Syamhanin AdnanSupervisors : Prof David PatersonDr Jason RobertsDr Steven WallisProf Jeffrey Lipman

Case study

PK/PD issues in critically ill

My PhD project : implication into practice

Project 1: The drain study

Project 2 : Amp/sul & MDR-Ab

Project 3 : ARC

Ertapenem in hypoalbuminaemia and ARC

Case 1 – 38yo male (175cm and 92kg) Admitted to ICU with hypoxia post Ivor-Lewis

Oesophagectomy Day 7 – Mediastinitis diagnosis

Tracheo-oesophageal fistula

E. cloacae isolated from ETA

Susceptible mero/erta

Ertapenem prescribed

▪ 1gm IV q12h (EUCAST MIC90 = 0.5-1mg/L)

What do we know about this drug that could mean standard dosing inaccurate?

90% bound to plasma proteins

Predominantly renal clearance

Toxicities – neuro, ATN, cholestatic

Time-dependent antibiotic

▪ maintain concentration for at least

40% f T>MIC and preferably 100% f T>MIC

Decreased albumin concentration increased availability to

distribute or be eliminated

Increased CrCL increased clearance of unbound drug

Dose = 1g IV q12h; level actually <0.1mg/L

Dose inc 1g q8h

Dose inc 1g q8h by

extended infusion

Level ‘therapeutic’

(target = 100% f T>MIC)

Day 17, a further E. cloacae isolate (sample collected day 14) was cultured

Ertapenem MIC E-test performed

Now resistant; MIC = 4mg/L Patient changed to meropenem (MIC = 0.3 mg/L) 4/52 course completed with meropenem

Highly protein bound drugs in ICU

PK dramatically changes

~50% of ICU patients have low albumin

Drugs with renal excretion

Clearance can dramatically change

ARC present in ~30% of patients

Lesson learn, the hard way

Demographic : 33 y/o lady CC :

Post trauma D4, MVA (car vs concrete pillar) HOPI

patient as passenger, car driven by a friend (both under alcohol influence and he died)

GCS full upon arrival, intubated later in view of tachypnoea and metabolic acidosis

Past Medical History

Left thyroid nodule (euthyroid on latest TFT) Social/Family History

Divorce with one child

stays with sister

Owns online business Medication

IV Pip/taz on 22/9 and de-escalate to IV Ceftriaxone on 24/9

Issues :

Transected body of pancreas with duodenal perforation (post laparotomy)

Septic shock secondary to pancreatitis

AKI

ARDS (resolved)

Hypoalbuminemia

No Antibiotic Dose Freq Date

start Indication D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14

1 Pip/tazobactam 22/9 -24/9 HKL 22/9 23/9 24/9

2 Ceftriaxone 24/9 HKL 24/9

3 Pip/tazobactam 2.25g QID

24/9 –

26/9 Empiric/ 24/9 25/9 26/9

Pancreatitis

4 Imipenem 500mg BD 26/9 Empiric/ 26/9 27/9 28/9 29/9 30/9 1/10 2/10 3/10 4/10 5/10 6/10 7/10 8/10 9/10

13/10 Pancreatitis

10 /

10

11 /

10

12/

10

5 Fluconazole 400mg stat 27/9-3/10 Empiric/ 27/9 28/9 29/9 30/9 1/10 2/10 3/10

200mg od Definitive ?(3/10)

