OUTLINE

INTRODUCTION

Cephalosporin
Agents
generation
cefazolin, cephalexin, cefadroxil,
1st generation
cephalothin, cephapirin,cephradine
cefuroxime, cefoxitin, cefotetan,
2nd generation cefprozil, loracarbef, cefmetazole,
cefonicid, cefamandole, cefaclor
ceftriaxone, cefotaxime,
ceftazidime, cefdinir, cefpodoxime,
3rd generation
cefixime, ceftibuten, cepoperazone,
ceftizoxime, cefditoren
4th generation cefepime
5th generation ceftaroline, ceftofibrole
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INTRODUCTION

2010: Ceftaroline

2011: Ceftaroline-R
Staphylococcus
 CEFTAROLINE
Informasi mengenai perijinan
FDA EMA TGA
Approval year 2010 2012 2013
Brand name Teflaro® Zinforo®
600 mg atau 400 mg serbuk 600 mg serbuk steril untuk larutan
Bentuk sediaan
steril dalam 20 ml vial (IV) injeksi (IV)
acute bacterial skin and skin structure infections (ABSSSI) dan
Indikasi
community-acquired bacterial pneumonia (CABP)‡
Informasi dari European Medicine Agency (EMA)
600 mg setiap 12 jam melalui infus selama 1 jam baik untuk ABSSSI (5-
Dosis
14 hari) dan CABP (5-7 hari) untuk pasien dewasa ≥ 18 tahun
FDA: food and drug administration (USA) | EMA: european medicine agency | TGA: therapeutics goods
administration (AUS)
‡FDA, TGA: untuk dewasa ≥ 18 tahun
EMA: neonate, infants, children, adolescent, adult
 CEFTAROLINE
Struktur dan aktivitas

Kelas terapi dan mekanisme aksi

• Merupakan antibiotik golongan beta-laktam (sefalosporin generasi 5)
• Ceftaroline bekerja dengan menghambat pembentukan dinding sel (peptidoglikan) melalui PBP 1a, 1b,
2a, 2b, 2x, 3 (enzim transpeptidase) yang menghubungkan D-ala (pada NAG) dan lisin (pada NAM), yang
disebut cross-linking.
• Memiliki aktivitas terhadap MRSA, namun tidak pada Pseudomonas aeruginosa → disebut anti-MRSA
cephalosporins
 CEFTAROLINE

Farmakokinetik Ceftaroline Fosamil

FK Keterangan
Cmax:
• 21,3 mcg/ml saat diberikan 600 mg secara IV infus setiap 12 jam selama 1 jam pada
A subyek sehat dalam 14 hari → tmax: 0,9 jam
• 32,5 mcg/ml saat diberikan 600 mg secara IV infus (50 ml) setiap 8 jam selama 5
menit dan 17,4 mcg/ml diberikan dalam 60 menit selama 5 hari
Vdss: 20,3 L (pada pasien dewasa sehat)
D Binding protein: 20%, ikatan O-P bisa menurun sedikit pada konsentrasi >50 mcg/ml
Ceftaroline fosamil merupakan pro-drug, namun bukan substrat CYP P450
M Ceftaroline fosamil diubah menjadi ceftaroline (aktif) oleh fosfatase di plasma. Cincin beta
laktam dihidrolisis menjadi ceftaroline M-1 (inaktif).
Ceftaroline dan metabolitnya diekskresi melalui ginjal (filtrasi glomerulus) dalam bentuk
E urin (64% as unchanged, 2% ceftaroline M-1) dan 6% diekskresi melalui feses
t1/2: 2,7 jam
 EVIDENCE - PNEUMONIA

MITT
• Seluruh pasien yang memenuhi protokol penelitian dan
terdiagnosis penyakit (CAP/SSTI) dengan/tanpa gejala klinis
yang memperoleh terapi antibiotik

cMITT
• Seluruh pasien pada MITT yang memiliki tanda dan gejala
klinis penyakit (CAP/SSTI) yang memperoleh terapi
antibiotik dengan/tanpa confounding factor dan test of
cure (TOC)

CE
• Pasien dalam cMITT tanpa confounding factor, dengan/
tanpa test mikrobiologi
Modified intention to treat (MITT)
Clinical modified intention to treat (cMITT) ME
Clinically evaluable (CE) • Pasien dalam CE dengan test mikrobiologi
Microbiologically evaluable (ME)
EVIDENCE - PNEUMONIA (1)
 EVIDENCE - PNEUMONIA (1)

