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The Role of Cefditoren in Lower
Respiratory Tract Infection
Soedarsono
Department of Pulmonology and Respiratory Medicine
Faculty of Medicine, Universitas Airlangga
Dr. Soetomo General Academic Hospital
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Pendahuluan • Lower respiratory tract infections (LRTIs) merupakan
diagnosis terbanyak pada pasien rawat jalan maupun rawat inap
di dunia.1,2
• 80% penggunaan antibiotik untuk pengobatan infeksi saluran pernafasan.3
• Terapi antibiotik secara empirik seringkali dipilih berdasarkan
pada luas spektrum antibakterinya.2
– kurang memperhatikan sifat farmakologi atau profil resistensi patogen di
suatu area.
• Terapi antibiotik yang tidak sesuai menyebabkan kegagalan
terapi juga timbulnya resistensi
– biaya pengobatan meningkat
1. Eur Rev Med Pharmacol Sci. 2014; 18: 321-32
2. J Chemother. 2017; 29(5): 274-86
3. Infect Drug Resist. 2010; 3: 35–43
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LRTI di RSUD Dr. Soetomo
• Patogen terbanyak dari 569 kasus community-acquired
pneumonia (CAP) yang menjalani rawat inap di RSUD
Dr. Soetomo:1
– Acinetobacter baumannii 19,4%
– Klebsiella pneumonia 14,8%
– Pseudomonas aeruginosa 7,7%
• vs isolat bakteri terbanyak di Eropa :2,3 – Streptococcus pneumoniae
– Streptococcus pyogenes
– Haemophilus influenza
1. Respirology. 2018; 23(Suppl. 2): 66-67Int
2. J General Med. 2012; 5: 455-64
3. Drug Des Dev Ther. 2011; 5: 85-94
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Antibiotik dengan sensitifitas tertinggi
di RSUD Dr. Soetomo
87.80%
81.90%
76.30%
70%
72%
74%
76%
78%
80%
82%
84%
86%
88%
90%
Amikacin Cefoperazone-Sulbactam Meropenem
Respirology. 2018; 23(Suppl. 2): 66-67
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Antibiotik dengan resistensi tertinggi
di RSUD Dr. Soetomo
Respirology. 2018; 23(Suppl. 2): 66-67
97.40%
86.60% 80.80%
0%
20%
40%
60%
80%
100%
120%
Ampicillin Cephazolin Amoxicillin-ClavulanicAcid
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Sejarah Pengembangan Cephalosporin Oral
Cefditoren
generasi III terkini
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B.fragilis G7004 50 >100 >100 >100
B.fragilis TMS26 0.78 12.5 100 >100
B.vulgatus ATCC29327 0.39 3.13 3.13 12.5
B.vulgatus TMS129 0.39 3.13 3.13 12.5
B.distasonis TMS58 0.78 12.5 100 >100
B.distasonis TMS128 0.78 25 100 >100
B.thetaiotaomicron WAL3304 0.78 12.5 100 >100
B.thetaiotaomicron TMS126 0.78 12.5 100 >100
F.nucleatum TMS110 ≦0.006 0.05 0.20 0.20
V.paruura GAI5602 0.012 0.05 0.20 1.56
P.asaccharolyticus GM1003 0.78 100 100 >100
P.asaccharolyticus TMS83 0.10 1.56 12.5 0.39
Organism Cefditoren cefpodo cefixime cefaclor xime
Antibacterial spectrum
Chemotherapy 40(s-2):16,1992
MIC(μg/ml) 106 cells/ml
Anaero
bic
bacte
ria
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Cefditoren • Merupakan sefalosporin oral generasi ke-3.1
• Memiliki aktivitas spektrum luas terhadap bakteri Gram-positif dan Gram-negatif ≈ patogen utama pada saluran pernafasan:2
– Streptococcus pneumoniae
– Haemophilus influenzae
– Moraxella catarrhalis
– Streptococcus pyogenes
– Klebsiella pneumoniae
– methicillin-susceptible strains of Staphylococcus aureus (MSSA)
1. Major drug introductions. Comprehensive medicinal chemistry II. Elsevier. 2007
2. Eur Rev Med Pharmacol Sci. 2014; 18: 321-32
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Efek bakteriologis berdasarkan kategori bakteri patogen
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Struktur Molekul Cefditoren Pivoxil
Antimicrobial Agents & Chemotherapy, 1988; 32 (9): 1321-26
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Difusi Cefditoren pada Jaringan Pernafasan
ELF: epithelial lining fluid Eur Rev Med Pharmacol Sci. 2014; 18: 321-32
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Efek Anti Bakterial pada Bakteri Patogen Komunitas (in-vitro)
PSSP/ PISP / PRSP = Penicillin susceptible/ intermediate resistant / Penicillin resistant S. pneumoniae b+ / b- = b-Lactamase positive / negative
Data source:Italy: Tempera G. et al. J Chemother, 2010 22: 153–159
n=2,510
・Sensitifitas yang superior (v.s Penicillins/Cephalosporins) ・Aktifitas bakterial yang stabil (including drug-resistant)
MIC90
n=2,510 (Total)
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Streptococcus pyogenes¶
(50 strains)
PSSP†
PCG MIC:≤0.06 μg/mL
(106 strains)
Cefditoren
Cefcapene
Cefdinir
Clarithromycin
Azithromycin
BLNAI ‡ Beta-lactamase (-)
ABPC MIC:2 μg/mL
(98 strains)
Moraxella catarrhalis¶ (50 strains)
Source:† J Infect Chemother 2013;19:495-503.
