MACROLIDES AND OTHER ANTIBIOTICS

MACROLIDE ANTIBIOTICS

• Group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are attached

• In 1950 the first drug of this class was isolated: Picromycin

• In 1952 Erythromycin and Carbomycin were introduced into clinic.

O

O O

O

CH3

HO

H3C

CH3

CH3

OH3C

H3CO

HO

CH3

N CH3

H3C

Picromycin

Macrolides: Erythromycin• It was isolated from Streptomyces erythreus in 1952

• It was the first of these drugs to find clinical application, both

as a drug of choice and an alternative to penicillin in

individuals who are allergic to β-lactam antibiotics

• Slightly water soluble

• Macrolides are stable in aqueous solutions at or below room

temperature. They are unstable in acidic or basic conditions

or at high temperatures.

Erythromycin: Mechanism of action

• Bacteriostatic at low but cidal at high concentrations

• Cidal action also depends on the organism and its

rate of multiplication

• More active in alkaline medium

• Acts by inhibiting bacterial protein synthesis

• Bind irreversibly to a site on the 50s subunit of the

ribosome and interferes with ‘translocation’

Erythromycin: Resistance• Becoming a serious problem

• Several mechanisms are:– Inability of organism to take up the antibiotic or presence of efflux

pump

– Decreased affinity

– Presence of plasmid associated erythromycin esterase

• Both clarithromycin and azithromycin show cross

resistance with erythromycin

• But telithromycin can be effective against macrolide-

resistant organisms

Pharmacokinetics

• Erythromycin base is acid labile but all others (newer)

are stable

• Given as enteric coated tablets

• Food delays absorption by retarding gastric emptying

• Its acid esters are better absorbed

• Widely distributed in the body except CSF

• Diffuses into prostatic fluid, accumulates in macrophages

• Concentrates in liver

• Inflammation allows greater tissue penetration

• 70-80% plasma protein bound

• Partly metabolized and excreted primarily in the active

form (some enterohepatic circulation)

• Renal excretion is minor (5%)

• Its plasma t1/2 is 1.5hr, but it persists longer in tissues

Pharmacokinetics Cont…

Adverse effects

• Epigastric distress

• Cholistatic jaundice

• Ototoxicity (at high doses)

• Hypersensitivity

Interactions

Uses• As an alternative to pencillin

– Strep. Inf, Diptheria, Tetanus, Syphylis and Gonorrhoea

• As a first choice drug for:– Atypical pneumania– Whooping cough– Chancroid

• As a second drug choice:– Campylobactor enteritis– Legionnaire’s pneumonia– Chlamydia trachomitis– Pencillin resistant Staphylococcal infections

Roxithromycin

• Acid stable

• Good enteral absorption and tissue penetration

• 95% plasma protein bound

• Has longer half life 12hrs

Clarithromycin• Acid stable

• Bioavailability is 50% due to first pass metabolism

• Follows zero order kinetics

• Longer half life (3-6hrs), its metabolite is also active

• Antibacterial spectrum is wider:

– Micobacterium avium complex

– M. leprae

– Toxoplasma gondii

Azithromycin• Extended spectrum

• Better tolerability

• More active against H.influenza but less active against gram

possitive cocci

• Rapidly absorbed from empty stomach

• Longest half life (3days)

• Spectrum is identical to clarithromycin, except that it is less

active against Staphylococci and Streptococci

Other antibiotics

Clindamycin

• Mechanism of action is same as that of erythromycin

• Resistant mechanisms are same as those of

erythromycin

• It inhibits most of the gram possitive cocci

• Highly active against a vareity of anaerobes, specially

B. fragilis

• Aerobic gram negative bacilli are not effective

• Absorption is good

• Distributes well but not to CSF and brain

• Excreted in urine and bile

• Plasma half life is 3hrs

Clindamycin Cont…

Adverse effects:

• Skin rashes

• Diarrhoea and pseudomembranous entero colitis

(C.difficile)

Clindamycin Cont…

Vancomycin

• Glycopeptide antibiotic

• Discovered in 1956 as a pencillin substitute

• Effective against MRSA, Strep.viridans, enterococci

and clost.difficile

• Acts by inhibiting cell wall phospholipid synthesis as

well as peptidoglycon polymerization (transglycolation

step)

Pharmacokinetics:

• No absorption from oral route

• Slow IV infusion is employed for treatment of

systemic infections or for prophylaxis

• Metabolism is minimal

• 90-100% excreted through glomeruar filtration

Vancomycin Cont…

Adverse effects:

• Fever, chills, phlebitis at the infusion site

• Flushing (red man syndrome)

• Dose related hearing loss

Vancomycin Cont…

Linezolid

• Was introduced recently to combat resistant

gram possitive organisms such as:

– MRSA and VRSA

– VR enterococcus faecium, E. faecalis

– Pencillin resistant streptococci

Mech of action:

• Inhibits bacterial protein synthesis by inhibiting the

formation of 70s initiation complex

Linezolid Cont…

Restance:

• Decreased binding to the target site confers resistance

Pharmacokinetics:

• Completely absorbed on oral administration

• IV preparations also available

• Widely distributed throughout the body

• Partly metabolized non enzymatically

• Excreted in urine

• Plasma half life is 5hrs

Linezolid Cont…

Side effects:

• Well tolerated

• GI upset, nausea, diarrhoea, headache and rash

• Thrombocytopenia (2%)

Linezolid Cont…

Polypeptide Antibiotics

• Low molecular weight cationic polypeptide antibiotics

• All are powerful bactericidal agents

• Not used systemically due to toxicity

• All are produced by bacteria• Clinically used ones are:

– Polymyxin B– Colistin– Bacitracin