Latar belakang: Hipersekresi mukus
Mukus terdiri dari campuran air,lemak, glycoconjugates, danprotein, garam, dan terbagi dualapisan (sol dan gel).
Bagian bersihan saluran napas(mucociliary clearance)
Latar belakang: Hipersekresi mukus
HIPERSEKRESI MUKUS:Inflamasi saluran napas (contoh: asma, PPOK, cystic fibrosis)
produksi mukus meningkat, hiperplasia sel goblet yang berkaitan dengan sintesis dan sekresi mukus dan hipertrofi kelenjar submucosal
HIPERSEKRESI MUKUS
Rogers, 2007
Sumber: https://creativemeddoses.com/topics-list/mucociliary-clearance/
SOLUSI MEMPERBAIKI MUCOCILIARY CLEARANCE: MUKOLITIK
Mukolitik Erdosteine.Erdosteine merupakan pro-drug (beradadalam bentuk inactive dan barumemberikan efek mukolitik setelahdimetabolisme di hati menjadi Metabolit-1(N-thio-diglycolyl-homocysteine)
Mekanisme kerja Erdosteine:1.Mukolitik2.Anti-adhesi bakteri3.Anti-inflamasi4.Anti-oksidan
Dua gugus thiol (S-H) pada erdosteine memutus rantai
disulfida mukus
Marchioni et al. 1995, Braga et al.2001; Dal Negro et al. 2008
Erdosteine pada PPOK
“Erdosteine telah lama digunakan sebagai terapi mukolitik pada pasien
dengan hipersekresi mukus baik akut maupun kronik.
The RESTORE study: the design
RESTORE study
•12-months treatment
•528 COPD patients recruited
•47 centres in 10 EU countries
•more than 100 Investigators involved
The RESTORE Study ERJ 2017
Erdosteine pada PPOK
“Saat diberikan bersama antibiotik, Erdosteine, tidak berinteraksi
dengan antibiotik bahkan bekerja sebagai antibiotic enhancer karena
bersifat sinergis meningkatkan efikasi kerja antibiotik”
“Kombinasi Erdosteine dan beberapa antibiotik menghambat
perlekatan bakteri pada sel mukosa. Hal ini menunjukkan Erdosteine
meningkatkan efek anti-adhesi antibiotik.”
Dal Negro et al. 2018
Erdosteine dengan Antibiotik
Antibacterial adhesion activity
Sebelum pemberian
Metabolit I
Setelah Pemberian
Metabolit I
Inhibition of S. Aureus adhesion to buccal epithelial cells
Scanning electron micrographs showing bacterial adhesion epithelial buccal cells before and after the exposure of
S. Aureus to 2.5 µg/ml of erdosteine Met I
Braga, 2000
Perbandingan Erdosteine vs N-acetylcysteine
Perbanding efek pelekatan bakteri setelah pemberian Erdosteine, Metabolit I dan NAC
Braga 1999
0
10
20
30
1,2
5
2,5 5 10
INH
IBIT
ION
OF
AD
HE
SIV
EN
ES
S F
OR
E. C
OL
I (%
)
Erdostein
e
Metabolit I Erdosteine
NA
C
μg/ml
β-lactam
NAC
Dal Negro et al. 2018, Saggers et al.1996; Goswami et al. 2010; Landini et al. 2016
Bagaimana interaksi N-acetylcysteine dengan antibiotik ?
“Beberapa data menunjukkan kombinasi NAC dengan beberapa molekul antibiotik
tidak direkomendasikan”
Hal ini disebabkan karena gugus thiol bebas pada NAC (R-SH), dapat berinteraksidengan molekul antibiotik.
N-ACETYLCYSTEINE SmPC
4.5 Interactions with other medicinal products
Antibiotics (e.g. aminoglycosides, penicillins, tetracycline) may not work as well when taken at the same time as acetylcysteine. If you need to take antibiotics and acetylcysteine you
should leave at least two hours between taking these medicines.
N-acetylcysteine dan Antibiotik
*SmPC: Summary of Products Characteristics
Erdosteine merupkan pro-drug, tanpa gugus thiol bebas (R-SH) dan
tidak berinteraksi dengan antibiotik saat digunakan dalam bentuk
kombinasi.
ERDOSTEINE SmPC
4.5 Interactions with other medicinal products
No harmful interactions with other drugs have been reported and the product can therefore be administered together with antibiotics.
