Mucolytics and Antibiotics:

Review of Erdosteine

Retno WihastutiWebinar Series 7 Respina

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

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

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

Results: safety profiles

Rogliani et al. 2019

Update Erdosteine terkait COVID-19

25

• 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.