Antibiotics basic

ANTIBIOTICSAntibiotics are obtained from

Fungi penicillins,cephalosporin,griseofulvinBacteria polymyxin B,Tyrothricin colistin,aztreonam,bacitracinActinomycetes aminoglycosides,macrolides,tetracyclines polyenes,chloramphenicol

CLASSIFICATION-A) Chemical structure

Β-lactam antibiotics- penicillins,cephalosporins,monobactams,carbapenems

Tetracyclins Oxytetracycline,doxytetracycline

Nitrobenzene derivative- chloramphenicol

AminoglycosidesStreptomycin,gentamycin,amikacin,neomycin

Macrolide antibioticsErythromycin,clarithromycin,azithromycin

Glycopeptide antibioticsVancomycin,teicoplanin

Lincosamide antibioticsLincomycin,clindamycin

Oxazolidinone- linezolid

Polypeptide antibioticsPolymyxin-B, colistin,bacitracin

Polyene antibioticsNystatin,amphotericin-B

B. Mechanism of action

1. Inhibit cell wall synthesis penicillins,cephalosporins,cycloserines vancomycin,bacitracin

2. Causes leakage from cell wall membrane Polypeptide-polymyxins,colistin,bacitracin Polyenes- amphotericin B,nystatin

3. Inhibit protein syntheis tetracyclins,chloramphenicol,erythromycin, clindamycin

4. Cause misreading of m-RNA code and affect permeability Aminoglycosides-streptomycin,gentamycin

SPECTRUM OF ACTIVITY

Narrow spectrum penicillin G streptomycin erythromycin

Broad spectrum tetracyclines chloramphenicol

PENICILLINS

First antibiotic to be used clinically in 1941

Originally obtained from fungus Penicillium notatum

Present source is a high yeilding mutant of P. chrysogenum

CHEMISTRY AND PROPERTIES

1- Thiazolidine ring2- β-lactam ring

CH C

CH3

CH3

CH

S

C NH

COOHC N

O

O

R

1 2

Benzyl side chain

PENICILLINS

Amide linkage

MECHANISM OF ACTION

- Inhibit transpeptidase so that cross linkingdoes not take place-When bacteria divide in presence of β-lactam antibiotics –cell wall deficient(CWD) forms are produced -because the interior of the bacterium is hyperosmotic ,the CWD forms swell & burst bacterial lysis

Lytic effect of these antibiotics may also be due to derepression of some bacterial autolysins which normally function during cell division

Penicillin G

Spectrum- narrow active only against gram +ve bacteriaCocci: Streptococci,Pneumococci gram –ve cocci- Neisseria gonorrhoeae N.meningitidis

Bacilli: gram +ve - Corynebacterium. Dephtheriae clostridia tetani garm –ve- Actinomyces israelii

BACTERIAL RESISTANCE

Many bacteria are inherently insensitive to PnGBecause in them the target enzyme & PBPs are locateddeeper under lipoprotein barrier wher PnG is unable to penetrate

Production of penicillinase it is a narrow spectrum β-lactamase which opens theβ-lactam ring and inactivates PnG.

Some bacteria become Penicillin tolerant –their target Enzymes are altered to have low affinity for penicillin

Gram –ve bacteria have porin channels located in their outer membrane.some gram –ve bacteria become resistantBy loss or alteration of porin channels.

PHARMACOKINETICS

A-PnG is acid labile-destroyed by gastric acidabsorption from i.m route is rapid & complete

D –Reaches most of the body fluidsPenetration in CSF is poor

M- Little metabolised because of rapid excretion

E-Very rapid renal excretion

ADVERSE EFFECTS

Local irritancy and direct toxicity pain at i.m injection site nausea on oral ingestion Larger dose injected i.v – Mental confusion Muscular twitching convulsions,coma.

Hypersensitivity rash,itching & fever

USES

1.Streptococcal infections

2. Pneumococcal infections

3.Meningococcal infections

4.Gonorrhoea

5.Syphilis

6. Diphtheria

7.Tetanus

8.Drug of choice for rare infections like anthrax,rat bite fever,trench mouth

SEMISYNTHETIC PENICILLINS

Shortcomings of PnG

-Poor oral efficacy

-Suseptibility to penicillinase

-Narrow spectrum of activity

-Hypersensitivity reactions

CLASSIFICATION1.Acid resistant alternative to PnG phenoxymethyl penicillin(Penicillin V)

2.Penicillinase-resistant penicillins methicillin,cloxacillin

3.Extended spectrum penicillins a) aminopenicillins: ampicillin.bacampicillin,amoxicillin b) carboxypenicillins: carbenicillin,ticarcillin c) ureidopenicillins: piperacillin,mezlocillin

β-lactamase inhibitorsClavulanic acid,sulbactum,tazobactum

1.Acid resistant alternative to PnG

-acid stable-oral absorption better-antibacterial spectrum identical to PnG-but it is1/5 as active against Neisseria

2.Penicillinase-resistant penicillins

-these have side chains that protect the β-lactam ring from attack by staphylococcal penicillinaseMethecillin- penicillinase resistant but not acid resistant

Cloxacillin-

Highly penicillinase resistant as well as acid resistant

3. Extended spectrum penicillins

Effective against gram-ve bacilli

1.Aminopenicillins-These have amino group in side chain-prodrugs-none is resistant to penicillinase

AMPICILLINUses-UTI-RTI-Meningitis-Gonorrhoea

BACAMPICILLIN Ester prodrug of ampicillinCompletely absorbed from g.i.t

AMOXICILLINClose congener of ampicillinNot a prodrugOral absorption is better

2. CARBOXYPENICILLINS

-active against pseudomonas aeruginosa & proteus- Carbenicillin is neither penicillinase resistant nor acid resistant-inactive orally

3.UREDOPENICILLINSPiperacillin-8 times more active than carbenicillin-used mainly in immunocompromised patients having serious gram-ve infections

BETA-LACTAMASE INHIBITORS

Clavulanic acidObtained from streptomyces clavuligerusHas β lactam ring but no antibacterial activity