Mucolytics and Antibiotics:
Review of Erdosteine
Retno Wihastuti Webinar Series 7 Respina
Latar belakang: Hipersekresi mukus
Mukus terdiri dari campuran air, lemak, glycoconjugates, dan protein, garam, dan terbagi dua lapisan (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 (berada dalam bentuk inactive dan baru memberikan efek mukolitik setelah dimetabolisme di hati menjadi Metabolit-1 (N-thio-diglycolyl-homocysteine)
Mekanisme kerja Erdosteine:
1.Mukolitik
2.Anti-adhesi bakteri 3.Anti-inflamasi
4.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
Erdosteine pada PPOK
Erdosteine masuk ke dalam rekomendasi GOLD:
GOLD, 2020
“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
INHIBITION OF ADHESIVENESS FOR E. COLI (%)
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 berinteraksi dengan 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 of biofilm formation) of Levofloxacin alone or plus Erdosteine (2-5-10 mcg/L)* against 24-h biofilms of MRSA
Hasil penelitian: Levofloxacin & Erdosteine
Antibacterial activity (RES: antibiotic activity) for Levofloxacin alone or plus Erdosteine (2-5-10 mcg/L)* against 24-h biofilms 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 of biofilm formation) of Linezolid alone or plus Erdosteine (2-5-10 mcg/L)* against 24-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
worst best
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
Results: safety profiles
Rogliani et al. 2019
Update Erdosteine terkait COVID-19
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