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