1. Drugs and Bugs
ICU acquired infections and microbiology issues in the ICU
Dr Andrew Ferguson

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. 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. Antimicrobial therapy

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. 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. Potential drug targets 3
• Protein synthesis machinery - Ribosome
50S
30S (a 16S rRNA + ribosomal proteins)

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. 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. 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. 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. 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. 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. 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. 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. 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. Organisms

18. COCCI
• Staphylococci
• Streptococci
• Enterococci
BACILLI
•
•
•
•
OTHER
Gram positives
• Yeasts
Corynebacterium spp (diphtheroids)
Clostridium
Listeria
Bacillus spp

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. Mob-rule
• Quorum sensing
– Signals between bacteria
– Same or different spp
• Effects
– Inhibition of growth (some species)
– Increased virulence e.g. Pseudomonas

21. Antibiotic resistance

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. Transmission of resistance
DNA TRANSFER from dead organisms
PLASMIDS
+ MUTATION
VIRAL TRANSFER (PHAGE)

24. Antibiotic prophylaxis

25. Risk factors for SSI

26. Know the guidelines!