Protein synthesis Protein synthesis inhibitors:inhibitors:

Chloramphenicol, Chloramphenicol, Tetracyclines, Tetracyclines,

Macrolides, Macrolides, Clindamycin Clindamycin

Streptogramins & Streptogramins & OxazolidinonesOxazolidinones

Pawitra Pulbutr, Pawitra Pulbutr,

M.Sc. In Pharm (Pharmacology)M.Sc. In Pharm (Pharmacology)

วั�ตถุ�ประสงค์�เชิ�งพฤต�กรรม

• เข้�าใจและอธิ�บายถุ�งกลไกการออกฤทธิ�" , กลไกการดื้%&อยา , เภส�ชิจลนศาสตร� , อาการไม*พ�งประสงค์�ท+,เก�ดื้จากการใชิ�ยา , การน-าไปใชิ�ประโยชิน�ทางค์ล�น�ก รวัมท�&งข้�อดื้+และข้�อเส+ยข้องยาต�านแบค์ท+เร+ยในกล�*ม Protein synthesis inhi

bitors ไดื้�แก* chloramphenicol, tetrac yclines, macrolides, clindamycin, s

treptogramins, oxazolidinones, ket olides ไดื้�

Bacterial protein synthesis

Drug acting as Drug acting as protein synthesis protein synthesis

inhibitorsinhibitors• ChloramphenicolChloramphenicol• TetracyclinesTetracyclines• MacrolidesMacrolides• ClindamycinClindamycin• KetolidesKetolides• OxazolidinonesOxazolidinones• StreptograminsStreptogramins• AminoglycosidesAminoglycosides• SpectinomycinSpectinomycin

ChloramphenicolChloramphenicolChloramphenicolChloramphenicol

• First synthetic antibacterial• Mechanism of action

– Bind with 50s subunit– Inhibit peptidyl transferase– Inhibit transpeptidation … connection

of peptide from P-site to A-site***– Bacteriostatic– Bactericidal to some bacteria >>>H.

influenzae, N. meningitidis, bacteroides

• Resistance– Decrease uptake– Chloramphenicol acetyl transferase

enzyme… destroy

Clinical usesClinical uses

o Serious rickettsial infectionoTyphus … alternative to doxycycline

o Bacterial meningitis (due to PRSP, meningococcus) … alternative to penicillin

o Eye infection** .. Topicalo Melioidosis … Burkholderia

pseudomalleri (gram negative rods)

ADRsADRs

• GI disturbance.. n/v, diarrhea, oral-vaginal candidiasis

• Bone marrow supression*** … dose dependent…> 50 mg/kg/day for 1-2 wks

• Aplastic anemia … idiosyncratic idiosyncratic reactionreaction… not dose dependent … 1 in 24,000-40,000 …. Fetal reaction– Unexplained infection/ Bleeding/ Fatigue

• Toxicity for newborn– Immature conjugation– Gray baby syndromeGray baby syndrome … vomiting, flaccidity,

hypothermia, gray color, shock, death– Not > 50 mg/kg in infants , > 25 mg in

immatures

Hydrochloride salt…

more water soluble

All chelates All chelates with with

divalent divalent metal metal ions***ions***

TetracyclinesTetracyclines

• chlortetracyclinechlortetracycline• oxytetracyclineoxytetracycline• tetracyclinetetracycline• demeclocyclinedemeclocycline• methacyclinemethacycline• doxycyclinedoxycycline• minocyclineminocycline

Mechanism of Mechanism of actionaction

•Bind with 30 s subunit• Inhibit binding of aminoacyl-

tRNA to A-site • Inhibit protein synthesis•Bacteriostatic

SpectrumSpectrum

• Broad spectrumBroad spectrum• gram positive, negative,

anaerobes• rickettsiae• chlamydia• mycoplasma• protozoa (ameba, plasmodium)

Clinical usesClinical uses• DOC for Mycoplasma pneumonia,

Chlamydia, Rickettsia infection• Acne**• Bronchitis• Community acquired pneumonia• Lyme disease• Leptospirosis**• Vibrio infection• Atypical mycobacterial infection• H. pyroli infection … Gastric ulcer• Protozoal infection** …

