PK/PD degli antibiotici utilizzati nella sepsi Dario Cattaneo, U.O. Farmacologia Clinica ASST Fatebenefratelli Sacco, Milano Bergamo, città alta
Variability of antibiotic concentrations in critically ill patients Drug Trough concentration (mg/l)* Variability Meropenem 12.1 (3.4 21.8) 6.7-fold Piperacillin 105.0 (74.4 204.0) 3.8-fold Tazobactam 3.8 (3.4 21.8) 10.5-fold Vancomycin 12.0 (9.8 16.0) 1.9-fold Ciprofloxacin 3.7 (3.0 5.6) 3.9-fold *median (interquartile range) - Roberts, Crit Care Med 2012 - How to explain such variability?!?
Common conditions: aging... Physiologic change Result PK parameter PK effect Reduced muscle mass and total water Accumulation of hydrophilic drugs Volume of distribution Increase of drug plasma concentrations Increased body fat Accumulation of lipophilic drugs Volume of distribution Increase of drug half-life - Klotz, Drug Metab Rev 2009 -
Daptomycin AUC [linezolid], mg/l 500 ** Age quartiles [Linezolid] trough < 40 yrs 4.6 ± 4.9 mg/l 40 60 yrs 6.1 ± 4.5 mg/l 60 80 yrs 10.0 ± 7.0 mg/l** > 80 yrs 12.6 ± 9.3 mg/l** 400 40 35 n=180 300 30 25 200 20 100 15 10 0 young (18-30 yr) geriatric (>75 yr) 5 0 0 20 40 60 80 100 Patients age, yrs - Dvorchik, J Clin Pharmacol 2006 - - Cattaneo, IJAA 2016-
The issue of drug-to-drug interactions the inductive effect of rifapicin on linezolid metabolism may persist up to 2-3 weeks after stopping the drug Effects of rifampicin on cytochrome P450 (CYP) enzymes
Proton Pump inhibitors can increase the absorption of some antibiotics through inhibition of intestinal P-gp - Pea, AAC 2010 -
In addition to these variables, critically ill patients may have also peculiar conditions that can affect the pharmacokinetics of antibiotics Critical illness - Roberts, Lancet Infect Dis 2014 -
..Augmented renal clearance can result in elevated renal elimination and subtherapeutic plasma concentrations, although whether this process solely involves augmented filtration or altered tubular secretion/reabsorption remains uncertain Antibacterials Drug CL in healthy subjects Drug CL in critically ill pts Cefpirome 102 ml/min 158 ml/min Ceftriaxone 19.8 ml/min 41 ml/min Ceftazidime 116 ml/min 125 ml/min Piperacillin 188 ml/min 396 ml/min Ertapenem 29.5 ml/min 200 ml/min. - Udy, Clin Pharmacokinet 2010 -
In addition to these variables, critically ill patients may have also peculiar conditions that can affect the pharmacokinetics of antibiotics Critical illness - Roberts, Lancet Infect Dis 2014 -
Changes in drug clearance for highly bound antibacterials in patients with hypoalbuminemia - Roberts, Clin Pharmacokinet 2013 -
Highly bound (>70%) Moderately bound (70-30%) Minimally bound (<30%) Cefazolin Azithromycin Amikacin Cefoperazone Aztreonam Amoxicillin Ceftriaxone Cefotaxime Ampicillin Clindamicin Cefuroxime Cefepime Daptomycin Ciprofloxacin Ceftazidime Ertapenem Clarithromycin Doripenem Erythromycin Levofloxacin Gentamycin Minocycline Linezolid Imipenem Rifampicin Piperacillin Meropenem Teicoplanin Ticarcillin Norfloxacin Tigecycline Vancomycin Tobramycin - Ulldemolins, Clin Pharmacokinet 2011 -
Volume of distribution (L) of b- lactam antibiotics in ICU patients Open circles: volume of distribution in healthy volunteers; filled squares: weighted means of volume of distribution in the studies; straight lines: ranges of the means of volume of distribution in the studies. V d = drug dose blood concentrations - Pereira, Critical Care 2011 -
Lipophilic antibiotics *Extra Vd due to loss of fluids (capillary leakage) Negligible dilution 100 L Normal Vd High dilution Hydrophilic antibiotics Normal Vd Extra Vd* 10 L 4 L (Vd + 40%) 4 L (Vd + 4%) Extra Vd*
- Awad, CID 2014 -
MIC MIC MIC MIC In VAP patients ceftobiprole elimination is increased by 40% and Vd is doubled... - Lagacé-Wiens, EODMT 2013 -