‡ J Infect Chemother 2013;19:510-516.
¶ Jpn J Antibiotics 2009;62:90-102.
MIC90 of
Clinical
Isolates
PISP†
PCG MIC:0.12~1 μg/mL
(229 strains)
PRSP†
PCG MIC:≥2 μg/mL
(124 strains)
BLNAS ‡
ABPC MIC: ≤1 μg/mL
(161 strains)
BLNAR ‡ Beta-lactamase (-)
ABPC MIC:≥4 μg/mL
(183 strains)
≤0.06
0.25
1
4
16
≥64 μg/mL BLPAR ‡
Beta-lactamase (+)
CVA/AMPC MIC:≤4 μg/mL
(19 strains)
BLPACR ‡
Beta-lactamase (+)
CVA/AMPC MIC:≥8 μg/mL
(23 strains)
Efek Anti Bakterial pada Bakteri Patogen Resisten
Komunitas (in-vitro)
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Farmakokinetik/Farmakodinamik
Cefditoren
• Cefditoren adalah bentuk aktif cefditoren pivoksil
• Pada pasien puasa, bioavailabilitas oral sefditoren pivoksil berkisar antara 15% hingga 20% – ketika obat diberikan bersamaan dengan makanan tinggi
lemak, konsentrasi maksimum rata-rata (Cmax) dan area under the concentration-time curve (AUC) meningkat menjadi masing-masing 50% dan 70 %.
• Nilai Cmax dan AUC setelah pemberian Cefditoren pivoksil 400 mg dua kali sehari selama 7 hari sama dengan yang setelah dosis tunggal – menunjukkan bahwa akumulasi obat tidak terjadi
Eur Rev Med Pharmacol Sci. 2014; 18: 321-32
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Serum Concentration During Fasting State
and After Meals
Shimada, K. : CHEMOTHERAPY 40(S-2):105, 1992
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Farmakokinetik/Farmakodinamik Cefditoren -2
• Beberapa reseptor antagonis H2 dan aluminium/ magnesium pada suspensi antasida, atau obat lain yang meningkatkan pH lambung dapat mengurangi Cmax dan AUC sefditoren. – pemberian obat-obatan ini secara bersamaan tidak
direkomendasikan
• Usia dan jenis kelamin dapat mempengaruhi farmakokinetik cefditoren, namun tidak relevan secara klinis – sehingga penyesuaian dosis berdasarkan usia dan jenis
kelamin tidak diperlukan
Eur Rev Med Pharmacol Sci. 2014; 18: 321-32
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Perbedaan aktifitas spektrum pada sefalosporin oral
terhadap Streptococcus pneumoniae
Klasifikasi Aktifitas Antibiotik MIC90 (mg/L)
PS PI PR
Generasi 1 Aktif terhadap bakteri
Gram-positif
Cephalexin Tidak tersedia 128 (a) Tidak tersedia
Cefadroxil >64 (a)
Generasi 2 - Kurang aktif
dibanding generasi
1 terhadap bakteri
Gram-positif
- Lebih aktif terhadap
bakteri Gram-
negatif, namun
kurang aktif
terhadap
Haemophilus
influenzae dan
Moraxella catarrhalis
Cefaclor 1 64 >64
Cefprozil 0,25 8 >16
Cefuroxime 0,12 4 8
PS: penicillin-sensitive ; PI: penicillin-intermediate ; PR: penicillin-resistant. (a): tidak ditentukan kepekaannya terhadap penicillin
J Chemother. 2017; 29(5): 274-86
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Perbedaan aktifitas spektrum pada sefalosporin oral
terhadap Streptococcus pneumoniae
Klasifikasi Aktifitas Antibiotik MIC90 (mg/L)
PS PI PR
Generasi 3 - Kurang aktif terhadap
bakteri Gram-positif,
termasuk
Streptococcus
pneumoniae
- Aktif terhadap bakteri
Gram-negatif
- Aktif terhadap bakteri
Gram-positif dan
Gram-negatif
spektrum luas
Cefpodoxime 0,06 – 0,12 2 4
Cefixime 0,12 - 1 16 >16
Ceftibuten 0,25 - 4 8- 16 >8 - <16
Cefditoren 0,015 – 0,03 0,25 – 0,50 0,5 - 1
PS: penicillin-sensitive ; PI: penicillin-intermediate ; PR: penicillin-resistant.
