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Antibiotics

MR. H GEE MD, FRCOG


Hon. Assoc. Clinical Professor
University of Warwick
Objectives
• By the end of this lecture you should be able to:

1) Classify commonly used antibiotics into six major antibiotic


classes of;
a) Beta lactams
b) Aminoglycosides
c) Fluoroquinolones
d) Macrolides
e) Tetracyclines
f) Glycopeptides
g) Metronidazole

2) Understand the mechanism of action of each antibiotic class.

3) Understand clinical use of each class of antibiotic

4) Possible major side effects.


There are Three in this Relationship

Drug

Infection
Host Bacteria
Host defence
Improving the probability of
positive outcomes
• Window of opportunity
– Early recognition and treatment of infection
– Selection of appropriate antibiotic
(e.g. through in vitro susceptibility determination)
– Optimization of DOSE using
Pharmacodynamic principles

– Use optimized dosing that would allow for the


minimization of selecting further resistance
Early recognition of infection
(Sepsis)
• Systemic inflammatory response syndrome (SIRS)
(Bone et al Crit Care med 1989.;17 :389)

Systemic activation of the immune response


 2 of the following in response to an insult:
• T > 38 .C or < 36.C
• HR > 90 bpm
• RR > 20 bpm
• WBC > 12 000 cells/mm3

• Sepsis
SIRS + suspected or confirmed infection
Key Message 1
• Diagnose sepsis early and give antibiotics
promptly to reduce mortality from sepsis
Antibiotics
Actions
Bactericidal
Kills bacteria, reduces bacterial load
Bacteriostatic
Inhibit growth and reproduction of bacteria
All antibiotics require the immune system to work
properly
Bactericidal appropriate in poor immunity
Bacteriostatic require intact immune system
ß-Lactams

Β-Lactam
Thiazolidine Ring
Ring
ß-Lactams
ß-Lactams
Penicillin
Narrow Spectrum
Cephalosporin •Benzylpenicillin (Penicillin G)
•Cefalexin •Phenoxymethylpenicillin (Pen V)
•Cefuroxime •Flucloxacillin
•Cefotaxime Broad Spectrum
•Ceftriaxone •Amoxicillin/Co-amoxiclav
•Ampicillin
Carbapenem •Piperacillin with Tazobactam
•Meropenem (Tazocin)
•Imipenem
•Doripenem
•Ertapenem
Mechanisms of Action

• Anti Cell Wall Activity


• Bactericidal
Beta Lactams Against Bacterial Cell
Wall
Cell wall

Osmotic
Pressure

Cell Membrane

Antibiotic against cell wall

Osmotic
Pressure
Cell membrane
Rupture
Spectrum of Activity
• Very wide
• Gram positive and negative bacteria
• Anaerobes
• Spectrum of activity depends on the agent
and/or its group
Adverse Effects

Penicillin hypersensitivity – 0.4% to 10 %


– Mild: rash
– Severe: anaphylaxis & death
• There is cross-reactivity among all
Penicillins
• Penicillins and cephalosporins ~5-15%
Resistance to ß-Lactams

•ß-Lactamase
•Other mechanisms are of less importance

•Augmentin
Important Points

• Beta lactams need frequent dosing for


successful therapeutic outcome
– Missing doses will lead to treatment failure
• Beta lactams are the safest antibiotics in
renal and hepatic failure
– Adjustments to dose may still be required in
severe failure
Summary
• Cell wall antibiotics
– Bactericidal
• Wide spectrum of use
– Antibiotics of choice in many infections
– Limitations
• Allergy
• Resistance due to betalactamase
• Very safe in most cases
– No monitoring required
Aminoglycosides
Inhibit bacterial protein synthesis by irreversibly binding to
30S ribosomal unit
•Naturally occurring:
•Streptomycin
•Neomycin
•Kanamycin
•Tobramycin
•Gentamicin

•Semisynthetic derivatives:
•Amikacin (from Kanamycin)
•Netilmicin (from Sisomicin)
30S Ribosomal Unit Blockage by
Aminoglycosides

•Causes mRNA decoding errors


Spectrum of Activity
• Gram-Negative Aerobes
– Enterobacteriaceae;
E. coli, Proteus sp., Enterobacter sp.
– Pseudomonas aeruginosa

