OPTIMIZATION OF ANTIMICROBIALS BASED ON PK (1).pptx

OPTIMIZATION OF ANTIMICROBIALS

1. OPTIMIZATION OF ANTIMICROBIALS in icu BASED ON PK/PD DR SALIM HASSANALI

2. Early and effective therapy is an appropriate antibiotic therapy AND is a significant determinant of clinical outcome Dosing AND TIMING of antibiotics is also an important component as choosing the right one The aim of appropriate antibiotic treatment is Maximize rate and extent bacterial killing Reduce drug resistance Reduce drug toxicity

3. inappropriate antimicrobial is associated with poor outcome Wrong antibiotic Narrow spectrum antibiotic Sub therapeutic dosing Wrong diagnosis Wrong antibiotic based on the site of the infection

4. Sub optimal dosing Poor clinical outcomes Poor clinical cure Increased mortality Increased incidence of resistance bugs or the superbugs Clin Infect Dis 2014;58:1072-83 Lancet Infect Dis 2014;14:498-509

5. Dosing based on PK/Pd principles' of various antibiotics achieves maximum antibiotic activity Pk principles determines whether appropriate dose of antimicrobial reaches the intended pathogen(S) ( WHAT THE BODY DOES TO THE DRUG ) Absorption Distribution Metabolism elimination

6. PD – RELATIONSHIP BETWEEN DRUG CONCENTRATION AND IT’S OBSERVED EFFECT ON THE PATHOGEN ( what the drug does to the body ) THE MAJOR INDICATOR OF THE EFFECT OF THE ANTIBIOTICS IS THE mic PK/PD INDEX – RELATIONSHIP BETWEEN DOSE ADMINISTERED AND THE RATE AND EXTENT OF BACTERIAL KILLING

7. Pharmacokinetic pharmacodynamics principles Pk - describes the fundamental processes of absorption, distribution, metabolism and elimination and the resulting concentration-versus-time profile of an agent administered in vivo PK studies describe parameters such as peak concentration (x) and cumulative exposure max (area-under-the-concentration-time curve [AUC]) for a given time period By applying PK principles, a clinician can determine whether an appropriate dose of antimicrobial will reach the pathogen(s).

8. Physico chemical properties of antimicrobial the relative solubility of the antimicrobial has a significant impact on its volume of distribution (Vd) and will affect the selection of agents and doses expected to attain adequate penetration to the site of infection

9. Certain anatomic compartments, including bone, cerebrospinal fluid and lungs, are penetrated poorly by some antibiotics most ß-lactams have bone: serum ratios between 0.1 and 0.3 while that for vancomycin is estimated to be 0.2 fluoroquinolones are lipophilic and have high Vd - achieve higher bone:serum ratios Clin Ther 2016;38:1930-47

10. Which antibiotic and at what dose ?

11. Lipophilic and hydrophilic In general, a high Vd implies that the drug is distributed extensively to tissue (lipophilic), whereas a low Vd that is similar to that of extracellular water suggests that the drug is concentrated in the plasma (hydrophilic) In critically ill patients there is high volume of distribution and because hydrophilic antibiotics will require use of loading doses to ensure early achievement of therapeutic concentrations. Crit Care 2011;15:R206.

12. Lipophilic antibiotics not greatly influenced by changes in fluid volume and may not require alterations in initial dosing

13. Critically ill patients have lowered protein concentrations and thus altered protein binding, unpredictable volumes of distribution, and vastly altered clearances compared to non-critically ill patients

14. Antibiotic dosing is affected by……!

15. Volume of distribution Increased in sepsis due to vasodilation and aggressive fluid resuscitation and creatinine clearance Important for hydrophilic antibiotics

16. Albumin concentration hypoalbuminemia has a direct impact on the PK of antibiotic Most drugs bind to albumin With an increase in the unbound drug, hypalbuminaemia likely increases the Vd and clearance of an antimicrobial, leading to lower and possibly suboptimal concentrations towards the end of the dosing interval Clin Pharmacokinet 2011;50:99-110

17. Augmented renal clearance While renal elimination can be reduced in the setting of acute kidney injury or renal failure, hyper dynamic conditions such as sepsis, increased ventricular preload following aggressive fluid resuscitation and vasopressors, may augment renal clearance by increased renal perfusion to as much as triple the normal rate and may be associated with treatment failure despite appropriate choice of antimicrobial agent Clin Pharmacokinet 2010;49:1-6. Crit Care Med 2014;42:520-7

18. Udy et al Clin Pharmacokinet 2010; 49:1-16

19. elimination kidney can excrete antimicrobials and their metabolites by glomerular filtration or by proximal tubular secretion Molecular size of the antibiotics is important in terms of rrt Clin Pharmacokinet 2007;46:997-1038.

