Antibiotikatherapie der Sepsis Tobias Welte Klinik für Pneumologie Medizinische Hochschule Hannover

Antibiotikatherapie der SepsisTobias Welte

Klinik für Pneumologie

Medizinische Hochschule Hannover

Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014

• Consequences of inappropriate MRSA NP therapy• Appropriate MRSA NP therapy

– Vancomycin MIC creep– PK of vancomycin and linezolid – Nephrotoxicity of vancomycin

• ZEPHyR study and results• Conclusions

Outline

MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia





Outline



Adequate vs inadequate antibiotic therapy

Mortality type

Hos

pita

l mor

talit

y (%

)p<0.001

p<0.001

Kollef et al. Chest 1999;115:462-74

Hospital mortality and infection-related mortality rates for infected patients from all causes (n=655) receiving either initially inadequate or adequate antimicrobial treatmentProspective US cohort study evaluating 2000 consecutive patients

88/169

114/486

71/169

86/48617.7%42.0%23.5%52.1%


Adequate versus inadequate initial antibiotic treatment and mortality

Ibrahim et al. Chest 2000;118:146-55

Prospective US study in ICUs (492 bloodstream infections)ICU, intensive care unit

Hos

pita

l mor

talit

y (%

)H

ospi

tal m

orta

lity

(%)

0

30

40

50

60

70

Adequate Inadequate

20

10

Initial antimicrobial treatment

p<0.001

91/147

98/345





Outline



• TEST programme = international surveillance with standardised BMD methodology • Looking for progression of vancomycin ‘creep’ into vancomycin resistance

Changes in vancomycin MIC have beenobserved in the clinical setting

Hawser et al. Int J Antimicrob Agents 2011;37:219-24p<0.001

Year IsolatesPhenotype

S. aureus MRSA MSSA

2004-2009 All (n)Vancomycin MIC ≥2 µg/mL, n (%)

20,004797 (4.0)

8249439 (5.3)

11,755358 (3.0)

2004 All (n)Vancomycin MIC ≥2 µg/mL, n (%)

2525101 (4.0)

115865 (5.6)

136736 (2.6)


2930 62 (2.1)

141139 (2.8)

151923 (1.5)


361294 (2.6)

153150 (3.3)

208144 (2.1)


4944160 (3.2)

202878 (3.8)

291682 (2.8)


4348253 (5.8)

1481136 (9.2)

2867117 (4.1)


1645127 (7.7)

64071 (11.1)

100556 (5.6)


Vancomycin treatment failures increase with MIC

Stevens. Clin Infect Dis 2006;42 Suppl 1:S51-7

MIC (μg/mL)

Fai

lure

rat

e (%

)

0.00

10

20

30

40

50

60

0.5 1.0 1.5 2.0

2227

31

51

Relationship between MIC and vancomycin treatment

MIC, minimum inhibitory concentration





Outline



• For vancomycin and linezolid– 24-hour AUC

appears to be the most important PK-PD parameter1,2

Importance of PK-PD parameters for optimal treatment of MRSA infection

1. Andes et al. Antimicrob Agents Chemother 2002;46:3484-9;2. Moise PA et al. Am J Health-Syst Pharm. 2000;57:S4-S9.

AUC, area under the curve; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus; PD, pharmacodynamic; PK, pharmacokinetic

MIC

Time (h)

24-hour AUC

An

tib

ioti

c (C

)

Peak


Time to MRSA eradication with vancomycin

Moise-Broder et al. Clin Pharmacokinet 2004;43:925-42

0 10 20 30Days of therapy until bacterial eradication

0

20

40

60

80

100C

ultu

re-p

ositi

ve p

atie

nts

(%)

p=0.04

AUC/MIC≥400 (n=18)AUC/MIC<400 (n=16)

AUIC, area under the inhibitory curve; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus


Probability of achieving AUIC/MIC ≥400 for vancomycin regimens of varying intensity

when Cmin was between 15 and 20 mg/L

Patel et al. Clin Infect Dis 2011;52:969-74

AUIC, area under the inhibitory curve; Cmin, trough concentration; q12h, every 12 hours; MIC, minimum inhibitory concentration

