Cell

 Wall  Synthesis  Inhibitors  

! lactams

PENICILLIN

Mechanism of Action

• Bacteriostatic to active bacteria

Binds to transpeptidase and inhibits cross linking (transpeptidation) of peptidoglycan
• Bactericidal to others
Activates murein hydrolase leading to autolysis as peptidoglycan is degraded

Resistance

• Causes of resistance • Solution: Co-administration with oxapenems

– Production of β lactamase (eg. E. coli) – Weak antibiotic activity on its own but has a strong affinity for β
– Transpeptidase mutation (eg. MRSA) lactamases that maintains penicillin activity
– Reduced permeability to the drug – Eg. clavulanic acid, sulbactam, tazobactam
– Increased active removal of the drug – Combinational therapy includes coamoxiclav, piptazo, sultamicillin

Pharmacokinetics

Absorption: • Oral availability of amoxicillin / ampicillin > cloxacillin > penicillin V

• Most cannot be consumed with food (except amoxicillin)
Distribution: • Wide distribution except to CSF due to lipophilic nature of drug

Metabolism: • Minimal hepatic metabolism

Excretions: • Mainly unchanged in urine – 90% glomerular filtration, 10% tubular secretion

Forms

Penicillins Generally narrow spectrum and β lactamase sensitive – Penicillin G derivatives

– Penicillin V (oral) or Benzylpenicillin (IV) or Potassium penicillin G (IV)
– Benzathine penicillin G & Procaine penicillin G = slow releasing IM

Isoaxyzopenicillin Generally narrow spectrum and β lactamase resistant

Staphylococcal penicillin – Cloxacillin and Flucloxacillin (good oral bioavailability)

Extended Spectrum Wide spectrum and β lactamase sensitive

Penicillin – Amoxicillin & Ampicillin have good oral bioavailability as they are acid stable
(Amoxicillin > Ampicillin)
– Piperacillin (IV) and Methicillin (discontinued)

Spectrum of Activity

Penicillins Most Gram Positives + Some Gram Negatives

[Gram Positive] Streptococci, Enterococci, Staphylococci, Clostridium, Actinomyces, Pneumococci
[Gram Negative] Neisseria

M2 Pharmacology by Tony & Joel | Antibiotics – Cell Wall Synthesis Inhibitors 1

 
 Isoaxyzopenicillin Some Gram Positives
Staphylococcal penicillin [Gram Positive] Staphylococci, Streptococci, Pneumococci

Extended Spectrum Most Gram Positives + More Gram Negatives than normal penicillin
Penicillin – Piperacillin can target Pseudomonas, Enterobactericeae, Klebsiella
– Amoxicillin used in combinational therapy for H. pylori

Side Effects

Allergies • Penicillin degradation products combine with host proteins to trigger immune response
• Can be acute (< 30min), accelerated (< 72hrs) or late response (days to weeks)
• Presents with
– Rashes, Fever, Steven Johnson Syndrome, Toxic Epidermal Necrolysis
– Anaphylaxis with laryngeal oedema, bronchoconstriction, that can cause asphyxiation

Neurotoxicity • Convulsions, Confusion, Hallucination

• Due to rise in blood [drug] often due to failure in excretion

Others • Usage of broad spectrum penicillin can lead to C. difficile associated diarrhoea (CDAD)

Due to preparation • Procaine in procaine penicillin G can lead to bizarre behavior

• Potassium in potassium procaine G can cause arrhythmias

Drug Interactions

Nil

CEPHALOSPORINS

Mechanism of Action

Same as Penicillin

Resistance

• Extended Spectrum β lactamases

– Normal β lactamases cannot act on cephalosporins
– E. coli & Klebsiella among others have developed special
extended spectrum β lactamases that degrade cephalosporins

Pharmacokinetics

Absorption: • Generally IM or IV preparations esp for 3rd and 4th generation

• Only 1st and 2nd generation cephalosporins can be given orally

• Ceftriaxone given as a single daily dose

Distribution: • Wide distribution

• 3rd and 4th generation cephalosporins can penetrate CSF well

Metabolism: • Minimal hepatic metabolism

Excretions: • Mainly via tubular secretions at the kidney

• Ceftriaxone is partially (40%) excreted in the bile after metabolism in the liver

M2 Pharmacology by Tony & Joel | Antibiotics – Cell Wall Synthesis Inhibitors 2

 
Forms

1st generation Most Gram Positives + Some Gram Negatives (low effectiveness)
Cefalexin (oral) [Gram Positive] Streptococci, Staphylococci, Pneumococci
Cefazolin (IM / IV) [Gram Negative] E. coli, Klebsiella

2nd generation Most Gram Positives + Some Gram Negatives (more effective than 1st gen)
Cefuroxime axetil (oral) [Gram Positive] including certain β lactamase producing species such as H. influenzae
Cefuroxime (IM / IV) [Gram Negative] especially Klebsiella and Bacteriodes fragilis
Cefaclor (oral)

3rd generation Most Gram Positives + Some Gram Negatives (low effectiveness)
Ceftriaxone (IM / IV) [Gram Positive] especially penicillin resistant Pneumococci
Ceftazidime (IM / IV) [Gram Negative] including Pseudomonas, Citrobacter

