2. 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.
3. There are Three in this RelationshipThere are Three in this Relationship
Drug
Bacteria
Resistance
Pharm
acodynam
ics
(PD)
Infection
Host defence
Toxicity
Pharm
acokinetics
(PK)
Host
4. 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
10. Spectrum of Activity
• Very wide
• Gram positive and negative bacteria
• Anaerobes
• Spirochetes
• Spectrum of activity depends on the agent
and/or its group
11. 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%
13. Important PointsImportant 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
14. 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
15. 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)
16. 30S Ribosomal Unit Blockage by
Aminoglycosides
•Causes mRNA decoding errors
17. 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)
18. 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
19. 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
20. Mechanisms of Resistance
• Inactivation by Aminoglycoside
modifying enzymes
– This is the most important mechanism
21. Important PointsImportant 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
22. 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
25. 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
26. 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
27. Mechanisms of Resistance -
Microlides
• Altered target sites
– Methylation of ribosomes preventing antibiotic binding
• Cross-resistance occurs between all macrolides
32. Mechanism of Action
• Prevent:
• Relaxation of supercoiled DNA before
replication
• DNA recombination
• DNA repair
33. Spectrum of Activity
• Gram-positive
• Gram-Negative (Enterobacteriaceae H.
influenzae, Neisseria sp. Pseudomonas
aeruginosa)
– Ciprofloxacin is most active
• Atypical bacteria: all have excellent activity
34. 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
36. Mechanism of Action
• Inhibit protein synthesis
• Bind reversibly to bacterial 30S ribosomal
subunits
• Prevents polypeptide synthesis
• Bacteriostatic
37. 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
38. Adverse Effects
• Oesophageal ulceration
• Photosensitivity reaction
• Incorporate into foetal and children bone
and teeth
Avoid in pregnancy and children
39. Summary
• Very good tissue penetration
• Use usually limited to;
– Skin and soft tissue infections
– Chlamydia
48. Use of Pharmacokinetics in Treatment
Beta lactams
Good/variable (Dependant on
individual antibiotic)
Soft tissue
Bone and joints
Lungs
CSF
Poor
Abscesses
Examples of good Tissue Penetrators
Tetracyclines
Macrolides
Quinolones
Clindamycin
Aminoglycosides
Good
Circulating organisms
Poor
Soft tissue
Bone and joints
Abscesses
Lungs
CSF
49. Key Message 2Key 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
50. Key Message 3Key Message 3
• Always check the impact of an antibiotic
on other drugs that a patient is on
– Consult BNF or equivalent
56. PK/PD Principles inPK/PD Principles in
Antibiotic Prescribing AndAntibiotic Prescribing And
Prescribing in Organ FailurePrescribing in Organ Failure
SAHD May 17, 2013SAHD May 17, 2013
Peter Gayo MunthaliPeter Gayo Munthali
Consultant MicrobiologistConsultant Microbiologist
UHCWUHCW
Honorary Associate Clinical ProfessorHonorary Associate Clinical Professor
University of WarwickUniversity of Warwick
57. 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 β-lactams have short elimination half-lives
58. 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
59. Clinical Use - Beta- Lactams
• UTI
– Commonest cause
• E. coli
– Which antibiotics
• Cephalexin
• Co-Amoxiclav
– Secondary choice, better non beta lactam alternatives exist
» Nitrofurantoin
» Trimethoprim
60. 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)
61. 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
62. 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)
63. 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
64. 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
66. 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
67.
68. Pharmacokinetics -
Fuoroquinolones• Absorption
• 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
69. Adverse Effects - Fluoroquinolones
• Cardiac
• Prolongation QTc interval
• Assumed to be class effect
• Articular Damage
• Cartilage damage
• Induced in animals with large doses
70. 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
71. 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
72. Clinical Use 2 -
Fluoroquinolones
• UTI
– Commonest cause
• E. coli
– Which antibiotics
• Ciprofloxacin
– High risk for C.difficile, safer alternatives should be
used
73. 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
74. Resistance - Tetracyclines
• Efflux
• Alteration of ribosomal target site
• Production of drug modifying enzymes
75. Clinical Use - Tetracyclines
• Cellulitis/Skin and soft tissues/ Bone
and Joint Infections
• Commonest causes
– Beta haemolytic streptococci
– Staphylococcus aureus
• Which Antibiotics?
– Doxycycline
78. Key Message 4&5Key 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