• Gram-Positive Aerobes (Usually in


combination with ß-lactams)
S. aureus and coagulase-negative staphylococci
Viridans streptococci
Enterococcus sp. (gentamicin)
Adverse Effects
• Nephrotoxicity
– Direct proximal tubular damage - reversible if caught early
– Risk factors: High troughs, prolonged duration of therapy,
underlying renal dysfunction, concomitant nephrotoxins
• Ototoxicity
– 8th cranial nerve damage – irreversible vestibular and
auditory toxicity
• Vestibular: dizziness, vertigo, ataxia
• Auditory: tinnitus, decreased hearing
– Risk factors: as for nephrotoxicity
• Neuromuscular paralysis
– Can occur after rapid IV infusion especially with;
• Myasthenia gravis
• Concurrent use of succinylcholine during anaesthesia
Prevention of Toxicity
a) Levels need to be monitored to prevent
toxicity due to high serum levels

b) To be avoided where risk factors for


renal damage exist
1) Dehydration
2) Renal toxic drugs
Mechanisms of Resistance

• Inactivation by Aminoglycoside
modifying enzymes
– This is the most important mechanism
Important Points

• Aminoglycosides should be given as a large single dose


for a successful therapeutic outcome
– Multiple small doses will lead to treatment failure and likely
to lead to renal toxicity

• Aminoglycosides are toxic drugs and require monitoring


– Avoid use in renal failure but safe in liver failure
– Avoid concomitant use with other renal toxic drugs
– Check renal clearance, frequency according to renal
function
Summary
• Restricted to aerobes
• Toxic, needs level monitoring
• Best used in Gram negative bloodstream
infections
• Good for UTIs
• Limited or no penetration
– Lungs
– Joints and bone
– CSF
– Abscesses
Macrolides
Macrolides
Lactone Ring
14

14

Erythromycin Telithromycin

15 14

Clarithromycin
Azithromycin
Mechanism of Action
• Bacteriostatic- usually
• Inhibit bacterial RNA-dependent
protein synthesis
– Bind reversibly to the 23S ribosomal
RNA of the 50S ribosomal subunits
• Block translocation reaction of the
polypeptide chain elongation
Spectrum of Activity
• Gram-Positive Aerobes:
– Activity: Clarithromycin>Erythromycin>Azithromycin
• MSSA
• S. pneumoniae
• Beta haemolytic streptococci and viridans streptococci

• Gram-Negative Aerobes:
– Activity: Azithromycin>Clarithromycin>Erythromycin
• H. influenzae, M. catarrhalis, Neisseria sp.
• NO activity against Enterobacteriaceae
• Anaerobes: upper airway anaerobes
• Atypical Bacteria
Mechanisms of Resistance -
Microlides

• Altered target sites


– Methylation of ribosomes preventing antibiotic binding

• Cross-resistance occurs between all macrolides


Clinical Use

• Cellulitis/Skin and soft tissue


– Beta haemolytic streptococci
– Staphylococcus aureus

• Intra-cellular organisms
– Chlamydia
– Gonococcus
Summary
• Bacteriostatic
• ALL hepatic elimination
• Gastrointestinal Sideeffects (up to 33 %)
(especially Erythromycin)
• Nausea
• Vomiting
• Diarrhoea
• Dyspepsia
• Best used in atypical pneumonia
• Excellent tissue and cellular penetration
– Very useful in susceptible intracellular infections
Fluoroquinolones
Fluoroquinolones
Quinolone pharmacore
Mechanism of Action

• Prevent:
• Relaxation of supercoiled DNA before
replication
• DNA recombination
• DNA repair
Spectrum of Activity
• Gram-positive
• Gram-Negative (Enterobacteriaceae H.
influenzae, Neisseria sp. Pseudomonas
aeruginosa)
– Ciprofloxacin is most active
• Atypical bacteria: all have excellent activity
Summary
• Wide range of activity against Gram positive and
negative bacteria.
• Sepsis from Intra-abdominal and Renal Sources
– Coliforms (Gram negative bacilli)
• UTI
– E. coli
• Very good tissue penetration
• Excellent oral bioavailability
• High risk for C.difficile
Tetracyclines

•Hydronaphthacene nucleus containing four fused rings


•Tetracycline
•Short acting

•Doxycycline
•Long acting
Mechanism of Action

• Inhibit protein synthesis


• Bind reversibly to bacterial 30S ribosomal
subunits
• Prevents polypeptide synthesis
• Bacteriostatic
Spectrum of Activity
• All have similar activities
• Gram positives aerobic cocci and rods
– Staphylococci
– Streptococci
• Gram negative aerobic bacteria

• Atypical organisms
– Mycoplasmas
– Chlamydiae
– Rickettsiae
– Protozoa
Adverse Effects
• Oesophageal ulceration
• Photosensitivity reaction
• Incorporate into foetal and children bone
and teeth

