Antibiotic Prescribing


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  • PALE: bacteria in the post-antibiotic phase are more susceptible to intracellular killing or to phagocytosis by leukocytes Sub MIC effects: at this concentration antibiotics are known to slow growth and produce morphological changes. Sub MIC concentrations can also prolong the duration of the PAE PAE: the persistent suppression of bacterial growth following exposure to an antimicrobial
  • Risk factors: Concurrent use of other nephrotoxic agents Prolonged therapy Continually elevated trough levels
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  • Antibiotic Prescribing

    1. 1. Antibiotic Prescribing dr shabeel pn
    2. 2. The Antibiotic Resistance Spiral Adapted from: J. Carlet. resistance RESISTANCE CONCERN SELECTION BROAD-SPECTRUM EMPIRIC THERAPY cross- transmission dosage duration new antibiotics (promotion from pharmaceutical industry)
    3. 3. Today’s presentation <ul><li>The AIR program </li></ul><ul><li>Ceftriaxone briefly </li></ul><ul><li>Aminoglycosides </li></ul><ul><li>Vancomycin </li></ul><ul><li>Surgical Prophylaxis Card </li></ul>
    4. 4. AIR Program - JHH <ul><li>Anti-Infective Registrations (AIR) </li></ul><ul><ul><li>Resistance </li></ul></ul><ul><ul><li>Pathogens (eg C. difficile ) </li></ul></ul><ul><ul><li>Safety (eg. IV clindamycin) </li></ul></ul><ul><ul><li>Cost </li></ul></ul><ul><li>Only 24 hours supply if not registered </li></ul><ul><li>Reviewed by ID pharmacist daily and at ID meeting weekly </li></ul><ul><li>“ Registration” not “Approval” system </li></ul>
    5. 5. Restricted Anti-infectives <ul><li>Require registration number at JHH: </li></ul><ul><ul><li>Aztreonam </li></ul></ul><ul><ul><li>Cefepime </li></ul></ul><ul><ul><li>Cefotaxime </li></ul></ul><ul><ul><li>Ceftazidime </li></ul></ul><ul><ul><li>Ceftriaxone </li></ul></ul><ul><ul><li>Clindamycin IV </li></ul></ul><ul><ul><li>Ticarcillin/clavulanate </li></ul></ul><ul><ul><li>Vancomycin IV </li></ul></ul><ul><li>Requires direct approval from Infectious Diseases: </li></ul><ul><ul><li>Caspofungin </li></ul></ul><ul><ul><li>Ciprofloxacin IV </li></ul></ul><ul><ul><li>Flucytosine </li></ul></ul><ul><ul><li>Linezolid </li></ul></ul><ul><ul><li>Liposomal amphotericin </li></ul></ul><ul><ul><li>Meropenem (except CF) </li></ul></ul><ul><ul><li>Moxifloxacin </li></ul></ul><ul><ul><li>Posaconazole </li></ul></ul><ul><ul><li>Teicoplanin (except cardiac Surg) </li></ul></ul><ul><ul><li>Tigecycline </li></ul></ul><ul><ul><li>Voriconazole </li></ul></ul>
    6. 8. “ Other ” – Don’t put “registrar wants it!”
