the bug, the drug and the mug dose: how much is enough? · betalactamin-induced central nervous...

The bug, the drug and the mugThe bug, the drug and the mugThe bug, the drug and the mugThe bug, the drug and the mug

Dose: How much is enough?

1

João Gonçalves Pereira

UCIP

Time

Conc

MIC

Dose: How much is enough?

Antibiotic Goals

• Promote bacteria death

• Prevent the emergence of resistance

• Avoid toxicity

Dose of Antibiotics

How much?

Antibiotic must not only attach to target but must occupy an

João G.P

ereira

• Avoid toxicity

Underdosing

Increase in Volume of distribution

Increase in clearance

adequate number of binding sites

That depends on drug concentration within the organism and also

on bacteria susceptibility – MIC

Usually antibiotic concentration must be over 3-5 times MIC

AminoglycosidesMetronidazol

AzithromycinFluoroquinolones

ConcentrationCmax

Area under the concentration curve

The magnitude required to clinical efficacy relates

Patterns of Antimicrobial Activity

João G.P

ereira

Fluoroquinolones

Beta-lactamsCarbapenemsGlycopeptides

Time (hours)T>MIC

MIC

The magnitude required to clinical efficacy relates with the number of molecules needed to kill bacteria (greater for Gram negative rods)

80

100

Time above MIC and eficcacy (animal model infected with S pneumoniae)

Penicillins

Cephalosporins

Patterns of Antimicrobial Activity

João G.P

ereiraCraig W - Diagn Microbiol Infect Dis 1996; 25. 213

40

60

T> MIC (%)

0 20 40 60 80 100

0

20

Fluoroquinolones

Clinical nad Microbiological Response (%)

80

100

Patterns of Antimicrobial ActivityClinical response (%)

80

100

6570

8389 92

Aminoglycosides

João G.P

ereira

Forrest Antimicrob Agents Chemother 1993; 37. 1073

Clinical nad Microbiological Response (%)

0-62.5 62.5-125125-250 250-500 >500

0

20

40

60

Clinical response (%)

Peak :MIC

0

20

40

60

2 4

55

65

6

70

8 10 12

24-Hr AUC/MIC

Moore J Infect Dis 1987;155. 93

Antibiotics in the critically ill

Increased

cardiac index

Leaky capillaries

and/or altered

protein binding

End organ dysfunction

(eg renal or hepatic)

Increased Increased volume

João G.P

ereira

Decreased

clearance

High serum

concentrations

Increased

clearance

Increased volume

of distribution

Low serum

concentrations

Roberts J – Clin Pharmacokinet 2006; 45; 755

Volume of Distribution (Vd)

••••••••

•••• ••••

Beta-Lactam

500 mg

Fluoroquinolone

500 mgVd (L)=Dose (mg)

Conc (mg/L)

João G.P

ereira

••••

••••

••••

••••

••••

•••• ••••

••••

••••

••••••••

••••

••••••••

••••••••

Vd 15-20 litersVd 80-200 liters

Sépsis

Concentration

Cmax Area under the curve

Pharmacokinetics / Pharmacodynamics

Increased Vd

João G.P

ereira

MIC

Concentration

Time (hours)

T>MIC

MIC

T>MIC

••••

••••

••••••••

••••

••••••••

••••••••

Increased Vd (5-10L)

15,00

20,00

25,00

30,00

Co

nce

ntr

atio

n

Median dose 7,4mg/Kg (n=32)


Increased Vd

João G.P

ereira

0,00

5,00

10,00

Time

11 patients maximum concentration less than 16 µg/mL

22 patients less than 20 µg/mL

No relationship with age, renal failure or sepsis severity

Gonçalves Pereira, Clin Microb Infect (e-pub ahead of print)

Pharmacokinetics and efficacy

1111

1,21,21,21,2

1,41,41,41,4

1,61,61,61,6

1,81,81,81,8

2222

VdVdVdVd

First day Vd of meropenem in critically ill patients

60 patients with febrile

Neutropenia

João G.P

ereira

0000

0,20,20,20,2

0,40,40,40,4

0,60,60,60,6

0,80,80,80,8

1111 2222 3333 4444 5555 6666 7777 8888

VdVdVdVd

Median 0,22 l/kg (0,16-1,85)

