Burning Up: Updates in the Management of Febrile Neutropenia

1
Burning Up Updates in the Management of Febrile
Neutropenia

• Stephanie Shuey, Pharm.D.
• PGY2 Oncology Specialty Resident
• stephanie.shuey_at_aurora.org

2
Disclosure
2

• I have nothing to disclose concerning possible
  financial or personal relationships with
  commercial entities that may have a direct or
  indirect interest in the subject matter of this
  presentation

3
Why is Febrile Neutropenia Important?
3

• Common toxicity of chemotherapy
• Solid tumors 10-50
• Hematologic malignancies gt80
• Compromises clinical outcomes
• Increased mortality
• Prolonged hospital stay
• Increased diagnostic and treatment costs
• Delayed chemotherapy courses
• Chemotherapy dose reductions

NCCN guidelines myeloid growth factors.
www.nccn.org.
4
Infectious Diseases Society of America Guidelines

• Published in 1997
• Updated in 2002 and 2011
• Highlights
• Risk assessment as the guiding principle of
  therapy
• Empiric therapy for high risk patients
• Empiric vs. pre-emptive antifungal therapy

5
Objectives
5

• List three criteria that would classify a patient
  with febrile neutropenia (FN) as high risk
• Choose two appropriate empiric antibiotic
  regimens for a patient with FN
• Compare the efficacy and safety of traditional
  and alternative dosing strategies for meropenem
  in FN
• Identify the optimal role of antifungals in
  patients with FN

6
Outline
6

• Overview of FN
• Patient assessment and risk stratification
• Empiric antibiotics
• Role of antifungals

7
Definition of FN
7

• Fever
• Single oral temperature gt38.3ºC (101ºF)
• Temperature gt38.0ºC (100.4ºF) sustained for gt1
  hour
• Neutropenia
• Absolute neutrophil count (ANC) lt500 cells/mm3
• ANC expected to decrease to lt500 cells/mm3 within
  48 hours

Freifeld AG, et al. CID. 201152(4)e56-e93.
8
Calculating ANC
8

• ANC WBC ((neuts or segs bands)/100)
• ANC reporting in Epic
• Automated differential -gt absolute neutrophil
• Manual differential -gt absolute segs

9
Infectious Sources
9

• Causative pathogens
• Identified in 30 of FN episodes
• Bacterial in 85-90 of cases
• Endogenous flora in 80 of cases
• Common sources of infection
• Respiratory tract
• Urinary tract
• Skin
• Gastrointestinal tract

Mebis J, et al. Journal of Chemotherapy.
201022(1)5-12.)
10
Summary Overview of FN
10

• Common toxicity of chemotherapy
• Compromises clinical outcomes
• Defined by threshold ANC and temperature
• Causative pathogen rarely identified

11
Outline
11

• Overview of FN
• Patient assessment and risk stratification
• Empiric antibiotics
• Role of antifungals

12
Assessment of Patients with FN
12

• Physical exam
• Classic signs of infection often lacking
• Close examination required
• Skin sites of previous procedures or catheters
• Oropharynx
• Alimentary tract
• Lungs
• Perineum

Freifeld AG, et al. CID. 201152(4)e56-e93.
13
Assessment of Patients with FN
13

• Detailed history
• New site-specific symptoms
• Antimicrobial prophylaxis
• Infectious exposures
• Prior documented infections or colonization
• Non-infectious causes of fever

Freifeld AG, et al. CID. 201152(4)e56-e93.
14
Assessment of Patients with FN
14

• Diagnostic testing blood cultures

When to Draw of Cultures Site(s) of Draws
Initial Evaluation At least two sets All CVC lumens Peripheral vein
Persistent Fever After Empiric Antibiotic Initiation Two sets x two days CVC or peripheral vein
Fever Recurrence After Defervescence At least two sets All CVC lumens Peripheral vein
CVCcentral venous catheter
Freifeld AG, et al. CID. 201152(4)e56-e93.
15
Risk Assessment

• Determines treatment course (A-II)
• Antibiotic route of administration
• Treatment setting
• Duration of antibiotic therapy
• High risk patients
• ANC lt100 x gt7 days and/or comorbidities (A-II)
• MASCC score lt21 (B-I)
• Low risk patients
• Neutropenia x lt7 days and no/few comorbidities
  (A-II)
• MASCC score gt21 (B-I)

MASCC Multinational Association of Supportive
Care in Cancer Freifeld AG, et al. CID.
201152(4)e56-e93.
16
Risk Stratification
16

• MASCC criteria
• Based on multinational prospective observational
  study
• Internationally validated scoring system
• Summation of weighted risk factors
• Low risk score gt21 points
• High risk score lt21 points

• MASCC Multinational Association of Supportive
  Care in Cancer
• Klastersky J, et al. J Clin Oncol.
  200018(16)3038-3051.

