Antibiotics

Antibiotic Properties

 

Bacteriocidal

- B Lactams

- Aminoglycosides

- Flouroquinolones

- Fusidic acid / rifampicin

- Co-trimoxazole / Nitroimidazoles

- Vancomycin

 

Bacteriostatic

- erythromycin / clindamycin

- tetracyclins

- suphonamides / trimethorim / nitrofurantoin

- Chloramphenicol

 

Bacteriostatic and bacteriocidal are relative terms and also depend on the organism

 

Method of Action

 

Cell wall synthesis

- B lactams

- Vancomycin

 

Protein synthesis

- Aminoglycosides

- Macrolides (erythromycin, clindamycin, azithromycin)

- Tetracyclines

- Chloramphenicol 

- Fusidic acid 

 

DNA replication

- Quinolones

 

DNA synthesis

- Nitroimidazoles

- Nitrofurans

 

RNA polymerase

- Rifampicin

 

Folate metabolism

- Trimethoprim

- Sulphonamides

 

1.  Penicillins

 

Source

- derived from moulds of Penicillium

 

Structure

- ß-lactam ring with attached Thiazolidine ring

- drugs vary with relation to attached radicals

 

MOA

 

Bacteriocidal

- inhibit bacterial cell wall synthesis

- bind to PBP's (penicillin binding proteins)

- inhibit membane-bound Transpeptidase

- inhibit Peptidoglycan synthesis

- leads to weakening of cell wall & death

 

Resistance

 

Beta-lactamase (penicillinase)

- Splits ß-lactam ring of penicillin nucleus

 

Organisms

- S Aureus

- Some E coli

- Proteus Mirabilis

- Pseudomonas Aeruginosa

 

Flucloxacillin & Clavulinic Acid

- resistant to penicillinase

- have high affinity for ß lactam

- bind it but are not hydrolysed 

 

Other forms of resistance exhibited by Staphylococci

- Absence of PBPs secondary to mutation

- Failure of drug to activate autolytic enzymes in cell wall

 

Classification

 

1.  Penicillinase Sensitive

 

A.  Penicillin G / Benzylpenicillin

- Acid-labile

- IV only

 

B.  Penicillin V / Phenoxymethylpenicillin (PVK)

- acid-resistant

- oral

 

Uses

- S pyogenes / S pneumoniae

- G-ve cocci / N Meningiditis

- G+ve Bacilli / Clostridium

- Treponema Pallidum / Syphilis

 

2.  Penicillinase Resistant

 

Flucloxacillin

- Oral & parenteral

- Resistance 2° absence PBP

 

Dicloxacillin

- ? Less Hepatoxicity 1:50 000

 

Uses

- S. aureus

 

3.  Broad Spectrum

 

Amoxycillin

- Effective against Gram negative

- Oral & parenteral

 

Uses

- All of Penicillin-sensitive group plus

- G-ve Bacilli / Haemophilus / Salmonella

 

Kinetics

 

Absorption

- Flucloxacillin is fairly well absorbed

- Amoxycillin is well absorbed

- Food decreases absorption

- Give before food

 

Penetration

- Penetrates most tissues well

- Penetrates CNS very well

 

Excretion

- in urine

- 90% by tubular excretion

- Can be blocked by Probenocid

- T1/2 30-60 min

 

Dosage

 

Benzylpenicillin - 600-1200mg q6h IV

PVK - 500 mg qid oral

Flucloxacillin

- 1-2 g q6h iv

- 500 mg qid

- Kids 25mg/kg/Dose IV q6/24

 

Adverse Affects

 

Hypersensitivity

- Occurs in up to 5%

- Antigens are degradation products of penicillin

- Use desensitisation if no other option available

- Desensitisation is dangerous 

 

Anaphylactic shock

- Rare 0.05%

- Fatal in 10%

 

Skin Rashes

- Common

- broad range

 

Stevens- Johnson Syndrome

- Usually occurs at 3-10 days

- Ampicillin causes specific maculopapular rash

 

Interactions

 

Probenocid

- inhibits renal tubular secretion of penicillin

- enhances effect of Penicillins

 

Clavulinic Acid

- Clavulinic Acid inhibits bacterial Penicillinase

- Combined with Amoxycillin

 

Cephalosporins

 

Source

- discovered in 1945 in Sardinian sewer

 

Structure

- ß-lactam

- dihydrothiazine ring fused with four-member beta-lactam ring

 

MOA

- Bind to enzymes involved in cell wall biosynthesis

- Penicillin-binding proteins (PBP's)

 

First Generation

 

Drugs

- Cephalothin / Cephalexin / Cefazolin

 

Activity

- active against most Gram positives

- limited Gram negative activity

- exception E coli / Klebsiella / Proteus

 

Second Generation

 

Drugs

- Cefoxitin (Mefoxin)

 

Activity

- generally less Gram positive activity

- more effective against Gram negatives

- more active against H Influenzae

 

Third Generation

 

