Introduction to Beta Lactam Antibiotics

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Introduction to beta lactam antibiotics and Pharmacology of Penicillins includind therapeutic uses and mechanisms of bacterial drug resistance

Transcript of Introduction to Beta Lactam Antibiotics

  • Beta-Lactam Antibiotics

    Dr. Vishaal Bhat

    Melaka Manipal Medical College

  • The Beta-Lactam Antibiotics

    Cell wall active agents

    Prevent the final step in the synthesis of the bacterial cell wall

    Range from very narrow spectrum to very broad spectrum

  • Introduction

    Most widely produced and used antibacterial drugs in the world since 1941.

    -Lactams are divided into several classes based on their structure and function.

    Often named by their origin, but all classes have a common -Lactam ring structure.


    (inhibitors of cell wall synthesis)

    The major subdivisions are:

    (a) penicillins whose official names

    usually include or end in cillin(b) cephalosporins which are

    recognized by the inclusion

    of cef or ceph in their official names.

    (c) carbapenems (e.g. meropenem,


    (d) monobactams (e.g. aztreonam)

    (e) beta-lactamase inhibitors (e.g.

    clavulanic acid, sulbactam).

  • I. PENICILLINSA. FLEMING(18811955)Penicillin G- P. notatum


  • Penicillium chrysogenum

  • History

    1928- Alexander Fleming discovers a mold which inhibits the growth of staphylococcus bacteria

    1940- penicillin is isolated and tested on mice by researchers at Oxford

    1941- penicillin mass produced by fermentation for use by US soldiers in WWII

    1950s- 6-APA is discovered and semi-synthetic penicillins are developed.

    1960s to today- novel -lactams/ -lactamase inhibitors are discovered and modified from the natural products of bacteria

  • Classification

    Penicillins Natural penicillins

    PenG, PenVK, Benzathine Pen, Procaine Pen


    Ampicillin, Amoxicillin

    Anti-Staph penicillins

    Oxacillin, Dicloxacillin, Methicillin, Nafcillin


    [Carboxy] Ticarcillin

    [Ureido] Piperacillin

  • How do they work?

    1. The -lactam binds to Penicillin Binding Protein (PBP)

    2. PBP is unable to crosslink peptidoglycan chains

    3. The bacteria is unable to synthesize a stable cell wall

    4. The bacteria is lysed

  • Penicillin binding


    Peptidoglycan Synthesis

  • Mechanism of Action

  • Bacterial Resistance

    Bacteria have many methods with which to combat the effects of -lactam type drugs.

    Intrinsic defenses such as efflux pumps can remove the -lactams from the cell.

    -Lactamases are enzymes which hydrolyze the amide bond of the -lactam ring, rendering the drug useless.

    Bacteria may acquire resistance through mutation at the genes which control production of PBPs, altering the active site and binding affinity for the -lactam .

  • PK/PD

    The -lactams are time-dependent killers The effect is directly proportional to the amount of TIME the

    concentration of the antibiotic at the site of infection is ABOVE the MIC of the organism.

    The -lactams are BACTERICIDAL (at therapeutically attainable levels)

  • Time Dependant

    H Derendorf

  • Absorption,distribution & metabolism

    Oral absorption of most penicillins is poor

    Exception: penicillin v


    Food interferes with absorption

    To increase GI absorption: give ester form: BacampicillinCarbenicillin

    DistributionWidely distributed

    Relatively insoluble in lipid

    Hence, have poor penetration into cells and BBB

    Inflammation ( eg. Meningitis ) permits entrance into CSF

  • Absorp., metabolism ( cont. )

    Protein binding differs :Ampicillin and penicillin G 20% boundNafcillin, oxacillin, 90% boundcloxacillin , dicloxacillin

    Metabolism and excretion

    Not metabolized in humanExcreted mostly unchanged in urine( except. Nafcillin,oxacillin, cloxacillin, dicloxacillin )Probenecid blocks their secretionHalf-life 30-60 min ( increased in renal failure)

  • Penicillin G

    Used i.m ,slow i.v or infusionHighest activity against Gram-positive organisms but susceptible to Beta-lactamase.

