Antibiotic Prescribing

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Antibiotic Prescribing

• Dr John Ferguson (ID Physician)
• Dr Robert Pickles (ID Physician)
• Kelly Cairns (ID Pharmacist)

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Todays presentation

• The AIR program
• Ceftriaxone briefly
• Aminoglycosides
• Vancomycin
• Surgical Prophylaxis Card

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AIR Program - JHH

• Anti-Infective Registrations (AIR)
• Resistance
• Pathogens (eg C. difficile)
• Safety (eg. IV clindamycin)
• Cost
• Only 24 hours supply if not registered
• Reviewed by ID pharmacist daily and at ID meeting
  weekly
• Registration not Approval system

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Restricted Anti-infectives

• Requires direct approval from Infectious
  Diseases
• Caspofungin
• Ciprofloxacin IV
• Flucytosine
• Linezolid
• Liposomal amphotericin
• Meropenem (except CF)
• Moxifloxacin
• Posaconazole
• Teicoplanin (except cardiac Surg)
• Tigecycline
• Voriconazole

• Require registration number at JHH
• Aztreonam
• Cefepime
• Cefotaxime
• Ceftazidime
• Ceftriaxone
• Clindamycin IV
• Ticarcillin/clavulanate
• Vancomycin IV

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Other Dont put registrar wants it!
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Write number on medication chart
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Restricted antibiotic indications

• See Sheet (available via AIR link)
• Note dosages
• Where in doubt, please contact ID Registrar, ID
  Physician or Clinical Microbiologist (49214000)

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Ceftriaxone

• A few reminders
• Ceftriaxone is not recommended as an empiric
  agent (excluding bacterial meningitis)
• Most adults only require ceftriaxone 1g daily
  (excluding bacterial meningitis)

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Aminoglycosides

• Gentamicin
• Tobramycin
• Amikacin

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Aminoglycosides

• Mechanisms of action
• Outer cell membrane disruption
• Inhibit protein synthesis (binding to ribosome)
• Rapidly bactericidal main value is as empiric
  agents (1 or 2 doses) for potential aerobic Gram
  negative sepsis
• Synergistic action with cell wall active agents
  such as beta-lactams
• Esp. of use for streptococcal and enterococcal
  endocarditis
• Poorly absorbed from the gastrointestinal tract

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Dosing

• Once daily dosing - suitable for most indications
• Exceptions include
• Enterococcal and some streptococcal endocarditis
• Patients with altered volume of distribution (eg.
  burns, ascites, post-partum)
• Recommended gentamicin and tobramycin starting
  doses

Doses should be based on ideal body weight in
obese patients Starting doses generally safe even
in renal impairment
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Once daily dosing

• Increases efficacy
• Concentration dependent killing
• Rate and extent of killing increases with drug
  conc
• Post-antibiotic effect
• Persistent suppression of bacterial growth after
  limited exposure to a drug
• Decreases toxicity
• Reduces uptake into renal tubules
• Saturable uptake into cochlear and vestibular
  apparatus

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Protects against bacterial regrowth when serum
concs fall below MIC
Bacteria are more susceptible to intracellular
killing or to phagocytosis by leukocytes
Aminoglycoside action MIC minimal inhibitory
concentration PAE post-antibiotic effect PALE
post-antibiotic leucocyte enhancement effect
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Monitoring

• Required for patients in whom gt 2 doses of
  gentamicin are planned
• Then
• Every 3 days thereafter in stable patients
• Daily in unstable patients
• If treatment is planned for gt3 days, it should be
  discussed with the Infectious Diseases team-
  relatively few indications for directed treatment
• Measured level at 6-14 hrs after dose
• Doses to be given at 11pm by infusion of at least
  20 minutes

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Dose adjustments

• As per the dosing nomogram in the
• back of the antibiotic guidelines

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What if the level is sub-therapeutic??

• Nomogram is more reliable for dose reductions
• If level is sub-therapeutic
• Dose adjustment depends on the patients clinical
  status
• If the patient appears clinically improved, you
  do not generally dose adjust upwards if the level
  is too low

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Toxicity

• Nephrotoxicity
• Potentiated by
• The concurrent use of nephrotoxic agents (eg.
  cyclosporin, radiographic contrast agents,
  amphotericin B, vancomycin)
• The presence of pre-existing renal impairment
• Age (gt70 yrs)
• Duration of treatment
• Partly reversible
• Ototoxicity
• Irreversible, may be delayed (rarely immediate)
• Can be vestibular or cochlear
• All patients should be questioned daily about
  their balance and hearing

