Using PK/PD Principles in Antibiotic Prescribing SAHD May 20, 2011

1. Using PK/PD Principles in Antibiotic PrescribingSAHD May 20, 2011 Peter Gayo Munthali Consultant Microbiologist UHCW Honorary Associate Clinical Professor University of Warwick

2. Objectives By the end of this session you should be able to: • Appreciate the importance of prescribing antibiotics in a timely manner • Understand the right dosing for major classes of antibiotics • Select antibiotics according to the site of infection • Safely prescribe Gentamicin and Vancomycin,be able to monitor levels logically and interpret them • Select safe antibiotics for use in renal and hepatic failure • Understand the consideration of antibiotic interactions with other drugs

3. There are Three in this Relationship Drug Toxicity Resistance Pharmacokinetics (PK) Pharmacodynamics(PD) Infection Host Host defence Bacteria

5. Improving the probability of positive outcomes • Window of opportunity • Early recognition and treatment of infection • Selection of appropriate antibiotic(e.g. through in vitro susceptibility determination) • Optimization of DOSE using Pharmacodynamic principles • Use optimized dosing that would allow for the minimization of selecting further resistance

6. Early recognition of infection (Sepsis) • Systemic inflammatory response syndrome (SIRS) Systemic activation of the immune response  2 of the following in response to an insult: • T > 38 .C or < 36.C • HR > 90 bpm • RR > 20 bpm or PaCO2 < 32 mmHg • WBC > 12 000 cells/mm3 , < 4 000 cells/mm3 or >10 % bands • Sepsis The systemic response to infection SIRS + suspected or confirmed infection (Bone et al Crit Care med 1989.;17 :389)

7. Sepsis • Severe sepsis • Sepsis+ organ dysfunction, hypoperfusion or hypotension • Septic shock • Severe sepsis + • unresponsive to fluid resuscitation • need for vasopressor agents • Multiple organ dysfunction syndrome • Organ dysfunction • Homeostasis cannot be maintained without intervention

8. Severe Sepsis Bundles Sepsis Resuscitation Bundle (To be completed as soon as possible and scored over first 6 hours) • Serum lactate measured • Blood culture obtained prior to antibiotic administration • From presentation, broad spectrum antibiotics administered within 3 hours for ED admission and 1 hour for non-ED ICU admission • In the event of hypotension and /or lactate >4mmol/l (36mg/dl): • Deliver an initial minimum of 20ml/Kg of crystalloid (or colloid equivalent) • Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure >65mmHg • In the event of persistent hypotension despite fluid resuscitation (septic shock) and /or lactate >4mmmol/L (36mg/dl): • Achieve central venous pressure (CVP) of >8mmHg • Achieve central venous oxygen saturation (ScvO2) of > 70%

9. Early treatment of infection prospective observational study on 101 consecutive adult patients with severe sepsis or septic shock • The rate of compliance with the 6-hour sepsis bundle was 52%. • non-compliant group had a more than twofold increase in hospital mortality • (49% versus 23%, RR 2.12 (95% CI 1.20 to 3.76), P = 0.01) • similar age and severity of sepsis both groups • Compliance with the 24-hour sepsis bundle in only 30% (21/69). Hospital mortality was increased in the non-compliant group from 29% to 50%, • 76% increase in risk for death(RR 1.76 (95% CI 0.84 to 3.64), P = 0.16). Critical Care 2005, 9:R764-R770

10. Role of Antibiotics (Kollef et al Chest 1999;115:462-474) • 2,000 consecutive patients admitted to surgical or medical ITU • 655 patients (33%) had either CA or HA infection • 169 infected patients (25.8%) received inadequate antimicrobial treatment • All Cause Hospital Mortality (RR 4.26, 95% CI 3.52-5.15, p < 0.001) • Adequate antimicrobial treatment • Mortality 12.2% • Inadequate antimicrobial treatment • Mortality 52.1% • Infection Related Mortality (RR 2.37, 95% CI 1.83-3.08, p < 0.001) • Adequate antimicrobial treatment • Mortality 17.7% • Inadequate antimicrobial treatment • Mortality 42.0% • Most important independent determinant of hospital mortality was inadequate antibiotic treatment (OR 4.27, 95% CI 3.35-5.44, p < 0.001)

11. Timing of Antibiotics(Kumar A et al. Crit Care Med 2006;34:1589–1596) • Retrospective, May 1999-June 2004, N=2731 • Outcome of antibiotic therapy after onset of recurrent or persistent hypotension • Overall mortality 56.2% • Survival decreased by 7.6% for each hour of delay • Applied to all subgroups of infections regardless of the source of infection or causative pathogens

12. Key Message 1 • Diagnose sepsis early and give antibiotics promptly to reduce mortality from sepsis

13. Pharmacodynamics

14. Drug Absorption Curve

15. MIC Calculation MIC

17. Beta-Lactams • The critical parameter is the time the antibiotic concentration remains above the MIC of the organism expressed as • T > MIC

18. Beta-Lactams: Optimising Exposure • The optimum level of exposure varies for different agents within the beta-lactam class • Required %T>MIC for efficacy: • ~ 50%–70% for cephalosporins • ~ 50% for penicillins • ~ 40% for carbapenems Drusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50.

19. Pharmacodynamics of Beta-Lactams and Macrolides in Otitis Media Craig et al, Ped Infect Dis 15: 255, 1996

20. Once-daily regimen Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens Concentration (mg/L) 14 12 Conventional (three-times daily regimen) 10 • Cmax:MIC model • For optimal response, • Peak concentration: MIC ratio should be between 8-12.1 8 6 4 MIC 2 0 0 4 8 12 16 20 24 Time (hours) Nicolau DP et al. Antimicrob Agents Chemother. 1995;39:650–655

21. Aminoglycosides—Relationship Between Cmax:MIC Ratio and Clinical Response Clinical response (%) Cmax:MIC Moore RD et al. J Infect Dis. 1987;155:93-99.

