MACROLIDES, CLINDAMYCIN &

CHLORAMPHENICOLCHLORAMPHENICOLDr. Deepak K. Gupta

Introduction

• Closely related compounds characterized by a macrocyclic lactone ring - deoxy sugars are attached to it

• Prototype drug – erythromycin derived from • Prototype drug – erythromycin derived from Streptomyces erythreus

• Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin

ERYTHROMYCIN

• Poorly soluble in water

• Dispensed as various esters and salts

• Bactericidal, particularly • Bactericidal, particularly at higher concentrations

• enhanced at alkaline pH

Mechanism of Action

• Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA

• Binding site near the peptidyltransferasecentercenter

• Transpeptidation: Peptide chain elongation is prevented

• Also inhibits the formation of the 50S ribosomal subunit

Antimicrobial Activity• Active against susceptible strains of gram-positive

organisms and Gram-negative organisms such as Neisseria sp.

• Resistance : Three mechanisms have been identified– reduced permeability of the cell membrane or active – reduced permeability of the cell membrane or active

efflux; – production (by Enterobacteriaceae) of esterases that

hydrolyze macrolides;– modification of the ribosomal binding site (so-called

ribosomal protection)

• Cross-resistance is complete between erythromycin and the other macrolides

Pharmacokinetics

• Destroyed by stomach acid - enteric coating

• Food interferes with absorption

• Serum half-life is approximately 1.5 hours normallynormally

• Excreted in the bile and lost in feces, and only 5% is excreted in the urine

• Distributed widely except to the brain and cerebrospinal fluid

• Traverses the placenta and reaches the fetus.

Clinical Uses

• Drug of choice in corynebacterial infections -diphtheria, corynebacterial sepsis, erythrasma

• In respiratory, neonatal, ocular, or genital chlamydial infections

• Treatment of community-acquired pneumonia• Treatment of community-acquired pneumonia• Penicillin substitute in penicillin allergic

individuals• prophylaxis against endocarditis during dental

procedures in individuals with valvular heart disease

Clinical Uses

• 0.25–0.5 g every 6 hours

• Oral erythromycin base (1 g) is sometimes combined with oral neomycin or kanamycinfor preoperative preparation of the colonfor preoperative preparation of the colon

• Intravenous dosage of erythromycin gluceptate or lactobionate is 0.5–1.0 g every 6 hours for adults

Adverse Reactions

• Anorexia, nausea, vomiting, and diarrhea are common

• Gastrointestinal intolerance – direct stimulation of gut motilitystimulation of gut motility

• May produce acute cholestatic hepatitis

• Fever, eosinophilia, and rashes

CLARITHROMYCIN

• Derived from erythromycin by addition of amethyl group

• improved acid stability and oral absorptioncomparablycomparably

• Similar antibacterial action and mechanism of actions but its more active against Mycobacterium avium complex, Mycobacterium leprae ,Toxoplasma gondii, and H influenzae

CLARITHROMYCIN

• Recommended dosage is 250–500 mg twice daily or 1000 mg of the extended-release formulation once daily

• Half-life : 6 hours• Half-life : 6 hours

• Penetrates most tissues well

• Metabolized in the liver

• Lower incidence of gastrointestinal intolerance and less frequent dosing

AZITHROMYCIN

• derived from erythromycin by addition of a methylated nitrogen into the lactone ring – 15 C lactone ring

• Antibacterial spectrum similar to those of clarithromycinclarithromycin

• slightly less active than erythromycin and clarithromycin - staphylococci and streptococci

• Slightly more active against H influenzae

• highly active against Chlamydia sp

AZITHROMYCIN• Differs - mainly in pharmacokinetic properties• Penetrates into most tissues (except CSF) and phagocytic

cells extremely well• Half-life approaching 3 days - once-daily dosing• 1-g dose of azithromycin is as effective as a 7-day course

of doxycyclineof doxycycline• Community-acquired pneumonia - 500-mg loading dose,

followed by a 250-mg single daily dose for the next 4 days• Not given - 1 hour before or 2 hours after meals• Free of the drug interactions that occur with

erythromycin and clarithromycin– 15-member lactone ring – does not inactivate cytochrome

P450 enzymes

CLINDAMYCIN

• Chlorine-substituted derivative of lincomycin

• Elaborated by Streptomyces lincolnensis

Mechanism of Action

• Inhibits protein synthesis– interfering with the formation of initiation

complexes and with aminoacyl translocation reactions

• Binding site on the 50S subunit of the bacterial • Binding site on the 50S subunit of the bacterial ribosome is identical with that for erythromycin

• Resistance• Mutation of ribosomal receptor site

• Modification of the receptor by a constitutively expressed methylase

• Enzymatic inactivation of clindamycin

Antibacterial Spectrum

• Streptococci, staphylococci, and pneumococci

• Both gram-positive and gram-negative anaerobes - susceptible

• Enterococci and gram negative aerobic • Enterococci and gram negative aerobic organisms (poor permeability) are resistant

