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 Source Therapeutic application
affecting cell wall
Penicillin Pencillium chrysogenum Gram +ve coccal infections, syphilis,
Pencillin notatum 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.

 Peptidoglycan synthesis
Cytoplasm Cell Membrane Cell wall

undecaprenol

sugar
UDP-M, UDP-G
amino
acid

Disaccharide pentapeptide 5
 Fosfomycin
Cytoplasm
Inactivating the enzyme
Pyruvyl transferase enzyme
Inhibits formation of UDP-M
X called a "Park nucleotide"
X
sugar
Cycloserine
alanine (ala) analog
Amino acid inhibits conversion L-ala to D-ala
UDP-M pentapeptide inhibits formation of D-ala-D-ala

X
X 6
 TRANSPORT OF PEPTIGOGLYCAN
SUBUNIT ACROSS MEMBRANE

Cell membrane Cell wall

undecaprenol

P
P

7
 TRANSPORT OF PEPTIGOGLYCAN
SUBUNIT ACROSS MEMBRANE

Cell membrane Cell wall

undecaprenol

P
P

8
 TRANSPORT OF PEPTIGOGLYCAN
SUBUNIT ACROSS MEMBRANE

Cell membrane Cell wall

undecaprenol

P
P
 TRANSPORT OF PEPTIGOGLYCAN
SUBUNIT ACROSS MEMBRANE

Cell membrane Cell wall

undecaprenol

P
P
 TRANSPORT OF PEPTIGOGLYCAN
SUBUNIT ACROSS MEMBRANE

Cell membrane Cell wall

undecaprenol
P
P
 TRANSPORT OF
PEPTIGOGLYCAN SUBUNIT
ACROSS MEMBRANE

Cell membrane Cell wall

undecaprenol

BACITRACIN
 Vancomycin
Cell wall

Vancomycin ( binds to D-alanyl-D- alanine protion

of terminal end of peptidoglycan pentapeptide
Makes transglycolase enzyme ineffectual
cause inhibition of elongation
 Beta lactam antibiotics
• penicillins
• Cephalosporins/cephamycins
• monobactams
 Beta lactams
•inhibit penicillin binding proteins(Transpeptidase) Cell wall
•stop cross-linking

•Activate autolysin enzyme

There functions are diverse: catalyze the

transpeptidase reaction, maintain shape, forms
septums during division, Inhibit autolytic
enzymes.

Penicillin binding protein

 BETA LACTAM ANTIBIOTICS

• Clinically useful families of beta-lactam

compounds include the
– Penicillins,
– Cephalosporins,
– Monobactams
– Carbapenems
 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
O
S
CH3
C NH CH CH C
2 1 CH3
O C N CH COOH

•Beta lactamase •Penicillanic acid

• Gastric 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 Semisynthetic

β- lactum β- lactum resistance β- lactum

•Narrow spectrum
•Acid liable sensitive Anti staphylococcal inhibitors
•β- lactum sensitive
Narrow spect Extended Acid Liable Acid Stable
Long acting Short acting
•Methicillin •Floxacillin
•Procaine pencillin •Pencillin-G Acid Stable
•Pencillin- V • •Oxacillin
•Benzethine Aminopencillins Neficillin •Cloxacillin
•Ampicillin •Dicloxacilin
•Becampacilllin
•Talampicillin
•Amoxicillin
Acid Liable/ Anti pseudomonal
Carboxy pen.
•Carbenpencillin
•Pencillin- V (Phenoxy methylpencillin) •Tricarben pencillin
Uridopen.
•Azlocillin
•Mezlocillin
•Pipera pencillin
Antimicrobial spectrum: Penicillin G
 Pharmacokinetics
Oral 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
 Pharmacokinetics Cont…

• 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,
 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
 Resistance mechansims
• Produce β lactamase (penicillinase)
– destroys antibiotic
• modified penicillin binding proteins
– don’t bind antibiotic
• modified porins
– no internalization of antibiotic

27
 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)
 Adverse effects Cont…

• 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

 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…
 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
G+Ve cocci
Staphylococcus (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
 2 line drug for
nd

• 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
 Beta-lactamase inhibitors Cont…

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
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