3. pencillin

DRUGS ACTING ON

CELL WALL

Site and Mechanism of action of Antibiotics

• Inside bacterial cell is much concentration of ions and metabolites

• It is required for cells to function normally : • to generate energy • Synthesize macromolecules • grow and divide

• It cause high osmotic pressure

Antibiotics affecting cell wall

Source Therapeutic application

Penicillin Pencillium chrysogenumPencillin notatum

Gram +ve coccal infections, syphilis, gonorrhoea, meningo coccal meningitis

Cephalosporin Cephalosporium spp Allergic to penicillin

Cycloserine Streptomyces TB caused by resistance bacilli

Bacitracin Bacillus licheniformis Sterilization of gut before surgery, topical application

Vancomycin Streptomyces orientalis Staphylococcal infection resistant to other drugs

Fofsomycin Active against +Ve, G-ve.

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Peptidoglycan synthesis

Cytoplasm Cell wall

undecaprenol

sugar

aminoacid

Cell Membrane

UDP-M, UDP-G

Disaccharide pentapeptide

6

Cycloserine

X

Cytoplasm

sugar

Amino acidUDP-M pentapeptide

X

X

X

alanine (ala) analog inhibits conversion L-ala to D-ala inhibits formation of D-ala-D-ala

Fosfomycin

Inactivating the enzyme Pyruvyl transferase enzymeInhibits formation of UDP-Mcalled a "Park nucleotide"

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TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE

Cell membrane

undecaprenol

PP

Cell wall

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Cell membrane

undecaprenol

PP

Cell wall


Cell membrane

undecaprenol

PP

Cell wall

BACITRACIN

Cell membrane

undecaprenol

P

Cell wall


Vancomycin

Cell wall

Vancomycin ( binds to D-alanyl-D- alanine protion of terminal end of peptidoglycan pentapeptideMakes transglycolase enzyme ineffectualcause inhibition of elongation

Beta lactam antibiotics

• penicillins • Cephalosporins/cephamycins • monobactams

Beta lactams

Cell wall

Penicillin binding protein

•inhibit penicillin binding proteins(Transpeptidase)

•stop cross-linking

•Activate autolysin enzyme

There functions are diverse: catalyze the

transpeptidase reaction, maintain shape, forms

septums during division, Inhibit autolytic

enzymes.

• Clinically useful families of beta-lactam

compounds include the

– Penicillins,

– Cephalosporins,

– Monobactams

– Carbapenems

BETA LACTAM ANTIBIOTICS

History

• The penicillins were the first antibiotics discovered as natural

products from the mold Penicillium.

• In 1928, Sir Alexander Fleming, professor of bacteriology at St.

Mary's Hospital in London, was culturing Staphylococcus aureus.

• He noticed zones of inhibition where mold spores were growing.

• He named the mold Penicillium rubrum.

• It was determined that a secretion of the mold was effective against

Gram-positive bacteria.

CHEMISTRY AND PROPERTIES

• 1-THIOZOLIDINE RING • 2-BETA LACTAM RING

C NH CH CH C

O

O C N CH

CH3

CH3

COOH

S

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•Beta lactamase

• Gastric acid

•Penicillanic acid

• The penicillin nucleus itself is the chief

structural requirement for biological activity;

• Metabolic transformation or chemical

alteration of this portion of the molecule

causes loss of all significant antibacterial

activity

Natural

•Narrow spectrum•Acid liable•β- lactum sensitive

Semisynthetic

Short acting Long acting•Pencillin-G•Procaine pencillin

•Benzethine

β- lactum inhibitors

β- lactum sensitive

Narrow spect Extended

β- lactum resistanceAnti staphylococcal

•Pencillin- V

Acid Liable Acid Stable•Methicillin•Neficillin

•Floxacillin•Oxacillin•Cloxacillin•Dicloxacilin

Aminopencillins•Ampicillin•Becampacilllin•Talampicillin•Amoxicillin

Carboxy pen.•Carbenpencillin•Tricarben pencillinUridopen.•Azlocillin•Mezlocillin•Pipera pencillin

Acid Stable

Acid Liable/ Anti pseudomonal

•Pencillin- V (Phenoxy methylpencillin)

Antimicrobial spectrum: Penicillin G

PharmacokineticsOral administration of Penicillin G:

• Acid labile –destroyed by gastric acid

• About one-third of an orally administered dose of penicillin G is

absorbed from the intestinal tract under favorable conditions.