    Effective against:

    Gram-positive aerobic cocci Staph. aureus- not producing penicillinase, S.pneumoniae ( group A ), S.pyogenes

    Gram-negative aerobic cocci- N.meningitides, N. gonorrhea-no longer of choice

    Gram- positive bacilli: Bacillus anthracis Spirochetes: T. pallidum drug of choice Anaerobes

    Clostridium spp but inactive against B.fragilis Actinomycetes israelii (actinomycosis)

  • Repository penicillins

    Developed to prolong duration of penicillin G in the blood

    1. Penicillin G procaine

    Duration 12- 24 hr

    It is given i.m and not i.v( risk of procaine toxicity)

    Seldom used now ( increased frequency of penicillinase producing N. gonorrhea

  • Repository penicillins ( cont.)

    2. Penicillin G benzathine (i.m)

    Duration 3- 4 weeks

    Painful at the injection site ( limits its use )


    1. Syphilis

    2. Rheumatic fever prophylaxis( inhibits

    group A beta- hemolytic streptococci)

    3. Streptococcal pharyngitis

  • Disadvantages of penicillin G

    A. Destroyed by gastric HCL

    B. Inactivated by penicillinase

    C. Narrow spectrum of activity

  • Acid resistant penicillins

    Phenoxy- methyl penicillin ( penicillin v), p.o.

    ( spectrum of activity is similar to penicillin G )


    Group A Streptococcal pharyngitis

    Prophylaxis against group A streptococci in pts with history of rheumatic heart disease.


    Readily hydrolyzed by beta-lactamase

  • Penicillinase-resistant penicillins

    Methicillin Oxacillin

    Cloxacillin Dicloxacillin

    Floxacillin Nafcillin

    Lower activity against G+ compared to Penicllin G


    Are the choice for infections caused by penicillinaseproducing S. aureus.

    However, MRSA & ORSA has emerged.

    Not effective against G- aerobes( E.coli, klebsiella, N.gonorrhea or pseudomonas spp.)

    Less active than penicillin on anaerobes.

    High protein and food binders

  • Extended- spectrum penicillins

    a) Ampicillin, Ampicillin- sulbactam, Bacampicillin, Amoxicillin, Amoxicillin- clavulanic acid.

    Less active than penicillin G against G+ cocci. Active against G- organisms.

  • Extended-spectrum penicillins

    UsesH. Influenza infections ( otitis media, sinusitis, chronic

    bronchitis, pneumonia, bacterial meningitis ).


    E. Coli infections ( Urinary & biliary infections ).

    Samonella infections ( typhoid fever )

    Shigella infections ( ampicillin )

    Gonococcal infections ( alternative for penicillin in the treatment of gonorrhea )

    Prophlaxis of infective endocarditis

    DisadvantagesAmoxicillin & ampicillin alone are readily destroyed by Staph.


  • Antipseudomonal penicillins ( cont )

    Ticarcillin-clavulanic acid, piperacillin,piperacillin-tazobactam ( Tazocin )


    Pseud. aeruginosa. For pseud. septicemia, they should be given together with an aminoglycoside

    ( eg. Gentamicin ).


    Ticarcillin and piperacillin alone are readily destroyed by S. penicillinase. High dose may lead to hypernatraemia due to sodium content.

  • Adverse effects of penicillins

    1.Hypersensitivity reactions ( occur in 1-10% of pts; fatality occur in 0.002%)

    ( immediate, accelerated & late allergic rxns) ** Cross-reactions

    Urticarial rash



    Serum sickness

    Exfoliative dermatitis

    Stevens- Johnson syndrome


    2. Super infections

    3. Diarrhoea

    4. May cause convulsions after high doses by i.v or in renal failure

  • -Lactamases

    -Lactamases were first discovered in 1940 and originally named penicillinases.

    These enzymes hydrolyze the -lactam ring, deactivating the drug, but are not covalently bound to the drug as PBPs are.

    Especially prevalent in Gram (-) bacteria.

    Three classes (A,C,D) catalyze the reaction using a serine residue, the B class of metallo- -lactamases catalyze the reaction using zinc.

  • -Lactamase Inhibitors

    How do you evade a -lactamase?1. Use a non--lactam agent

    2. Steric Inhibition

    Penicillins with large side chains


    3. -lactam + -lactamase inhibitors

    Not all -lactamases are inhibitable (!)

  • -Lactamase Inhibitors

    There are currently three clinically available -lactamase inhibitors which are combined with -lactams; all are produced through fermentation.

    These molecules bind irreversibly to -lactamases but do not have good activity against PBPs. The rings are modified to break open after acylating the enzyme.

  • -Lactam/Inhibitor combinations




    Extended-Spectrum Penicillins