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Cystic Fibrosis

• Larger doses of aminoglycosides needed
• Unique metabolism and physiology higher
  aminoglycoside clearance
• CF patients need higher doses of tobramycin
• Monitoring
• Combination of CMax and AUC
• Better prediction of efficacy and toxicity
• Ideal AUC 100mg.h/L (range 90-100)
• TCI works (Bayesian calculations)
• Contact Respiratory Advanced Trainee (Dr Scott
  Twaddell)
• Dosing (Adults)
• First dose 7mg/kg
• Given at 6am
• Levels to be checked 2nd daily
• Tobramycin levels to be taken 4 and 6 hours post
  dose (peripheral blood)

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Vancomycin
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Vancomycin

• A glycopeptide antibiotic
• Mechanism of action
• Inhibition of cell wall elongation
• Bactericidal
• Killing is best correlated with the Area under
  the curve (AUC) measure (technically the ratio
  Drug AUC/Bug MIC) rather than concentration or
  time above MIC
• Ensuring an adequate trough level is a suitable
  proxy for measurement of AUC

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PK and PD

• Not absorbed from GIT
• Administered orally only as second line treatment
  of Clostridium difficile
• Little perfusion into the CSF
• Increased in meningeal inflammation
• High molecular weight
• Limiting spectrum of activity to gram positive
  organisms
• Poor lung penetration
• Hydrophilic and bulky molecule
• Renal excretion

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Dosing (See Therapeutic Guidelines Antibiotic)

• Starting doses for adults and children gt12yrs
• Normal renal function
• 25mg/kg up to 1g 12-hourly USE ACTUAL BODY
  WEIGHT
• Impaired renal function
• CrCl gt50mL/min 25mg/kg up to 1g 12th hourly
• CrCl 10-50mL/min 25mg/kg up to 1g 24 hourly
• CrCl lt10mL/min 25mg/kg up to 1g check levels
  after 48 hours
• Patients gt 65 yrs generally require a once daily
  dose
• Young adults and children often require high
  doses - shift to 6-8hrly by preference see TG
  Antibiotic
• Dose adjustment up and down according to trough
  level generally by half to one vial (ie. 250mg
  500mg) or from 12 hourly to daily

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Monitoring

• Trough levels
• Aim for 10-20mg/L (6hrly dosing in children
  15-25mg/kg)
• Level to be taken immediately before the 4th dose
• Thereafter, levels to be taken 2 to 3 times per
  week (or more frequently depending on the
  clinical situation eg. changing renal function)
• NB MRSA bacteraemia
• Use aggressive initial dosing to achieve
  therapeutic levels
• Levels lt10mg/L risk factor for hVISA infection

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Toxicity

• High trough levels are responsible for the
  majority of adverse effects
• Nephrotoxicity
• Ototoxicity
• Red man syndrome
• Due to histamine release
• Can be avoided by slow infusion
• 10mg/min (or 500mg over at least 60 minutes)

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Bacterial Resistance Mechanisms

• Inactivation of antibiotic (eg. ?-lactamase)
• Prevent access of antibiotic to site of action
  (eg. alteration of membrane porins to reduce
  influx - quinolones, tetracycline)
• Modification/replacement of target structure to
  reduce binding of antibiotic (eg. VRE, MRSA,
  macrolide resistance)
• Active efflux of the antibiotic (eg. tetracycline)

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Cell -wall active antibiotics - Beta-lactams -
Glycopeptides (vancomycin)
mecA Encodes penicillin binding protein 2a with
low affinity for beta-lactam antibiotics
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Emergence of resistance in Staph. and other Gram
positive bacteria
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Vancomycin-resistant Enterococcal types

• Type Van Tei Site Species
• VanA R R Plasmid/chr E. faecium
• dala-dlac E faecalis
• VanB R S Plasmid/chr E. faecalis
• dala-dlac E. faecium
• VanC1 R S Chromosome E. gallinarum
• VanC2 R S E. casseliflavus
• VanC3 R S E. flavescens
• dala-dser
• VanD R S Plasmid? E. faecium
• dala-dlac
• VanE R S ? Enterococcus sp.
• dala-dser
• VanF 12-16 S ? Enterococcus faecalis (QLD)
• VanG 12-16 S ? SA isolate

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VRE epidemiology in Australia

• Predominance of vanB isolates
• Recognition of community carriage of the same
  cassette (transposon) of vanB genes in Clostridia
  and related species
• Capacity for endogenous generation of VRE under
  antibiotic exposure by transfer of vanB genes in
  to enterococci
• Also evidence of clonal spread within hospitals
  importance of -
• Antibiotic control
• Hand hygiene by HCW (5 Moments)
• Environmental cleaning in hospitals
• Contact isolation of known VRE patients

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CAP/HAP Surgical Prophylaxis

• Prescribing Cards available
• Hands up if you dont have a copy

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Surgical Prophylaxis
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Any questions?