• Gastric juice at pH 2 rapidly destroys the antibiotic.

Parenteral Administration of Penicillin G:

• From im site absorption is rapid and complete

• Peak plasma levels attained in 30min

• Penicillin G is distributed widely throughout the body, but the concentrations in

various fluids and tissues differ widely.

• Approximately 60% of the penicillin G in plasma is reversibly bound to albumin.

• Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and

intestine

• Cerebrospinal Fluid. Penicillin does not readily enter the CSF when the

meninges are normal. However, when the meninges are acutely inflamed,

penicillin penetrates into the CSF more easily.

• Little metabolized because rapid excretion

Pharmacokinetics Cont…

• The half-time for elimination is about 30 minutes in normal

adults (upto 10 hours in renal failure) .

• Approximately 10% of the drug is eliminated by glomerular

filtration and 90% by tubular secretion.

• While probenecid markedly decreases the tubular secretion

of the penicillins,

Pharmacokinetics Cont…

Preparations and dose

• Benzylpenicillin (sodium and potassium salts)• Repository preparations:

• Insoluble salts, only im injection never iv injection

– Procaine penicillin– Benzathine penicillin

Unitage of Penicillin

1 U OF CRYSTALLINE SOD. BENZYL PENICILLIN =0.6 µg OF THE STANDARD PREPARATION

1GM =1.6 MILLION UNITS

1 MU = 0.6 GM

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Resistance mechansims

• Produce β lactamase (penicillinase)–destroys antibiotic

• modified penicillin binding proteins – don’t bind antibiotic

• modified porins–no internalization of antibiotic

Adverse effects

• Hypersensitivity Reactions. Hypersensitivity reactions are most

common adverse effects noted with the penicillins, and these

agents probably are the most common cause of drug allergy.

• The basis of which is the fact that degradation products of

penicillin combine with host protein and become antigenic.

(Penicilloic acid)

• In approximate order of decreasing frequency, manifestations

of allergy to penicillins include maculopapular rash, urticarial

rash, fever, bronchospasm, vasculitis, serum sickness,

exfoliative dermatitis, Stevens-Johnson syndrome, and

anaphylaxis

• The overall incidence of such reactions to the penicillins varies

from 0.7% to 10% in different studies.

Adverse effects Cont…

• Very high doses of penicillin G can cause

seizures in kidney failure.

• Pain at im injection site

• Nausea on oral ingestion

• Thromboplebitis of injected vein

Adverse effects Cont…

Penicillin V

• Orally active

• Used for the treatment of bacteremia and oral

infections

• Higher minimum bactericidal concentration

• The major draw backs of benzylpenicillin are:

– Inactivation by gastric acid

– Short duration of action

– Poor penetration into the CSF

– Narrow spectrum of activity

– Susceptibility to Penicillinase

– Development of resistance

– Possibility of anaphylaxis

Penicillinase-resistant penicillins(antistaphylococcal penicillins)

• These congeners have side chains that protect the beta

lactam ring from attack by staphylococcal penicillinase

• Indicated in infections caused by penicillinase producing

staphylococci (drugs of choice, except in MRSA)

– Methicillin, Cloxacillin

– Oxacillin, Nafcillin, Dicloxacillin

Extended spectrum penicillins

• Active against a variety of gram-negative bacilli as well

• Can be grouped according to their spectrum of activity

1. Aminopenicillins:

Ampicillins:

• Active against all organisms sensitive to PnG; in addition, many

gram-negative bacilli

Extended spectrum penicillins Cont…

Pharmacokinetics:

• Acid resistant

• Oral absorption is incomplete but adequate

• Primary excretion is kidney, partly enterohepatic circulation occurs

• Plasma half life is 1hr

Uses:

• UTI, RTI, Meningitis, Gonorrhoea, typhoid fever, bacillary dysentery,

Cholisystitis, Subacute bacterial endocarditis and Septicemias


Adverse effects:

• Diarrhoea

• Rashes

• Hypersensitivity

Interactions:

• Hydrocortisone –inactivates ampicillin if mixed in the iv solution

• OC –failure of oral contraception

• Probenecid –retards renal excretion


• Bacampicillin –ester prodrug of ampicillin

• Talampicillin, Pivampicillin and Hetacillin are other Prodrugs of

ampicillin

Amoxicillin:

• Close congener of ampicillin but not a prodrug• Similar to it in all aspects except:

– Better oral absorption– Higher and sustained blood levels are produced– Incidence of diarrhoea is lower– Less effective against Shigella and H. influenzae


2. Carboxypenicillins (Carbenicillin, Ticarcillin) and

3. Ureidopenicillins (Piperacillin)


• These are called antipseudomonal penicillins

• Piperacillin is more potent among these

• Carbenicillin is less effective against Salmonella, E. Coli and

enterobacter but not active against Klebshiella and gram-positive

cocci

• Piperacillin has good activity against Klebshiella, and is used mainly

in neutropenic/ immunocompromised patients having serious

gram-negative infections and in burns


G+Ve cocciStaphylococcus (Boils, bone, joint, infections of wounds)• Non Beta lactamase producing- Pencillin G or V• Beta lactamase producing – Flucloxacillin

Streptococcus, haemolytic types( Bacterimia, scarlet fever, toxic shock syndrome) – Pencillin-G or Pencillin V

Enterococcus (endocarditis)- Pencillin G + gentamicin

Pneimococcus (pneumonia) Pencillin G or Pencillin V or ampicillin or macrolide

G –ve cocci• Morasella catarrhalis(Sinusitis) amoxicillin+clavunic acid• Neisseria gonorrhoeae (gonorrhoea) amoxicillin+clavunic acid

G+ve rods • Clostridium (tetanus, gangrene)- Pencillin G • Listeria monocytogenes (Rarely cause meningitis) -

Amocillin±aminoglycoside

G-ve rods • Haemophilius influenzae (R.T.I, ear, sinuses, meningitis)

Ampicillin or cefuroxime• Pasterurella multocida (wound infection, abcess)

Amoxicillin+ calvulanic acid • H. pylori Metroindazole + amoxicillin+ Ranitidine

Other• Oropharyngeal infection- Pencillin G• Rheumatic fever - Prophylactic

Spirochaetes• Treponema (syphillis, yaws)- Pencillin G• Leptospira (weil’s disease) - Pencillin G• Actinomyces (abscesses) - Benzylpencillin

2nd line drug for

• Corynebacterium (diphtheria)- Macrolide- Pencillin G• UTI- extend spectrum pencillins(Amoxicillin)• Shigella (dysentery) – Q -ampicillin• Salmonella (typhoid)- Quinolone- amoxicillin• Whooping cough – Macrolide - Ampicillin• Borella recurrentis (relapsing fever)- Benzylpencillin

Beta-lactamase inhibitors

• Clavulanic acid, Sulbactam and

Tazobactam

• They contain beta-lactam ring but

themselves, do not have

significant antibacterial activity

Clavulanic acid:

• Obtained from Streptomyces clavuligerus

• Called a suicide inhibitor

• Pharmacokinetics matches amoxicillin with which it is used

Sulbactam:

• Semisynthetic beta-lactamase inhibitor

• Related chemically as well as in activity to clavulanic acid

• It is also a progressive inhibitor

• Combined with ampicillin

Beta-lactamase inhibitors Cont…

Tazobactam:

• Similar to Sulbactam

• Pharmacokinetics matches with Piperacillin with which it is used for used

in severe infections like peritonitis, pelvic/urinary/respiratory infections

• However, the combination is not effective against piperacillin-resistant

Pseudomonas

Beta-lactamase inhibitors Cont…

Ampicillin Amoxycillin

Oral incomplete absorption Oral complete absorption

Food Dec. absorption No

CSF meningitis No

Shigella respond No

Streptococci viridans respond Respond

Bacilliary desentry responds No

Gentamicin Synergistic action No

Dec. OC pills activity No

Salbactum Clavulanic acid

250-500mg of QID Equals to 250-500mg TDS

----- Used in H.Pylori Regimens

3. pencillin

Health & Medicine

penicillin nucleus

bacterial cell

acid labile

formation of d

beta lactams

autolysin enzyme

formation of udp

mold spores