therapeutic drug monitoring of antibiotics

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therapeutic drug monitoring of antibiotics

  1. 1. Therapeutic Drug Monitoring of antibiotics Is the time ripe ? Dr Ashok Rattan, Chief Scientific Officer, RAK Hospital COO & Medical Director,
  2. 2. Therapeutic Drug Monitoring • Definition: TDM refers to analysis and subsequent interpretation of drug concentration in biological fluids. • TDM should be used to – Maximize efficacy – Minimize toxicity
  3. 3. Personalized dosing • To increase probability of therapeutic success • To decrease probability of toxicity • To prevent development of resistance
  4. 4. Personalized dosing
  5. 5. Consequences of antibiotic use •Inhibition of non pathogenic bacteria •Selection of resistant mutants •Toxicity / side effects •Clinical cure
  6. 6. PK / PD consideration & application •Inhibition of non pathogenic bacteria •Selection of resistant mutants Clinical cure •Toxicity / side effects
  7. 7. Maximize efficacy & Minimize toxicity & decrease development of MDR • Determination of correct antibiotic to which pathogen is susceptible in vitro • Understanding PK & PD of antibiotic determining antibiotic efficacy • Use the correct dose and frequency
  8. 8. TDM is NOT required • Drugs whose clinical end points can be easily monitored – Blood Pressure – Blood cholesterol – Body temperature – Urine volume • Drugs whose serum concentration doesnot correlate with therapeutic or toxic effects • Drugs that are not used to treat life threatening conditions
  9. 9. Drugs suitable for TDM • • • • • • • Anticancer drugs Immunosuppressive drugs Cardiac drugs Anti epileptic drugs Bronchodilators Psychotic drugs Antibiotics – Toxicity : aminoglycosides, glycopeptides – efficacy :
  10. 10. Drugs suitable for TDM • Drug Factors: – Large between subject variability – Small therapeutic index – An established concentration effect relationship – Therapeutic response is not obvious • Patient Factors : – Suspected drug interaction – Suspected drug toxicity – Unexplained failure of therapy – Suspected noncomplince
  11. 11. Discovery & Development of Anti-bacterials is one of the most important discovery of the 20th Century
  12. 12. Power of antibiotics Disease Pre Antibiotic era deaths Deaths with antibiotics Change in deaths due to antibiotics CAP (1) 35% 10% - 25% HAP 60% 30% - 30% 100% 25% - 75% > 80% < 20% - 60% 11% < 0.5% -10% (2) Heart Infection (3) Brain Infections Skin Infection (5) (4) By comparison…. Treatment of heart attacks with aspirin or clot busting drugs (6) - 3% Ref.: (1) IDSA Position Paper. Clin Infect Dis 2008; 47 (S3): S 249 – 65 (2) IDSA/ACCP/ATS/SCCM position paper. CID 2010; 51 (S1): 51 – 3 (3) Kerr AJ. SABE Lancet 1935; 226: 383 – 4 (4) Waring et al. Am J Med 1948; 5: 402 – 18 (5) Spellberg et al CID 2009; 49: 383 – 91 (6) Lancet 1998; 351 : 233 – 41.
