Febrile Neutropenia Updates

Panduan Tatalaksana Febril Panduan Tatalaksana Febril NeutropeniaNeutropenia

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Pendahuluan

● Febril Netropeni merupakan komplikasi pada penderita kanker yang menjalani kemoterapi

● Febril Neutropeni :

● NCI ( National Cancer Institute, USA) 1969, 50 % meninggal akibat bakterimia Pseudomonas auroginosa ok:

● Terapi terlambat● Fokal infeksi yang tidak terdeteksi● Antibiotik yang tidak tepat

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DefinisiDefinisi

1. DemamSuhu aksila ≥ 38o C dua kali pengukuran dalam 1 jam atau

lebih ( Tumor Solid) dan ≥ 37,5o C ( Hematologi) atau ≥38,3oC 1 kali pengukuran dan tidak terdapat infeksi

2. NetropeniJumlah netrofil (Batang dan segmen) < 500 sel/mm3 atau

< 1000 sel/mm3 dengan kecendrungan turun 500 sel/mm3 dalam 2 hari berikutnya

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PerhitunganPerhitungan ANC ANC

● ANC = Leukosit ((neutrofil segmen + batang)/100)

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DDerajat Faktor resikoerajat Faktor resiko

1. Resiko Rendah

a. Solid tumor

b. Kemoterapi konvensional

c. Tak ada komorbiditas

d. Netropeni berlansung ≤ 3 hari

e. Tidak ada klinis infeksi berat

f. Tidak ada tanda sepsis atau syok

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2. Resiko Sedang

a.Solid tumor atau keganasan hematologi

b.Kemoterapi intensif

c.Komorbiditas (+/-)

d.Klinis infeksi (+/-)

e.Tanda sepsis atau syok (+/-)

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3.Resiko tinggia.Keganasan hematologib.Kemoterapi agresifc.Komorbiditas (+/-)d.Netropeni berlangsung>7 harie.Klinis infeksi (+/-)f.Tanda sepsis atau syok (+/-)

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Penatalaksanaan DiagnostikPenatalaksanaan Diagnostik

1. Pemeriksaan fisik● Dilakukan setiap hari● Keutuhan kulit dan mukosa● Kateter dan bekas suntikan● Sal. Nafas● Sal. Kemih● Abdomen dan reg. Perianal● Vital sign

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Penatalaksanaan DiagnostikPenatalaksanaan Diagnostik

2. Pemeriksaan Laboratorium

a.Khusus : Kultur

b.Umum : Hematologi dan kimia darah

c.Tata cara pengambilan sampel kultur

3. Pemeriksaan Radiologis●Foto toraks AP/Lat●CT scan, MRI, USG atau lainnya ( atas indikasi)

4. Spektrum bakteri patogen●Gram positif●Gram negatif●Anaerob●Jamur

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Penatalaksanaan pengobatan Penatalaksanaan pengobatan AntimikrobaAntimikroba

a. Prinsip Pengobatan1. Prompt2. Empirik3. Bakterisidal4. Broadspektrum

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2. Memulai dan Menghentikan Pengobatan• Segera memulai antimikroba karena demam dan

netropeni• Segera memulai pengobatan bila terdapat tanda

infeksi atu klinis sepsis / sepsis syok• Pengobatan dihentikan apabila tidak terdapat demam

dan stabil dalam 72-96 jam (resiko rendah) atau 7 hari tanpa demam setelah granulosit > 1000 sel/mm3 tanpa demam 2 hari resiko tinggi)

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C. Pengobatan dengan antibiotik berdasarkan

derajat faktor resiko

1. RESIKO RENDAH1. RESIKO RENDAH

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2. RESIKO SEDANG2. RESIKO SEDANG

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2. Resiko sedang2. Resiko sedang

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3. RESIKO TINGGI3. RESIKO TINGGI

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3. Resiko tinggi3. Resiko tinggi

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d. Modifikasi pengobatanDapat dilakukan dalam hal :1.Perburukan tanda vital2.Tanpa perbaikan klinis3.Resistensi4.Demam tidak turun5.Alergi antibitoka6.Ada riwayat infeksi jamur sebelumnya

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1. AntiJamur● Fluconazole● AmphoB● Itraconazole● Dll2. Antivirus● Tidak dipergunakan anti empirik● Di indikasikan bila ada bukti klinis dan lab.● Cth : Valacyclovir dan Famcyclovir

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Penatalaksanaan pengobatan LainPenatalaksanaan pengobatan Lain( Growth Factor, Imunodulator, Immunoglobulin)( Growth Factor, Imunodulator, Immunoglobulin)