Erdosteine dan Antibiotik
*SmPC: Summary of Products Characteristics
The interaction between Erdosteine and antibiotics on biofilm formation
Prof. F. Scaglione
University of Milan, Clinical Pharmacology
BACTERIA
• Methicillin Resistant Streptococcus Aureus
(MRSA different strains)
• Methicillin Sensible Streptococcus Aureus
(MSSA different strains)
ANTIBIOTICS TESTED
•Vancomycin
•Linezolid
•Levofloxacin
Review: studi Erdosteine vs biofilm bakteri
Bahan dan metode studi in vitro
✓ Pembentukan Biofilm ditentukan dengan microtiter plate assay
✓ Saat biofilm telah terbentuk, Erdosteine dalam beberapa
konsentrasi dikombinasi dengan antibiotik dan diujikan ke media
pertumbuhan bakteri
✓ Konsentrasi Erdosteine yang digunakan pada studi in vitro (2 – 5 –
10 mcg/L) sama dengan konsentrasi Erdosteine in vivo pada
manusia
RES vanco
RES vanco erd 2*
RES vanco erd 5*
RES vanco erd
10*
Antibacterial activity (RES: antibiotic activity) for Vancomycin alone or plus Erdosteine (2-5-10 mcg/L)* against 24-h biofilms of MRSA
Concentration-response (CV: inibition of biofilm formation) of Vancomycin alone or plus Erdosteine (2-5-10 mcg/L)* against 24-h biofilms of MRSA
Hasil penelitian: Vancomycin & Erdosteine
CV vanco
CV vanco erd 2*
CV vanco erd 5*
CV vanco erd
10*
CV LVX
CV LVX erd 2*
CV LVX erd 5*
CV LVX erd
10*
Concentration-response (CV: inibition ofbiofilm formation) of Levofloxacin alone orplus Erdosteine (2-5-10 mcg/L)* against24-h biofilms of MRSA
Hasil penelitian: Levofloxacin & Erdosteine
Antibacterial activity (RES: antibioticactivity) for Levofloxacin alone or plusErdosteine (2-5-10 mcg/L)* against 24-hbiofilms of MRSA
RES LVX
RES LVX erd 2*
RES LVX erd 5*
RES LVX erd
10*
CV lin
CV lin erd 2*
CV lin erd 5*
CV lin erd
10*
Concentration-response (CV: inibition ofbiofilm formation) of Linezolid alone orplus Erdosteine (2-5-10 mcg/L)* against24-h biofilms of MRSA
Hasil penelitian: Linezolid & Erdosteine
Antibacterial activity (RES: antibiotic activity) for Linezolid alone or plus Erdosteine (2-5- 10 mcg/L)* against 24-h biofilms of MRSA
RES lin
RES lin erd 2*
RES lin erd 5*
RES lin erd
10*
Erdosteine interaction with antibiotics
Erdosteine menunjukkan aktivitas mendukung kinerja antibiotik karena:
•Tidak ada interaksi negatif secara kimiawi
•Memiliki efek anti-adhesi bakteri
•Terbukti meningkatkan penetrasi antibiotik terhadap bacterial biofilm
Keamanan ERDOSTEINE ?
Efficacy and safety profile of mucolytic/antioxidant agents in chronic obstructive pulmonary disease: a comparative analysis across Erdosteine, Carbocysteine, and N-acetylcysteine
Paola Rogliani, Maria Gabriella Matera, Clive Page, Ermanno Puxeddu, Mario Cazzola and Luigino Calzetta
Results: efficacy profiles
The GRADE (Grading of Recommendations Assessment, Development and Evaluation) analysis indicated:
• high quality of evidence (++++) for erdosteine
• moderate quality of evidence (+++) for NAC
• low quality of evidence (++) for carbocysteine
(surface under the cumulative ranking curve)
Rogliani et al. 2019
bestworst
The pooled analysis of safety profile
showed that AEs were very common in
patients treated with NAC, and common in
those treated with either Erdosteine and
Carbocysteine, or that received placebo.
However, AEs were mild in severity and
generally well tolerated.
Results: safety profiles
Rogliani et al. 2019
• Real-life observational study
• 20 patients with COVID-19-related pneumonia and severe respiratory failure
Therapy: Erdosteine 300 mg twice daily 15 days after hospital discharge
Study Results
In patients with COVID-19-related pneumonia and severe respiratory failure, after hospital discharge Erdosteine 300 mg bid significantly improved: 1) Respiratory symptoms Particularly, dyspnoea and cough significantly improved during the 15 days post-discharge.
2) HRQoL (Health-Related Quality of Life)The improvements in overall HRQoL were clinically significant in approximately two-thirds of patients and were accompanied by significant improvements in the management of symptoms and daily activities.
TAKE HOME MESSAGE
1. Hipersekresi mukus dapat meningkatkan risiko infeksi bakteri
2. Penggunaan mukolitik dapat meningkatkan kerja dari
antibiotik.
3. Erdosteine dengan antibiotik jika digunakan bersama, maka
secara klinis terbukti bersifat sinergis.
4. Efikasi dan profil keamanan Erdostein adalah baik, dan
direkomendasikan pada terapi PPOK.
5. Penggunaan Erdostein pada pasien pasca COVID-19 masih
dalam penelitian.