Avoid in pregnancy and children


Summary

• Very good tissue penetration


• Use usually limited to;
– Skin and soft tissue infections
– Chlamydia
Glycopeptides
• Vancomycin
• Teicoplanin

Vancomycin
Mechanism of Action

• Inhibit peptidoglycan synthesis in the


bacterial cell wall
• Prevents cross linkage of peptidoglycan chains
Summary
• Large molecule
• Only active against Gram positive bacteria
• Second choice in all its uses except;
– MRSA
– C.difficile
Metronidazole

• Antibiotic
• Amoebicide
• Anti-protozoal
– Trichomonas Vaginalis
Mechanisms of Action

• Molecular reduction
– Nitroso intermediates
– Sulfamides

• Melatbolised
– Bacterial DNA de-stabilised
Spectrum of Activity & Uses

• Anaerobes
– Bacterial Vaginosis
– Pelvic Inflammatory Disease
– C. Diff
Bio-Availability
• Oral
• Intra-venous
– Expensive
• Rectal
– Cheap
Summary

• Wide spectrum of activity


• Anaerobes
• In combination
Use of Pharmacokinetics in Treatment
Beta lactams Aminoglycosides
Good/variable (Dependant on
individual antibiotic) Good
Soft tissue Circulating organisms
Bone and joints
Lungs
Poor
CSF Soft tissue
Poor Bone and joints
Abscesses
Abscesses
Lungs
CSF

Examples of good Tissue Penetrators


Tetracyclines
Macrolides
Quinolones
Clindamycin
Key Message 2
• When selecting an antibiotic consider the
following;
– Where is the infection?
– Which antibiotics will reach the site of
infection
• Match the two and select your antibiotic
Key Message 3

• Always check the impact of an antibiotic


on other drugs that a patient is on
– Consult BNF or equivalent
PHEW!!!

Any Questions?
Chlamydia Trachomatis
• Obligate, intracellular bacterium
• Rigid cell wall but NO peptidoglycan layer
• Cervicitis
• Slapingitis
• Pelvic Inflammatory Disease
• Neonate - mucopurulent conjunctivitis
• Reiter's syndrome(urethritis, uveitis, arthritis)
• Lymphogranuloma Venereum
Chlamydia Trachomatis
• Diagnosis
– Giemsa stain
• Inclusion bodies in epithelial cells
• Gram stain of no value
– ELISA - antigens in exudates or urine
– Immunofouresence
– PCR
– Culture
Chlamydia Trachomatis
• Life Cycle
Elementary Body
Cell

Release from Reticulate


Cell Body

Binary Fission
Daughter
Elementary Bodies
Chlamydia Trachomatis

• Treatment
– Tetracyclines (Doxicycline)
– Erythromycin
– Azythromycin
PK/PD Principles in
Antibiotic Prescribing And
Prescribing in Organ Failure
SAHD May 17, 2013
Peter Gayo Munthali
Consultant Microbiologist
UHCW
Honorary Associate Clinical Professor
University of Warwick
Pharmacokinetics - Beta-
Lactams
• Absorption
– PO forms have variable absorption
– Food can delay rate and extent of absorption
• Distribution
– Widely to tissues & fluids
– CSF penetration:
IV – limited unless inflamed meninges

