3. pencillin
TRANSCRIPT
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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TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
Cell membrane
undecaprenol
PP
Cell wall
TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
Cell membrane
undecaprenol
PP
Cell wall
TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
Cell membrane
undecaprenol
PP
Cell wall
TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
Cell membrane
undecaprenol
PP
Cell wall
BACITRACIN
Cell membrane
undecaprenol
P
Cell wall
TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE
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
Extended spectrum penicillins Cont…
Adverse effects:
• Diarrhoea
• Rashes
• Hypersensitivity
Interactions:
• Hydrocortisone –inactivates ampicillin if mixed in the iv solution
• OC –failure of oral contraception
• Probenecid –retards renal excretion
Extended spectrum penicillins Cont…
• 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
Extended spectrum penicillins Cont…
2. Carboxypenicillins (Carbenicillin, Ticarcillin) and
3. Ureidopenicillins (Piperacillin)
Extended spectrum penicillins Cont…
• 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
Extended spectrum penicillins Cont…
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