Antibiotics

1
Antibiotics

• MR. H GEE MD, FRCOG
• Hon. Assoc. Clinical Professor
• University of Warwick

2
Objectives

• By the end of this lecture you should be able to
• Classify commonly used antibiotics into six major
  antibiotic classes of
• Beta lactams
• Aminoglycosides
• Fluoroquinolones
• Macrolides
• Tetracyclines
• Glycopeptides
• Metronidazole
• Understand the mechanism of action of each
  antibiotic class.
• Understand clinical use of each class of
  antibiotic
• Possible major side effects.

3
There are Three in this Relationship
Drug
Toxicity
Resistance
Pharmacokinetics (PK)
Pharmacodynamics(PD)
Infection
Bacteria
Host
Host defence
4
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

5
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 gt 38 .C or lt 36.C
• HR gt 90 bpm
• RR gt 20 bpm
• WBC gt 12 000 cells/mm3
• Sepsis
• SIRS suspected or confirmed infection

6
Key Message 1

• Diagnose sepsis early and give antibiotics
  promptly to reduce mortality from sepsis

7
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

8
ß-Lactams
?-Lactam Ring
Thiazolidine Ring
9
ß-Lactams
ß-Lactams

• Penicillin
• Narrow Spectrum
• Benzylpenicillin (Penicillin G)
• Phenoxymethylpenicillin (Pen V)
• Flucloxacillin
• Broad Spectrum
• Amoxicillin/Co-amoxiclav
• Ampicillin
• Piperacillin with Tazobactam (Tazocin)

• Cephalosporin
• Cefalexin
• Cefuroxime
• Cefotaxime
• Ceftriaxone

• Carbapenem
• Meropenem
• Imipenem
• Doripenem
• Ertapenem

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Mechanisms of Action

• Anti Cell Wall Activity
• Bactericidal

11
Beta Lactams Against Bacterial Cell Wall
Cell wall
Osmotic Pressure
Cell Membrane
Antibiotic against cell wall
Osmotic Pressure
Cell membrane Rupture
12
Spectrum of Activity

• Very wide
• Gram positive and negative bacteria
• Anaerobes
• Spectrum of activity depends on the agent and/or
  its group

13
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
  

14
Resistance to ß-Lactams

• ß-Lactamase
• Other mechanisms are of less importance
• Augmentin

15
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

16
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

17
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)

18
30S Ribosomal Unit Blockage by Aminoglycosides

• Causes mRNA decoding errors

19
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)

20
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

21
Prevention of Toxicity

• Levels need to be monitored to prevent toxicity
  due to high serum levels
• To be avoided where risk factors for renal damage
  exist
• Dehydration
• Renal toxic drugs

22
Mechanisms of Resistance

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

23
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

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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
Macrolides
26
Macrolides

Lactone Ring
14
14

Erythromycin
Telithromycin
14
15


Clarithromycin
Azithromycin

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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

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Spectrum of Activity

• Gram-Positive Aerobes
• Activity ClarithromycingtErythromycingtAzithromycin
  
• MSSA
• S. pneumoniae
• Beta haemolytic streptococci and viridans
  streptococci
• Gram-Negative Aerobes
• Activity AzithromycingtClarithromycingtErythromycin
  
• H. influenzae, M. catarrhalis, Neisseria sp.
• NO activity against Enterobacteriaceae
• Anaerobes upper airway anaerobes
• Atypical Bacteria

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Mechanisms of Resistance - Microlides

• Altered target sites
• Methylation of ribosomes preventing antibiotic
  binding
• Cross-resistance occurs between all macrolides

30
Clinical Use

• Cellulitis/Skin and soft tissue
• Beta haemolytic streptococci
• Staphylococcus aureus
• Intra-cellular organisms
• Chlamydia
• Gonococcus

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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

32
Fluoroquinolones
33
Fluoroquinolones
Quinolone pharmacore
34
Mechanism of Action

• Prevent
• Relaxation of supercoiled DNA before replication
• DNA recombination
• DNA repair

35
Spectrum of Activity

• Gram-positive
• Gram-Negative (Enterobacteriaceae H. influenzae,
  Neisseria sp. Pseudomonas aeruginosa)
• Ciprofloxacin is most active
• Atypical bacteria all have excellent activity

36
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

37
Tetracyclines

• Hydronaphthacene nucleus containing four fused
  rings
• Tetracycline
• Short acting
• Doxycycline
• Long acting

