Lactam antibiotics

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  • -LactamAntibioticsAntibiotics

    Dr. Deepak Kr. Gupta

  • Introduction Penicillin, cephalosporins, monobactams,

    carbapenems, and -lactamase inhibitors

    Four-membered lactam ring.

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


  • PenicillinPenicillin

  • Penicillin

    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

  • Chemistry Thiazolidine ring (A) is

    attached to a -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


  • Classification

    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

    -lactumase inhibitors: Clavulanic acid, Sulbactam, Tazobactam

  • 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)


    terminates in D-alanyl-D-alanine

  • 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

    -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

  • 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

  • Pharmacokinetics

    Destroyed by gastric juice

    Food interferes with its absorption hence given 2 hr after food

    Doesnt readily cross BBB, but Doesnt 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

  • Clinical Use drug of choice for infections caused

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

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

    negative anaerobic

  • 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

  • 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)

  • 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

  • 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.

  • 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

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

    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

  • Methicillin

    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

  • Cloxacillin

    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.

  • 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 -lactamases.

    Ex: Ampicillin, Bacampicillin, Pivampicclin, Talampcillin, Amoxicillin

  • Ampicillins

    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

  • Ampicillins


    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)



  • Ampicillins


    Hydrocortisone inactivates ampicillin if mixed

    in the I.V solutionin the I.V solution

    Oral contraceptive failure of oral


    Probenecid retards renal excretion

  • Ampicillins


    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


    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 unaffect