17
MASCC Criteria
17
Klastersky J, et al. J Clin Oncol.
200018(16)3038-3051.
Characteristic Weight
Burden of FN with No or mild symptoms Moderate symptoms Severe symptoms or moribund 5
Burden of FN with No or mild symptoms Moderate symptoms Severe symptoms or moribund 3
Burden of FN with No or mild symptoms Moderate symptoms Severe symptoms or moribund 0
No hypotension (systolic blood pressure gt90 mmHg) 5
No chronic obstructive pulmonary disease 4
Solid tumor or hematologic malignancy with no previous fungal infection 4
No dehydration requiring parenteral fluids 3
Outpatient status 3
Age lt60 years 2
18
Risk Stratification
18
Neutropenia
Duration lt7 days
Comorbidities
No active medical comorbidities Renal and hepatic function Stable Adequate
and
Freifeld AG, et al. CID. 201152(4)e56-e93.
19
Risk Stratification
19
Comorbidities
Hemodynamic instability Severe oral or GI mucositis GI symptoms New onset neurologic or mental status changes Intravascular catheter infection New pulmonary infiltrate or underlying chronic lung disease Hepatic or renal insufficiency
Neutropenia
Depth ANC lt100 cells/mm3 Duration gt7 days
and/or
Hepatic insufficiency AST/ALT gt5 x normal
values Renal insufficiency CrCl lt30 ml/min
Freifeld AG, et al. CID. 201152(4)e56-e93.
20
Risk Factors for Developing FN
20
Regimen-Related Patient-Related
Agent(s) used Dose density Dose intensity Age gt65 Previous chemotherapy or radiation therapy Pre-existing conditions Poor performance status Poor renal function Liver dysfunction
NCCN guidelines myeloid growth factors.
www.nccn.org.
21
Summary
21

• Thorough initial patient assessment is crucial
• Absence of classic signs of infection
• Infectious and antimicrobial exposures
• gt 2 sets of blood cultures recommended
• Enhanced sensitivity
• Detection of central-line associated blood stream
  infections (CLABSIs)
• Risk assessment should guide therapy
• Based on characteristics of neutropenia and
  comorbidities

22
The Case of FS

• HPI
• 72 yo female
• Recurrent, stage III ovarian cancer
• Began third-line treatment with topotecan 4 mg/m2
  IV weekly 7 days ago
• Presents to ED with complaint of fever

• Vital signs
• Temp 101.2ºF
• BP 128/77
• HR 68
• RR 18
• Labs
• ANC 100 cells/mm3
• CrCl 55 ml/min
• AST 23 units/L
• ALT 37 units/L
• Total bilirubin 0.4 mg/dL

23
The Case of FS

• Which of the following characteristics classify
  FS as high risk?
• Age
• ANC
• History of previous chemotherapy
• More information is needed to classify risk

24
Outline
24

• Overview of FN
• Patient assessment and risk stratification
• Empiric antibiotics
• Role of antifungals

25
Bacterial Infections
25

• Common pathogens

Gram-positive Gram-negative
Coagulase-negative staphylococci Staphylococcus aureus Enterococcus species Viridans group streptococci Streptococcus pneumoniae Streptococcus pyogenes Escherichia coli Klebsiella species Enterobacter species Pseudomonas aeruginosa Citrobacter species Acinetobacter species Stenotrophomonas maltophilia
Freifeld AG, et al. CID. 201152(4)e56-e93.
26
Bacterial Infections
26

