SS-Lactam Antibiotics Antibiotics: Dr. Deepak Kr. Gupta

ß-Lactam
Antibiotics
Dr. Deepak Kr. Gupta
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–)
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Penicillin
Penicillin
• Penicillin was discovered
by chance in 1928.
• Flemings (1929) found
that a diffusable
substance was elaborated
by Penicillium mould
which destroy
staphylococcus on culture
plate
Chemistry
• Thiazolidine ring (A) is
attached to a β-lactam
ring (B) that carries a
secondary amino group
(RNH–).
• 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
Classification
• Natural – Penicillin G
• Semisynthetic
– Acid Resistant: Penicillin V
– penicillinase-resistant: methicillin, cloxacillin
– Aminopenicillin: Ampicillin, Amoxicillin, Bacampicillin,
– Antipseudomonal Penicillin
• Carboxypenicillin: Cerbenicillin, ticarcillin
• Ureidopenicillins: Piperacillin, Mezlocillin
– ß-lactumase inhibitors: Clavulanic acid, Sulbactam,
Tazobactam
Mechanism of Action
• Inhibit bacterial growth by interfering with the
transpeptidation reaction of bacterial cell
wall synthesis.
• 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
– peptidoglycan
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
Penicillin G
• Narrow spectrum
antibiotic
• Primarily to gram
positive cocci, bacilli
and few gram negative.
• Obtained from
fermentations of the
mold Penicillium
chrysogenum
• Benzylpenicillin
Pharmacokinetics
• Destroyed by gastric juice
• Food interferes with its
absorption – hence given 2 hr
after food
• 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 min
Clinical Use
• drug of choice for infections caused
by
– Streptococci
– Meningococci,
– some Enterococci,
– Penicillin-susceptible Pneumococci,
– 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 www.facebook.com/trigemclasses
organisms.
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
intravenous infusion – severe
infection
• Benzathine penicillin and procaine
penicillin G for intramuscular
injection yield low but prolonged
drug levels
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
– 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)
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, thrombophlebitis
on 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
Disadvantage of Natural Penicillin
• They are not effective orally
• Narrow spectrum of activity
• Susceptible to b-lactamase
• It can cause hypersensitivity
• Very high doses of penicillin G can cause
seizures in kidney failure.
Penicillin V
• Orally active
• Used for the treatment of bacteremia and oral
infections
• Higher minimum bactericidal concentration.
• DOSE
– 250-500 mg. Given 6 hourly.
– Infants: 60mg
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.
• 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
Methicillin
• Acid labile
• Not used clinically, except to identify resistant strains
• MRSA is susceptible to Vancomycin/linezolid and rarely
Ciprofloxacin
• It is highly penicillinase resistant but not acid resistant-
must be injected.
• Adverse reaction- haematuria, albuminuria, reversible
interistial nephritis
Cloxacillin
• Highly Penicillinase and Acid resistant
• More active than methicillin
• Less active against PnG sensitive organisms: should not be used as its
substitute
• 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.
Extended spectrum penicillins
• These drugs retain the antibacterial spectrum
of penicillin and have improved activity
against gram-negative organisms.
• Like penicillin, however, they are relatively
susceptible to hydrolysis by β-lactamases.
• Ex: Ampicillin, Bacampicillin, Pivampicclin,
Talampcillin, Amoxicillin
Ampicillins
• Active against all organisms sensitive to PnG; in
addition, many gram-negative bacilli
Pharmacokinetics:
• Acid resistant
• Oral absorption is incomplete but adequate
• Primary excretion is kidney, partly enterohepatic
circulation occurs
• Plasma half life is 1hr
Ampicillins
Uses:
• UTI, RTI, Meningitis, Gonorrhoea, typhoid fever, bacillary dysentery,
Cholisystitis, Subacute bacterial endocarditis and Septicemias
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
Ampicillins
Interactions:
• Hydrocortisone –inactivates ampicillin if mixed
in the I.V solution
• Oral contraceptive –failure of oral
contraception
• Probenecid –retards renal excretion
Ampicillins
DOSE-
• 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
CARBEPENICILLIN
• Penicillin conger.
• Special feature- its activity against peudomonas
aeriginosa and indole positive Proteus.
• It has Gram-negative coverage which
includes Pseudomonas aeruginosa but
limited Gram-positive coverage
• Less active against- salmonella, E.coli,
Enterobacter.
• Klebisella and gram positive cocci are remain
unaffected
CARBEPENICILLIN
• Use
– Burns
– Urinary infection.
– Septecimia.
– 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
UREIDOPENICLLINS- (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
Dosage
• t ½ =1 hr.
• Dose = 100-150 mg/kg/day.
• Trade name=
Piprapen 1g, 2g vials
Pipracil inj 2g, 4g
Pipracillin+tazobactam ( noscomial infection )-
Novacillin plus (pipracillin Na 4g + tazobactam
0.5 g)
Beta-lactamase inhibitors
• Clavulanic acid, Sulbactam and Tazobactam
• They contain beta-lactam ring but
themselves, do not have significant antibacterial
activity.
• Inactivate bacterial beta-lactamases and are
used to enhance the antibacterial actions of
beta-lactam antibiotics.
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
reversible intially but becomes covalent later – inhibitition
increasing with time.
• Called a suicide inhibitor , it gets inactivated after binding to
enzyme.
Pharmacokinetics
• Rapid oral absorption.
• Bioavailability – 60%
• t ½ = 1 hr
• Pharmacokinetics matches amoxicillin with which
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.
Use
• Coamoxiclav is indicated for
 Odontogenic infection
 Skin and soft tissue infection.
 Respiratory tract 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.v
6-8 hourly for severe infection.
Side Effect
• As same as amoxicillin alone.
• Poor G.I tolerance.(specially in children)
• Other side effect-
– Candida stomatitis.
– Vaginitis.
– Rashes.
– some cases of hepatic injury have been reported
Sulbactam
• Semisynthetic beta-lactamase inhibitor
• Related chemically as well as in activity to clavulanic acid
• It is also a progressive inhibitor
• 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.
Dose
They are available only in fixed combinations with

specific penicillins:
• 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)
Dose
• Sulbacin, Ampitum : Ampicillin 1 g &

Sulbactam 0.5 g per vial inj.
• Sulbacin 375 mg tab
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
References
• Essential of medical pharmacology.
K D Tripathi. th edition
• Manual of pharmacolgy and therapeutics.
Goodman and Glickman .
• Poisoning and drug overdose, Kent R.Olson.
5th edition
• Katzung 9th edition.

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ß-Lactam

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

• Maximum- 2-4 g/ day

They are available only in fixed combinations with

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

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

• Piperacillin + Tazobactam sodium (2g+0.25g

• Sulbacin, Ampitum : Ampicillin 1 g &

• Sulbacin 375 mg tab

• Pharmacokinetics matches with Piperacillin with

• However, the combination is not effective against

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