• Metabolism & Excretion


– Primarily renal elimination
– Some have a proportion of drug eliminated via the liver
– ALL -lactams have short elimination half-lives
Clinical Use - Beta- Lactams
• Cellulitis/Skin and soft tissues
• Commonest causes
– Beta haemolytic streptococci
– Staphylococcus aureus
• Which Antibiotics?
– Benzylpenicillin (Streptococci only)
– Flucloxacillin (Staphylococcus aureus and streptococci)
• Other beta lactams can be used but spectrum too wide
Clinical Use - Beta- Lactams
• UTI
– Commonest cause
• E. coli
– Which antibiotics
• Cephalexin
• Co-Amoxiclav
– Secondary choice, better non beta lactam alternatives exist
» Nitrofurantoin
» Trimethoprim
Clinical Use - Beta- Lactams
• Sepsis from Intra-abdominal and Renal
Sources
• Commonest causes
– Coliforms (Gram negative bacilli)
• Which antibiotics?
– Co-Amoxiclav
– Tazocin
– Meropenem/imipenem/ertapenem (ESBL
suspected)
Pharmacokinetics - Aminoglycosides
• All have similar pharmacologic properties
• Gastrointestinal absorption: unpredictable but always
negligible
• Distribution
– Hydrophilic: widely distributes into body fluids but very poorly into;
• CSF
• Vitreous fluid of the eye
• Biliary tract
• Prostate
• Tracheobronchial secretions
• Adipose tissue
• Elimination
– 85-95% eliminated unchanged via kidney
– t1/2 dependent on renal function
– In normal renal function t1/2 is 2-3 hours
Clinical Use 1 -
Aminoglycosides
• Sepsis from Intra-abdominal and Renal
Sources
• Commonest causes
– Coliforms (Gram negative bacilli)
• Which antibiotics?
– Gentamicin/Amikacin (with beta lactam and or
metronidazole)
Clinical Use 2 -
Aminoglycosides
• UTI
• Very effective in UTI as 85-95% of the drug
is eliminated unchanged via kidney
• Commonest cause
– E. coli
– Which antibiotics
• Gentamicin
– Secondary choice, better alternatives exist
» Nitrofurantoin
» Trimethoprim
» Beta lactams
Pharmacokinetics 1- Microlides
• Erythromycin ( Oral: absorption 15% - 45%)
• Short t1/2 (1.4 hr)
• Acid labile
• Absorption (Oral)
– Erythromycin: variable absorption of 15% - 45%
– Clarithromycin: 55%
– Azithromycin: 38%
• Half Life (T1/2)
– Erythromycin 1.4 Hours
– Clarithromycin (250mg and 500mg 12hrly) 3-4 & 5-7 hours respectively
– Azithromycin 68hours
– Improved tolerability
• Excellent tissue and intracellular concentrations
– Tissue levels can be 10-100 times higher than those in serum
• Poor penetration into brain and CSF
• Cross the placenta and excreted in breast milk
Pharmacokinetics 2 - Microlides
• Metabolism & Elimination
– ALL hepatic elimination
Adverse Effects - Microlides
• Gastrointestinal (up to 33 %) (especially
Erythromycin)
• Nausea
• Vomiting
• Diarrhoea
• Dyspepsia
• Thrombophlebitis: IV Erythromycin &
Azithromycin
• QTc prolongation, ventricular arrhythmias
• Other: ototoxicity with high dose erythromycin in
renal impairment
Pharmacokinetics -
• Absorption
Fuoroquinolones
• Good bioavailability
• Oral bioavailability 60-95%
• Divalent and trivalent cations (Zinc, Iron, Calcium, Aluminum,
Magnesium) and antacids reduce GI absorption
• Distribution
• Extensive tissue distribution but poor CSF penetration
• Metabolism and Elimination
• Combination of renal and hepatic routes
Adverse Effects - Fluoroquinolones
• Cardiac
• Prolongation QTc interval
• Assumed to be class effect
• Articular Damage
• Cartilage damage
• Induced in animals with large doses
Resistance - Fluoroquinolones

• Altered target sites due to point mutations.


• The more mutations, the higher the resistance
to Fluoroquinolones
• Most important and most common
• Altered cell wall permeability
• Efflux pumps
• Cross-resistance occurs between
fluoroquinolones
Clinical Use 1-
Fluoroquinolones
• Sepsis from Intra-abdominal and Renal
Sources
• Commonest causes
– Coliforms (Gram negative bacilli)
• Which antibiotics?
– Ciprofloxacin
• High risk for C.difficile, safer alternatives
should be used
Clinical Use 2 -
Fluoroquinolones
• UTI
– Commonest cause
• E. coli
– Which antibiotics
• Ciprofloxacin
– High risk for C.difficile, safer alternatives should be
used
Pharmacokinetics - Tetracyclines

• Incompletely absorbed from GI, improved by


fasting
• Metabolised by the liver and concentrated in bile
(3-5X higher than serum levels)
• Excretion primarily in the urine except
doxycycline ( 60% biliary tract into faeces,40% in
urine)
• Tissue penetration is excellent but poor CSF
penetration
– Incorporate into foetal and children bone and teeth
Resistance - Tetracyclines
• Efflux
• Alteration of ribosomal target site
• Production of drug modifying enzymes
Clinical Use - Tetracyclines
• Cellulitis/Skin and soft tissues/ Bone
and Joint Infections
• Commonest causes
– Beta haemolytic streptococci
– Staphylococcus aureus
• Which Antibiotics?
– Doxycycline
Pharmacodynamics
Drug Absorption Curve
Key Message 4&5
• Aminoglycosides are toxic drugs and require monitoring
– Avoid use in renal failure but safe in liver failure
– Avoid concomitant use with other renal toxic drugs
– Check renal clearance, frequency according to renal function
• Beta lactams are the safest antibiotics in renal and hepatic
failure
– Adjustments to dose may still be required in severe failure

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