• GN lt GP
• Emergence of drug-
• resistant organisms

• GN lt GP
• Increasing use of CVCs

• GN lt GP
• Quinolone px
• High dose cytarabine
• PPIs
• Indwelling catheters

Mebis J, et al. Journal of Chemotherapy.
201022(1)5-12. Freifeld AG, et al. CID.
201152(4)e56-e93.
GPgram-positive, GNgram-negative, CVCscentral
venous catheters, pxprophylaxis, PPIsproton
pump inhibitors
27
Empiric Antibiotics High Risk Patients
27

• Monotherapy with IV anti-pseudomonal ß-lactam in
  inpatient setting (A-I)
• Avoid routine addition of vancomycin (A-I)
• Treat afebrile neutropenic patients with
  signs/symptoms of infection as high risk (B-III)

Freifeld AG, et al. CID. 201152(4)e56-e93.
28
Monotherapy vs. Combination Therapy

• 2002
• Monotherapy
• Two drug combination in complicated cases or if
  antimicrobial resistance is a concern
• 2011
• Monotherapy only

Freifeld AG, et al. CID. 201152(4)e56-e93. Hughe
s WT, et al. CID. 200234(6)730-51.
29
Monotherapy vs. Combination Therapy
Evidence for Monotherapy
29
Paul M, et al. Cochrane Database of Syst Rev. 2010, Issue 3CD003038. Paul M, et al. Cochrane Database of Syst Rev. 2010, Issue 3CD003038.
Design Systematic review of 68 trials More than 10,000 patients
Population Mainly adult cancer patients with hematologic malignancies High risk subgroups ANC lt100 cells/mm3 Microbiologically documented infection Documented P. aerguinosa infection Bacteremic patients Patients with underlying hematologic malignancy or BMT
Antibiotic Regimens ß-lactam monotherapy vs. ß-lactam aminoglycoside Same ß-lactam in each arm 15 trials (22) Most common ceftazidime (7 trials) Different ß-lactam in each arm 53 trials (78) Most common carbapenem vs. cephalosporin (18)
30
Monotherapy vs. Combination Therapy
Evidence for Monotherapy
30
Paul M, et al. Cochrane Database of Syst Rev. 2010, Issue 3CD003038. Paul M, et al. Cochrane Database of Syst Rev. 2010, Issue 3CD003038.
Mortality All cause decreased with monotherapy (RR 0.87) Infection-related decreased with monotherapy (RR 0.80)
Super Infections Bacterial equivalent (RR 1.00) Fungal less frequent with monotherapy (RR 0.70)
Adverse Events Any AE less frequent with monotherapy (RR 0.85) Nephrotoxicity Any less frequent with monotherapy (RR 0.45) Severe less frequent with monotherapy (RR 0.16)
Conclusion Monotherapy can be regarded as standard of care for empirical treatment of FN Trend towards improved mortality with monotherapy Combination therapy associated with increased AEs and no survival benefit
Statistically significant AE adverse event
31
Recommended Empiric Antibiotics in High Risk
Patients

• 2002
• 2011

Monotherapy
Antipseudomonal ß-lactam Ceftazidime or cefepime Meropenem or imipenem-cilastatin Piperacillin-tazobactam
Two-Drug Combination
Aminoglycoside with Ticarcillin-clavulanic acid or piperacillin-tazobactam Ceftazidime or cefepime Meropenem or imipenem-cilastatin
OR
Monotherapy
Antipseudomonal ß-lactam Cefepime Meropenem or imipenem-cilastatin Piperacillin-tazobactam
Freifeld AG, et al. CID. 201152(4)e56-e93. Hughe
s WT, et al. CID. 200234(6)730-51.
32
Spectrum of Activity
VRE
PSSA
E. coli
Neisseria
P. mirabilis
Streptococcus
Serratia spp.
H. influenzae
MSSA/MSSE
Enterococcus
Klebsiella spp.
M. catarrhalis
Pseudomonas
Acinetobacter
MRSA/MRSE
Citrobacter spp.
Enterobacteriace
33
Susceptibilities at Aurora Health Care
33