6 Amikacin 750mg od 27/9 Empiric 27/9

1gm od 1/10-8/10 1/10 2/10 3/10 3/10 4/10 5/10 6/10

7 Vancomycin 1g od 29/9-1/10 Empiric 29/9 28/9 29/9 30/9

1g EOD 2/10-9/10 2/10 3/10 4/10 5/10 6/10 7/10 8/10

8Colistiin 2 MU TDS 14/10 CRE

14/

10

15/

10

16/

10

17/

10

18/

10

19/

10

Date Source Pathogen Sensitivity Resistant

26/9

1/10 Blood NG

26/9

29/10 T/Asp NG

26/9 Urine NG

29/9

5/10 Blood NG

29/9

1/10 NPA (Respiratory) NG

29/9

30/9 SP (Abd) Mixed Growth

30/9

3/10 SP (Abd) NG

2/10

7/10 Pleural Fluid NG

2/10

7/10 Abd Fluid NG

3/10 Body Fluid Candida non-albicans Probably contaminant

8/10

14/10 Blood CRE

Tigecycline

Polymycin

Colistin

All carbapenems

No Antibiotic Dose Freq Date

start Indication D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14

4 Imipenem 500mg BD 26/9 Post op 26/9 27/9 28/9 29/9 30/9 1/10 2/10 3/10 4/10 5/10 6/10 7/10 8/10 9/10

13/10

WBC 31.5 41.83 37.38 33.53 30.88 30.84 27.31 21.6 14.5 13.7 12.9 14.3

Temperature 38.1 37.6 36.9 38.3 37.8 37.0 38.0 38.0 37.7 37.7 37.5 38.6 37.8

CrCl (ml/min) 35 39 38 34 33 36 47 53 77 73 97 100

Urine output

(ml/hr) 80 60 50 100 50 100 100

10 /

10

11 /

10

12/

10

WBC 14.1 13.2 14.5 12.3

Temperature 38.4 37.7 37.2 37.0

CrCl (ml/min) 118 111 126 147

Urine output

(ml/hr)

Patient have multiple drains :▪ Drain A : 10-50cc, Drain B : 400-550cc, pelvis, pigtail

Elevated renal function ▪ CrCl >100ml/min on D11 of imepenem▪ ICU Pharmacist suggest to increase dose to 1gm bd in view of

penetration and high WBC on D5 of imipenem▪ T/o to HDW on D12 of imipenem

Prolonged duration of imipenem▪ HPB Pharmacist inform that patient already completed D14 of

imipenem on 10/10/2014

CRE isolated on D17 of imipenem

Demographic :68 y/o male CC :

Post trauma, MVA (motorbike vs lorry) HOPI

Refer to HSB

Intubated for poor GCS

Bilateral decompressive craniectomy with EVD insertion

Issues :

Generalized cerebral edema

HAP

Ventriculitis

AF

29/12/2014 1/1/2015 CSF Staphylococcus coagulase negative

20

(Lymphoc

ytes)

2.1 1.96

31/12/2014 5/1/2015 Blood Staphylococcus coagulase negative

31/12/2014 3/1/2015 CSF Staphylococcus coagulase negative

5

(Polymor

phs &

Lymphocy

tes)

2.4 2.86

31/12/2014 1/1/2015 MSU No growth

31/12/2014 1/1/2015 T. aspMixed growth of 3 organisms

isolated

6/1/2015 10/1/2015 CSFMixed growth 3 types of gram

positive organisms isolated

0

(Polymor

phs &

Lymphocy

tes)

3.1 1.77

7/1/2015 10/1/2015 Blood Staphylococcus coagulase negative

9/1/2015 19/1/2015 CSFVancomycin resistant Enterococcus

durans & Enterococcus faecium

3

(Lymphoc

ytes)

2.3 2.04Linezolid,

Tigecycline

Vancomycin,

Ampicillin

12/1/2015 19/1/2015 CSFVancomycin resistant Enterococcus

durans & Enterococcus faecium0 1.8 2.49

Linezolid,

Tigecycline

Vancomycin,

Ampicillin

Date (Sampling) Date (Results) Source Microorganism CSF WCC CSF Glu CSF Prot Sensitivity Resistant

Date 1-Jan 2-Jan 3-Jan 4-Jan 5-Jan 6-Jan 7-Jan 8-Jan 9-Jan 10-Jan 11-Jan 12-Jan 13-Jan 14-Jan 15-Jan 16-Jan 17-Jan

Antibiotic

Meropenem 2g Q8H

Vancomycin 1.25g stat &500mg Q12H

Vancomycin 750mg Q12H

Vancomycin 750mg Q8H

Cefo/sulbactam 4g Q8H

Linezolid 600mg Q12H until 6/2

Date 7-Jan 8-Jan 9-Jan 10-Jan 11-Jan 12-Jan 13-Jan 14-Jan 15-Jan 16-Jan

Dose 500mg Q12H 500mg Q12H 750mg Q12H 750mg Q12H 750mg Q12H 750mg Q12H 750mg Q12H 750mg Q8H 750mg Q8H 750mg Q8H

SrCr umol/L 53.13 50.5 49.15 49.9 42.9 38.3 43.6 43.5 39.8 44.3

CrCl (ml/min) 83.34 87.68 90.09 88.74 103.22 115.61 101.56 101.79 111.26 99.95

Vancomycin level (umol/L) 5.48 3.21 5.53

Vancomycin level (mg/dL) 7.94 4.65 8.01

Roberts, J.A. and J. Lipman, Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med, 2009. 37(3): p. 840-51; quiz 859.