Primary outcome:
• Overall clinical cure – tanda dan gejala klinis pneumonia atau perbaikan kondisi pada saat
berhenti menggunakan antibiotik. Dinilai pada saat end of test (EOT) dan test of cure
(TOC)
Secondary outcome:
• Risiko kejadian adverse effect (ringan, sedang, dan berat), discontinuation karena AE,
relapse rate, mortalitas
 EVIDENCE - PNEUMONIA (1)

OUTCOME 1:
overall clinical cure
rates
based on patient population
 EVIDENCE - PNEUMONIA (1)

OUTCOME 1:
overall clinical cure
rates
based on patient group
 EVIDENCE - PNEUMONIA (1)

OUTCOME 1:
overall clinical cure
rates
based on patient group
 EVIDENCE - PNEUMONIA (1)

OUTCOME 1:
overall clinical cure
rates
based on patogens
 EVIDENCE - PNEUMONIA (1)

OUTCOME 1:
overall clinical cure
rates
based on patogens
 EVIDENCE - PNEUMONIA (1)

OUTCOME 1:
overall clinical cure
rates
based on patogens

OUTCOME 2:
Risk of adverse effect

TEAE: treatment-emergent adverse events

 EVIDENCE - PNEUMONIA (1)

OUTCOME 2:
Risk of adverse effect
 EVIDENCE - PNEUMONIA (1)

OUTCOME 2:
Risk of adverse effect

DC: discontinue | SAE: serious adverse events

 EVIDENCE – PNEUMONIA (2)

14 studies

CEFTAROLINE VS CEFTRIAXONE / VANCO/LINZ / OTHERS

CAP, HAP, VAP, HCAP / adult, elderly vs younger, MRSA (van/linz)

 EVIDENCE – PNEUMONIA (2)

14 studies
CEFTAROLINE VS CEFTRIAXONE / VANCO/LINZ / OTHERS

CAP, HAP, VAP, HCAP / adult, elderly vs younger, MRSA (van/linz)

Outcome:
• Efficacy/effectiveness dari Ceftaroline fosamil pada pasien pneumonia (CAP, HAP, VAP,
HCAP) yang terukur pada salah satu outcome berikut:
❑ Respon pada hari ke 4 terapi
❑ Tingkat kesembuhan pada end of therapy (EOT)
❑ Tingkat kesembuhan pada test of cure (TOC)
❑ Keberhasilan klinis hari ke 14 dari diagnosis pneumonia
• Keamanan – adverse effect
 EVIDENCE – PNEUMONIA (2)
OUTCOME 1: Efficacy/efffectiveness

Overall efficacy/effectiveness in all

case of pneumonia 81.2% (95% CI:
79.9–82.6; I2: 1.2%)
 EVIDENCE – PNEUMONIA (2)
OUTCOME 1: Efficacy/efffectiveness

Tingkat keberhasilan terapi

ceftaroline pada CAP adalah 81.3%
(95% CI: 80.0–82.7; I2: 7.7%)
 EVIDENCE – PNEUMONIA (2)
OUTCOME 1: Efficacy/efffectiveness

Keberhasilan klinis terapi ceftaroline

pada HAP/VAP/HCAP adalah (83.0%,
95% CI: 65.0–95.0; I2: -)
 EVIDENCE – PNEUMONIA (2)
OUTCOME 1: Efficacy/efffectiveness

Relative risk of clinical cure was 1.1

(95% CI: 1.1–1.2; I2: 0.0%)
 EVIDENCE – PNEUMONIA (2)
OUTCOME 1: Efficacy/efffectiveness

Keberhasilan klinis dan mikrobiologi

(Streptococcus pneumoniae) 82.6%
(95% CI: 78.6–86.4; I2: 0.0%)
 EVIDENCE – PNEUMONIA (2)
OUTCOME 1: Efficacy/efffectiveness

Keberhasilan klinis dan mikrobiologi

(MDR Streptococcus pneumoniae)
93.0% (95% CI: 77.0–100.0; I2: 0.0%)
 EVIDENCE – PNEUMONIA (2)
OUTCOME 1: Efficacy/efffectiveness

Keberhasilan klinis dan mikrobiologi

(MSSA) 72.3% (95% CI: 64.5–79.4; I2:
0.0%)
 EVIDENCE – PNEUMONIA (2)
OUTCOME 1: Efficacy/efffectiveness