Data not published

Neutropenia

Meropenem Vd 0,22l/kg

Ariano, Ann Pharm 2005; 39. 3

42 responders – T>MIC 83%

18 failures – T>MIC 59%

0

5

10

15

20

Plasma Muscle Fat

Volunteers

Septic patients


Increased Vd

João G.P

ereira

� Piperacillin pharmacokinetics is different in septic shock patients:

� Decrease plasmatic and tissue AUC

� Increase volume of distribution

� Decrease of tissue concentration

Joukhadar - Crit Care Med 2001; 30. 1478

Insufficient concentration (always under MIC) in fat tissue

Piperacillin Tazobactam – Insufficient concentration in ELF of the lung of the critically ill patient (dose of 4,5 g 8-8 h)

Boselli E - Int Care Med 2004; 36. 1500

Continuous infusion of Beta-Lactams

Continuous infusion increase T>MIC either in plasma and tissue

in septic patents

Mean tissue concentration

João G.P

ereira

Piperacillin tazobactam simulated plasma and muscle

concentrations in septic patients

Dose 16g (bolus) or 12g (continuous infusion)

Mean tissue concentration at day 2:

0,8 µg/mL vs 5,2 µg/mL (p=0,45)

Time to plasma-tissue 50% concentration equilibrium – 173h

Roberts Crit Care Med, 2009, 37, 926

Sepsis

Concentration


Increased Clearance

Area under the curve

Cmax

João G.P

ereira

MIC

Concentration

Time (hours)

T>MIC

Renal hiperfiltration – 17,5% of patients, mean of 142 mL/min

Fuster-Lluch Anaesth Intensive Care 2008; 36. 674

150

200

250

Drug Clearance (mL/min)


Increased Clearance

João G.P

ereira

0

50

100

0 50 100 150 200 250 300Creatinine Clearance (mL/min)

Drug Clearance (mL/min)

Cefepime Cefpirome

Lipman Anesth Analg 2003; 97. 1149

Mean Levofloxacin concentrations:Critically ill patients vs controls

Concentration (mg/mL) ICU patients

Healthy volunteers65

78

João G.P

ereira

Rebuck Pharmacother 2002; 22. 1216

Concentration (mg/mL)

Time (Hours)2 4 6 8 10 12 14

012345

0 16 18 20 22 24

500 mg dose

Magnitude of PK/PD parameter of GemifloxacinS. pneumoniae wild type and mutant in thighs of neutropenic mice

Bacteria

Conc

AUC/MIC

Pharmacokinetics and Susceptibility

João G.P

ereira

BacteriaMIC

Susceptible 0.015

Gyrase, PAR C or E 0.03-2.0

Efflux 0.12-0.25

Craig & Andes ICAAC 2000; Craig NCCLS, 2003

Time

MIC

AUC/MIC

82.3

MIC 31.3

5.8MIC

Pathogen eradication of Levofloxacin against ciprofloxacin-resistant S. pneumoniae 500 mg versus 750 mg

Levo MIC: 1.8 µg/mL

6

7

8

9

10

CFU/mL

Control

500 mg678

910 Levo MIC: 3.2 µg/mL

João G.P

ereira

Lister Diagn Microbiol Infect Dis. 2002; 44. 43

0

1

2

3

4

5

6

0 4 8 14 16 20 24 28 32Time (Hours)

