyPre-transplant posaconazole (begin at presentation if not already on) for:1. MDS, aplastic anemia or any neutropenia lasting ≥ 1 week immediately preceding start of conditioning2. Systemic corticosteroid use ≥1 mg/kg/day within one month of transplant

NO

YES

Autologoustransplant

Allogeneictransplant

Fluconazole starting at conditioning:

Adults: 200 mg/day (po/iv) Children<12 years: 5 mg/kg/day (max 200 mg/day)

Stop fluconazole:if <0.5 mg/kg/day steroids: resolution of neutropenia and mucositis

If ≥0.5 mg/kg/day steroids: day +75

Fluconazole starting at conditioning:

Adults: 400 mg/day (po/iv) Children<12 years: 5 mg/kg/day (max 400 mg/day)

Steroids ≥ 1 mg/kg/day or total dose ≥ 0.8 mg/kg/qod (for any reason)

NO

Continue fluconazoleuntil day +75

Posaconazole 200 mg po tiduntil discontinuation of steroids

YES

Continue therapy

Hold voriconazole or posaconazole at conditioningSubstitute: Ambisome 5 mg/kg/day or micafungin 100 mg/day

Restart vori/posa therapy on day 0Obtaining ID input for stopping post-transplant

Reduction of Invasive Aspergillosis

• Despite constant construction at SCCA Outpatient Clinic and UWMC, number of aspergillus cases has dropped nearly 5-fold over last 7 years

• May be attributable to improved early diagnostics or prophylactic antifungal strategies

Conclusions (1)• Infections are a significant cause of morbidity and

mortality among neutropenic patients with cancer• Several well-defined risk factors help to identify

neutropenic patients at highest risk of infection and death

• Neutropenic patients are susceptible to many types of infection, including blood stream infections, pneumonia, urinary tract infections and intra-abdominal infections

• Antibiotic prophylaxis significantly reduces infections in neutropenic patients

Conclusions (2)• VRE is an increasing problem in cancer patients

and aggressive empiric therapy is warranted• Prevention and treatment of mould infections is

an emerging area of research• Rational use of antibiotics is essential to prevent

toxicities, resistance and unnecessary costs– Understand antimicrobial spectrum– Change antibiotics for well-defined and validated

reasons– Follow FHCRC Standard Practice Algorithms and

consult FHCRC Infectious Disease attendings with questions