49 y/o male

Alleged MVA, referred from HTAR

Cerebral bleed, complicated with ventriculitis

MRSA from nasal swab and sputum

Treated with IV Vancomycin

0

5

10

15

20

25

10-May 11-May 12-May 13-May 14-May

Van

com

ycin

le

vel (

mg/

L)

Patient level

Min level

Max level

1.5g Q8H

1 Q6H

1.75g

incremental dose

2 hour infusion Q6H

0

500

1000

1500

2000

2500

3000

3500

Urine Output (ml)

Urine Output (ml)

10/25/2015 36

Vd : volume in which the total amount of drug

distributed to produce the observed blood

concentrations 13

CL : volume of drug cleared per unit time14

Hydrophilic drugs – Vd consistent with TBW (0.2-0.7 L/kg)

Lipophilic drugs – large Vd(can be variable eg. morphine 3L/kg amiodarone 70L/kg)

▪ Lipophilic drugs have very good distribution throughout body tissue

The volume into which a drug appears to be

distributed with a concentration equal to

that of plasma

Pharmacokinetic issues for antibiotics in the critically ill patient, Jason A. Roberts, B Pharm

(Hons); Jeffrey Lipman, FJFICM, MD, Crit Care Med 2009 Vol. 37, No. 3

-accumulation of fluids in extra-vascular compartment7

Sepsis

Hepatic failure

Fluid resuscitation

Burns

Others

-anti-inflammatory cytokines- capillary leakage

- dehydration-aggressive fluid therapy

Acute Kidney Injury

- impaired sodium excretion

- fluid expansion

- capillary leakage

- i.e pregnancy etc

-40 -50% of critically ill patients had hypoalbuminemia10

- less albumin available causing more free drug initially

- to achieve equilibrium state with the bounded drug, the extra free drug will later distributes into extravascular compartment

-less free drug available to exert pharmacological effect

el Castillo JRE, Elsener J, Martineau GP. Pharmacokinetic modeling of in-feed tetracyclines in pigs using a meta-analytic compartmental approach. Swine Health Prod. 1998;6(5):189-202.

The rate of drug elimination from body

Hydrophilic drugs – predominates through kidneys

Lipophilic drugs – predominates through liver

Acute kidney injury

Liver failure

Cardiovasculardysfunction

- 35% of ICU patient had AKI 8

- AKI patient had reduce glomerular filtration

- impaired drug metabolism- impaired elimination

- impaired perfusion - affecting drug distribution

-26.8% of sepsis patient will be prescribed with renal replacement therapy9

ARC

Increased systemic perfusion and cardiac output due to SIRS

Lead to an increased in renal blood flow

Enhanced renal elimination due to increased renal blood flow

Udy, A.A., et al., Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet, 2010. 49(1): p. 1-16.

Distribution phase

Elimination phase

Vd : volume in which the total amount of drug

distributed to produce the observed blood concentrations

CL : volume of drug cleared per unit time

increasedistribution

causing inadequate

concentrations

decreased elimination

causing accumulation

Consider decrease dose

interval 14

Reduced dose/prolong

interval 14

increased elimination inadequate

concentrations

Consider loading dose15

Project 1 : Dosing of Meropenem and Piperacillin in Patients with indweling surgical drains

Project 2 : Dosing of Ampicillin/Sulbactam in MDR-Ab

Project 2 : Prevalence of Augmented Renal Clearance : Experience in Malaysian Intensive Care Unit

Time concentration profile of meropenem and piperacillin in critically ill patients with indwelling surgical drains

Black lines : plasma concentrations

Grey lines : surgical drain concentrations

Dashed black line : EUCAST MIC breakpoint for P. aeruginosa (2mg/L for meropenem and 16mg/L for piperacillin)

Linear regression analysis showing relationship between drain clearance and output volume of surgical drains

Meropenem(r2=0.89; p=0.05)

Piperacillin (r2=0.63; p=0.20).

Acinetobacter spp is responsible for 25.4% of the organisms isolated in the presence of VAP in Malaysian ICU

Few options available: cefoperazone/sulbactam, ampicillin/sulbactamand/or polymyxin, sulbactam has intrinsic antimicrobial activity against Acinetobacter spp.

Since sulbactam is a bacteriostatic agent, it is recommended for use as high doses; which can increase the risk of toxicity.

