ß Lactam antibiotics

ß-Lactam Antibiotics Antibiotics Dr. Deepak Kr. Gupta

Transcript of ß Lactam antibiotics

Page 1: ß Lactam antibiotics


Dr. Deepak Kr. Gupta

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Introduction• Penicillin, cephalosporins, monobactams,

carbapenems, and β-lactamase inhibitors

• Four-membered lactam ring.

• Thiazolidine ring (A) is attached to a β-lactam ring (B) that carries a secondary amino group (RNH–)(B) that carries a secondary amino group (RNH–)


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• Penicillin was discovered by chance in 1928.

• Flemings (1929) found that a diffusablethat a diffusablesubstance was elaborated by Penicillium mould which destroy staphylococcus on culture plate


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Chemistry• Thiazolidine ring (A) is

attached to a β-lactamring (B) that carries a secondary amino group (RNH–).

• Substituents (R) decide • Substituents (R) decide the types of penicillin.

• Structural integrity of the 6-aminopenicillanic acid nucleus (rings A plus B) is essential for the biologic activity of these compounds


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• Natural – Penicillin G

• Semisynthetic– Acid Resistant: Penicillin V

– penicillinase-resistant: methicillin, cloxacillinpenicillinase-resistant: methicillin, cloxacillin

– Aminopenicillin: Ampicillin, Amoxicillin, Bacampicillin,

– Antipseudomonal Penicillin• Carboxypenicillin: Cerbenicillin, ticarcillin

• Ureidopenicillins: Piperacillin, Mezlocillin

– ß-lactumase inhibitors: Clavulanic acid, Sulbactam, Tazobactam


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Mechanism of Action

• Inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cellwall synthesis.

• Cell wall is composed of a complex, • Cell wall is composed of a complex,

– cross-linked polymer of polysaccharides

• alternating amino sugars, N-acetylglucosamine (NAG) and N -acetylmuramic acid (NAM)

– polypeptides,

• terminates in D-alanyl-D-alanine

– peptidoglycanwww.facebook.com/trigemclasses

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Mechanism of Action• Penicillin binding protein (PBP, an enzyme)

removes the terminal alanine in the process of forming a cross-link with a nearby peptide

• ß-Lactam Antibiotics - structural analogs of the natural D-Ala-D-Ala substrate

• Covalently bind to the active site of PBPs• Covalently bind to the active site of PBPs


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Penicillin G

• Narrow spectrum antibiotic

• Primarily to gram positive cocci, bacilli and few gram negative.and few gram negative.

• Obtained from fermentations of the mold Penicilliumchrysogenum

• Benzylpenicillinwww.facebook.com/trigemclasses

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• Destroyed by gastric juice

• Food interferes with its absorption – hence given 2 hr after food

• Doesn’t readily cross BBB, but • Doesn’t readily cross BBB, but inflammed menninges –therapeutic concentration is acieved

• Probencid blocks the renal tubular secretion of penicillin –prolongs its duration of action.

• T1/2 = 30 minwww.facebook.com/trigemclasses

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Clinical Use• drug of choice for infections caused

by– Streptococci– Meningococci, – some Enterococci, – Penicillin-susceptible Pneumococci, – non-β-lactamase-producing – non-β-lactamase-producing

Staphylococci,– Treponema pallidum– Certain other spirochetes, – Clostridium species,– Actinomyces– Certain other gram-positive rods, – non-β-lactamase-producing gram-

negative anaerobic organisms.www.facebook.com/trigemclasses

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Clinical Use• 4 and 24 million units per day

administered intravenously in four to six divided doses

• Depending on the organism, the site, and the severity of infection –dose is decided

• High-dose penicillin G - continuous • High-dose penicillin G - continuous intravenous infusion – severe infection

• Benzathine penicillin and procaine penicillin G for intramuscular injection yield low but prolonged drug levels


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Clinical Use

• Orodental infection – since its active against variety of aerobic and anaerobic MCO

• Sod.Penicillin G inj-0.5-5 MU i.m./i.v. 6-12 Hourly

• BENZYL PENicillin G• BENZYL PENicillin G– 0.5-1MU I

• Repository Penicillin G inj- these are insoluble salts of PnG which must be given by deep i.m (Never i.v.) slowly at the site of inj.

