Pharmacology of Antibiotics• Makrolida ( Macrolide )

• Aminoglikosida ( Aminoglycoside )

• Polimiksin ( Polymyxin )

Lecturer :

Dharma Permana, Apt, PhD

Macrolide antibiotics- Specific agents:• ERYTHROMYCIN • CLARITHROMYCIN • AZITHROMYCIN • ROKSITROMISIN• SPIRAMICIN

- Active orally, bacteriocidal and bacteriostatic- Indikasi/ spektrum antibakteri hampir sama

dengan golongan Penisilin dan merupakan sebagai alternatif dari golongan penisilin

- Broad spectrum

Macrolide antibiotics Mechanism of action

- Menghambat sintesis protein dengan cara mengikat 23 s RNA pada ribosom sub unit 50 S

Macrolide antibiotics Mechanism of action

“Medical Pharmacology at a Glance” Neal

Macrolide antibiotics Antimicrobial spectrum

• H. influenzae • N.gonorhoe• Penicillin G-resistente Staphylococus• Streptococus• Mycobacterium avium-intracellulare• Mykoplasma pneumoniae• Ureaplasma urealyticum• Chlamydia trachomatis• Bordetella pertussis• Legionella pneumophila• Listeria monocytogenes• Campylobacter jejuni• Moraxella catarrhalis

Macrolide antibiotics Antimicrobial spectrum

• Erythromycin has activity against gram-positive cocci (eg S.aureus, β-haemolytic streptococci), and some gram-negative organisms (eg B.pertussis, M.pneumoniae, L.pneumophilia, Chlamydia and Neisseria sp).

• Roxithromycin has similar activity to erythromycin

• Spiramycin has similar activity to erythromycin. It is also used to treat toxoplasmosis

Macrolide antibiotics Antimicrobial spectrum

• Clarithromycin has greater activity against H.influenzae, M.catarrhalis, Non TB mycobacterium, Mycobacterium

Avium Complex (MAC) and H.pylori.• Azithromycin has greater activity

against gram-negative organisms, particularly genitourinary pathogens

(eg C.trachomatis, U.urealyticum, N.gonorrhoeae, and T.pallidum).

Macrolide antibiotics Clinical Uses

• Respiratory tract infections (sinusitis, pharyngitis and particularly atypical organisms).

• Skin and soft tissue infections.• Cervicitis/urethritis (eg. azithromycin

for C.trachomatis infections).• Mycobacterial infections (eg.

clarithromycin).• H.pylori infections (clarithromycin, as

part of triple therapy).

Macrolide antibiotics Erythromycin

Erythromycin is an orally effective antibiotic discovered in 1952 in the metabolic products of a strain of Streptocyces erythreus

Macrolide antibiotics Resistensi kuman thd erythromycin

• Permeabilitas dinding sel mikroba ↓

• Perubahan reseptor obat pd ribosom bakteri

• Hidrolisis lactone ring oleh esteracea yg dihasilkan kuman

Macrolide antibioticsPharmakokinetic of Erithromycin

• Tdk stabil dlm suasana asam bentuk garam atau sediaan enteric

tablet/ capsul• Kadar puncak dlm darah 4 jam (0,3-1,9

ug/ml), T1/2 eliminasi 1,6 jam• Eksresi 2-5 % urin• Pemekatan dalam jaringan hati ( 100x

kadar dlm plasma garam estolat• Berdifusi ke berbagai jaringan kecuali

otak dan serebrospinal• Ibu Hamil meningkatkan kadar

SGOT/SGPT (Temporary )

Macrolide antibioticsSide effetcs of Erithromycin

• Oral nyeri perut ( iritasi sal cerna), mual,

muntah

• IM menimbulkan sakit bila dose > 100 mg

• IV infus 1 g tromboflebitis

Macrolide antibiotics Drugs Interactions of Erithromycin

*Meningkatkan toksisitas :-karbamazepin-kortikosteroid-siklosporin-digoksin-warfarin

