Antibiotics

1. Applied Sciences Lecture Course Antibiotics Dr Cathy Armstrong SpR In Anaesthesia & Clinical Fellow in Undergraduate Medical Education Manchester Royal Infirmary March 2011

2. Objectives Understand the classification of bacteria Discuss the broad mechanisms of action of antibiotics Consider important features of the main classes of antibiotic Understand penicillin allergy Understand the definitions of SIRS, sepsis & septic shock Be aware of some prescribing strategies & where to access help / information

3. Definitions • Antibiotic • Molecules that kills or stop the growth of microorgansims • Bactericidal • Antibiotics that kill bacteria • Bacteriostatic • Antibiotics that stop the growth of bacteria

4. Bacteria Pili Ribosome DNA Flagella

5. Classification bacteria • Gram positive • Retain the original blue colour of Gram stain • Gram negative • Original blue colour washed away by acetone, counterstained red

6. Classification of bacteria Peptidoglycan cell wall Gram Positive Plasma membrane outer membrane Gram negative Peptidoglycan cell wall Periplasmic space Plasma membrane

7. Classification of bacteria Bacteria Aerobic Anaerobic Gram +ive Gram -ive Gram +ive Gram -ive Cocci Cocci Bacilli Cocci Bacilli Bacilli Bacilli

8. Gram positive bacteria • Aerobic • Strep pneumoniae • CAP, septic shock, meningitis • Staph aureus • Cellulitis, septic shock, endocarditis • Strep A • pharyngitis • Anaerobic • Clostridium • Tetanus • Abdominal sepsis

9. Gram negative bacteria • Aerobic • E. Coli • UTI, septic shock • Klebsiella • UTI, septic shock, pneumonia • Pseudomonas • UTI, pneumonia, septic shock • Anaerobic • Bacteroides • Abdo sepsis

10. Classification of antibiotics • Class by coverage • Gram negative Vs. Gram Positive • Anaerobic vs aerobic • atypical • Class by group • Beta lactams • penicillins • Cephalosporins • Carbapenems • Glcopeptides • Aminoglycosides • Macrolides • Quinilones • Sulphonamides • tetracyclines

11. Classification of antibiotics • Class by mechanism of action • Inhibit cell wall synthesis • Inhibit protein synthesis • Inhibit nucleic acid synthesis

12. Inhibition of cell wall synthesis • Beta lactams • Penicillins • Cephalosporins • Carbapenems • Glycopeptides

13. Which of these is the safest option in penicillin allergy? • Co-amoxiclav • teicoplanin • flucloxacillin • Tazocin • Cefuroxime • Meropenem

14. Beta lactam antibiotics • Single largest group • Penicillins, Cephalosporins, Carbapenems, Monobactams • All contain a beta lactam ring in chemical structure • Target penicillin binding proteins (PDP’s) • Peptidoglycan Cell wall synthesizing enzymes found in plasma membrane • Not present in mamalian cells • Bacteriocidal • Synergistic action

15. Beta lactam resistance • Enzymatic destruction of -lactam (-lacatamase or penicillinase) • Bacterial modification of PDP target (MRSA) • Impermeability of cell membrane to -lactam • Active excretion by bacteria (mainly Gram neg)

16. Penicillins • Narrow spectrum • Benzylpencillin • Most Gram pos, anaerobes, some Gram neg • Most S. Aureus resistant (-lactamase) • Flucloxacillin • Unaffected by staphylococcal -lactamase Classically given together in cellulitis (staph / strep infections)

17. Penicillins • Broad Spectrum • Amoxicillin • Gram pos & some Gram neg • -lactamase resistance common • Piperacillin • Similar to amoxicillin + pseudomonas cover • Destroyed by -lactamase Combined with -lactamase inhibitors Amoxicillin + claulanic acid = co-amoxiclav Piperacillin + Tazobactam = Tazocin

18. What is the incidence of penicillin allergy resulting in anaphylaxis? • 0.0005% • 0.05% • 5% • 15%

19. Penicillin allergy • Anaphylactic reactions are rare (0.05%) • BUT - fatal in up to 10% of cases • General hypersensitivity reaction (e.g. rashes) occurs in 1-10% of exposed patients • Patients who have vague symptoms or GI upset are probably not “allergic”