Ampicillin is T>MIC; sulbactam : AUC/MIC, emerging data suggests T>MIC

for sulbactam. CLSI MIC breakpoints for ampicillin/sulbactam for susceptible, intermediate and resistant A. baumannii are 8/4 mg/L, 16/8 mg/L and 32/16 mg/L, respectively.

Conclusion from review Amp/sul demonstrates extensive penetration into many infection sites

Sulbactam has strong intrinsic antibiotic activity against multidrug-resistant (MDR) bacteria, including Acinetobacter baumannii

Decline in susceptibility - lower doses (4/2 g/day) has been linked with a 30% reduced success rate in critically ill patients

Dose recommendation varies; from 4g/day – 12g/day, with most of these recommendations were not derived from PK studies in critically ill patients.

PK studies of ampicillin/sulbactam in critically ill patients is a necessity

-one third patient >60 y/old with CrCl <100ml/min-half of the patient had CrCl>130ml/min

Significant correlation between drug clearance and renal clearance

risk of excessive drug concentrations with decreased renal function when high doses is used (>50mg amp/>20mg sul)

risk of inadequate drug concentrations with elevated renal function (>130ml/min); <10mg amp/<5mg sul)

Increased drug distribution for amp/sul in critically ill patients

risk of inadequate drug concentrations for those with increased drug distribution (Vd)

some patients did not achieve PK/PD target for sulbactam.

Dosing simulation for sulbactam showed failure to achieve the PK/PD target for MICs ≥ 4 mg/L with our current dosing regimens (6g/day) for patients with GFR ≥ 100 mL/min.

The probability of target attainment was obtained by counting the subjects who achieved 50% fT>MIC.

The target MIC’s were 0.5, 1, 2, 4 and 8 mg/L.

Dose adjustment of ampicillin/sulbactamaccording to the renal function to avoid potential toxicity in impaired renal function

Higher dose required for those patients with potential increased drug distribution

Current amp/sul dosing (12/6g per day) may not be optimal for those patients with creatinine clearance >100ml/min

Dose reduction of renally cleared drugs is common for impaired renal function but not for elevated renal clearance.

Recent article - discontinuation of industry-sponsored clinical trials due to poor outcomes in the study drug arm. Many were younger, higher renal clearances, with

no dose adjustment - may have led to inferior outcomes

Augmented renal clearance, ARC is defined by an elevated creatinine clearance which is used as a surrogate of GFR. Values ≥ 130 ml/min/1.73m2, have been proposed as a useful threshold

Inclusion criteria :1) admission to the ICU with expected length of stay >24 hours, 2) admission serum creatinine concentration <120 µmol/L)3) no history of chronic kidney disease, or renal replacement therapy.

Excluded criteria : 1) absence of invasive haemodynamic monitoring2) absence of an indwelling urinary catheter (IDC) 3) “Risk” stage of AKI (> 1.5 fold increase in serum creatinine from

baseline or urine output< 0.5ml/kg/hr for > 6hrs prior to enrolment

39% of the studied cohort manifested ARC on admission; since the studied cohort only represent 18% of the population - true prevalence of 7%

Trauma patients undergone emergency operations more likely manifest ARC on ICU admission

The majority of ARC patients suffered traumatic brain injury (TBI)

Poor relationship between CG estimated and measured urinary Crcl in ARC patients

Bland-Altman analysis confirms significant bias and imprecision

Bias becomes significantly larger in patients exhibiting ARC

Accurately identifying patients with ARC in the ICU setting is important.

Since bias becomes significantly larger in patients exhibiting ARC, it is suggested that a measured urinary Crcl be used for ICU patients at risk of ARC.

Studies have shown that PK/PD targets may not achieved in ARC patients

Recent simulations of doripenem dosing demonstrated that extended infusions are an effective tool in patients with ARC

Unlike prescribing behaviours in the presence of decreasing GFR, elevated renal clearance is rarely associated with dose modification.

Patient at risk of under-dosing :

Hydrophilic antibiotics in :▪ Fluid overloaded

▪ Drainage

▪ Elevated renal clearance ( young, male, post trauma, neurosurgical patient)

High protein bound antibiotics in hypoalbuminemiapatient

Lipophilic antibiotics in 0bese patient

Quran, Surah Ar-Rahman: 7-9

`..and He made the balance that you may not be inordinate in respect of the measure and keep up the balance with equity and do not make the measure deficient.."