    7. 9. Write number on medication chart
    8. 10. Restricted antibiotic indications <ul><li>See Sheet (available via AIR link) </li></ul><ul><li>Note dosages </li></ul><ul><li>Where in doubt, please contact ID Registrar, ID Physician or Clinical Microbiologist (49214000) </li></ul>
    9. 13. Ceftriaxone <ul><li>A few reminders: </li></ul><ul><ul><li>Ceftriaxone is not recommended as an empiric agent (excluding bacterial meningitis) </li></ul></ul><ul><ul><li>Most adults only require ceftriaxone 1g daily (excluding bacterial meningitis) </li></ul></ul>
    10. 14. Aminoglycosides Gentamicin Tobramycin Amikacin
    11. 15. Aminoglycosides <ul><li>Mechanisms of action: </li></ul><ul><ul><li>Outer cell membrane disruption </li></ul></ul><ul><ul><li>Inhibit protein synthesis (binding to ribosome) </li></ul></ul><ul><li>Rapidly bactericidal: main value is as empiric agents (1 or 2 doses) for potential aerobic Gram negative sepsis </li></ul><ul><li>Synergistic action with cell wall active agents such as beta-lactams </li></ul><ul><ul><li>Esp. of use for streptococcal and enterococcal endocarditis </li></ul></ul><ul><li>Poorly absorbed from the gastrointestinal tract </li></ul>
    12. 16. Dosing <ul><li>Once daily dosing - suitable for most indications </li></ul><ul><li>Exceptions include: </li></ul><ul><ul><ul><li>Enterococcal and some streptococcal endocarditis </li></ul></ul></ul><ul><ul><ul><li>Patients with altered volume of distribution (eg. burns, ascites, post-partum) </li></ul></ul></ul><ul><li>Recommended gentamicin and tobramycin starting doses: </li></ul>Doses should be based on ideal body weight in obese patients Starting doses generally safe even in renal impairment 2mg/kg/single dose Surgical prophylaxis 7mg/kg/day Septic shock Pseudomonas aeruginosa sepsis 5mg/kg/day Intra-abdominal sepsis, urosepsis, severe pneumonia, neutropenia Starting dose Clinical condition
    13. 17. Once daily dosing <ul><li>Increases efficacy: </li></ul><ul><li>Concentration dependent killing </li></ul><ul><ul><li>Rate and extent of killing increases with drug conc </li></ul></ul><ul><li>Post-antibiotic effect </li></ul><ul><ul><li>Persistent suppression of bacterial growth after limited exposure to a drug </li></ul></ul><ul><li>Decreases toxicity: </li></ul><ul><li>Reduces uptake into renal tubules </li></ul><ul><li>Saturable uptake into cochlear and vestibular apparatus </li></ul>
    14. 18. 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
    15. 19. Monitoring <ul><li>Required for patients in whom > 2 doses of gentamicin are planned </li></ul><ul><ul><li>Then: </li></ul></ul><ul><ul><ul><li>Every 3 days thereafter in stable patients </li></ul></ul></ul><ul><ul><ul><li>Daily in unstable patients </li></ul></ul></ul><ul><li>If treatment is planned for >3 days, it should be discussed with the Infectious Diseases team- relatively few indications for directed treatment </li></ul><ul><li>Measured level at 6-14 hrs after dose </li></ul><ul><ul><li>Doses to be given at 11pm by infusion of at least 20 minutes </li></ul></ul>
    16. 20. Dose adjustments <ul><li>As per the dosing nomogram in the </li></ul><ul><li>back of the antibiotic guidelines </li></ul>= (2.7/5.4) x 5 mg/kg = 2.5 mg/kg Next dose = (target concentration/actual concentration) x initial dose 2.7mg/L Target concentration, calculated from the midpoint of the two lines 5.4mg/L Actual concentration at 9 hours on day 3 5mg/kg Dose of aminoglycoside
