Drugs against bugs - antibiotics in the ICU

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Drugs against bugs - antibiotics in the ICU

  1. 1. Drugs and Bugs ICU acquired infections and microbiology issues in the ICU Dr Andrew Ferguson
  2. 2. Curriculum (Annex C and F) • • • • • • • • • • • • • • • • • • • • • Manages antimicrobial drug therapy Epidemiology and prevention of infection in the ICU Types of organisms - emergence of resistant strains, mode of transfer, opportunistic and nosocomial infections; difference between contamination, colonisation and infection Local patterns of bacterial resistance and antibiotic policy Indications, complications, interactions, selection, monitoring, and efficacy of common antimicrobial drugs (antibacterial, antifungal, antiviral, antiprotozoal, antihelminthics) Indications for and basic interpretation of drug concentrations in blood or plasma Principles of prescribing initial empirical therapy and modification / refinement with further clinical and microbiological information Impact of drug therapy on organ-system function Risk factors for nosocomial infection and infection control measures to limit its occurrence Ventilator associated pneumonia: definition, pathogenesis and prevention Risks of inappropriate antimicrobial therapy on the patient and the environment Requirements for microbiological surveillance and clinical sampling Effects of concomitant treatment and/or co-morbid conditions on an individual patient's response to treatment Prophylactic therapies and indications for their use Circumstances when treatment is unnecessary Concept of gastrointestinal microbial translocation Safe use of therapies which modify the inflammatory response Collaborate with microbiologists / infectious diseases clinicians to link clinical, laboratory and local (hospital / regional / national) microbiological data Establish a management plan based on clinical and laboratory information Prescribe appropriate antimicrobial therapy based on history, examination and preliminary investigations
  3. 3. Scenarios • 47 year old with community-acquired pneumonia • 65 year old with perforated colonic diverticulum • 48 year old alcoholic with delayed presentation of perforated DU • 18 year old diabetic with axillary abscess and septic shock • 75 year old with central line sepsis • 65 year old with recurrent renal stones and UTI
  4. 4. Antimicrobial therapy
  5. 5. Potential drug targets 1 • Defensive structures – cell wall – Peptidoglycan based – Multiple similar layers (gram +ve) with teichoic acids – 2 membranes (gram –ve) with LPS on outer
  6. 6. Potential drug targets 2 • Replication enzymes – DNA processes – DNA gyrase (a topoisomerase) to relax supercoils – Helicase to separate the strands – Primase - RNA polymerase => primers for DNA replication. – DNA polymerase I: DNA repair – DNA polymerase III: synthesize complementary DNA strands. – DNA polymerases II, IV, V: DNA repair – DNA ligase: forms covalent bonds between fragments
  7. 7. Potential drug targets 3 • Protein synthesis machinery - Ribosome 50S 30S (a 16S rRNA + ribosomal proteins)
  8. 8. How antibiotics work Disrupt cell wall b-lactams inhibit peptidoglycan synthesis Vancomycin disrupts peptidoglycan cross-links Disrupt membranes Polymyxins detergent-like action on membrane Inhibit protein synthesis (ribosome) Inhibit DNA/RNA processes Disrupt metabolism Aminoglycosides irreversibly bind 30S proteins Tetracyclines block t-RNA binding to 30S Chloramphenicol, Macrolides, Clindamycin, Linezolid bind 50S Quinolones inhibit DNA gyrase/topoisomaerase Metronidazole metabolic product disrupts DNA Rifampicin binds DNA-dependent RNA polymerase Fusidic acid inhibits RNA transferase Sulfonamides, dapsone, trimethoprim disrupt folate synthesis