  13. 13. Mankind has always had the benefit of “good” advice “By the year 2000, nearly all experts agree that bacterial and viral diseases will have been virtually wiped out…” The futurists: looking toward year 2000 (Time magazine, february 25, 1966) US surgeon general William Stewart: The time has come to close the book on infectious diseases” (1969) “
  14. 14. Increasing Incidence of Resistance in the US MRSE, MRSA, VRE, PRSP, GISA 1980-2006 100 Percentage of Pathogens 80 Resistant to Antibiotics 60 MRSE MRSA PRSP 40 VRE 20 VRSA VISA 0 1975 1980 1985 1990 1995 1997 2000 2006
  15. 15. We have a basic problem We must make the best use of what we have Ne wa nd no ve l an tib iot ns ics e og ath tp n rta po m in i nce ista s Re
  16. 16. In vitro Parameters of Antimicrobial Activity • Potency: – MIC – MBC • Time course of activity – Rate of killing & effect of increasing concentration – Persistant effects • PAE, SMPAE, PALE
  17. 17. In vivo Pharmacology of Antimicrobial Therapy Time course of levels in tissues Dosage Regimen Time course of pharma & tox effect Time course of serum levels Absorption Distribution Metabolism Elimination Time course of levels at site Pharmacokinetics What the body does to the drug Time course of antimicrobial activity Pharmacodynamics What the drug does to the body & bacteria
  18. 18. What body does to the drug What drug does to the body & the bacteria
  19. 19. PK/PD terminology & central role of MIC C max/ MIC AUC / MIC t > MIC 32 16 8 Serum Conc. 4 (ug/ml) C max 2 1 0.5 MIC 0.25 Time > MIC 0.12 0.06 0
  20. 20. PK/PD parameters predictive of success • Cmax / MIC • AUC / MIC • T > MIC > 10 > 100 > 40 % of dosing interval • Variables affecting concentration: • Volume of distribution (Vd) • Clearance (Cl) • T ½ = 0.693 x Vd Cl
  21. 21. Patterns of antimicrobial activity Kill Kinetics of Synercid IV against MRSA 562 12 9 log cfu/ml •Concentration dependent killing and prolonged persistant effect •Seen with Aminoglycosides, Quinolones, daptomycin, ketolides, amphotericin B •Goal of dosing: maximize concentration •AUC/MIC and Cmax/MIC major parameters of efficacy 6 3 0 0hr 1hr 3hr 6hr 24hr Hours X MIC 32X MIC 2X MIC control 4X MIC 8X MIC 16X MIC
  22. 22. Patterns of antimicrobial activity Kill Kinetics Of Linezolid Against E.faecalis Sp346 Logcfu/ml •Concentration independent killing •Minimal to moderate persistent effects •Seen with all β lactams, clindamycin, macrolides, oxazolidinones, Flucytosine •Goal of dosing: Optimize duration •t > MIC major parameter of efficacy 10 9 8 7 6 5 4 3 2 1 0 0 1 2 4 6 24 hours 1X MIC 8x MIC 2X MIX 16X MIC 4X MIC 32x MIC
  23. 23. Experimental models to investigate PK/PD relationships: Overview • Use neutropenic animals • Evaluate 20 - 30 different dosing regimens (5 dose levels, 4-6 different intervals) • Measure efficacy by change in Log10 cfu per thigh or lung at end of 24 hours therapy • Correlate efficacy with various PK/PD parameters • (t > MIC, • Cmax/MIC, • 24 hours AUC/MIC)
  24. 24. K. pneumoniae & Imipenem
  25. 25. K. pneumoniae & Imipenem
  26. 26. S. pneumoniae & Levofloxacin
  27. 27. PK/PD relationship is class dependent
  28. 28. PK/PD correlation with efficacy •T > MIC –Penicillin –Cephalosporins –Carbapenems –Monobactam –Macrolides –Clindamycin –Oxazolidinones –Glycylcyclines –Flucytosine •AUC or Cmax/MIC –Aminoglycosides –Fluoroquinolones –Metronidazole –Daptomycin –Ketolides –Azithromycin –Streptogramin –Glycopeptides –Amphotericin –Fluconazole
  29. 29. Mortality after 4 days of therapy (%) Relationship between time > MIC and efficacy in animal infection models infected with S. pneumoniae 100 Penicillins Cephalosporins 80 60 40 20 0 0 20 40 60 80 Craig W.Time serum conc. is above MIC25:213–217. Diagn Microbiol Infect Dis 1996; (%) 100
  30. 30. Levofloxacin PK/PD correlation
  31. 31. PK PD for new break points PK of Imipenem 500 mg x 4 1G x 4 Epidemiological cut offs Dosage Cmax (mg/L) 30 – 40 Cmin 0.25 – 0.5 Total body Clearance (L) T ½ (hr) 1 Fraction Unbound 80 Volume of Distribution (L/kg) 14 – 15 60 – 70 0.5 – 1 11 – 15 1 11 – 15 80 14 – 15 PD of Imipenem % f T>MIC (experimental) % f T>MIC (clinical) GNB 25 – 40 54 GPC 15 – 20 Probable Target Attainments