Growth factor

1. Profilaksis primer :●CSFs diberikan sebelum kemoterapi siklus I●Diberikan hanya pada regimen kemoterapi yg terbukti memberikan grade 3-4 netropenia sebesar >40 %2. Profilaksis sekunder●Diberikan pada penderita yg sebelumnya mengalami neutropenia3. Afebril netropeni●Penderita demam tanpa netropeni●Diberikan bila terjadi netropeni sebelum kemoterapi selanjutnya dimulai

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4. Febril Netropeni

●Kriteria febril netropeni

●Diberikan pada FN dengan hipotensi, MOF, infeksi bakteri/jamur, ANC<100/uL atau usia >65 tahun

5. Leukemia akut dan MDS

●Dapat diberikan segera sesudah kemo induksi terutama usia>55 tahun ( AML/ALL)

●Netropenia berat / riwayat infeksi berulang(MDS)

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Immunomodulator

Tidak di rekomendasikan secara rutin karena belum ada bukti nyata

Immunoglobulin

Terbatas pada pasien yg terbukti terdapat defisiensi immunoglobulin

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TERIMAKASIHTERIMAKASIH

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Recommended Empiric Antibiotics in Recommended Empiric Antibiotics in High Risk PatientsHigh Risk Patients

2002

2011

Freifeld AG, et al. CID. 2011;52(4):e56-e93.Hughes WT, et al. CID. 2002;34(6):730-51.

Monotherapy Monotherapy

●Antipseudomonal β-lactam ─Ceftazidime or cefepime─Meropenem or imipenem-cilastatin─Piperacillin-tazobactam

Two-Drug CombinationTwo-Drug Combination●Aminoglycoside with:

─ Ticarcillin-clavulanic acid or piperacillin-tazobactam─ Ceftazidime or cefepime─ Meropenem or imipenem-cilastatin

OR

Monotherapy Monotherapy ●Antipseudomonal β-lactam

─Cefepime─Meropenem or imipenem-cilastatin─Piperacillin-tazobactam

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Comparison of Monotherapies

DrugDrug Dose for FNDose for FN Clinical PearlsClinical Pearls

Cefepime 2 gm IV Q8H •Dose adjust for CrCl <60 ml/min•Risk of neurotoxicity

Piperacillin-tazobactam

3.375 gm IV Q8H •Dose adjust for CrCl <20 ml/min•Extended infusion dosing•Risk of drug-induced neutropenia

Meropenem 500 mg IV Q6H – 1000 mg IV Q8H

•Dose adjust for CrCl <50 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. 2011;31(4):408-23.Piperacillin-tazobactam (Zosyn®) [package insert]. 9/2009.

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Modifications to Empirical Antibiotics

● Persistent fever● Clinically stable

● Persistent fever●Clinically unstable

● Defervesced●Cultures negative

High risk patientsHigh risk patientsUnexplained feverUnexplained fever

Day 2-4 after empirical abxDay 2-4 after empirical abx

Continue abx until ANC >500 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

Freifeld AG, et al. CID. 2011;52(4):e56-e93.

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Modifications to Empirical Antibiotics

High risk patientsHigh risk patientsDocumented infectionDocumented infection

Modify abx according to cx results and/or infection site

●At least 7-14 days of abx as appropriate for infection●Consider continuing abx until ANC >500 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 instabilityabx = antibiotics, bx = biopsy, cx = culture

Freifeld AG, et al. CID. 2011;52(4):e56-e93.

Responding Not Responding

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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 >500 cells/mm3 and signs and symptoms of infection resolving

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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

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Conclusions

● Empiric antibiotic therapy─ Guided by risk stratification and resistance patterns─ Monotherapy with antipseudomonal β-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 >4 days and expected duration of neutropenia >7 days

─ Preemptive therapy may produce comparable clinical outcomes to empiric therapy while reducing costs

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ReferencesReferences

● 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. 2006;43(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. 2011;52(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. 2002;34(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. 2000;18(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. 2004:61:1264-70.

● Kuti JL, Maglio D, Nightingale CH, et al. Economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts. Am J Health Syst Pharm. 2003;60:565-68.

● Mebis J, et al. Antibiotic management of febrile neutropenia: current developments and future directions. Journal of Chemotherapy. 2010;22(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. 2011;31(4):408-23.

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ReferencesReferences

● 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 3:CD003038.

● Patel GW, Duquaine SM, McKinnon PS. Clinical outcomes and cost minimization with an alternative dosing regimen for meropenem in a community hospital. Pharmacotherapy. 2007;27(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. 2003;98(5):1039-47.

● Vancomycin added to empirical combination antibiotic therapy for fever in granulocytopenic cancer patients. J Infect Dis. 1991;163(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. 2007;67(7):1027-52

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Febrile Neutropenia Updates