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)
b)
c)
d)
e)
f)
g)
Beta lactams
Aminoglycosides
Fluoroquinolones
Macrolides
Tetracyclines
Glycopeptides
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
Ring
Thiazolidine Ring
ß-Lactams
ß-Lactams
Cephalosporin
•Cefalexin
•Cefuroxime
•Cefotaxime
•Ceftriaxone
Carbapenem
•Meropenem
•Imipenem
•Doripenem
•Ertapenem
Penicillin
Narrow Spectrum
•Benzylpenicillin (Penicillin G)
•Phenoxymethylpenicillin (Pen V)
•Flucloxacillin
Broad Spectrum
•Amoxicillin/Co-amoxiclav
•Ampicillin
•Piperacillin with Tazobactam
(Tazocin)
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
15
Azithromycin
Telithromycin
14
Clarithromycin
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
Reticulate
Body
Release from
Cell
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 - BetaLactams
• 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
• Absorption
Pharmacokinetics 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 1Fluoroquinolones
• 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