MIC value (mg/L)

Per

cent


Vancomycin: penetration in the lung tissue

Vancomycin

6 hours post-injection

ELF: mean 2.03 µg/ml

(1-2.77 µg/ml)1

Healthy volunteers

52%2

Patients with pneumonia

9-18%1,3

1. Georges et al. Eur J Clin Microbiol Infect Dis 1997;16:385-8; 2. Rybak. Clin Infect Dis 2006;42 Suppl 1:S35-9;

3. Lamer et al. Antimicrob Agents Chemother 1993;37:281-6

No relationship between clinical outcomes and pharmacokinetics has been established

Data represent the drug level in ELF as a percentage of the simultaneous levels in plasma

ELF, epithelial lining fluid

*

*

*


Linezolid: high penetration in the lung tissue

Linezolid

8 hours post-injection

ELF: mean 31.4 µg/ml

(8.3-89.2 µg/ml)1

Healthy volunteers

~400%1

Patients with pneumonia

105%2

Data represent the drug level in ELF as a percentage of the simultaneous levels in plasma ELF, epithelial lining fluid

1. Conte Jr et al. Antimicrob Agents Chemother 2002;46:1475-80; 2. Boselli et al. Crit Care Med 2005;33:1529-33;


*

*

*


• 16 critically ill VAP patients studied at steady state

– All with late-onset VAP

– 12 with organisms: 3 MRSA,1 MSSA, 8 enteric Gram-negatives (4 enterobacteriaceae and 4 P. Aeruginosa)

• Serum and ELF concentrations after 2 days of therapy

• Blood at 10, 20, 30, 45 minutes and 1, 2, 4, 8, 12 hours after infusion

• BAL 1 and 12 hours after infusion• Similar levels in serum and ELF

– Range of peak penetration: 34-188%

– Range of trough penetration: 28-220%

Linezolid: high bioavailability in ELF

Boselli et al. Crit Care Med 2005;33:1529-33

Mean steady-state plasma (red circles) and ELF (blue circles) concentrations with NP (n=16). The dotted line represents the susceptibility breakpoint (4 mg/L) of staphylococci for linezolid (1). Error bars represent standard deviationsBAL, bronchoalveolar lavage; ELF, epithelial lining fluid; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-sensitive S. aureus; VAP, ventilator-associated pneumonia

0

4

8

12

16

20

Lin

ezo

lid c

on

cen

tra

tion

(m

g/L

)

−1 0 2 4 6 8 10 12Time (hours)

SerumELF



• Prospective randomised study

• Designed to compare continuous vs intermittent vancomycin in 119 critically ill patients with MRSA infections

• Microbiological and clinical outcomes and safety were similar

• No statistically significant difference was found between the two treatment groups

Continuous vs intermittent infusion vancomycin

Adapted from Wysocki et al. Antimicrob Agents Chemother 2001;45:2460-7

0

10

20

30

40

50

60

No pathogen (day 5)

Treatment failure (day 10)

Infection-related deaths (day 10)

Intermittent infusion (n=58)Continuous infusion (n=61)

Pat

ient

s (%

)

n=30 n=28 n=15 n=13 n=7 n=5





Outline



0

10

20

30

40

50

60

70

<15 15-20 >20

Renal effects related to vancomycin concentration

Adapted from Jeffres et al. Clin Ther 2007;29:1107-15

Nep

hrot

oxic

ity (

%)

p=0.002

Maximum vancomycin steady-state trough concentrations (g/mL)a

Renal toxicity was defined as increased

creatinine by 0.5 mg/dL or

doubling of baseline value

Aggressive dosing and prolonged administration of vancomycin are associated with a greater risk of nephrotoxicity in patients with MRSA HCAP

aMaximum vancomycin serum trough concentrations ≥15 µg/mL (n=49); maximum vancomycin serum trough concentrations <15 µg/mL (n=45)Retrospective US observational single-centre studyHCAP, healthcare-associated pneumonia; MRSA, methicillin-resistant S. aureus