• Imipenem 68
• Piperacillin/tazobactam 87
• Meropenem 73
• Cefepime 67

34
Comparison of Monotherapies
Drug Dose for FN Clinical Pearls
Cefepime 2 gm IV Q8H Dose adjust for CrCl lt60 ml/min Risk of neurotoxicity
Piperacillin-tazobactam 3.375 gm IV Q8H Dose adjust for CrCl lt20 ml/min Extended infusion dosing Risk of drug-induced neutropenia
Meropenem 500 mg IV Q6H 1000 mg IV Q8H Dose adjust for CrCl lt50 ml/min Seizure risk Drug interaction valproic acid
Cefepime (Maxipime) package insert.
3/2009. Meropenem (Merrem) package
insert.12/2010. Miller AD, et al.
Pharmacotherapy. 201131(4)408-23. Piperacillin-t
azobactam (Zosyn) package insert. 9/2009.
35
Meropenem Traditional vs. Alternative Dosing
1000 mg IV Q8 hours vs. 500 mg IV Q6 hours

• Rationale for alternative dosing
• Maintains adequate bactericidal exposure (TgtMIC)
• Produces comparable clinical outcomes
• Decreases cumulative daily dose
• Decreases cost
• 38/patient/day
• 205 - 406/patient/regimen

Kotapati S, et al. Am J Health Syst Pharm.
2004611264-70. Kuti JL, et al. Am J Health Syst
Pharm. 200360565-68. Patel GW, et al.
Pharmacotherapy. 200727(12)1637-43.
36
Alternative Dosing in FN
Arnold HM, et al. Pharmacotherapy. 200929(8)914-23. Arnold HM, et al. Pharmacotherapy. 200929(8)914-23.
Design Retrospective, single center, cohort study
Cohorts I-C Imipenem-cilastatin 500 mg IV Q6 hours (n40) ADM meropenem 500 mg IV Q6 hours (n58) TDM meropenem 1000 mg IV Q8 hours (n29)
Time to Defervescence Similar among all groups (I-C vs. ADM vs. TDM) 3 days vs. 3 days vs. 2 days (ADM vs. I-C HR 0.88)
Need for Other Antibiotics Similar among all groups (I-C vs. ADM vs. TDM) 20 vs. 14 vs. 17 (p0.71)
Treatment Duration Similar among all groups (I-C vs. ADM vs. TDM) 10 days vs. 8 days vs. 8 days (ADM vs. I-C HR 1.33)
Mortality In-hospital and 30-day similar among all groups (p0.92 p0.64)
Seizure Rate No seizure activity in any group
I-C imipenem-cilastatin, ADM
alternatively-dosed meropenem, TDM
traditionally-dosed meropenem
37
Alternative Dosing in FN
Arnold HM, et al. Pharmacotherapy. 200929(8)914-23. Arnold HM, et al. Pharmacotherapy. 200929(8)914-23.
Conclusions ADM may be as safe and efficacious as TDM in patients with FN No differences in time to defervescence, need for additional antibiotics, treatment duration, mortality, or seizure rate Additional studies needed to confirm findings
ADM alternatively-dosed meropenem, TDM
traditionally-dosed meropenem
38
Alternative Dosing at Aurora Health Care

• Orders for imipenem-cilastatin substituted to
  meropenem
• Automatic adjustment of initial dose to 500 mg Q6
  hours (or renally-adjusted equivalent)
• Exceptions

CNS infection Patients with cystic fibrosis
Ventilator-associated pneumonia Organisms resistant to meropenem
Pediatric patients
39
Assessment of Alternative Dosing in FN at Aurora
St. Lukes Medical Center
Design Retrospective analysis of meropenem use on 12ST (11/2010-11/2011)
Cohorts ADM meropenem 500 mg IV Q6 hours (n4) TDM meropenem 1000 mg IV Q8 hours (n9)
Time to Defervescence Afebrile x 24 hours (ADM vs. TDM) 3 days vs. 2 days Afebrile x 72 hours (ADM vs. TDM) 7.5 days vs. 5 days
Treatment Duration ADM vs. TDM 11 days vs. 6 days
Mortality Rate No deaths in either group
Conclusions ADM and TDM resulted in similar clinical outcomes Meropenem use for FN is limited on 12ST TDM more common than ADM
ADM alternatively-dosed meropenem, TDM
traditionally-dosed meropenem
40
Empiric Antibiotics High Risk Patients
40