  9. 9. Bactericidal v Bacteriostatic Bactericidal Bacteriostatic b-lactams Macrolides (clarithormycin etc.) Nitroimidazoles (metronidazole) Tetracyclines Rifampicin Lincosamides (Clindamycin) Aminoglycosides Fusidic acid Quinolones Chloramphenicol Polymyxins e.g. colistin ? Trimethoprim/sulfamethoxazole ? Trimethoprim/sulfamethoxazole Oxazolidinones e.g. Linezolid (in general) Glycopeptides e.g. vanco, teico Linezolid (some Streptococci) Lipopeptides e.g. Daptomycin Quinupristin/dalfpristin (in combo) Tigecycline
  10. 10. Pharmacodynamics of effect 1. Concentration-dependent killing 2. Time-dependent killing – with no prolonged effect 3. Time dependent killing – with prolonged effect • Minimum Inhibitory Concentration (MIC) – Lowest [ ] that inhibits growth after 16-20 hrs incubation. • CMax = Peak antibiotic concentration • Area under the curve (AUC) – Amount of antibiotic delivered over a specific time.
  11. 11. Concentration-dependent killing • Moderate to prolonged persistent effects • Goal of dosing = maximize concentrations • PK parameter determining efficacy – CMax – CMax:MIC ratio (>10 for AG’s) – AUC/MIC (>125 for FQ’s, 70 for metronidazole) • Examples – Aminoglycosides, Flouroquinolones, Colistin, Metronidazole, Ampho B.
  12. 12. Time dependent killing 1 • Prolonged persistent effects • Goal of dosing = optimize amount of drug • PK parameter determining efficacy – AUC/MIC – Time above MIC • Examples – Vancomycin, tetracyclines, fluconazole.
  13. 13. Time dependent killing 2 • Without prolonged effects • Goal of dosing = maximize exposure duration • PK parameter determining efficacy – Time above MIC (T>MIC) • Time above MIC >70% for b-lactams, >85% linezolid – AUC/MIC • AUC/MIC > 80 • Examples – Beta lactam, macrolides, clindamycin, flucytosine, linezolid.
  14. 14. Why treatment fails • You’ve given the wrong drug at the right time! Really BAD • You’ve given the right drug at the wrong time! BAD • You’ve given too small a dose of the right drug BAD • There’s an insufficient concentration at site • The drug’s being cleared too fast BAD • They’re not infected!!! Really BAD BAD
  15. 15. PK/PD alterations in critical illness • Poor tissue penetration – Microvascular shutdown – Interstitial fluid • Increased Vd - interstitial fluid volume – – – – Rapid fluid boluses Pleural effusions Ascites Hypoalbuminaemia • Increased clearance – Severe hyperdynamic circulation • Young polytrauma and sepsis – renal hyperfiltration – Severe burns – Leukaemia
  16. 16. Optimising use • Shock & Awe!!! – Aggressive dosing up-front • Short, sharp courses • De-escalation – Of dose, based on response and PK/PD – Of drug, based on cultures & sensitivity • Antibiotic cycling • PK/PD modelling • Dose strategies – prolonged or continuous infusion
  17. 17. Organisms
  18. 18. COCCI • Staphylococci • Streptococci • Enterococci BACILLI • • • • OTHER Gram positives • Yeasts Corynebacterium spp (diphtheroids) Clostridium Listeria Bacillus spp
  19. 19. BACILLI • • • • • • • H. influenzae B. pertussis Brucella spp Francisella spp Legionella spp Vibrio spp Pseudomonas spp Proteus spp Campylobacter spp Yersinia spp Shigella spp Salmonella spp COCCI • • • • • • N. meningitidis • N. gonorrhoeae BACILLI COCCO-BACILLI Gram negatives • • • • • Klebsiella spp E. coli Enterobacter Citrobacter Serratia Fermenters
  20. 20. Mob-rule • Quorum sensing – Signals between bacteria – Same or different spp • Effects – Inhibition of growth (some species) – Increased virulence e.g. Pseudomonas
  21. 21. Antibiotic resistance
  22. 22. Antimicrobial resistance Antibiotic Mechanism of resistance Chloramphenicol Reduced uptake into cell Tetracycline Active efflux from the cell β-lactams, Erythromycin, Lincomycin Eliminates or reduces binding of antibiotic to cell target β-lactams, Aminoglycosides, Chloramphenicol Enzymatic cleavage or modification to inactivate antibiotic molecule Sulfonamides, Trimethoprim Metabolic bypass of inhibited reaction Sulfonamides, Trimethoprim Overproduction of antibiotic target (titration)
  23. 23. Transmission of resistance DNA TRANSFER from dead organisms PLASMIDS + MUTATION VIRAL TRANSFER (PHAGE)
  24. 24. Antibiotic prophylaxis
  25. 25. Risk factors for SSI
  26. 26. Know the guidelines!

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