4th generation Most Gram Positives + Some Gram Negatives (highest activity among cephalosporins)
Cefepime (IM / IV) [Gram Positive] especially penicillin resistant Pneumococci, Staphylococci, Haemophillus
[Gram Negative] including Pseudomonas, Enterobactericeae, Neisseria

Side Effects

Allergies • Presents as rashes or anaphylaxis

• Cross reactivity with penicillin
GIT Disturbances • Diarrhoea especially in oral formulations
• C. difficile associated diarrhoea (CDAD)

Thrombophlebitis • Emboli can form due to haemodynamic changes and endothelial activation due to
irritation by cephalosporins leading to other complications
• Minimized by slow infusions at different infusion sites to minimize cumulative irritation

Drug Interactions

• Ceftriaxone must not be given with any calcium containing agents (diluents or solutions) as it can lead to fatal
precipitates in the lungs and kidneys

CARBAPENEMS

Mechanism of Action Forms

Same as Penicillin • Imipenem (IM or IV) is usually administered

Resistance
• Rare but beginning to
develop
– NDM-1: New Delhi
metallo β lactamase
– No new antibiotics in
the pipeline to replace
Carbapenems
• Resistant strains include
– MRSA
– C. difficile
– Bulkholderia cepacia
– Stenophomas maltophilia
with cilastatin to inhibit renal dehydropeptidase
to prolong half life
• Meropenem is only given IV
• Broad spectrum as it is able to penetrate
outer membrane of gram negatives – most
effective β lactam against anaerobes

M2 Pharmacology by Tony & Joel | Antibiotics – Cell Wall Synthesis Inhibitors 3

 
Pharmacokinetics

Absorption: • Poor oral bioavailability and is administered IV

Distribution: • Wide distribution and enters CSF

Metabolism: • Imipenem is broken down by dehyropeptidase in renal tubular cells

• Meropenem is not metabolized

Excretions: • Meropenem is excreted unchanged in the urine

Side Effects

Allergies • Presents as rashes or anaphylaxis

GIT Disturbances • Nausea, Vomiting Diarrhoea

• C. difficile associated diarrhoea and other superinfections

Neurotoxicity • Seizures, Convulsions, Hallucinations when [drug] is too high

Drug Interactions

Nil

MONOBACTAMS

Mechanism of Action Forms

Same as Penicillin Aztreonam

BUT low cross reactivity to penicillin • High therapeutic index with low potential toxicity
Mainly used against Gram Negative Aerobes • Resistant to the action of most β lactamases

Pharmacokinetics Side Effects

Absorption: • Parenteral only Allergies • Rashes, Fever

Distribution: • Wide distribution; enters CSF Others • GIT Disturbances such as

when the meninges are inflamed diarrhoea, nausea

Metabolism: • Transaminaemia
• Minimal hepatic metabolism

Excretions: • 60 – 70% renal excretion

Drug Interactions

Nil

M2 Pharmacology by Tony & Joel | Antibiotics – Cell Wall Synthesis Inhibitors 4

 
Non ! lactams

VANCOMYCIN

Mechanism of Action Usage for

• Inhibits biosynthesis of peptidoglycans • Treatment of patients with penicillin allergy

• Binds to D-Ala-D-Ala terminus of transpeptidase, blocks
further reactions sterically (umbrella effect)
– Prevents the synthesis of the long polymers that form the
backbone strands of the bacterial cell wall
– Prevents the backbone polymers that do manage to form
from cross-linking with each other
• Active against Gram Positives (with peptidoglycan cell wall)
Resistance
• Rare but beginning to develop
– Mutation to terminal D-Ala to D-lactate that causes loss of
the original binding site thus preventing vancomycin activity
– Eg. VRSA, VRE
• Antibody associated PMC especially when
microbe is resistant to metronidazole
• Only active against Gram Positives
• Empirical cover in MRSA while awaiting
sensitivity cultures and confirmation
• Prophylaxis for:
– Implant / Prosthetics surgeries when
MRSA is common
– Endocarditis in penicillin allergic patients

Pharmacokinetics

Absorption: • Poor oral bioavailability and usually administered parentrally

• IV administration except for treatment of PMC or some colonic infections (oral)

Distribution: • Wide distribution and poor penetration of CSF

Metabolism: • No hepatic metabolism

Excretions: • Most renal excretion by glomerular filtration (affected in renal failure)

Side Effects

Allergies • Presents as rashes or anaphylaxis

• Red Neck / Red Man syndrome where there is a characteristic rash above the nipple
line due to histamine release. Can be prevented by slower infusion of vancomycin

Nephrotoxicity & • Rare

Ototoxicity • Can be triggered when used in conjunction with other nephrotoxic or ototoxic agents
such as aminoglycosides and amphotericin B

Thrombophlebitis • With fevers and chills

Drug Interactions

Nil

M2 Pharmacology by Tony & Joel | Antibiotics – Cell Wall Synthesis Inhibitors 5

 
Cell Membrane Targeting Drugs

POLYMYXINS

Mechanism of Action General Application

• Derived from Bacillus polyxma • Parentral, Oral or topical

• Affinity for LPS in Gram Negatives, causes detergent like damage • Generally oral preparations are not given
• Resistance may develop when the binding site is modified such as absorption in the GIT is poor
that polymyxin is no longer able to bind

Side Effects

Nephrotoxicity • Low toxicity but damage still might occur

M2 Pharmacology by Tony & Joel | Antibiotics – Cell Wall Synthesis Inhibitors 6