    17. 21. What if the level is sub-therapeutic?? <ul><li>Nomogram is more reliable for dose reductions </li></ul><ul><li>If level is sub-therapeutic: </li></ul><ul><ul><li>Dose adjustment depends on the patients clinical status </li></ul></ul><ul><ul><li>If the patient appears clinically improved, you do not generally dose adjust upwards if the level is too low </li></ul></ul>
    18. 22. Toxicity <ul><li>Nephrotoxicity </li></ul><ul><ul><li>Potentiated by: </li></ul></ul><ul><ul><ul><li>The concurrent use of nephrotoxic agents (eg. cyclosporin, radiographic contrast agents, amphotericin B, vancomycin) </li></ul></ul></ul><ul><ul><ul><li>The presence of pre-existing renal impairment </li></ul></ul></ul><ul><ul><ul><li>Age (>70 yrs) </li></ul></ul></ul><ul><ul><ul><li>Duration of treatment </li></ul></ul></ul><ul><ul><li>Partly reversible </li></ul></ul><ul><li>Ototoxicity </li></ul><ul><ul><li>Irreversible, may be delayed (rarely immediate) </li></ul></ul><ul><ul><li>Can be vestibular or cochlear </li></ul></ul><ul><ul><li>All patients should be questioned daily about their balance and hearing </li></ul></ul>
    19. 23. Cystic Fibrosis <ul><li>Larger doses of aminoglycosides needed </li></ul><ul><ul><li>Unique metabolism and physiology – higher aminoglycoside clearance </li></ul></ul><ul><ul><li>CF patients need higher doses of tobramycin </li></ul></ul><ul><li>Monitoring: </li></ul><ul><ul><li>Combination of CMax and AUC </li></ul></ul><ul><ul><ul><li>Better prediction of efficacy and toxicity </li></ul></ul></ul><ul><ul><li>Ideal AUC: 100mg.h/L (range: 90-100) </li></ul></ul><ul><ul><li>TCI works (Bayesian calculations) </li></ul></ul><ul><ul><li>Contact Respiratory Advanced Trainee (Dr Scott Twaddell) </li></ul></ul><ul><li>Dosing (Adults): </li></ul><ul><ul><li>First dose: 7mg/kg </li></ul></ul><ul><ul><li>Given at 6am </li></ul></ul><ul><ul><li>Levels to be checked 2 nd daily </li></ul></ul><ul><ul><li>Tobramycin levels to be taken 4 and 6 hours post dose (peripheral blood) </li></ul></ul>
    20. 24. Vancomycin
    21. 25. Vancomycin <ul><li>A glycopeptide antibiotic </li></ul><ul><li>Mechanism of action: </li></ul><ul><ul><li>Inhibition of cell wall elongation </li></ul></ul><ul><ul><li>Bactericidal </li></ul></ul><ul><li>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 </li></ul><ul><ul><li>Ensuring an adequate trough level is a suitable proxy for measurement of AUC </li></ul></ul>
    22. 26. PK and PD <ul><li>Not absorbed from GIT </li></ul><ul><ul><li>Administered orally only as second line treatment of Clostridium difficile </li></ul></ul><ul><li>Little perfusion into the CSF </li></ul><ul><ul><li>Increased in meningeal inflammation </li></ul></ul><ul><li>High molecular weight </li></ul><ul><ul><li>Limiting spectrum of activity to gram positive organisms </li></ul></ul><ul><ul><li>Poor lung penetration </li></ul></ul><ul><ul><li>Hydrophilic and bulky molecule </li></ul></ul><ul><li>Renal excretion </li></ul>
    23. 27. Dosing (See Therapeutic Guidelines: Antibiotic) <ul><li>Starting doses for adults and children >12yrs </li></ul><ul><ul><li>Normal renal function: </li></ul></ul><ul><ul><ul><li>25mg/kg up to 1g 12-hourly USE ACTUAL BODY WEIGHT </li></ul></ul></ul><ul><ul><li>Impaired renal function: </li></ul></ul><ul><ul><ul><li>CrCl >50mL/min: 25mg/kg up to 1g 12 th hourly </li></ul></ul></ul><ul><ul><ul><li>CrCl 10-50mL/min: 25mg/kg up to 1g 24 hourly </li></ul></ul></ul><ul><ul><ul><li>CrCl <10mL/min: 25mg/kg up to 1g – check levels after 48 hours </li></ul></ul></ul><ul><ul><li>Patients > 65 yrs generally require a once daily dose </li></ul></ul><ul><ul><li>Young adults and children often require high doses - shift to 6-8hrly by preference : see TG: Antibiotic </li></ul></ul><ul><li>Dose adjustment up and down according to trough level generally by half to one vial (ie. 250mg – 500mg) or from 12 hourly to daily </li></ul>