Log10CFU/mL

500 mg

750 mg

01

234

56

0 4 8 14 16 20 24 28 32

Time (Hours)Cipro MIC: 4µg/mL Cipro MIC: 16µg/mL

Antibiotic Increased Normal Moderately impaired Severely impaired

Piperacillin/tazobatam 16/2 g q24h CI 4/0.5 g q6h 3/0.375 g q6h 2/0.25 g q6h

Cefotaxime 4 to 6 g q24h CI 2 g q6-8h 1 g q6-8h 2 g q4-6h

Ceftazidime 4 to 6 g q24h CI 2 g q8h 1 g q8-12h 0.5 to 1 g q24h

Cefepime 4 to 6 g q24h CI 2 g q8h 2 g q12h 1 g q24h

Imipenem 500 mg q4h 500 mg q6h 250 mg q6h 250 mg q12h

Meropenem 1 g q6h over 6 hours 500 mg q6h 250 mg q6h 250 mg q12h

Recommended dosing regimens

renally excreted antimicrobials

João G.P

ereira

Meropenem 1 g q6h over 6 hours 500 mg q6h 250 mg q6h 250 mg q12h

Ertapenem ND 1 g q24h 1 g q24h 500 mg q24h

Gentamycin 9 to 10 mg/kg q24h 7 mg/kg q24h 7 mg/kg q36-48h 7 mg/kg q48-96h

Tobramycin 9 to 10 mg/kg q24h 7 mg/kg q24h 7 mg/kg q36-48h 7 mg/kg q48-96h

Amikacin 20 mg/kg q24h 15 mg/kg q24h 15 mg/kg q36-48h 15 mg/kg q48-96h

Ciprofloxacin 600 mg q12h 400 mg q12h 400 mg q12h 400 mg q24h

Levofloxacin 500 mg q12h 750 mg q24h 500 mg q24h 500 mg q48h

Vancomycin 30 mg/kg q24h CI 500 mg q6h 500 mg q12h 500 mg q24-72h

Daptomycin ND 6 mg/kg q24h 6 mg/kg q24h 6 mg/kg q48h

Pea Crit Care 2009; 13. 214

Probability of pharmacodynamic target attainment in HAP

OPTAMA Monte Carlo Simulation

Microbiological data from 2007 MYSTIC program

Bacteria prevalence according to 2000 SENTRY Surveillance study

João G.P

ereiraKim Clin Therap 2009; 31. 2765

Bacteria prevalence according to 2000 SENTRY Surveillance study

Pharmacokinetic data from critically ill patients

Accumulation and Toxicity

Ceftriaxone 2 g/d

Accumulation in renal failure

Cr Cl >50 mL/min <50 mL/min

Day 1 19,5 µg/mL 46,5 µg/mL

µg/mL µg/mL

João G.P

ereira

Day7 38,5 µg/mL 125 µg/mL

Heinemeyer Int Care Med 1990; 16; 448

Betalactamin-induced central nervous side effects include

confusion, disturbances of behaviour, hallucinations, asterixis,

myoclonic jerks, and generalised convulsive or nonconvulsive

seizures. Those are probably underreported but may contribute to

morbidity and mortality.

Chatellier Int Care Med 2002; 28. 214

Concentration Cmax


Aminoglycosides

CmaxRenal failure

João G.P

ereira

Time (hours)

MIC

�Pharmacodynamic parameter of efficacy: Peak/MIC

�Toxicity (Renal accumulation): Trough concentration

••••••••

••••••••

Optimisation of minimum concentration/MIC ratio

Placebo

T>MIC=84%

T>MIC=100% & Cmin/MIC=6

T>MIC=100% & Cmin/MIC=10

0 1 2 3 4 5

12

8

4

0Time (days)

Log 10 cfu/m

L

10

8

Log 10 cfu/m

L

0 1 2 3 4 5

10

8

4

0

6

2

10

8

Time (days)

Log 10 cfu/m

LLo

g 10 cfu/m

L

João G.P

ereira

T>MIC=100% Cmin/MIC=1.7+ tobramycinT>MIC=100% & Cmin/MIC=1.7

0 1 2 3 4 5

4

0Time (days)

Log 10 cfu/m

L

0 5

10

8

4

0

Log 10 cfu/m

L

Time (days)

2 3 41

0 1 2 3 4 5

8

4

0

6

2

0 1 2 3 4 5

10

8

4

0

6

2

Time (days)

Time (days)

Log 10 cfu/m

LLo

g 10 cfu/m

L

Tam Antimicrob Agents Chemother 2005; 49. 4920

Wild type

Amp C mutant

Clinical Application of Pharmacodynamics

High, aggressive dosing should be routinely used for systemic infections� The more severe the infection, the higher the doses that should be used

� Consider patterns of antibiotic activity•Increase peak and AUC of concentration dependent drugs

(higher doses)

João G.P

ereira

(higher doses)•Increase time of exposure of time dependent drugs

(shorter intervals) Risk-versus-benefit considerations are important

–Potential for increased efficacy–Potential for prevention of resistance–Potential for increased toxicity (consider organ failure)

•Monitor MIC and antibiotic concentration(whenever possible)

The person who takes medicine must recover twice, once from the disease and

João G.P

ereira

recover twice, once from the disease and once from the medicine.

- William Osler, M.D.

Porto, 25 de Março de 2010

the bug, the drug and the mug dose: how much is enough? · betalactamin-induced central nervous...

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