• Procaine Penicillin G inj- 0.5-1 MU( i.m) 12-24 hourly as aqueous suspension. ( PROCAINE PENICILLIN-G 0.5 MU dry powder in vial)


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Side effects

• Hypersensitivity – most common cause of drug allergy.– h/o of penicclin allergy should be taken or scratch test or

intradermal test performed.

• Local – pain at the site of injection, thrombophlebitison IV injection

• CNS : large dose of Png produces confusion, muscle twitching, convulsion and coma

• Suprainfection : rare – narrow spectrum of activity

• Jarish-Herxheimer reaction – syphillis – sudden destruction of spirochetes and release lytic products –severe fevere, myalgia, shivering, exacerbation of syphilitic lesion and vascular collapse


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Disadvantage of Natural Penicillin

• They are not effective orally

• Narrow spectrum of activity

• Susceptible to b-lactamase

• It can cause hypersensitivity• It can cause hypersensitivity

• Very high doses of penicillin G can cause seizures in kidney failure.


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Penicillin V

• Orally active

• Used for the treatment of bacteremia and oral


• Higher minimum bactericidal concentration.• Higher minimum bactericidal concentration.


– 250-500 mg. Given 6 hourly.

– Infants: 60mg


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Penicillinase-resistant penicillins• Antistaphylococcal penicillins• These penicillins are resistant to staphylococcal β-

lactamases. • They are active against staphylococci and streptococci

but not against enterococci, anaerobic bacteria, and gram-negative cocci and rods.gram-negative cocci and rods.

• 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


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• Acid labile

• Not used clinically, except to identify resistant strains

• MRSA is susceptible to Vancomycin/linezolid and rarely


• It is highly penicillinase resistant but not acid resistant-

must be injected.

• Adverse reaction- haematuria, albuminuria, reversible

interistial nephritis


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• Highly Penicillinase and Acid resistant

• More active than methicillin

• Less active against PnG sensitive organisms: should not be used as its


• Incompletely but dependably absorbed (oral route)• Incompletely but dependably absorbed (oral route)

• >90% protein bound, eliminated primarily by kidney, also partly by liver

• Plasma half life is about 1hr

• Given in staphylococcus infection resistant to benzyl penicillin

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


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• These drugs retain the antibacterial spectrum of penicillin and have improved activity against gram-negative organisms.

• Like penicillin, however, they are relatively

Extended spectrum penicillins

• Like penicillin, however, they are relatively susceptible to hydrolysis by β-lactamases.

• Ex: Ampicillin, Bacampicillin, Pivampicclin, Talampcillin, Amoxicillin


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• Active against all organisms sensitive to PnG; in addition, many gram-negative bacilli


• Acid resistant• Acid resistant

• Oral absorption is incomplete but adequate

• Primary excretion is kidney, partly enterohepatic

circulation occurs

• Plasma half life is 1hr


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

Cholisystitis, Subacute bacterial endocarditis and Septicemias

Adverse effects:Adverse effects:

• Diarrhoea(it is incompletely absorbed – the unabsorbed drug

irritates the lower intestine as well as causes marked alteration of

bacterial flora)

• Rashes

• Hypersensitivity


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• Hydrocortisone –inactivates ampicillin if mixed

in the I.V solutionin the I.V solution

• Oral contraceptive –failure of oral


• Probenecid –retards renal excretion


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• Adult- 250- 500 mg every 6 hr

• Child- 50-100 mg/kg given in equally divided

doses every 6 hr

• Maximum- 2-4 g/ day


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• Penicillin conger.• Special feature- its activity against peudomonas

aeriginosa and indole positive Proteus.• It has Gram-negative coverage which

includes Pseudomonas aeruginosa but includes Pseudomonas aeruginosa but limited Gram-positive coverage

• Less active against- salmonella, E.coli, Enterobacter.

