Transcript Antibiotics F.A. Fehintola

Antibiotics
F.A. Fehintola
Introduction
Selective toxicity:
 Basic principle of chemotherapy
 Seeks to exploit certain characteristics
peculiar to organisms or cell groups towards
its elimination with a view to improving the
health status of the host.
Introduction
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Antibiotics
Are products of various species of micro-organisms
including bacteria and fungi that suppress growth of
other micro-organisms
The term is sometimes used interchangeably with
antibacterial, thus including such synthetic agents
as:
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Sulphonamides
Quinolones
Mechanism of action
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Inhibition of cell wall synthesis
Membrane dysfunction
Ribosome dysfunction
DNA dysfunction
Others:
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Anti-metabolites
Nucleic acid analogue
Mechanism of action
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Inhibition of cell wall:
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Penicillins
Cephalosporins
Cycloserine
Vancomycin
Bacitracin
Mechanism of action
Cell membrane dysfunction:
 Polymixin
Ribosome dysfunction:
 Tetracyclines
 Aminoglycosides
 Chloramphenicol
 Clindamycin
 Macrolides
Mechanism of action
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DNA dysfunction:
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DNA dependent RNA polymerase inhibitor
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Rifamycins
DNA gyrase inhibitor
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quinolones
Mechanism of action
Anti-metabolites:
 Sulphonamides
 Trimethoprim
Nucleic acid analogue
 antiviral agents
Drug resistance
The organism survives and/or multiplies in the
presence of a given antibiotic
This may be:
 Chromosomal: mutation
 Extra-chromosomal: plasmid
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Propagation may be vertical or horizontal
Drug resistance
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Mutation is followed by vertical transmission
AND
Horizontal acquisition involves:
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Transformation
Transduction
Conjugation
Drug resistance:
Mutation
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Organism previously sensitive
Random process
Alteration of drug target or production of inactivating
enzyme
Ribosomal mutation
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DNA gyrase mutation
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Aminoglycosides
Tetracyclines
quinolones
RNA polymerase gene mutation
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Rifampicin
Drug resistance: transduction,
transformation, conjugation
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Transduction:
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Involves bacteriophage
Plasmid transfer of resistance trait
Commonly occurs in Staph. aureus for the
production of penicillinase
Transformation:
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Direct ‘capture’ of genetic materials from the
environment
Alteration of target e.g. PBP
Drug resistance: transduction,
transformation, conjugation
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Conjugation
Direct contact between the donor and
recipient
Genetic material traverses the sex pilus
Common among Gram –ve bacteria
May occur between pathogenic and nonpathogenic bacteria
Drug resistance
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Biochemical expression
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Destructive enzymes
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Altered target
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Aminoglycosides
penicillins
chloramphenicol
Antifolates
Rifamycins
quinolones
Reduced penetration
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Aminoglycosides
tetracyclines
Guides to successful antibiotic use
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Sound clinical judgement
Bacteriological back-up
Individualisation of therapy
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Except in special circumstances antibiotics should
be used only after ‘definitive’ diagnosis
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Immune status, age, genetics, co-morbidity
Severe infection, chemoprophylaxis
Pharmacology of the antibiotics esp. when used in
combination
The Beta Lactam antibiotics
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Penicillins
Cephalosporins
Monobactam
Carbapenem
Penicillins
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Mechanism of action involves:
Inhibition of cross-linkage between units of
peptidoglycan
Peptidoglycan consists of
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Polysaccharide
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N-acetyl muramic
N-acetyl glucosamine
Pentapeptide
Bacterial transpeptidase enzyme also binds the
penicillin since it is similar to its original substrate (Dalanyl- D-alanine)
Penicillins
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Classes:
Penicillins
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Aminopenicillins
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Methicilin
Nafcillin
oxacillin
Antipseudomonal
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Ampicillin
amoxicyllin
Antistaphylococcal
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Benzyl penicillin
Carbenicillin
ticarcillin
Beta lactamase inhibitors: sulbactam, clavulanic acid, tazobactam
Penicillin G
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Spectrum of activity
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Gram +ve organisms mainly
Gram –ve cocci
Some anaerobes (non lactamase producing)
Effective dose 4-24 m units per day in divided doses
Penicillin V is oral formulation
Benzathine penicillin and procaine penicillin belong to this
class
Half or quarter dose in renal failure depending Cr. clearance
aminopenicillin
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Also known as extended spectrum
Ampicillin & amoxycillin are examples
Enhanced activity against G-ve organisms
Susceptible to lactamases
Amoxycillin enjoys better absorption
Effective in anaerobes, entorococci, E. coli, Shigella,
salmonella spp.