22. Key Message 2 • Beta lactams need frequent dosing for successful therapeutic outcome • Missing doses will lead to treatment failure • Aminoglycosides should be given as a large single dose (except in infective endocarditis) for a successful therapeutic outcome • Multiple small doses will lead to treatment failure and likely to lead to renal toxicity

23. Pharmacokinetics

24. Where do bugs Hide? Early Endosomes Inclusions Brucella spp Salmonella spp Francisella tularensis Chlamydia spp Endosomes Phagosomes Lysosomes Mycobacterium spp ER Cytosol Legionella pneumophila Coxiella bruneti Staphylococcus aureus Legionella pneumophila Listeria monocytogenes Shigella flexeneri Rickettsia spp Nucleus

25. Aminoglycosides Good Circulating organisms Poor Soft tissue Bone and joints Abscesses Lungs CSF Use of Pharmacokinetics in Treatment Beta lactams Good/variable (Dependant on individual antibiotic) Soft tissue Bone and joints Lungs CSF Poor Abscesses Examples of good Tissue Penetrators Tetracyclines Macrolides Quinolones Clindamycin

26. Extra and Intracellular Pharmacokinetics Accumulation factor =Cellular conc /extracellular conc Infect Dis Clin N Am 17(2003) 615-634 V.fast < 3min, Fast 3-15min, slow 15min-3hrs, V.slow >3hrs

27. Key Message 3 • When selecting an antibiotic consider the following; • Where is the infection? • Which antibiotics will reach the site of infection • Match the two and select your antibiotic

28. Antibiotics, Renal Function and Hepatic Function

29. Renal Function Estimated Creatinine clearance (Cockcroft-Gault formula) 140-AgexMass (Kg) x Constant Serum Creatinine in µmol/l Constant 1.04 for Women, 1.23 for Men

31. Antibiotic Renal Handling • Major Renal Excretion i.e. ≥ 50% • Generally innocuous • Examples • Penicillins • Cephalosporins • Carbapenems • Tetracyclines • Not Innocuous • Examples • Aminoglycosides • Polymyxin B, Colistin • Vancomycin • Amphotericin • Excretion Less than 15% in urine and • Generally innocuous • Examples • Macrolides (erythromycin) • Sodium fusidate • Clindamycin • Generally no dosage adjustment required • Exception • Chloramphenicol-not innocuous

32. Excretion Less than 15% in urine and Generally innocuous Dose adjustment required only at moderate to severe renal impairment Examples

33. Major Renal Excretion i.e. ≥ 50% Generally innocuous

34. Major Renal Excretion i.e. ≥ 50% AND Poisonous

35. Gentamicin monitoring 1 Hartford Nomogram 7 mg/Kg OD • PreciseTimes of collection required • Collection 6-12Hrs after dose

36. Gentamicin monitoring 2 • Gentamicin 5-7mg/Kg OD • Collect around 24Hrs post dose • Aiming for <1mg/l • Checking if patient is clearing gentamicin • High levels • Blood collected too early • Patient not clearing Gentamicin • Blood collected from lumen used to infuse Gentamicin earlier on

37. Gentamicin monitoring 2 • Corrective measures • Re-check levels • Stop, look for alternative antibiotic • Omit dose and repeat levels after 12 Hrs • Frequency • 2-3x/week after steady state • More frequently if renal function changing or concurrent nephrotoxic drugs

38. Vancomycin Monitoring • Glycopeptide • ONLY active against Gram-positive bacteria including MRSA • IV only except for Clostridium Difficile associated diarrhoea when oral route is used (NOT absorbed from GI and not enough levels get into GI by IV route) • 1g BD IV standard dose • Vancomycin trough level • Collect serum specimen 30 minutes or less before next dose • Frequency of collection: • First level at steady state (3rd - 5th dose) • Subsequent levels once or twice/week • More frequently if renal function changing or concurrent nephrotoxic drugs

40. Hepatic failure

42. Key Message 4&5 • Aminoglycosides are toxic drugs and require monitoring • Avoid use in renal failure but safe in liver failure • Avoid concomitant use with other renal toxic drugs • Check renal clearance, frequency according to renal function • Vancomycin dosing should be BD dose and adjusted according to levels at steady state • Frequency of monitoring depends on renal function • Beta lactams are the safest antibiotics in renal and hepatic failure • Adjustments to dose may still be required in severe failure

43. Antibiotic Interactions

45. Key Message 6 • Always check the impact of an antibiotic on other drugs that a patient is on • Consult BNF

46. And So!

47. Necrotising Fascitis • Patient • Severe sepsis with septic shock • Acute renal failure • On Gentamicin, Clindamycin, • co-amoxiclav Beta haemolytic Streptococcus group A isolated from tissue Sensitive to: Amoxicillin, meropenem, Clindamycin Gentamicin, doxycycline, Vancomycin, Erythromycin, Gentamicin Beta haemolytic Streptococcus group A

48. What would you do? • Stop Gentamicin • Switch Co-amoxiclav to Benzylpenicillin • Continue with the same treatment • Add meropenem to the current treatment

49. What would you do? On 11/05/11 you are called by a nurse at 2300hrs to make a decision whether to give gentamicin or not since the level was not done that day. Previous Renal Function and Gentamicin Levels

50. How do you proceed? • Send urgent Gentamicin levels before giving it • Change to another antibiotic until you get levels back the following day • Omit Gentamicin dose • Give the Gentamicin and check levels the following day