• Klebisella and gram positive cocci are remain unaffected


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– Urinary infection.

– Septecimia.

– Uncomplicated gonorrhea– Uncomplicated gonorrhea

• Pharmacokinetics– It is neither penicillinase resistant nor acid resistant.

– Inactive orally.

– Excreted rapidly in urine.

– t ½ = 1hr

– Dose= 1-2 g i.m, 1-5 g i.v.

– Trade name - Pyogen, Carbelin 1g, 5 g per vial inj


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• 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-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


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• t ½ =1 hr.

• Dose = 100-150 mg/kg/day.

• Trade name=

Piprapen 1g, 2g vialsPiprapen 1g, 2g vials

Pipracil inj 2g, 4g

Pipracillin+tazobactam ( noscomial infection )-

Novacillin plus (pipracillin Na 4g + tazobactam0.5 g)


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Beta-lactamase inhibitors

• Clavulanic acid, Sulbactam and Tazobactam

• They contain beta-lactam ring but

themselves, do not have significant antibacterial


• Inactivate bacterial beta-lactamases and are

used to enhance the antibacterial actions of

beta-lactam antibiotics.


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Clavulanic acid

• Obtained from Streptomyces clavuligerus.

• It has beta lactam ring but no antibacterial activity of its own.

• It inhibit wide variety Class II to class V of beta lactamase.

• It is a progressive inhibitor : binding with beta lactamase is • It is a progressive inhibitor : binding with beta lactamase is

reversible intially but becomes covalent later – inhibitition

increasing with time.

• Called a suicide inhibitor , it gets inactivated after binding to



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• Rapid oral absorption.• Bioavailability – 60%• t ½ = 1 hr• Pharmacokinetics matches amoxicillin with which

it is used.it is used.• Addition of clavunic acid restablises the activity of

amoxicillin against beta lactamase producing resistant Staph.aureus, H. inflenza, N.Gonorrhoeae, E coli proteus, klebisella, salmonella and bacteria Fragilis.


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• Coamoxiclav is indicated for Odontogenic infection Skin and soft tissue infection. Respiratory tract infection. Intra abdominal and gynaecological infection Intra abdominal and gynaecological infection• Dose- Agumentin- Amoxicillin 250mg + Clavunic

acid125mg ( TDS)Agumentin – amoxicillin 1 g & clavunic acid 0.2 g

vial. i.m /i.v6-8 hourly for severe infection.


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Side Effect

• As same as amoxicillin alone.

• Poor G.I tolerance.(specially in children)

• Other side effect-

– Candida stomatitis.– Candida stomatitis.

– Vaginitis.

– Rashes.

– some cases of hepatic injury have been reported


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• Semisynthetic beta-lactamase inhibitor

• Related chemically as well as in activity to clavulanic acid

• It is also a progressive inhibitor

• Combined with ampicillin.• Combined with ampicillin.

• On the weight basis , it is less potent than clavunic acid for most

type of enzymes, but the same level of inhibition can be obtained

at the higher concentration achieved clinically.

• Oral absorption of sulbactam is inconsistent.

• Therefore , it is preferably given parentally.


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They are available only in fixed combinations with

specific penicillins:

• Ampicillin + Sulbactam (1g+0.5g I.V/I.M inj)• Ampicillin + Sulbactam (1g+0.5g I.V/I.M inj)

• Amoxycillin + Clavulanic acid (250mg+125mg tab)

• Piperacillin + Tazobactam sodium (2g+0.25g

I.V/I.M inj)


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• Sulbacin, Ampitum : Ampicillin 1 g &

Sulbactam 0.5 g per vial inj.

• Sulbacin 375 mg tab• Sulbacin 375 mg tab


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• Similar to Sulbactam

• Pharmacokinetics matches with Piperacillin with

which it is used for used in severe infections like 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


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• Essential of medical pharmacology.

K D Tripathi. th edition

• Manual of pharmacolgy and therapeutics. Goodman and Glickman . Goodman and Glickman .

• Poisoning and drug overdose, Kent R.Olson. 5th edition

• Katzung 9th edition.