38
Mechanism of Action

• Inhibit protein synthesis
• Bind reversibly to bacterial 30S ribosomal
  subunits
• Prevents polypeptide synthesis
• Bacteriostatic

39
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

40
Adverse Effects

• Oesophageal ulceration
• Photosensitivity reaction
• Incorporate into foetal and children bone and
  teeth

Avoid in pregnancy and children
41
Summary

• Very good tissue penetration
• Use usually limited to
• Skin and soft tissue infections
• Chlamydia

42
Glycopeptides

• Vancomycin
• Teicoplanin

Vancomycin
43
Mechanism of Action

• Inhibit peptidoglycan synthesis in the bacterial
  cell wall
• Prevents cross linkage of peptidoglycan chains

44
Summary

• Large molecule
• Only active against Gram positive bacteria
• Second choice in all its uses except
• MRSA
• C.difficile

45
Metronidazole

• Antibiotic
• Amoebicide
• Anti-protozoal
• Trichomonas Vaginalis

46
Mechanisms of Action

• Molecular reduction
• Nitroso intermediates
• Sulfamides
• Melatbolised
• Bacterial DNA de-stabilised

47
Spectrum of Activity Uses

• Anaerobes
• Bacterial Vaginosis
• Pelvic Inflammatory Disease
• C. Diff

48
Bio-Availability

• Oral
• Intra-venous
• Expensive
• Rectal
• Cheap

49
Summary

• Wide spectrum of activity
• Anaerobes
• In combination

50
Use of Pharmacokinetics in Treatment

• Beta lactams
• Good/variable (Dependant on individual
  antibiotic)
• Soft tissue
• Bone and joints
• Lungs
• CSF
• Poor
• Abscesses

• Aminoglycosides
• Good
• Circulating organisms
• Poor
• Soft tissue
• Bone and joints
• Abscesses
• Lungs
• CSF

Examples of good Tissue Penetrators Tetracyclines
Macrolides Quinolones Clindamycin
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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

52
Key Message 3

• Always check the impact of an antibiotic on other
  drugs that a patient is on
• Consult BNF or equivalent

53
PHEW!!!

• Any Questions?

54
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

55
Chlamydia Trachomatis

• Diagnosis
• Giemsa stain
• Inclusion bodies in epithelial cells
• Gram stain of no value
• ELISA - antigens in exudates or urine
• Immunofouresence
• PCR
• Culture

56
Chlamydia Trachomatis

• Life Cycle

Elementary Body
Cell
Reticulate Body
Release from Cell
Binary Fission
Daughter Elementary Bodies
57
Chlamydia Trachomatis

• Treatment
• Tetracyclines (Doxicycline)
• Erythromycin
• Azythromycin

58
PK/PD Principles in Antibiotic Prescribing And
Prescribing in Organ FailureSAHD May 17, 2013

• Peter Gayo Munthali
• Consultant Microbiologist
• UHCW
• Honorary Associate Clinical Professor
• University of Warwick

59
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

60
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

61
Clinical Use - Beta- Lactams

• UTI
• Commonest cause
• E. coli
• Which antibiotics
• Cephalexin
• Co-Amoxiclav
• Secondary choice, better non beta lactam
  alternatives exist
• Nitrofurantoin
• Trimethoprim

62
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)

63
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

64
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)

65
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

66
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

67
Pharmacokinetics 2 - Microlides

• Metabolism Elimination
• ALL hepatic elimination

68
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

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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

71
Adverse Effects - Fluoroquinolones

• Cardiac
• Prolongation QTc interval
• Assumed to be class effect
• Articular Damage
• Cartilage damage
• Induced in animals with large doses

72
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

73
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

74
Clinical Use 2 - Fluoroquinolones

• UTI
• Commonest cause
• E. coli
• Which antibiotics
• Ciprofloxacin
• High risk for C.difficile, safer alternatives
  should be used

75
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

76
Resistance - Tetracyclines

• Efflux
• Alteration of ribosomal target site
• Production of drug modifying enzymes

77
Clinical Use - Tetracyclines

• Cellulitis/Skin and soft tissues/ Bone and Joint
  Infections
• Commonest causes
• Beta haemolytic streptococci
• Staphylococcus aureus
• Which Antibiotics?
• Doxycycline

78
Pharmacodynamics
79
Drug Absorption Curve
80
Key Message 45

• 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