Antibiotic Prescribing
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Transcript of Antibiotic Prescribing
Antibiotic Prescribing
The Antibiotic Resistance Spiral
Adapted from: J. Carlet.
resistance
RESISTANCE
CONCERN
SELECTION
BROAD-SPECTRUMEMPIRIC THERAPY
cross-transmission
dosageduration
new antibiotics(promotion from pharmaceutical
industry)
Today’s presentation The AIR program
Ceftriaxone briefly
Aminoglycosides
Vancomycin
Surgical Prophylaxis Card
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
Restricted Anti-infectives
Require registration number at JHH: Aztreonam Cefepime Cefotaxime Ceftazidime Ceftriaxone Clindamycin IV Ticarcillin/clavulanate Vancomycin IV
Requires direct approval from Infectious Diseases: Caspofungin Ciprofloxacin IV Flucytosine Linezolid Liposomal amphotericin Meropenem (except CF) Moxifloxacin Posaconazole Teicoplanin (except cardiac
Surg) Tigecycline Voriconazole
“Other” – Don’t put “registrar wants it!”
Write number on medication chart
Restricted antibiotic indications
See Sheet (available via AIR link) Note dosages Where in doubt, please contact ID Registrar, ID
Physician or Clinical Microbiologist (49214000)
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)
Aminoglycosides
Gentamicin
Tobramycin
Amikacin
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
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:
Clinical condition Starting doseIntra-abdominal sepsis, urosepsis, severe pneumonia, neutropenia
5mg/kg/day
Septic shock
Pseudomonas aeruginosa sepsis
7mg/kg/day
Surgical prophylaxis 2mg/kg/single dose
Doses should be based on ideal body weight in obese patients
Starting doses generally safe even in renal impairment
Once daily dosingIncreases 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
Aminoglycoside action:
MIC= minimal inhibitory concentration
PAE= post-antibiotic effect
PALE= post-antibiotic leucocyte enhancement effect
Aminoglycoside action:
MIC= minimal inhibitory concentration
PAE= post-antibiotic effect
PALE= post-antibiotic leucocyte enhancement effect
Protects against bacterial regrowth when serum concs fall below MIC
Bacteria are more susceptible to intracellular killing or to phagocytosis by leukocytes
Monitoring Required for patients in whom > 2 doses of gentamicin
are planned Then:
Every 3 days thereafter in stable patients Daily in unstable patients
If treatment is planned for >3 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
Dose adjustments
Dose of aminoglycoside 5mg/kg
Actual concentration at 9 hours on day 3
5.4mg/L
Target concentration, calculated from the midpoint of the two lines
2.7mg/L
Next dose =
(target concentration/actual concentration) x initial dose
= (2.7/5.4) x 5 mg/kg
= 2.5 mg/kg
As per the dosing nomogram in the back of the antibiotic guidelines
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
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 (>70 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
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)
Vancomycin
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
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
Dosing (See Therapeutic Guidelines: Antibiotic)
Starting doses for adults and children >12yrs Normal renal function:
25mg/kg up to 1g 12-hourly USE ACTUAL BODY WEIGHT
Impaired renal function: CrCl >50mL/min: 25mg/kg up to 1g 12th hourly CrCl 10-50mL/min: 25mg/kg up to 1g 24 hourly CrCl <10mL/min: 25mg/kg up to 1g – check levels after 48 hours
Patients > 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
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 <10mg/L risk factor for hVISA infection
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)
Bacterial Resistance Mechanisms
1. Inactivation of antibiotic (eg. -lactamase)
2. Prevent access of antibiotic to site of action (eg. alteration of membrane porins to reduce influx - quinolones, tetracycline)
3. Modification/replacement of target structure to reduce binding of antibiotic (eg. VRE, MRSA, macrolide resistance)
4. Active efflux of the antibiotic (eg. tetracycline)
mecA
Encodes penicillin binding protein 2a with low affinity for beta-lactam antibiotics
mecA
Encodes penicillin binding protein 2a with low affinity for beta-lactam antibiotics
Cell -wall active antibiotics
- Beta-lactams
- Glycopeptides (vancomycin)
Cell -wall active antibiotics
- Beta-lactams
- Glycopeptides (vancomycin)
Emergence of resistance in Staph. and other Gram positive bacteria
Drug Penicillin Methicillin Vancomycin
Introduction 1942 1959 1965
First Resistance
1946 1960
(Pen, streptom, tetrac, eryth)
1988 – VRE
1996 – VISA
2002 - VRSA
Vancomycin-resistant Enterococcal types
Type Van Tei Site SpeciesVanA R R Plasmid/chr E. faeciumdala-dlac E faecalisVanB R S Plasmid/chr E. faecalisdala-dlac E. faeciumVanC1 R S Chromosome E. gallinarumVanC2 R S “ E. casseliflavusVanC3 R S “ E. flavescensdala-dserVanD R S Plasmid? E. faeciumdala-dlacVanE R S ? Enterococcus sp.dala-dserVanF 12-16 S ? Enterococcus faecalis (QLD)VanG 12-16 S ? SA isolate
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
CAP/HAP & Surgical Prophylaxis
Prescribing Cards available
Hands up if you don’t have a copy
Surgical Prophylaxis
Any questions?