Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

Multimembered lactone ring structure

ERYTHROMYCIN- Streptmyces erythreus

ROXITHROMYCIN, CLARITHROMYCIN,AZITHROMYCIN- semisynthetic derivatives

SPIRAMYCIN –streptomycin ambafaciens

1. Inhibits protein synthesis by reversibly binding to the 50Sribosomal subunit .

2. Suppression of RNA-dependent protein synthesis3. Macrolides typically display bacteriostatic activity, but may

be bactericidal when present at high concentrations againstvery susceptible organisms

4. Time-dependent activity5. Selective toxicity

Advantage of newer macrolides:Broader spectrum, higher activity, Orally effectiveHigh blood concentration, Longer t ½,Less toxicityMainly used in respiratory tract infection

Active efflux (accounts for 80% ) – mef gene encodes for anefflux pump which pumps the macrolide out of the cellaway from the ribosome; confers low level resistance tomacrolides

Altered target sites – encoded by the erm gene which altersthe macrolide binding site on the ribosome; confers highlevel resistance to all macrolides, clindamycin .

Cross-resistance occurs between all macrolides

G+ve-S. pneumoniae, C.diptheriaeG-ve- L.pneumophila, B.pertusisAnaerobes – activity against upper airway anaerobesAtypical Bacteria – all macrolides have excellentActivity against atypical bacteria including:

▪ Legionella pneumophila▪ Chlamydia sp.▪ Mycoplasma sp.▪ Ureaplasma urealyticum

Other Bacteria – Mycobacterium avium complex (MAC – only Aand C), Treponema pallidum, Campylobacter, Borrelia,Brucella, Pasteurella

Erythromycin –stearate, ethylsuccinate, lactobionateAs penicillin substitute in penicillin-allergic or resistant patients

with infections caused byStaphylococci, Streptococci and PneumococciPertussis，diphtheriaeLegionella and mycoplasma pneumonia

Clarithromycin- O methyl derivativeActive metabolite- 14-hydroxyclarithromycinHas the strongest activity on Gram-positive bacteria,legionella pneumophila, Chlamydia pneumoniaeH.pylori-clar + Ome +AmoxHas the strongest activity against Mycoplasma pneumoniaeRenal toxicity

AzithromycinMore effective on Gram-negative bacteriaWell tolerated, once dailyMainly used in respiratory tract infection

Roxythromycin The highest blood concentration, F -72%~85% Respiratory tract infection and soft tissue infection Low adverse effects long acting, acid stable

Erythromycin – variable absorption (F = 15-45%);food may decrease the absorptionBase: destroyed by gastric acid; enteric coatedEsters and ester salts: more acid stable

Clarithromycin – acid stable and well-absorbed (F =55%) regardless of presence of food

Azithromycin –acid stable; F = 38%; food decreasesabsorption of capsules

1. Extensive tissue and cellular distribution – clarithromycinand azithromycin with extensive penetration

2. Minimal CSF penetration3. Clarithromycin is the only macrolide partially eliminated

by the kidney (18% of parent and all metabolites);requires dose adjustment when CrCl < 30 ml/min

4. Hepatically eliminated: ALL5. NONE of the macrolides are removed during

hemodialysis!6. Variable elimination half-lives (1.4 hours for erythro; 3 to

7 hours for clarithro; 68 hours for azithro)

Atypical pneumonia Legionnaire’s pneumonia Whooping cough Eradication of corynebacterium diptheriae Camphylobacter gastroenteritis Chancroid due to H.ducreyi Chlamydial conjunctivitis and urethritis

1. Gastrointestinal – up to 33 %Nausea, vomiting, diarrhea, dyspepsiaMost common with erythro; less with new agents

2. Cholestatic hepatitis – rare> 1 to 2 weeks of erythromycinestolate

3. Thrombophlebitis – IV Erythro and AzithroDilution of dose; slow administration

4. Ototoxicity (high dose erythro in patients with RI); QTcprolongation; allergy

Erythromycin and Clarithromycin – are inhibitors ofcytochrome p450 system in the liver; may increaseconcentrations of:

Theophylline Digoxin, DisopyramideCarbamazepine Valproic acidCyclosporine Terfenadine, AstemizolePhenytoin CisaprideWarfarin Ergot alkaloids

Anti-inflammatory property & Motilin receptor agonists Diffuse panbronchiolitis (DPB) Cystic fibrosis (CF) Acute bacterial sinusitis (ABS) Asthma Chronic obstructive pulmonary disease (COPD) Bronchiectasis Chronic bronchitis

Lincomycin Clindamycin

Antibacterial spectrum: lincosamides are active againststaphylococci, gram-positive and gram-negative anaerobes,including Bacteroides fragilis.

MechanismBinding to 50s ribosome subunit and inhibiting protein synthesisPharmacokineticsAbsorbed well, Penetrate well into most tissues includingBone but not CSF.About 90% protein-boundExcretion via the liver, bile, and urine

Alteration of 50s ribosomal subunit by adeninemethylation

Chromosomal mutation of 50s ribosomal protein Drug inactivationDose -150-300mg every 6th hourly

1. Severe anaerobic infection2. Acute or chronical suppurative osteomylitis ,

arthritis caused by susceptive organisms especiallyStaphylococci aureus

aerobic G+ cocci infection3. Combination with pyrimethamine for AIDS-related

toxoplasmosis (600, 75)4. Combination with primaquine for AIDS-related

pneumocystis carinii pneumonia

Gastrointestinal effects: severe diarrhea andpseudomembranous enterocolitis caused by Clostridiumdifficile

Higher IV dose –neuromuscular blockadeOther :Impaired liver function , neutropenia, hypersensitivity

TELITHROMYCIN, CETHROMYCIN Telithromycin is semisynthetic derivative of erythomycin Tighter binding to ribosomes Decreased incidence of resistance Longer post antibiotic effect T1/2- 13hrs Has activity against erythromycin resistant G+ve cocci Mainly for macrolide resistant CAP, chronic bronchitis Dose -800mg OD for 10 days

More potent than telithromycin Used against macrolide resistant Streptococci and Enterococci

Resistance -Ribosomal modification via inducible or constitutivemethylation .

Ribosomal modification via point mutation- H.pyloriDrug efflux- S.pyogenes

Adverse reactionsDiarrhea, nausea

Drug interactionProlonged QT interval (cisapride, terfenadine)Increased blood levels of theophylline, midazolam