* Menghambat metabolisme methyl xanthine (teofilin & cafein) CNS stimulan ↑

*Aritmia Astemizole, terfenadin,cisaprid

Macrolide antibioticsdosage form of Erythromycin

• Eritromisin base Cap/tab 250 & 500 mg

• Eritromisin stearat Cap/tab 250 & 500 mg

• Eritromisin etil suksinat Tab Kunyah 200 mg, suspensi oral 200

mg/5ml, oral drop 125 mg/2,5mlDose : dewasa 4 x 250-500mg /hari anak2 30-50 mg/Kg/BB

Tab Kunyah (chewable) 400-600 mg tiap 6 jam

Macrolide antibioticsdose of Erythromycin

- Streptococus Faringitis 30 mg/ kg/BB di bagi 4 dosis 10 hari- S. aureus sal nafas atas, infeksi kulit & luka 4

x 500 mg selama 7 hari- GastroenteritisC.Jejuni 4 x 250 mg- Clamidiauretra, endoserviks, rektum, epididimis merupakan alternatif TETRASIKLIN terpilih utk ibu hamil& anak2 4X 500mg (7 days)

Macrolide antibioticsdose of Erythromycin

- Infeksi sal Nafas bawah Pneumonia pneumococus 4x 250-500mg mycoplasma 4 x 500 mg legionnaire 4 x 0,5-1 g - Sifilis stadium dini 2-4 g sehari ( 10-15 hari)- Gonorhoe 4 x 500mg ( 5 days )- Difteria eritromisin obat terpilih

Macrolide antibiotics Clarythromycin

• Derifat eritromisin dgn efektivitas antimikroba yg lebih kuat dr eritromisin

• Efek samping hampir sama dgn eritromisin

Tetapi iritasi lambung lebih jarang• Interaksi obat= eritromisin• Ibu hamil embriotoksik

Macrolide antibiotics Pharmacokinetics of Clarythromycin

• Aborpsi baik dan tidak dipengaruhi makanan

• Metabolisme hati

• Ekskresiurin

• Waktu paruh 2-5 jam

• Dosis: 250-500 mg 2x1 ( 7-10 days )

Macrolide antibiotics Azithromycin

• Makrolida dgn aktifitas antimikroba paling rendah

• Absorspsi obat dipengaruhi makanan• Waktu paruh 2-4 hari ( slowly

eliminated) Diberikan 1 x sehari• Kadar obat dlm plasma rendah, tapi dlm

jaringan lebih tinggi ( 10-100 x dlm plasma )

• Single dose efektif urethritis & cervicitis ( C. thracomatis)

Macrolide antibiotics Azithromycin

• Single dose efektif urethritis & cervicitis ( C. thracomatis) 500 mg 1x1 ( 3 days )

• Chlamidia di genital 1g 1x1 ( 3 days)

Macrolide antibiotics Roxithromycin

• Diserap baik secara oral dan jarang menimbulkan iritasi lambung

• Bioavibilitas dipengaruhi makanan• Kadar obat lebih tinggi diplasma

dibandingkan eritromisin• Waktu paruh eliminasi 10 jam, pemberian 2 x1Dosis oral dewasa 2 x 150 mg anak2 5-8 mg/Kg/BB dlm 2 dosisIndikasi = eritromisin

Macrolide antibioticsSpiramycin

• Dihasilkan oleh streptomyces ambofaciens• Aktifitas antimikroba lebih rendah dari

eritromisin• Absopsi dlm sal cerna tdk begitu baik, tapi tdk

dipengaruhi makan• Kadar obat dalam berbagai jaringan lebih tinggi

dari pada makrolida lain dan bertahan lama walaupun dlm plasma sdh turun rendah

• Indikasi = eritromisin, dose 3-4 x 500 mg/hari• Alternatif utk pengobatan Toksoplasma 2-3g/hari ( 3 week ) dan dilanjutkan 2 minggu

kemudian

Aminoglycoside Antibiotics

Specific agents

- Streptomycin

- Gentamycin (Garamycin)

- Tobramycin (Nebcin)

- Amikacin (Amikin)