Lack activity against klebsiella, pseudomonas
proteus etc
antipseudomonal
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Carbenicillin, ticarcillin are examples
Pseudomonas infections are usually treated
with penicillins in combination with
aminoglycosides
Antipseudomonal drugs may be combined
with lactamase inhibitor to further extend
their activities
Adverse effects
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Hypersensitivity
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Haemolytic anaemia
Interstitial nephritis
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Anaphylaxis
Serum sickness
angioedema
urticaria
Methicillin
Pseudomembranous colitis
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ampicillin
Cephalosporins
Cephalosporins
Cephalosporium fungus
 Ring structure derived from 7- amino
cephalosporanic acid
 B lactam antibiotics
 In general, G-ve activity increases as the G+ve
activity decreases
 Freq of dosing also decreases with newer generation
 Relatively stable in acid and aqueous media
Classification
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1st generation: cephalexin cephradine
cefadroxil
2nd generation: cefuroxime cefoxitin cefaclor
ceproxil
3rd generation: cefotaxime ceftriaxone
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Antipseudomanas: ceftazidime cefoperazone
4th generation: cefepime
Mechanism of action
 Inhibition of cell wall synthesis* thus disrupting functional
stability of the bacteria
Resistance
 Plasmid mediated synthesis of B- lactamase enzyme – major
 Minor ones incl: reduced cell penetration and altered target site
(PBP)
* Blockade of transpeptidation, the final process of peptidoglycan synthesis
Absorption Distribution Elimination
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Oral, and parenteral routes employed
Widely distributed throughout the body (penetrates well
into CNS aqueous humour, synovial fluid and crosses placenta)
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Some – ceftriazone, cefuroxime, cefotaxime cross
blood-brain barrier readily
Extn; tubular secretion in the kidney*
* Probenecid interferes with this
NB: Notable exceptions 40-50% of ceftriazone and 75% of cefoperazone are excreted in bile
Clinical applications
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Pre-op to prevent wound infection
Klebsiella, Serratia, Enterobacter, Proteus,
Haemophilus infections
Gonorrhoea
Meningitis – cefotaxime, ceftriaxone, ceftazidime*
Treatment of anaerobes- used in combination with
other antibiotics to clear aerobes
* in case of Pseudomonas meningitis
Clinical applications
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Community acquired pneumonias
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cefuroxime
ceftriaxone
cefotaxime
Typhoid – ceftriaxone, cefoperazone
Lyme Dx – ceftriaxone, cefotaxime
Neutropenic patients
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usually combined with aminoglycosides
Cephalexin
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An e.g of 1st generation
Orally administered
Spectrum: Strept & Staph
NOT effective in enterococcal
infection
Not metabolized: parent drug eliminated in the urine
Usual dose 25-100 mg per Kg per day (determined by
severity of infection)
Cephalexin
ADR:
 Pseudomembranous colitis,
 GI upset, Anaphylaxis, fever,
 Arthalgia, erythema multiforme, cholestatic
jaundice,
 Blood disorders, interstial nephritis,
 Hypertonia, sleep disturbances, confusion.
Cefuroxime
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Both oral and parenteral routes employed
Spectrum: klebsiella, E. coli, Proteus, Haemophilus
Activity against G+ve less than 1st generation
T1/2 about 2 hours and given 8-12 hrly
CNS 10% conc in plasma
The cefuroxime axetil, given orally; is 30-50%
absorbed
ADR: As for 1st generation
Ceftriaxone
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Relatively long half-life
Administered once or 2ce daily
Spectrum: Enterobacteriaceae, Pseudomonas,
Serratia, Neisseria, Staph and Strep
50-60% recovered from urine and rest secreted in
bile
ADRs:
As above; may displace bilirubin in plasma and
should be avoided in <6/52 olds
Also caution in hepatic disease
Classification
First
Second
inactive against G+ve
organism
Third
activity against
G+ve org similar to 1st
Cefazolin,
cephalexin
Cefuroxime,
cefaclor
Ceftriazone,
cefotaxime
Fourth more β lactam cefepime
resistant than 3rd
generation
Staph, strept
E. coli,
Haemophilus,
Proteus
Enterobacteriace
ae, Staph,
Serratia, strept
= 3rd generation
Vancomycin
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Cell wall active antibiotic
Binds to the D-alanyl D alanine terminus of cell wall
precursor
Affects only the Gram +ve organism
Resistance follows alteration of the target
Cross resistance may occur with*:
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Teicoplanin
Daptomycin
* Other glycopeptides
Vancomycin
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Poorly absorbed if taken orally
Usual adult dose is 1 g I.V infusion (may be given orally to treat
pseudomembranous colitis 250 mg 6hrly)
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Elimination half is 6 hours
About 55% plasma protein binding
CSF conc. ~ 7-30% in inflammation
~90% excreted by kidney, so accumulates in CRF
Synergism with aminoglycosides (and ADRs too!)
Vancomycin
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Recommended for only serious infections like MRSA
Also useful in penicillin-sensitive staph. Infections
ADRs: hypersensitivity reactions including
anaphylaxis
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Phlebitis, pain, fever
Red man syndrome (intense flushing, tachycardia and hypotension)
Nephrotoxicity
Ototoxicity