20. Cephalosporins • Classified in “generations” • 1st generation mainly Gram positive cover, successive generations increasing potency against Gram negative • E.g. • 1st - cephalexin • 2nd - cefuroxime • 3rd - cefotaxime / ceftriaxone Cefotaxime & ceftriaxone readily cross BBB - used in meningitis

21. Can cephalosporins be given in penicillin allergy? • Traditionally 10% cross-reactivity stated • Based on 1975 study • Historically contraindicated in patients with severe immediate allergic reaction to penicillin (urticaria / anaphylaxis) • Recent epidemiological studies • Suggest for 2nd generation - cross reactivity much less

22. “The principal side-effect of the cephalosporins is hypersensitivity and about 0.5-6.5% of penicillin-sensitive patients will also be allergic to the cephalosporins. Patients with a history of immediate hypersensitivity to penicillin should not receive a cephalosporin. If a cephalosporin is essential in these patients because a suitable alternative antibacterial is not available, then cefixime, cefotaxime, ceftazidime, ceftriaxone, or cefuroxime can be used with caution; cefaclor, cefadroxil, cefalexin, and cefradine should be avoided”. BNF 61 (March 2011)

23. Carbapenems • Similar mode of action to other -lactams • Greater affinity for PBP-2 • Faster bacterial death • Extremely broad spectrum • E.g. imipenem / meropenem • Used for severe hospital aquired infections

24. Glycopeptides • Prevent bacterial cell wall synthesis • Bind to amino acids in cell wall • Active against Gram positive bacteria. • Don’t penetrate outer membrane of Gram neg bacteria (polar molecules) • E.g. Teicoplanin, vancomycin • Used in severe Gram pos infection • Vancomycin • Needs levels monitoring (after 3-4 doses in normal renal function) • “red man syndrome”

25. Inhibit protein synthesis • Affect 30s ribosome unit (bactericidal) • Aminoglycosides • gentamicin • Tetracyclines • Affect 50s ribosome unit (bacteriostatic) • Macrolides • Clarithromycin, erythromycin • Chloramphenicol

26. Aminoglycosides • Gentamicin • Good Gram neg cover, some Gram pos cover • Used for serious Gram neg infections • Synergistic action with -lactams • Side effects • Nephrotoxic & ototoxic • Toxicity directly related to plasma levels • “once daily dosing” • Caution in renal failure

27. Inhibit nucleic acid synthesis • Affect DNA • Quinolones • ciprofloxacin • Nitro-imidazoles (metronidazole) • Trimethoprim • Sulphonamides • Affect RNA • Rifampicin Inhibit folate synthesis

28. Side effects • Common • GI disturbances • Less common • Anaphylaxis / hypersensitivity reactions • Thrombocytopenia • ARF • Hepatotoxicity • Photosensitivity • Drug interactions • OCP

29. Which of the following is most likely to cause C. Diff? • Clindamycin • Metronidazole • Benylpenicillin • Vancomycin

30. When to Prescribe • Prophylaxis • Surgery • Endocarditis • Treat infection

31. Which of the following is NOT considered as part of the criteria for SIRS? • RR > 20/min • Heart rate < 60 • Temp <360C or >380C • PaCO2 < 32mmHg

32. SIRS • Systemic inflammatory response syndrome • 2 or more of the following criteria: • Temperature < 36 0C or > 38 0C • HR > 90 • PaCO2< 32mmHg • RR > 20 • WBC > 12.0 < 4.0, or > 10% immature (band) forms (? Include change in mental state / hyperglycaemia in absence of diabetes)

33. Associated definitions • Sepsis • Documented infection together with 2 or more SIRS criteria • Severe sepsis • Sepsis associated with organ dysfunction • Septic shock • Sepsis with refractory hypotension or hypoperfusion abnormalities in spite of adequate fluid resuscitation

34. Rationale • Ideally narrow spectrum • Consider likely organisms • Start broad spectrum then narrow with culture results

35. Other considerations • Route • Length of course • Appropriate dose • Renal failure

36. Information / guidelines • BNF • Local guidelines • Microbiologist

39. Summary • Classification of bacteria • Gram Negative Vs. Gram Positive • Discussed the broad mechanisms of action of antibiotics • Consider important features of some of the main classes of antibiotic • Discussed penicillin allergy • Defined SIRS, sepsis & septic shock • Discussed prescribing strategies & where to access help / information All Figures were produced using Servier Medical Art - www.servier.com