J Chemother. 2017; 29(5): 274-86
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Efikasi Klinis Cefditoren pada
Pengobatan LRTI
• Penelitian di Jepang melaporkan effikasi tertinggi, yang merupakan rasio kesembuhan pada test of cure (TOC), yaitu pada 5-10 hari setelah pengobatan berhenti.1
• Cefditoren pivoksil merupakan alternatif yang dapat digunakan untuk terapi antibiotik pada pasien PPOK eksaserbasi berulang.1
• Penggunaan Cefditoren berhubungan dengan reduksi interleukin-6 (IL-6) dan Krebs von den Lundgen-6 (KL-6) secara signifikan2
– IL-6 dan KL-6 merupakan mediator utama pada inflamasi paru dan kerusakan epitel.
1. J Infect Chemother. 2019; https://doi.org/10.1016/j.jiac.2019.03.018
2. Ther Clin Risk Manag. 2013; 9: 55-64
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Efikasi Klinis Cefditoren Pivoksil
Evaluasi Jumlah pasien (%)
[95% confidence interval]
Efficacy
rate (%)
Respon klinis pada TOC
(primary endpoint)
Cured 15 (62,5%) [40,6-81,2]a, [43,1-81,9]b 65,2%
Uncured 8 (33,3%)
Indeterminate 1 (4,2%)
Missing 5
Respon pengobatan
pada EOT (secondary
endpoint)
Effective 18 (72%) [50,6-87,9]a, [54,4-89,6]b 75%
Ineffective 6 (24%)
Indeterminate 1 (4%)
Missing 4
Respon pengobatan
pada hari ke-4
(secondary endpoint)
Effective 19 (65,5%) [45,8-82,1]a, [48,2-82,9]b 67,9%
Ineffective 9 (31%)
Indeterminate 1 (3,4%)
Missing 0
J Infect Chemother. 2019; https://doi.org/10.1016/j.jiac.2019.03.018
TOC: test of cure, EOT: end of treatment
Efficacy rate (%) = (“cured” atau kasus “effective”) / (semua kasus - kasus “indeterminate”) x 100 a Metode Clopper-Pearson b Metode Normal approximation
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• Studi di korea mengevaluasi aktifitas antimikroba secara in vitro pada cefditoren terhadap 5 patogen pernafasan utama dari 11 Negara Asia.
• Cefditoren menunjukkan aktifitas yang superior terhadap patogen yang dievaluasi kecuali: – Methicillin-resistant Staphylococcus aureus (MRSA) dan
– extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae.
• Hasil ini menunjukkan bahwa Cefditoren dapat menjadi pilihan terapi yang efektif untuk LRTI di Negara Asia
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Efek Samping Cefditoren
• Dalam uji klinis, 4.834 pasien diobati dengan
tablet cefditoren pivoksil dosis yang
direkomendasikan (200 mg atau 400 mg BID)
– Sebagian besar efek samping adalah ringan dan
sembuh dengan sendirinya
– Tidak ada kematian atau cacat permanen yang
dikaitkan dengan cefditoren.
Spectracef (cefditoren pivoxil): formulary submission. Purdue Pharma. 2005
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Efek Samping Cefditoren -2
Efek samping karena pengobatan pada pasien usia ≥12 tahun
Cefditoren
200 mg BID
(N=2.675)
400 mg BID
(N=2.159)
Komparator*
Insidens ≥1% Diare 11% 15% 8%
Mual 4% 6% 5%
Sakit kepala 3% 2% 2%
Nyeri perut 2% 2% 1%
Vaginal moniliasis 3% 6% 6%
Gangguan
pencernaan
1% 2% 2%
Muntah 1% 1% 2%
*termasuk amoxicillin/clavulanate, cefadroxil mohohydrate, cefuroxime axetil, cefpodoxime proxetil,
clarithromycin, dan penicillin
Spectracef (cefditoren pivoxil): formulary submission. Purdue Pharma. 2005
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Dosis Cefditoren
Tipe infeksi Dosis Durasi
(hari)
Community-acquired pneumonia 400 mg BID 14
Eksaserbasi akut bronkitis kronis 400 mg BID 10
Faringitis/ tonsilitis 200 mg BID
Uncomplicated Skin and Skin
Structure Infections
*diminum setelah makan
Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Fifth
Edition; Approved Standard, NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, 2000
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Dosis Cefditoren-2
• Pada pasien dengan gangguan fungsi ginjal derajat sedang:
<200 mg BID.1
• Pasien dengan gangguan fungsi ginjal derajat berat: 200 mg
QD.1
• Tidak ada penyesuaian dosis pada pasien dengan gangguan
fungsi hati derajat ringan atau sedang.1
• Pada pasien dengan gangguan fungsi hati kategori berat, belum
ada penelitian tentang penyesuaian dosis sefditoren.2
• Tidak ada rekomendasi dosis untuk pasien yang sedang
menjalani hemodialisis.3
1. Siriraj Med J. 2005; 57(10): 454-6
2. Eur Rev Med Pharmacol Sci. 2014; 18: 321-32
3. Cephalosporins and related antibiotics review. Provider Synergies. USA. 2009
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Cefditoren
in LRTI
Strong antibacterial
activity
Simple adminitration
High Safety
Broad Spectrum
Reduction of lung
inflammation and epithelial
damage
Ringkasan
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