• Monotherapy with IV anti-pseudomonal ß-lactam in
  inpatient setting (A-I)
• Avoid routine addition of vancomycin (A-I)
• Treat afebrile neutropenic patients with
  signs/symptoms of infection as high risk (B-III)

Freifeld AG, et al. CID. 201152(4)e56-e93.
41
Vancomycin for Empirical Therapy
41

• Recommendation unchanged since 2002
• Rationale for withholding
• No evidence of improvement in clinical outcomes
• Lack of urgent need for vancomycin at onset of FN
• Contribution to drug resistance

Freifeld AG, et al. CID. 201152(4)e56-e93.
42
Indications for Empirical Vancomycin
Indication 2002 2011
Hemodynamic instability or other evidence of severe sepsis ? ?
Clinically suspected serious catheter-related infection ? ?
Colonization Penicillin-resistant Streptococcus pneumoniae (2002 and 2011) Methicillin-resistant Staphylococcus aureus (2002 and 2011) Vancomycin-resistant enterococcus (2011 only) ? ?
Preliminary positive blood culture for gram () bacteria ? ?
Severe mucositis secondary to chemotherapy ?
Quinolone px ?
Severe mucositis IF quinolone px AND empirical ceftazidime ?
Pneumonia documented radiographically ?
Skin or soft-tissue infection at any site ?
Freifeld AG, et al. CID. 201152(4)e56-e93. Hughe
s WT, et al. CID. 200234(6)730-51.
Px prophylaxis
43
Vancomycin for Empiric Therapy
Drug Dose for FN Clinical Pearls
Vancomycin 15-20 mg/kg Q12 hours Trough goal of 15-20 mcg/mL Dose adjust for renal dysfunction Risk of nephrotoxicity with concomitant nephrotoxic agents Discontinue after 2 days if no evidence for gram () infection
Vancomycin in DRUGDEX System Internet
database.
44
Empiric Antibiotics High Risk Patients
44

• Monotherapy with IV anti-pseudomonal ß-lactam in
  inpatient setting (A-I)
• Avoid routine addition of vancomycin (A-I)
• Treat afebrile neutropenic patients with
  signs/symptoms of infection as high risk (B-III)

Freifeld AG, et al. CID. 201152(4)e56-e93.
45
The Case of FS

• Physical exam
• Ht 64 inches
• Wt 54 kg
• IBW 54.7 kg
• No signs/symptoms of skin/soft tissue infection
• Labs
• CrCl 55 ml/min
• Cultures
• Blood x 2 sets pending
• () MRSA PCR nasal swab from previous admit (6
  weeks ago)

• PMH
• Type II diabetes
• Hypertension
• Depression
• No medication allergies
• Home medications
• Metformin 500 mg PO BID
• Lisinopril 20 mg PO daily
• Sertraline 50 mg PO daily

46
The Case of FS

• What would be the most appropriate empiric
  antibiotic regimen for FS?
• Piperacillin/tazobactam 3.375 gm IV Q8 hours
• Meropenem 500 mg IV Q6 hours vancomycin 1250 mg
  daily
• Cefepime 2 gm Q12 hours vancomycin 1250 mg
  daily
• B or C

47
Modifications to Empirical Antibiotics
Freifeld AG, et al. CID. 201152(4)e56-e93.
High risk patients Unexplained fever Day 2-4 after empirical abx
Persistent fever Clinically stable
Persistent fever Clinically unstable
Defervesced Cultures negative
Continue abx until ANC gt500 cells/mm3
No changes in empirical abx Discontinue vanco if no evidence of gram () infection Assess for infection sites
Broaden coverage Cephalosporin ? carbapenem Add vanco in combination with AG, cipro, or aztreonam
AG aminoglycoside, abx antibiotics, cipro
ciprofloxacin, vanco vancomycin
48
Modifications to Empirical Antibiotics
Freifeld AG, et al. CID. 201152(4)e56-e93.
High risk patients Documented infection
Modify abx according to cx results and/or infection site
Responding
Not Responding
At least 7-14 days of abx as appropriate for infection Consider continuing abx until ANC gt500 cells/mm3
Examine and re-image Cx/bx/drain sites of worsening infection Review abx for adequacy of dosing and spectrum Consider adding empirical antifungal coverage Broaden antimicrobial coverage for hemodynamic instability
abx antibiotics, bx biopsy, cx culture
49
Summary