- Neomycin

-Kanamycin

Aminoglycoside Antibiotics• Mechanism of action Inhibition of bacterial

protein synthesis, Primary site of action is 30s ribosome subunit

• relatively broad spectrum, bacteriocidal• Resistance increasing• Very poor GIT absorption• Rapid IM absorption• Excretion in glomerular filtration• High conc. in renal cortex → nephrotoxicity; & In endolymph & perilymph of inner ear →

ototoxicity

Aminoglycoside Antibiotics Antimicrobial spectrum

-Aerobic gram-negative organisms

Pseudomonas, Klebsiella, Proteus, E. coli, others

• Streptomisin dan kanamisin juga aktif terhadap kuman TBC (Mycobacterium tuberculosis)

Digunakan utk alternatif terapi TBC

Aminoglycoside Antibiotics

Adverse Effects • Ototoxicity (damage to the organs of hearing ) - Serious ototoxicity can occur with ear drops - Risk of toxicity depends upon high dose, long duration, inefficient renal clearance and dehydration - Streptomycin, Gentamicin – Vestibular dysfunction - Amikacin, Kanamycin – Auditory dysfunction

• Nephrotoxicity Signs and symptoms of nephrotoxicity may include protein in the

urine (proteinuria), hematuria (blood in the urine), increase in the blood urea nitrogen level, decrease in urine output, and an increase in the serum creatinine concentration

• Neurotoxicity Signs and symptoms of neurotoxicity include numbness, skin

tingling, circumoral(around the mouth) paresthesia, peripheral paresthesia, tremors, muscle twitching, convulsions, muscleweakness

Aminoglycoside Antibiotics

• Sediaan obat :

1. Sistemik IV dan IM : streptomisin, amikasin, gentamisin,

tobramisin dan kanamisin

2. Topikal

kanamisin, neomisin, gentamisin dan streptomisin

Aminoglycosidesclinical uses

Sebagai alternatif antibiotik lain, hal ini disebabkan banyak resistensi, toksisitas dan ada antibiotik lain yg lebih efektif

terbatas utk Infeksi bakteri aerobik gram negatif

Pemakaian topikal harus diperhitungkan kemungkinan terjadinya toksisitas

CONTRAINDICATIONS 0f

Aminoglycosides

• preexisting hearing loss,

• parkinsonism

• during lactation or pregnancy

• Patients with renal failure

Aminoglycosides Drugs interactions

• with the cephalosporins may increase the risks of nephrotoxicity

• When the aminoglycosides are administered with diuretics there is an increased risk of ototoxicity (irreversible hearing loss )

• There is an increased risk of neuromuscular blockage (paralysis of the respiratory muscles) if the aminoglycosides are given shortly after general anesthetics (neuromuscular junction blockers).

Polymyxin Antibiotics

• Polimiksin B

• Kolistin (Polimiksin E)

- Infeksi gram negatif

-Topical application, not absorbed

by GI tract

– Relatively high systemic toxicity

Polimiksin B

• Toksisitas tinggi jika digunakan secara sistemik

-neurotoxicity (paresthesisis, dizzines, ataxia)

-Acute renal necrosis• Hanya digunakan secara TOPIKAL,

keuntungan tdk diserap mukosa kulit• Topical terapi pseudomonas

aeruginosa dan enterobacter

Polimiksin B Bentuk sediaan

• Salep kulit, salep mata, cream 5000-1000 UI/g

• Tetes mata & telinga 20000 UI/ml

Kolistin

• Infeksi gram negatif ( = Polimiksin B )• Utk antibakteri lokal sal cerna ( sterilisasi

usus)• Topikal tetes mata & telinga• Dosis oral sterilisasi usus 1,5-3 juta

UI/8jam• IM,IV dan IV infus 2 juta UI/8jam• Inhalasi > 40 kg1 juta UI/12 jam• Efek samping : Oral : neurotoksik dan nefrotoksik Inhalasi: broncospasme

•Terima Kasih

Sir Alexander Fleming (1881 –1955)