In addition to these variables, critically ill patients may have also peculiar conditions that can affect the pharmacokinetics of antibiotics Critical illness - Roberts, Lancet Infect Dis 2014 -
The pharmacokinetics of hydrophilic antibiotics is greatly altered in patients with renal insufficiency hydrophilic lipophilic
tigecycline - Mistry, J Clin Pharmacol 2006 - - Korth-Bradley, J Clin Pharmacol 2011 - ertapenem
not everything is black or white... According to the USP monograph, the PKs of linezolid are not altered in patients with any degree of renal insufficiency - Cattaneo, Exp Opin Drug Metab Toxicol 2016 - - Sasaki, Antimicrob Agents Chemother 2011 -
In addition to these variables, critically ill patients may have also peculiar conditions that can affect the pharmacokinetics of antibiotics Critical illness - Roberts, Lancet Infect Dis 2014 -
1 st : 66-year-old man on PD since 2012 given linezolid to treat lumbar spondylodiscitis. This resulted in a progressive reduction in platelet count, reaching a nadir of 53 10 3 cells/ml. Linezolid trough concentration: 25.5 mg/l. 2 nd : 74-year-old woman on PD since 2010 given linezolid for leg ulcers. Linezolid trough concentrations: 22.5 mg/l. 3 rd : 87-year-old woman on PD since 2013 given linezolid for Enterococcus faecalis peritonitis.the patient experienced pancytopenia and an increase in blood lactate values. Linezolid trough concentrations: 30 mg/l. 4 th : 57-year-old woman on PD since 2009 given linezolid for MDR Staphylococcus epidermidis peritonitis. Linezolid was withdrawn 20 days later due to severe pancytopenia. Three days later, the patient experienced severe lactic acidosis and was transferred to the ICU, where she died. A plasma sample collected nearly 90 h after stopping linezolid revealed a plasma concentration of 1.5 mg/l (estimated trough: 20 30 mg/l).
E possibile quantificare il contributo di queste variabili nella pratica clinica? TDM is defined as the regular measurement of drugs concentrations requiring close 'titration' of doses in order to ensure that there are sufficient levels in the blood to be therapeutically effective, while avoiding potentially toxic excess
The issue of drug overexposure: the case of linezolid [Linezolid], mg/l 20 18 16 14 12 10 8 6 4 2 0 Hematological Toxicity p = 0.01 No hematologic Toxicity - Cattaneo, Int J Antimicrob Agents 2013 - Thrombocytopenia associated with [linezolid] >7 mg/l Thrombocytopenia associated with [linezolid] >8.2 mg/l - Pea, JAC 2012 - - Matsumoto Int J AA 2014 -
Drug TDM target Amikacin C max 40-60 mg/l Ciprofloxacin C min 0.5-3.0 mg/l Colistin 2-5 mg/l Daptomycin C min <25 mg/l Gentamicin C min 0.5-2.0 mg/l or C max 5-10 mg/l Levofloxacin C max 5-15 mg/l Linezolid C min 2-8 mg/l Meropenem - Piperacillin - Rifampicin C max 8-24 mg/l Sulfamethoxazole C max 100-150 mg/l Tobramycin C max >10 mg/l or C min <1.0 mg/l Teicoplanin C min 10-60 mg/l Trimethoprim C min 1-4 mg/l or C max 5-10 mg/l Vancomycin C min 10-20 mg/l or C max 30-40 mg/l - Jager, Exp Rev Clin Pharmacol 2016 -
Oltre alla safety, esistono anche dei cutoff di concentrazioni anche per l efficacia???
...for drugs that are C max /MIC-dependent you can measure C max for efficacy, and eventually C min for toxicity...
...AUC/MIC-dependent... - Holmes, AAC 2013 - AUC can be estimated with 2 blood samples (C min and C max )
...Time>MIC-dependent... - Pea, IJAA2017 -
so in conclusion or, better to say, as starting point Giving the right dose is highly likely to increase the probability of clinical cure from infection and suppress the emergence of resistant pathogens. To enable optimized dosing, the use of customized dosing regimens through either evidence-based dosing nomograms or preferably through the use of dosing software supplemented by therapeutic drug monitoring data should be embedded into daily practice