  32. 32. What are the PK/PD parameters predictive of antimicrobial’s success ? In case of concentration dependent antibiotics like FQ, Aminoglycosides In case of concentration independent of time dependent antibiotics like β lactams and cepahlosporins
  33. 33. PK/PD correlation with efficacy •T > MIC (>40%) –Penicillin –Cephalosporins –Carbapenems –Monobactam –Macrolides –Clindamycin –Oxazolidinones –Glycylcyclines –Flucytosine •AUC or Cmax/MIC •>100 >10 –Aminoglycosides –Fluoroquinolones –Metronidazole –Daptomycin –Ketolides –Azithromycin –Streptogramin –Glycopeptides
  34. 34. TDM for aminoglycosides • Small, hydrophilic molecules: – Streptomycin, Gentamicin, Tobramycin, Amikacin, Neomycin, Spectinomycin, Paromomomycin – For t/t severe GNB infection, with Beta lactam for GPC – No activity against anaerobes • • • • Acts by binding to aminoacyl site of 16S rRNA Leading to misreading of genetic code & Inhibition of translocation, bactericidal Resistance due to – Efflux pump, inactivating enzymes, methylation of RNA
  35. 35. • Volume of distribution 0.2 to 0.4 L/kg • Clearance proportional to GFR, excreted unchanged • C Max / MIC is predictor of efficacy, target > 10 • Drugs given OD so C Max no issue • • • • If pt has sepsis or sever burns, Vd If compromised renal function, Clearance Collect sample 6 hours post dose (trough level) Increase or decrease dosing interval
  36. 36. TDM for Vancomycin • Glycopeptide active against GPC, bactericidal activity on cell wall, no action against GNB • Limited absorption orally, administered IV • Volume of distribution 0.4 to 1 L/kg • Limited CSF penetration • Excreted unchanged via urine • Related to creatinine clearance • Toxicities: Red man syndrome, Nephrotoxicity, Ototoxicity
  37. 37. • • • • • • • Target : AUC / MIC > 400 Trough conc correlates with AUC Dose: loading dose of 35 mg/ml Daily dose: 1 G BD slow IV Aim for trough value of 15 ug/ml before 4th dose Collect sample 30 minutes before 4th or 5th dose Creatinine Clearance data with nomogram as surrogate dose adjustment method
  38. 38. Vancomycin TDM • Whom to monitor : – Patient with invasive infection receiving prolonged vancomycin treatment – Patient with fluctuating renal function, fluctuating fluid balance, haemodynamic instability, critically ill, morbid obesity, receiving dialysis – Patient with increased risk of nephrotoxicities or receiving aminoglycosides
  39. 39. Linezolid • • • • Nearly 100 % oral bioavailability Low protein binding (30%) Penetrates into all parts of the body Volume of distribution equals total body water (30 to 50 L) • Active only against Gram Positives • No activity against Gram Negatives
  40. 40. • • • • • Target : AUC/ MIC > 100 C min of 2 ug/ml correlates with this C min of 10 ug/ml is associated with toxicity Bone marrow depression common toxicity Especially when co-administered with – Omeprezole – Aminodipine
  41. 41. Daptomycin (Cubicin) • • • • Discovered by Eli Lilly in 1960s Cyclic lipopeptide active only against GPC Calcium dependent depolarisation of bacterial cell wall Lipophilic tail binds inserts itself into bacterial membrane & forms a channel that causes efflux of intracellular potassium
  42. 42. • Inactivated by alveolar surfactant • Creatine phosphokinase (CPK) elevated, myopathy, rhabdomyolysin, eosinophilic pneumonia • Dosed BD caused increased in CPK • Discontinued clinical development • Cubist acquired it for 0.5 million US$ • Concentration dependent activity • Stays within the blood vessels, inactivated in lungs • Cmin > 24 ug/ml associated with increased CPK • Changed dosing frequency to OD • Monitor: Baseline CPK, CPK weekly, 5x normal
  43. 43. beta lactam antibiotics • Large margin of safety • Blondiaux et al 2010 [Int J Antimicrobio Agents] – Initial dose of piperacillin + tazobactam – 50% pts achieved conc above redefined target level of > 4 x MIC – Proportion increased ti 75% if TDM dose adjustment

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