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- 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: 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 Relationship Drug Bacteria Infection Host defence Host
- 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 > 38 .C or < 36.C • HR > 90 bpm • RR > 20 bpm • WBC > 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
- 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
- 10. Mechanisms of Action • Anti Cell Wall Activity • Bactericidal
- 11. Beta Lactams Against Bacterial Cell Wall Cell wall Osmotic Pressure Antibiotic against cell wall Osmotic Pressure Cell membrane Rupture Cell Membrane
- 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 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
- 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
- 24. 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
- 27. 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
- 28. 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
- 29. 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
- 31. 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
- 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
- 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 Examples of good Tissue Penetrators Tetracyclines Macrolides Quinolones Clindamycin Aminoglycosides Good Circulating organisms Poor Soft tissue Bone and joints Abscesses Lungs CSF
- 51. 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
- 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 Binary Fission Daughter Elementary Bodies Release from Cell
- 57. Chlamydia Trachomatis • Treatment – Tetracyclines (Doxicycline) – Erythromycin – Azythromycin
- 58. 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
- 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
- 70. 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
- 80. 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