Keberhasilan klinis dan mikrobiologi

(MRSA) 71.7% (95% CI: 59.7–82.3; I2:
67.9%)
 EVIDENCE – PNEUMONIA (2)
OUTCOME 2: Safety due to adverse effect
 EVIDENCE – PNEUMONIA (2)
OUTCOME 2: Safety due to adverse effect
EVIDENCE - SSTI
EVIDENCE – SSTI (1)
 EVIDENCE – SSTI (1)

Primary outcome:
• Overall clinical cure – tanda dan gejala klinis cSSSI atau perbaikan kondisi pada saat
berhenti menggunakan antibiotik. Dinilai pada saat test of cure (TOC) → 8-15 hari setelah
dosis terakhir

Secondary outcome:
• Tingkat kegagalan terapi dari segi klinis
• Risiko kejadian adverse effect → treatment-emergent AEs (TEAEs), AE serius, dan
penghentian terapi karena AE
 EVIDENCE – SSTI (1)

OUTCOME 1:
overall clinical cure
rates
 EVIDENCE – SSTI (1)

OUTCOME 2:
overall clinical
failure rates
Based on different pathogen
 EVIDENCE – SSTI (1)

OUTCOME 2:
overall clinical
failure rates
Based on different pathogen
 EVIDENCE – SSTI (1)

OUTCOME 3:
Risiko adverse
effects
 EVIDENCE – PNEUMONIA/SSTI (1)

Pengarang Diagnosis pasien Terapi Outcome

FOCUS 1
Community acquired
FOCUS 2 Ceftaroline vs ceftriaxone Primary outcome:
pneumonia (CAP)
ZHONG 2014 • clinical cure
CANVAS 1 Ceftaroline vs Secondary outcome:
CANVAS 2
Complicated skin and vancomycin+aztreonam • mortalitas
skin structure infections • adverse effect
(cSSSI) Ceftaroline vs vancomycin
TALBOT 2007
with/without aztreonam
 EVIDENCE – PNEUMONIA/SSTI (1)

OUTCOME 1: clinical cure

 EVIDENCE – PNEUMONIA/SSTI (1)

OUTCOME 2: mortalitas
 EVIDENCE – PNEUMONIA/SSTI (1)
OUTCOME 3: adverse effect
EVIDENCE – PNEUMONIA/SSTI in PEDIATRIC (1)
EVIDENCE – PNEUMONIA/SSTI in PEDIATRIC (1)
EVIDENCE – PNEUMONIA/SSTI in PEDIATRIC (1)
 EVIDENCE – PNEUMONIA/SSTI in PEDIATRIC (1)
OUTCOME: adverse effect
GUIDELINE CAP – ATS/IDSA 2019
GUIDELINE VAP – IDSA 2016

Ceftaroline?
GUIDELINE HAP – IDSA 2016

Ceftaroline?
GUIDELINE CAP - TAIWAN 2019
GUIDELINE CAP – NICE 2019

Ceftaroline?
GUIDELINE HAP – NICE 2019

Ceftaroline?
GUIDELINE SSTI – IDSA 2014
GUIDELINE ABSSi – IDSA 2019
 GUIDELINE SUMMARY

IDSA NICE 2019

Indication Taiwan 2019
CAP 2019 HAP/VAP 2016 (CAP/HAP)
Recommended as
Ceftaroline for Recommended as
Not recommended alternative therapy for Not recommended
pneumonia standard regimen
moderate to severe CAP

IDSA
Indication
2014 2019
Ceftaroline for ABSSSi Recommended for MRSA SSTI
 RESTRICTION – WHO AWaRe CLASSIFICATION