E. histolytica, Plasmodium (malaria)

MacrolidesMacrolides

• Macrocyclic lactone ringMacrocyclic lactone ring• ErythromycinErythromycin• RoxithromycinRoxithromycin• ClarithromycinClarithromycin• AzithromycinAzithromycin

Mechanism of Mechanism of actionaction

• Bind 50s subunit• Inhibit aminoacyl translocationInhibit aminoacyl translocation• Inhibit translocation of tRNA from Inhibit translocation of tRNA from

A-site to P-site A-site to P-site • Resistance• Decrease uptake or Efflux pump• Produce esterase enzyme …

destroy drugs• Alteration of ribosomal binding Alteration of ribosomal binding

site …. Methylasesite …. Methylase ***… ***… MLS-BMLS-B

Clinical usesClinical uses

•DOC for …– Corynebacterium infection

(diphteria*, corynebacterial sepsis, erythasma)

– Respiratory, neonatal, ocular, genital Chlamydial infection*

– Community acquired pneumonia• PneumococciPneumococci• MycoplasmaMycoplasma• LegionellaLegionella

Alternative to penicillin in..

• streptococci

• staphylococci

• pneumococci

• pharyngitis

• skin & soft tissue infection

• pneumonia

Many are resistant to

macrolide too!!

Endocarditis prevention in valvular heart disease pt undergoes dental surgery

KetolidesKetolides

•Telithromycin •Macrolide like … macrocyclic

lactone ring•3- keto group•No L-cladinose sugar• Macrolide like mechanism of Macrolide like mechanism of

actionaction•Bind to 50s subunit•Higher affinity

SpectrumSpectrum

• RTI caused byRTI caused by … beta-lactam, beta-lactam, macrolide, tetracyclines, co-macrolide, tetracyclines, co-trimoxazoletrimoxazole resistant bacteria resistant bacteria – S. pneumoniae– H. influenzae– M. catarrhalis– Effective to MLS-B resistance***Effective to MLS-B resistance***– No MLS-B inducerNo MLS-B inducer

ClindamycinClindamycino Cl derivative of lincomycinCl derivative of lincomycino Erythromycin like mechanism of

action… bind at 50 s subunito Erythromycin binding siteo Spectrum

o Streptococcio Staphylococcio Pneumococcio Bacteroides & Other anaerobes***Bacteroides & Other anaerobes***o Not effective to gram negative

(poor permeability) , enterococci, Clostridium difficile

StreptograminsStreptogramins

o Quinupristin-dalfopristin (Synercid®)Quinupristin-dalfopristin (Synercid®)o Quinupristin = Streptogramin B 30%o Dalfopristin = Streptogramin A 70%o Macrolide like mechanism of action … Macrolide like mechanism of action …

bind at 50s subunitbind at 50s subunito Spectrum

o Gram positive bacteria**Gram positive bacteria**o Multidrug resistant streptococcio Penicillin resistant pneumococci (PRSP)**(PRSP)**o MRSA**MRSA**o Enterococcus faecium (not E. faecalis)o Not to gram negative***

Clinical usesClinical uses ….…. IV infusionIV infusion

• Vancomycin resistant Vancomycin resistant E. E. faeciumfaecium (VRE)(VRE) infection infection

• MRSA infectionMRSA infection• Streptococci infectionStreptococci infection• Penicillin resistant/ Penicillin resistant/

susceptible pneumococci susceptible pneumococci infection infection

OxazolidinonesOxazolidinones• Linezolid (Zyvox®)Linezolid (Zyvox®)• Mechanism of action

– Bind at Bind at 23s rRNA of 50s subunit23s rRNA of 50s subunit – Inhibit Ribosomal assemblyInhibit Ribosomal assembly– Unique binding siteUnique binding site … No cross … No cross

resistanceresistance– Time dependent killingTime dependent killing

• Spectrum – Gram Gram positivepositive which resistant to other which resistant to other

drugsdrugs– Staphylococci, Streptococci,

Enterococci– Gram positive anaerobes, rods– MRSA,VRE, PRSP ***MRSA,VRE, PRSP ***– No activity on gram negativeNo activity on gram negative

Clinical useClinical use

• VRE infection• Other multidrug resistant

Tetracyclines

Bind at 30s subunit

Chloramphenicol bind at 50s

Macrolides/ Ketolides/ Clindamycin/

Streptogramins

Bind at 50s subunit

Oxazolidinones … bind at 23s rRNA