• High risk patients
• Monotherapy preferred to combination therapy
• Antipseudomonal ß-lactams considered equivalent
• Routine empiric vancomycin not recommended
• Modification of empirical therapy based on
  clinical course
• Change in antibiotics not warranted by persistent
  fever alone
• Continue therapy until ANC gt500 cells/mm3 and
  signs and symptoms of infection resolving

50
Outline
50

• Overview of FN
• Patient assessment and risk stratification
• Empiric antibiotics
• Role of antifungals

51
Role of Antifungals High Risk Patients

• Indications for empirical antifungal therapy
  (A-I)
• Persistent or recurrent fever after 4-7 days of
  antibiotics
• Expected duration of neutropenia gt 7 days
• Recommended agents (B-III)
• Consider IV agent from a different class if
  patient receiving prophylaxis

Freifeld AG, et al. CID. 201152(4)e56-e93.
52
Role of Antifungals High Risk Patients

• Preemptive antifungal therapy
• Antifungal therapy initiated only in patients
  with findings suggestive of invasive fungal
  infection
• Indications (B-II)
• Persistently febrile after 4-7 days of
  antibiotics
• Clinically stable
• No clinical or radiologic signs of fungal
  infection
• Negative serologic assay results for evidence of
  invasive fungal infection
• No recovery of fungi from any body site

53
Empiric vs. Preemptive Antifungals
Cordonnier C, et al. Clin Infect Dis. 200948(8) 1042-51. Cordonnier C, et al. Clin Infect Dis. 200948(8) 1042-51.
Population High risk patients with hematologic malignancies (n293) Persistent or recurrent fever for at least 48 hours despite antibiotics
Treatment Arms Empirical therapy initiated for recurrent/persistent fever occurring Day 4-14 of empirical antibiotics (n150) Preemptive therapy initiated for fever after Day 4 of empirical antibiotics in patients with sign/symptoms of fungal infection (n143) Antifungal Amphotericin B deoxycholate 1 mg/kg/day Liposomal amphotericin B 3 mg/kg/day
Overall Survival Empirical vs. preemptive 97.3 vs. 95.1 (not significant)
Invasive Fungal Infection Empirical vs. preemptive 2.7 vs. 9.1 (significant)
Use of Antifungal Agents Empirical vs. preemptive 59.8 vs. 1.8 (plt0.001)
significant
54
Invasive fungal infection plt0.0001
Antifungal use plt0.02
55
Empiric vs. Preemptive Antifungals
Cordonnier C, et al. Clin Infect Dis. 200948(8) 1042-51. Cordonnier C, et al. Clin Infect Dis. 200948(8) 1042-51.
Conclusions Preemptive antifungal treatment given to neutropenic patients with persistent or recurrent fever was not inferior to empirical treatment in terms of survival Exception patients receiving induction chemotherapy
56
Summary

• Empiric antifungal therapy
• Consider in high risk patients with persistent or
  recurrent fever after 4 days of antibiotics
• Preemptive antifungal therapy
• Place in therapy not yet established

57
The Case of FS

• Persistently febrile after 4 days of antibiotic
  therapy
• Culture results negative for bacteria and fungi
• Clinically stable
• ANC 100 cells/mm3
• Should FS receive empiric antifungal therapy?
• Yes
• No

58
Conclusions

• Empiric antibiotic therapy
• Guided by risk stratification and resistance
  patterns
• Monotherapy with antipseudomonal ß-lactam
  appropriate for most high risk patients
• Alternative dosing strategies may produce
  adequate clinical outcomes while reducing costs
• Modifications and duration of therapy guided by
  clinical status, cultures, and ANC
• Antifungal therapy
• Typically considered in patients with persistent
  fever gt4 days and expected duration of
  neutropenia gt7 days
• Preemptive therapy may produce comparable
  clinical outcomes to empiric therapy while
  reducing costs

59
Burning Up Updates in the Management of Febrile
Neutropenia

• Stephanie Shuey, Pharm.D.
• PGY2 Oncology Specialty Resident
• stephanie.shuey_at_aurora.org