Drugs

- Cefotaxime / Ceftriaxone / Ceftazidime

 

Activity

- even less effective against Gram positives

- more effective against Gram negative organisms

- effective against Gram negative enterics (Klebsiella Proteus Enterobacter Serratia)

- Ceftazidime is effective against Pseudomonas

 

Pharmacological Properties

 

Route

- most not orally absorbed (except cephalexin)

 

Distribution

- variable protein binding (Cephalexin 15% - Ceftriaxone 90%)

- widely distributed (Interstitial & Peritoneal fluids / Urine)

- CSF - 3rd Generation only

- all enter bone

- all have excellent synovial fluid concentrations

 

Excretion

- via kidney

- active tubular secretion and Glomerular filtration

- accumulate with CRF (T1/2 of Cephalexin increases from 1 hr to 20 hrs)

 

Adverse Reactions

 

Hypersensitivity

- anaphylaxis rare

- skin rash 1-5%

- cross sensitivity with Penicillin ~ 5%

- no CI if delayed Penicillin SE i.e. Rash

- avoid with immediate Penicillin SE

 

GIT

- diarrhoea in 1-10%

- pseudomembranous colitis uncommon

 

Other

- Cephalothin may potentiate nephrotoxicity of Gentamicin

 

Indications

 

S. Aureus Infections

- first generation

- drug of choice in Penicillin allergy

 

Strep Infections

- first generation

 

Ceftazidime

- pseudomonas OM

 

Prophylaxis 

 

First generation are drugs of choice

- effective against common org

- inexpensive

- low toxicity

- achieve high concentration in bone and soft tissue

 

Cefazolin is drug of choice

- longer T1/2 than Cephalothin

- may achieve better bone levels

 

Aminoglycosides

 

Source

- discovered in 1940's

- derived from soil bacteria

 

MOA

 

Multifactorial bacteriocidal effect 

- bind to Gram negative bacterial cell wall & affect permeability

- bind to bacterial ribosomes & affect protein synthesis

 

Gentamicin

- attaches to specific receptor protein on bacterial 30s ribosome

- block initiation complex of peptide formation

- results in misreading of mRNA & non functional protein

- ribosome breaks up into fragments

- result is cell death

 

Resistance

 

1.  Lack of receptor on ribosome 

- chromosomal mutation

 

2. Produce drug destroying enzymes

- plasmid-induced

 

3. Permeability defect

- plasmid-induced

 

Pharmacokinetics

 

Concentration-Dependent killing

- one single bolus dose works better than divided doses in 24 hrs

- concentration-dependent

- dose is 4-5 mg/kg over 60 min

- peak levels not required

- level at 18 hours to check trough

 

Antimicrobial synergy

 

Synergy between Aminoglycoside & Penicillin / cephalosporin for Gram positive cocci

 

Distribution

 

Administered IV over 30 minutes

- minimal absorption from GIT

- large volume of distribution

- cross membranes poorly / blood brain barrier

- exception is renal tubular & inner ear cells

- enters synovial fluid easily

 

Metabolism

 

Not metabolised

- 99% excreted unchanged in kidney

 

Side Effects

 

Allergies rare

 

Kidney damage

- injury to renal PCT 

 

Inner ear damage

- damage to cochlea & vestibular apparatus

- appears to be less with once daily dose

- idiosyncratic & dose related

 

Indications

 

Effective against the vast majority of gram negatives

- Aerobic G - Bacillus

- Klebsiella

- Enterobacter

- Serratia

- Pseudomonas (Tobramicin)

 

Resistance rare

 

Ciprofloxacin

 

Structure

- Fluoroquinolone

 

Mechanism

- interfere with bacterial DNA synthesis

- inhibits the A subunit of bacterial topoisomerase  

 

Side Effect

- toxic to paediatric cartilage

 

Indication

- broad spectrum

- gram negative and positive

- potent oral antipseudomonal

- not as effective against staph as cephalosporins

 

Vancomycin

 

MOA

- bacteriocidal

- anti cell wall synthesis

- different mechanisms to B Lactams

- inhibits early stage of Peptidoglycan synthesis intracellular

- requires cell wall penetration

 

Indications

- Pseudomembranous Colitis orally

- MRSA

- prophylaxis if high rates methicillin resistance in community

 

Kinetics

 

Absorption

- very poorly GIT absorbed

- very irritant to veins

 

Excretion

- renally excreted unchanged 

- T1/2 8 hrs

 

Administration

- dilute in 200 ml saline

- administer over 2 hr

 

Side Effects

 

Ototoxicity

- dose-related

- don't use with hearing impairment

- Withdraw if tinnitus occurs

 

Nephrotoxicity

- dose-related

- don't use with renal impairment

- monitor renal function

 

Hypersensitivity

- "Red man's syndrome"

- due to Histamine release

- from too rapid infusion

 

Tissue necrosis

- from extravasation

 

Interactions

 

Care with other nephrotoxic drugs

- Aminoglycosides