• Cross resistance to macrolides

Pharmacokinetics

• Penetrates well into most tissues, with brainand cerebrospinal fluid as well as abscesses

• Metabolized by the liver

• Excreted in bile and urine• Excreted in bile and urine

• Half-life - 2.5 hours

• Oral dosages: 0.15–0.3 g every 8 hours, Intravenously: 600 mg every 8 hours

Clinical Uses

• Treatment of skin and soft-tissue infections caused by streptococci and staphylococci

• Community-acquired strains of methicillin-resistant S aureus (MRSA) - common cause of resistant S aureus (MRSA) - common cause of skin and soft tissue infections

• Anaerobic infections caused by Bacteroides sp

• Combination with an aminoglycoside or cephalosporin – treat penetrating wounds of the abdomen and the gut

Clinical Uses

• Infections originating in the female genital tract -septic abortion, pelvic abscesses, or pelvic inflammatory disease; and lung abscesses

• Alternative to Penicillin allergy – prophylaxis of • Alternative to Penicillin allergy – prophylaxis of endocarditis in patients with valvular heart disease undergoing certain dental procedures

• Clindamycin plus primaquine – effective alternative to trimethoprim-sulfamethoxazole

Adverse Effects

• Diarrhea, nausea, and skin rashes.

• Impaired liver function

• Neutropenia

• Risk factor for diarrhea and colitis due to C • Risk factor for diarrhea and colitis due to C difficile

Chlramphenicol

• Crystalline chloramphenicol is a neutral, stable compound

• Soluble in alcohol but poorly soluble in water

• Chloramphenicol succinate - parenteral• Chloramphenicol succinate - parenteraladministration (highly water-soluble)

Mechanism of Action

• potent inhibitor of microbial protein synthesis

• binds reversibly to the 50S subunit of the bacterial ribosome

• inhibits peptide bond formation • inhibits peptide bond formation

• bacteriostatic broad-spectrum

• Resistance due to– less permeable to the drug

– Chloramphenicol acetyltransferase - inactivatesthe drug

Antimicrobial Activity

• Active against both aerobic and anaerobic gram-positive and gram-negative organisms

• Active also against Rickettsiae but notChlamydiaeChlamydiae

• Bactericidal - H influenzae, Neisseriameningitidis , and some strains of bacteroides

Pharmacokinetics• Rapidly and completely absorbed• Widely distributed to virtually all tissues and body fluids,

including the central nervous system• Prodrug

– Oral route : Chloramphenicol palmitate is hydrolyzed in the intestine to yield free chloramphenicol

– Parentral : Chloramphenicol succinate, which hydrolyzes to yield – Parentral : Chloramphenicol succinate, which hydrolyzes to yield free chloramphenicol

• Inactivated either by– conjugation with glucuronic acid– by reduction to inactive aryl amines

• Active chloramphenicol (10%) and its inactive degradation products (90%) are eliminated in the urine

• A small amount of active drug is excreted into bile and feces.• Usual dosage : 50–100 mg/kg/d

Clinical Uses

• Potential toxicity, bacterial resistance, and the availability of many other effective alternatives - rarely used

• Serious rickettsial infections such as typhus and Rocky Mountain spotted feverMountain spotted fever

• Alternative to a β-lactam antibiotic for treatment of bacterial meningitis - hypersensitivity reactions to penicillin : 50–100 mg/kg/d in four divided doses.

• Topically in the treatment of eye infections– broad spectrum

– penetration of ocular tissues and the aqueous humor

Adverse Reactions• Gastrointestinal disturbances - nausea, vomiting, and

diarrhea• Oral or vaginal candidiasis• Dose-related reversible suppression of red cell production -

exceeding 50 mg/kg/d after 1–2 weeks.• Aplastic anemia - idiosyncratic reaction unrelated to dose• Gray baby syndrome• Gray baby syndrome

– Newborn infants lack an effective glucuronic acid conjugation mechanism

– dosages above 50 mg/kg/d, the drug may accumulate– vomiting, flaccidity, hypothermia, gray color, shock, and vascular

collapse

• To prevent this dose should be carefully decided in infants and kept below 50 mg/kg/d

Adverse Reactions

• Inhibits hepatic microsomal enzymes -metabolize several drugs

• Half-lives of these drugs are prolonged

– Phenytoin– Phenytoin

– Tolbutamide

– Chlorpropamide

– Warfarin

Summary

References

• Basic & Clinical Pharmacology Bertram G. Katzung Twelfth Edition

• Essential of medical pharmacology - K.D. Tripathi6th edition

Lippincott - Modern Pharmacology With Clinical • Lippincott - Modern Pharmacology With Clinical Applications 6E

• Color Atlas Of Pharmacology, 2Nd Ed (Lüllmann, Thieme 2000)