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?