20. Antimicrobial pharmacodynamics relationship between the antimicrobial concentration and the observed effect on the target pathogen in the body Mic is the best indicator

21. Pk/pd indices fT > MIC time that the unbound (f) drug concentration in the plasma that remains above the MIC of the infecting organism Fcmax /MIC ratio between the maximum concentration (x) of the unbound drug and the MIC AUC/MIC ratio of the 24-hour AUC and the MIC. J Antimicrob Chemother 2005;55:601-7.

22. post-antibiotic effect the persistence of bacterial suppression after drug levels are less than the MIC In general, agents that alter protein or nucleic acid synthesis tend to display a prolonged PAE against any susceptible organism, as it takes considerably longer for bacteria to regenerate these elements compared to cell wall components J Antimicrob Chemother 1993;31 Suppl D: 149-58

23. Time dependent vs concentration dependence

24. Beta lactams Cephalosporins Penicillins Carbapenems Pd effects on the pathogen is affected by the cumulative percentage of time that free drug concentration exceeds the mic Veiga and Paiva Critical Care (2018) 22:233 Clin Infect Dis 1998;26:1-0

25. Prolonged infusion vs intermittent boluses Most ß-lactam antibiotics are stable for at least 24 hours at room temperature, and thus can be administered as a 24-hour continuous infusion the carbapenems (imipenem, meropenem and doripenem ), ampicillin, and the newest cephalosporin, ceftaroline , are not stable at room temperature for a full 24 hours Expert Rev Anti Infect Ther 2013;11:585-95 Clin Infect Dis 2013;56:272-82 Lancet Infect Dis 2018 18(1):108–120

26. Vancomycin Pk/pd target of auc/mic ≥ 400 achieves clinical improvement and microbiologic eradication Trough concentrations are used as a surrogate For a mic of 1 a trough of 15 MG/L IS EQUIVALENT TO AUC/MIC RATIO OF 400 IF THE MIC IS > 2MG/L AN ALTERNATIVE ANTIBIOTIC SHOULD BE USED IN CRITICALLY ILL PATIENTS A LOADING DOSE FO 25-30MG/KG SHOULD BY GIVEN Continuous infusion better Clin Pharmacokinet 2004;43:925-42 Clin Infect Dis 2011;52:975-81 Int J Antimicrob Agents 2016 47(1):28–35

27. Linezolid Prospective observational study : 30 critically ill patients given 600 mgs bd Auc 24 range was 50.1 -453.9 with a median of 143.3 mg/l Auc 24 <200gm.h/l were observed in 63% of patients Optimizing dose and administration is essential Zoller critical care 2014

28. FLUOROQUINOLONES LOW CMAX LOWER PROTEIN BINDING HIGH TISSUE UPTAKE AUC/MIC VALUE OF 125 TO 250 Clin Infect Dis 2000;31 Suppl 2:S40-4 J Antimicrob Chemother 2010;65:1725-32

29. aminoglycosides Rapidly bactericidal Concentration dependence Cmax /mic ratio of 8 to 10 Infect Dis Clin North Am 2003;17:503-28

30. polymyxins polymyxin B : preferred agent for routine systemic use in invasive infections. Colistin :preferred polymyxin for the treatment of lower urinary tract infections given renal clearance of the pro drug CMS that then converts to the active moiety colistin in the urinary tract Pharmcotherapy volume39,number 1.2019

31. Monotherapy vs combination therapy? Meta-analyses of randomized controlled trials (RCTs) comparing beta-lactams vs. beta lactams combined with another agent demonstrate no difference in clinical outcomes in a variety of infections caused by Gram-negative pathogens There was no survival benefit except for one study but there was clinical and microbiological cure rates Cochrane Database Syst Rev 20141:CD003344 Clin Infect Dis 2012 55(7):943–950 Pharmcotherapy volume39,number 1.2019

32. Increment study 437 patients with bsi due to cre suggest that true benefit of combination therapy might be limited to patients with greater severity of illness Aida trial Study included cre and carbapenem resistant p aeruginosa but 77 % had crab Not in favour of combination therapy Limiatations Open label Larger number of patients were treated for pneumonia Low sofa scores Pharmcotherapy volume39,number 1.2019

33. Role for loading dose?

34. Loading dose Bacteria that does not get killed is a collection of genes that can mutate Prescribing the most active agent at optimal doses Loading dose should be given irrespective of renal / hepatic function

