PK/PD degli antibiotici utilizzati nella sepsi

Dario Cattaneo, U.O. Farmacologia Clinica

ASST Fatebenefratelli Sacco, Milano

Bergamo, città alta

- Roberts, Crit Care Med 2012 -

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)

Variability of antibiotic concentrations in

critically ill patients

How to explain such variability…?!?

- Klotz, Drug Metab Rev 2009 -

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

Common conditions: aging...

- Dvorchik, J Clin Pharmacol 2006 - - Cattaneo, IJAA 2016-

Dap

tom

ycin

AU

C

young

(18-30 yr)geriatric

(>75 yr)

0

100

200

300

400

500**

0

5

10

15

20

25

30

35

40

0 20 40 60 80 100

[lin

ezo

lid

], m

g/L

Patients’ age, yrs

n=180

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**

Effects of rifampicin on cytochrome P450 (CYP) enzymes

“…the inductive effect of

rifapicin on linezolid

metabolism may persist up

to 2-3 weeks after stopping

the drug…”

The issue of drug-to-drug interactions…

- Pea, AAC 2010 -

Proton Pump inhibitors can increase the absorption of

some antibiotics through inhibition of intestinal P-gp…

…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 renalelimination and subtherapeutic plasma concentrations,although whether this process solely involves augmentedfiltration or altered tubular secretion/reabsorption remainsuncertain…”

- Udy, Clin Pharmacokinet 2010 -

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

….

…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 -

- Roberts, Clin Pharmacokinet 2013 -

Changes in drug clearance for highly

bound antibacterials in patients with

hypoalbuminemia

- Ulldemolins, Clin Pharmacokinet 2011 -

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

- Pereira, Critical Care 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.

drug dose

blood concentrationsVd =

100 L

High dilution

Negligible dilution*Extra Vd due to

loss of fluids

(capillary leakage)

Hydrophilic antibiotics

Lipophilic antibiotics

10 L

4 L (Vd + 40%) 4 L (Vd + 4%) Extra Vd*

Normal Vd

Extra Vd*

Normal Vd

- Awad, CID 2014 -

- Lagacé-Wiens, EODMT 2013 -

“…In VAP patients ceftobiprole elimination

is increased by 40% and Vd is doubled...”

MIC

MIC

MIC

MIC

…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

- Korth-Bradley, J Clin Pharmacol 2011 -

- Mistry, J Clin Pharmacol 2006 -

ertapenem

tigecycline

- Cattaneo, Exp Opin Drug Metab Toxicol 2016 -

“…According to the USP monograph, the PKs of linezolid are

not altered in patients with any degree of renal insufficiency…”

- Sasaki, Antimicrob Agents Chemother 2011 -

…not everything is black or white...

…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 -

1st: 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 53×103 cells/mL. Linezolid trough concentration: 25.5 mg/L.

2nd: 74-year-old woman on PD since 2010 given linezolid for leg ulcers. Linezolid

trough concentrations: 22.5 mg/L.

3rd: 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.

4th : 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).

“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”

E’ possibile “quantificare” il

contributo di queste variabili nella

pratica clinica?

- Pea, JAC 2012 -

Thrombocytopenia associated with [linezolid] >7 mg/L

- Matsumoto Int J AA 2014 -

Thrombocytopenia associated with [linezolid] >8.2 mg/L

20p = 0.01

Hematological

Toxicity

[Lin

ezo

lid

], m

g/L

0

2

4

6

8

10

12

14

16

18

No hematologic

Toxicity

- Cattaneo, Int J Antimicrob Agents 2013 -

The issue of drug overexposure:

the case of linezolid…

Drug TDM target

Amikacin Cmax 40-60 mg/L

Ciprofloxacin Cmin 0.5-3.0 mg/L

Colistin 2-5 mg/L

Daptomycin Cmin <25 mg/L

Gentamicin Cmin 0.5-2.0 mg/L or Cmax 5-10 mg/L

Levofloxacin Cmax 5-15 mg/L

Linezolid Cmin 2-8 mg/L

Meropenem -

Piperacillin -

Rifampicin Cmax 8-24 mg/L

Sulfamethoxazole Cmax 100-150 mg/L

Tobramycin Cmax >10 mg/L or Cmin <1.0 mg/L

Teicoplanin Cmin 10-60 mg/L

Trimethoprim Cmin 1-4 mg/L or Cmax 5-10 mg/L

Vancomycin Cmin 10-20 mg/L or Cmax 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 Cmax/MIC-dependent you can measure Cmax for efficacy, and eventually Cmin for toxicity...

- Holmes, AAC 2013 -

AUC can be estimated with 2 blood samples (Cmin and Cmax)

...AUC/MIC-dependent...

...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