60
References
60

• Bow EJ, Noskin GA, Laverdiere M, et al. A
  randomized, open-label, multicenter comparative
  study of the efficacy and safety of
  piperacillin-tazobactam and cefepime for the
  empirical treatment of febrile neutropenic
  episodes in patients with hematologic
  malignancies. Clin Infect Dis. 200643(4)447-59.
• Cefepime (Maxipeme) package insert. Princeton,
  NJ Bristol-Myers Squibb Company 3/2009.
• Daptomycin (Cubicin) package insert.
  Lexington, MA Cubist Pharmaceuticals, Inc.
  11/2010.
• Freifeld AG, Bow EJ, Sepkowitz KA, et al.
  Clinical practice guidelines for the use of
  antimicrobial agents in neutropenic patients with
  cancer 2010 update by the Infectious Diseases
  Society of America. CID. 201152(4)e56-e93.
• Hughes WT, Armstrong D, Bodey GP, et al. 2002
  guidelines for the use of antimicrobial agents in
  neutropenic patients with cancer. CID.
  200234(6)730-51.
• Linezolid (Zyvox) package insert. New York
  City, NY Pharmacia and Upjohn Company 2/2012.
• Imipenem-cilastatin (Primaxin) package insert.
  Whitehouse Station, NJ Merck Co., Inc.
  2/2010.
• Klastersky J, Paesmans M, Rubenstein EB, et al.
  The Multinational Association for Supportive Care
  in Cancer risk index a multinational scoring
  system for identifying low-risk febrile
  neutropenic cancer patients. J Clin Oncol.
  200018(16)3038-3051.
• Kotapati S, Nicolau DP, Nightingale CH, et al.
  Clinical and economic benefits of a meropenem
  dosage strategy based on pharmacodynamic
  concepts. Am J Health Syst Pharm.
  2004611264-70.
• Kuti JL, Maglio D, Nightingale CH, et al.
  Economic benefit of a meropenem dosage strategy
  based on pharmacodynamic concepts. Am J Health
  Syst Pharm. 200360565-68.
• Mebis J, et al. Antibiotic management of febrile
  neutropenia current developments and future
  directions. Journal of Chemotherapy.
  201022(1)5-12.
• Meropenem (Merrem) package insert. Wilmington,
  DE AstraZeneca 12/2010.
• Miller AD, Ball AM, Bookstaver PB, et al.
  Epileptogenic potential of carbapenem agents
  mechanism of action, seizure rates, and clinical
  considerations. Pharmacotherapy.
  201131(4)408-23.

61
References

• NCCN Clinical Practice Guidelines in Oncology
  myeloid growth factors (Version 1.2012). National
  Comprehensive Care Network, Inc 2012.
  www.nccn.org. Accessed February 26, 2012.
• NCCN Clinical Practice Guidelines in Oncology
  prevention and treatment of cancer-related
  infections (Version 2.2011). National
  Comprehensive Care Network, Inc 2011.
  www.nccn.org. Accessed February 26, 2012.
• Paul M, Schlesinger A, Grozinsky-Glasber S, et
  al. Beta-lactam versus beta-lactam-aminoglycoside
  combination therapy in cancer patients with
  neutropenia. Cochrane Database of Syst Rev. 2010,
  Issue 3CD003038.
• Patel GW, Duquaine SM, McKinnon PS. Clinical
  outcomes and cost minimization with an
  alternative dosing regimen for meropenem in a
  community hospital. Pharmacotherapy.
  200727(12)1637-43.
• Piperacillin-tazobactam (Zosyn) package
  insert. Philadelphia, PA Wyeth Pharmaceuticals
  9/2009.
• Raad II, Escalante C, Hachem RY, et al. Treatment
  of febrile neutropenic patients with cancer who
  require hospitalization. Cancer.
  200398(5)1039-47.
• Vancomycin added to empirical combination
  antibiotic therapy for fever in granulocytopenic
  cancer patients. J Infect Dis. 1991163(5)951-58.
  
• Vancomycin in DRUGDEX System Internet
  database. Greenwood Village, Colo Thomson
  Reuters (Healthcare) Inc. Updated periodically.
• Zhanel GG, Wiebe R, Dilay L, et al. Comparative
  review of the carbapenems. Drugs.
  200767(7)1027-52