A Wa Re
access watch reserve
Amikacin Cloxacillin Azithromycin Gatifloxacin
Cefaclor Gemifloxacin
Amoxicillin Dicloxacillin Cefamandole Imipenem/Cil
Amoxicillin/Clav Doxycycline Cefepime Kanamycin
Cefixime Levofloxacin
Ampicillin Flucloxacillin Cefoperazone Lincomycin
Aztreonam Fosfomycin (IV)
Ampicillin/Sulbac Gentamicin Cefotaxime Meropenem Ceftaroline fosamil Linezolid
Benzathine benzylP Metronidazole (IV/O) Cefoxitin Moxifloxacin Ceftazidime/avibac Meropenem/Vabor
Cefpodoxime Neomycin
Cefadroxile Nitrofurantoin Ceftibuten Norfloxacin Ceftobiprole med Minocycline (IV)
Cefalexin Oxacillin Ceftriaxone Oxytetracycline Ceftolozane Polymixin B
Cefalotin SMX/TMP Cefuroxime Piperacillin Colistin Televacin
Ciprofloxacin Piperacillin/tazo
Cefazoline Tetracycline Clarithromycin Rifampicin Daptomycin Tigecycline
Cefradine Thiamphenicol Doripenem Spiramycin
Ertapenem Streptomycin
Chloramphenicol TMP Erythromycin Tobramycin
Clindamycin Fosfomycin (oral) Vancomycin (IV/Oral)
OFF LABEL USE OF CEFTAROLINE
OFF LABEL USE OF CEFTAROLINE
 AVAILABILITY
INDONESIA: belum tersedia
Harga:
Merk Harga Total perkiraan biaya bila Total perkiraan biaya bila digunakan
digunakan untuk CAP untuk SSTi
Pneumonia pengobatan 5-7 hari 2 SSTi pengobatan 5-14 hari 2 x 600
£ 375.00 ~ Rp. 6.778.415 untuk x 600 mg mg
Zinforo® 10 vial @600 mg (BNF; 2018)
(Pfizer Ltd) 1 hari = Rp. 1.354.000,- 1 hari = Rp. 1.354.000,-
Maka 1 vial = ± Rp. 677.000,- Total biaya= ± Rp. 6.770.000 – Rp. Total biaya= ± Rp. 6.770.000 – Rp.
9.478.000 18.956.000
Pneumonia pengobatan 5-7 hari 2 SSTi pengobatan 5-14 hari 2 x 600
$2,015.24 ~ Rp. 28.318.354
x 600 mg mg
untuk 10 vial @400 mg atau 600
Teflaro®
mg (drug.com)
(Allergan plc) 1 hari = Rp. 5.662.000,- 1 hari = Rp. 1.354.000,-
Total biaya= ± Rp. 28.310.000 – Rp. Total biaya= ± Rp. 6.770.000 – Rp.
Maka 1 vial = ± Rp.2.831.000,-
39.634.000 18.956.000

The Scottish Medicines Consortium, has advised (Dec 2012) that ceftaroline fosamil (Zinforo ®) is accepted for RESTRICTED
use within NHS Scotland when meticillin– resistant S. aureus is suspected in complicated skin and soft-tissue infection and
vancomycin cannot be used. (BNF; 2018)
 AVAILABILITY

Harga:
Zinforo (Ceftaroline) Viccilin Sx (Ampicillin/ Broadced (Ceftriaxone) Lancef (Cefotaxime)
Sulbactam)
1 gram/vial = Rp. 164.500 1 gram/vial = Rp. 126.000,-
1,5 gram x 10 vial = Rp. 82.000
1 vial 8.200
Dosis guideline: 1-2 Dosis guideline: 1-2 gram setiap 8
1 hari 2 vial = Rp.
gram/hari jam (3x sehari)
1.354.000,- Sehari 1,5-3 gram setiap 6 jam
4 vial 1,5 gram= Rp. 32.800
Sehari= Rp. 164.500 – Rp. 3x1 gram = Rp. 378.000
8 vial 1,5 gram= 65.600
329.000 3x2 gram = Rp. Rp. 756.000

The Scottish Medicines Consortium, has advised (Dec 2012) that ceftaroline fosamil (Zinforo ®) is accepted for RESTRICTED
use within NHS Scotland when meticillin– resistant S. aureus is suspected in complicated skin and soft-tissue infection and
vancomycin cannot be used. (BNF; 2018)
 CONCLUSION

1. Berdasarkan beberapa penelitian Ceftaroline terbukti efektif dan aman bila digunakan
untuk mengatasi CAP dan SSTi. Beberapa panduan terapi, salah satunya IDSA
merekomendasikan penggunaan Ceftaroline untuk indikasi CAP dan SSTi. Hal tersebut
dapat disebabkan oleh tingkat kejadian infeksi akibat community acquired MRSA (Ca-
MRSA) relatif tinggi.

2. Dengan mempertimbangkan: 1) data prevalensi dan sensitivitas Ca-MRSA, khususnya di

RKZ yang belum diketahui; 2) biaya pengobatan yang relatif tinggi; 3) Ceftaroline termasuk
antibiotik kategori RESERVED berdasarkan kategori AWaRe dari WHO, maka Ceftaroline
dapat digunakan sebagai “LAST RESORT” antibiotik untuk pengobatan CAP dan SSTi
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