35. What about dosing in obese patients

36. Dosing obese patients Have a high volume of distribution and creatinine clearance Depending on the class of antibiotics the dosing will be calculated based on lean body weight or actual body weight Lean or adjusted body weight for aminoglycosides Total body weight for glycopeptides Lean body weight for beta lactams Adjusted or total body weight for fluoroquinolones

37. Ideal and adjusted body weight Ideal body weight For men: 50 + 2.3 × ( height in inches – 60 inches ) For women: 45 + 2.3 × ( height in inches – 60 inches Adjusted body weight Ajbw = Ideal body weight + 0.4 ( ACTUAL BODY WEIGHT – IDEAL BODY WEIGHT) Am J Health Syst Pharm 2015;72:1357-64 Infect Dis Clin North Am 2003;17:503-28

38. Things to note when prescribing antibiotics

39. Target site penetration Remember in vitro sensitivity does not translate to in vivo sensitivity Tigecycline and echinocandins are not useful in UTI due to poor concentration Daptomycin not useful in pneumonia due to surfactant inactivation of the antibiotic

40. clearance Augmented renal clearance in sepsis Due to high co Reduced albumin concentration Decreased clearance of hydrophilic antibiotics in aki Decreased clearance of lipophilic antibiotics in hepatic dysfunction

41. What about in patients with aki ?

42. RECENT PAPER LOOKED GIVING NORMAL DOSING FOR UPTO 48HRS IN PATIENTS WITH AKI AND THEN DOSE ADJUSTING IF THE RENAL FUNCTIONS WERE STILL DERANGED. NORMAL DOSE TO BE GIVEN IN PATIENTS UNDERGOING CRRT Patrick M. Honore et al., PK/PD in CRRT Anaesthesiology Intensive Therapy 2017, vol. 49, no 5, 412–418

43. Anaesthesiology Intensive Therapy 2017, vol. 49, no 5, 412–418 Antimicrobial dose recommendations for continuous veno-venous hemofiltration

44. Use of pct to guide therapy

45. Pct guided therapy 6708 patients from 26 eligible trials in 12 countries Mortality at 30 days was significantly lower in pct guided therapy Mortality similar across sub groups Pct guided therapy was also associated with a 2.4 reduction in antibiotic exposure ( 5,7 vs 8.1 days ) Antibiotic related side effects were less Schuetz lancet ID 2017

46. Duration of treatment? Direct therapy to clinical response / crp / pct 7 days on average, 10 days for pseudomonas Discontinue if : non infectious etiology or clinical resolution Lobo SM Crit Care 2012 Povoa P et al Ann intensive care 2012 Lisboa T Crit Care 2011 Karlson S et al Crit Care2010

47. In summary

48. Pk/ pd fosters rational and individualized dosing IMPROVES OUTCOMES LIMITING TOXICITY OF ANTIMICROBIALS

49. Dosing considerations Loading dose and timing of 1 st dose Target site penetration Clearance Volume of distribution Time vs concentration dependent Dosing in obese Renal replacement techniques unique to icus

50. De escalation De escalate whenever possible Conversion to monotherapy or narrow spectrum once culture results available

51. TREATMENT FAILURE! host factors advanced age immunosuppressed, chronic lung disease ventilator dependence

52. bacterial factors drug- resistant pathogens, opportunistic pathogens therapeutic factors inappropriate antibiotics, delayed initiation of therapy, insufficient duration of therapy, suboptimal dosing, inadequate local concentration of drugs

53. COMPLICATIONS OF THE INITIAL EPISODE ABSCESS EMPYEMA OTHER INFECTIOUS SITE NON INFECTIOUS MIMICS

54. Doses and administration: normal renal function Meropenem 2 gm stat then 2gm q8hrs over 3 hours infusion Imipenem 1gm stat then 1gm q6 -8hrs over 3 hours infusion Doripenem 1gm q 8hrs over 4 hours infusion Ertapenem I gm 12 hourly infusion over 1 hour Cefepime 2gm stat and 6gm daily over 24 hours infusion Ceftazidime 2gm stat and 6gm over 24 hours Pip- tazo 4.5gm stat then 18gm infusion daily Tigecyline 200 mgs stat then 100 mg bd Brink AJ et al Int Antimicrob Agents 2009 Kolle MH et al Crit Care 2012 Ibrahim et al Drug Design, Development and Therapy 2018:12 4171–4179

55. Rationalizing antimicrobial therapy in the ICU: a narrative review: 2019 Intensive Care Med

56. Rationalizing antimicrobial therapy in the ICU: a narrative review: 2019 Intensive Care Med

57. Rationalizing antimicrobial therapy in the ICU: a narrative review: 2019 Intensive Care Med

58. Thank you