Drugs and BugsICU acquired infections and microbiology issues in the ICU

Dr Andrew Ferguson

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

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

Antimicrobial therapy

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

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

Potential drug targets 3

• Protein synthesis machinery - Ribosome

50S

30S (a 16S rRNA + ribosomal proteins)

How antibiotics work

b-lactams inhibit peptidoglycan synthesis

Vancomycin disrupts peptidoglycan cross-links

Polymyxins detergent-like action on membrane

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

Disrupt cell wall

Disrupt membranes

Inhibit protein synthesis

(ribosome)

Inhibit DNA/RNA processes

Disrupt metabolism

Bactericidal v Bacteriostatic

Bactericidal Bacteriostaticb-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

Pharmacodynamics of effect1. 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.

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.

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.

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.

BAD

Why treatment fails

• You’ve given the wrong drug at the right time!

• You’ve given the right drug at the wrong time!

• You’ve given too small a dose of the right drug

• There’s an insufficient concentration at site

• The drug’s being cleared too fast

• They’re not infected!!!

Really BAD

BAD

BAD

BAD

Really BAD

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

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

Organisms

Gram positives

• Staphylococci

• Streptococci

• Enterococci

• Corynebacterium spp (diphtheroids)

• Clostridium

• Listeria

• Bacillus spp

• Yeasts

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Gram negatives

• H. influenzae

• B. pertussis

• Brucella spp

• Francisella spp

• Legionella spp

• Vibrio spp

• Pseudomonas spp

• Proteus spp

• Campylobacter spp

• Yersinia spp

• Shigella spp

• Salmonella spp

• N. meningitidis

• N. gonorrhoeae

• Klebsiella spp

• E. coli

• Enterobacter

• Citrobacter

• Serratia

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Fermenters

Mob-rule

• Quorum sensing

– Signals between bacteria

– Same or different spp

• Effects

– Inhibition of growth (some species)

– Increased virulence e.g. Pseudomonas

Antibiotic resistance

Antimicrobial resistance

Antibiotic Mechanism of resistance

Chloramphenicol Reduced uptake into cell

Tetracycline Active efflux from the cell

β-lactams, Erythromycin, LincomycinEliminates 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)

Transmission of resistance

PLASMIDS

VIRAL TRANSFER (PHAGE)

DNA TRANSFER from dead organisms

+ MUTATION

Antibiotic prophylaxis

Risk factors for SSI

Know the guidelines!