    24. 28. Monitoring <ul><li>Trough levels </li></ul><ul><ul><li>Aim for 10-20mg/L (6hrly dosing in children 15-25mg/kg) </li></ul></ul><ul><ul><li>Level to be taken immediately before the 4th dose </li></ul></ul><ul><ul><li>Thereafter, levels to be taken 2 to 3 times per week (or more frequently depending on the clinical situation eg. changing renal function) </li></ul></ul><ul><li>NB: MRSA bacteraemia </li></ul><ul><ul><li>Use aggressive initial dosing to achieve therapeutic levels </li></ul></ul><ul><ul><ul><li>Levels <10mg/L risk factor for hVISA infection </li></ul></ul></ul>
    25. 29. Toxicity <ul><li>High trough levels are responsible for the majority of adverse effects </li></ul><ul><ul><li>Nephrotoxicity </li></ul></ul><ul><ul><li>Ototoxicity </li></ul></ul><ul><li>Red man syndrome </li></ul><ul><ul><li>Due to histamine release </li></ul></ul><ul><ul><li>Can be avoided by slow infusion </li></ul></ul><ul><ul><ul><li>10mg/min (or 500mg over at least 60 minutes) </li></ul></ul></ul>
    26. 30. Bacterial Resistance Mechanisms <ul><li>Inactivation of antibiotic (eg.  -lactamase) </li></ul><ul><li>Prevent access of antibiotic to site of action (eg. alteration of membrane porins to reduce influx - quinolones, tetracycline) </li></ul><ul><li>Modification/replacement of target structure to reduce binding of antibiotic (eg. VRE, MRSA, macrolide resistance) </li></ul><ul><li>Active efflux of the antibiotic (eg. tetracycline) </li></ul>
    27. 31. mecA Encodes penicillin binding protein 2a with low affinity for beta-lactam antibiotics Cell -wall active antibiotics - Beta-lactams - Glycopeptides (vancomycin)
    28. 32. Emergence of resistance in Staph. and other Gram positive bacteria 1988 – VRE 1996 – VISA 2002 - VRSA 1960 (Pen, streptom, tetrac, eryth) 1946 First Resistance 1965 1959 1942 Introduction Vancomycin Methicillin Penicillin Drug
    29. 33. Vancomycin-resistant Enterococcal types <ul><li>Type Van Tei Site Species </li></ul><ul><li>VanA R R Plasmid/chr E. faecium </li></ul><ul><li>dala-dlac E faecalis </li></ul><ul><li>VanB R S Plasmid/chr E. faecalis </li></ul><ul><li>dala-dlac E. faecium </li></ul><ul><li>VanC1 R S Chromosome E. gallinarum </li></ul><ul><li>VanC2 R S “ E. casseliflavus </li></ul><ul><li>VanC3 R S “ E. flavescens </li></ul><ul><li>dala-dser </li></ul><ul><li>VanD R S Plasmid? E. faecium </li></ul><ul><li>dala-dlac </li></ul><ul><li>VanE R S ? Enterococcus sp. </li></ul><ul><li>dala-dser </li></ul><ul><li>VanF 12-16 S ? Enterococcus faecalis (QLD) </li></ul><ul><li>VanG 12-16 S ? SA isolate </li></ul>
    30. 34. VRE epidemiology in Australia <ul><li>Predominance of vanB isolates </li></ul><ul><li>Recognition of community carriage of the same cassette (transposon) of vanB genes in Clostridia and related species </li></ul><ul><li>Capacity for endogenous generation of VRE under antibiotic exposure by transfer of vanB genes in to enterococci </li></ul><ul><li>Also evidence of clonal spread within hospitals: importance of - </li></ul><ul><ul><li>Antibiotic control </li></ul></ul><ul><ul><li>Hand hygiene by HCW (5 Moments) </li></ul></ul><ul><ul><li>Environmental cleaning in hospitals </li></ul></ul><ul><ul><li>Contact isolation of known VRE patients </li></ul></ul>
    31. 35. CAP/HAP & Surgical Prophylaxis <ul><li>Prescribing Cards available </li></ul><ul><li>Hands up if you don’t have a copy </li></ul>
    32. 36. Surgical Prophylaxis
    33. 37. Any questions?