Vancomycin relationships: toxicity and target attainment

AUC/MIC ratio ≥400 Nephrotoxic event

MIC value 0.5 mg/L (%)

1.0 mg/L (%)

2.0 mg/L (%)

Non-ICU(%)

ICU(%)

500 mg IV q12h 57 15 0.7 3 10

1000 mg IV q12h 90 57 15 6 16

1500 mg IV q12h 97 79 38 9 25

2000 mg IV q12h 98 90 57 14 34

Patel et al. Clin Infect Dis 2011;52:969-74

AUC, area under the curve; ICU, intensive care unit; MIC, minimum inhibitory concentration


Vancomycin concentration-time profile

• Retrospective US study correlating the vancomycin nephrotoxicity with its pharmacokinetics in166 non-neutropenic patients

– Baseline creatinine <2.0 mg/dL

– Vancomycin >48 h

• 21 patients with nephrotoxicty(50% or 0.5 mg/dL increase in the serum creatinine level from baseline)

• The results indicate that a vancomycin exposure–toxicity response relationship exists. The vancomycin trough value is the pharmacodynamic index that best describes this association

Lodise et al. Clin Infect Dis 2009;49:507-14

Logistic regression-derivednephrotoxicity probability functions

Pro

bab

ility

of N

eph

roto

xici

ty

Initial Vancomycin Trough Value, mg/L

0.00

0.20

0.40

0.60

0.80

1.00

0 5 10 15 20 25 30

ICU patients Non-ICU patientsICU patients Non-ICU patients

ICU, intensive care unit





Outline



ZEPHyR study: design overview and objective

Design overview• Phase IV, randomised, double-blind, multicentre, international

comparator-controlled study in MRSA VAP, HAP or HCAP– Fixed-dose linezolid vs dose-optimised vancomycin

– Non-inferiority study with a nested superiority hypothesis

Study objective• To prospectively assess the efficacy, safety and tolerability of linezolid

compared with vancomycin in MRSA nosocomial pneumonia

Wunderink et al. Clin Infect Dis 2012;54:621-9HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; MRSA, methicillin-resistant S. aureus; VAP, ventilator-associated pneumonia


ZEPHyR study: randomisation and interventions

Linezolid IV 600 mg q12h

Vancomycin IV 15 mg/kg q12h

7-14 days

EOTvisit

EOSvisit

7-30 days after EOT

Vancomycin dose adjusted by unblinded pharmacist per local protocolsbased on trough levels and renal impairment

Gram-negative coverage (not MRSA active)

1:1randomisation

Within 5 days of EOT

Wunderink et al. Clin Infect Dis 2012;54:621-9

Follow-up call: survival status at day 60

EOT, end of treatment; EOS, end of study; MRSA, methicillin-resistant S. aureus


Statistically superior clinical efficacy of linezolid vs vancomycin in MRSA NP in the ZEPHyR study

Patients with EOS outcome of ‘indeterminate’ were excluded from the efficacy analysis


Pat

ient

s w

ith c

linic

al r

espo

nse

(%) p=0.042

95% CI 0.5-21.6 95% CI 0.1-19.8

95% CI 4.9-22.0 95% CI 4.0-20.7

Primary end point Secondary end points

CI, confidence interval; EOS, end of study; EOT, end of treatment; mITT, modified intent-to-treat; MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia; PP, per protocol

95/165

81/174102/186

92/205

150/180

130/186

161/201

145/214


Statistically-significant higher rates of microbiological success with linezolid vs vancomycin in the ZEPHyR study


Pat

ient

s w

ith m

icro

biol

ogic

al

resp

onse

(%

)

95% CI 0.4-21.5

EOS

Linezolid Vancomycin Linezolid Vancomycin Linezolid Vancomycin Linezolid Vancomycin

EOT EOS EOT

PP population Patients with respiratorysecretions for culture

63.9%(62/97) 68.3%

(56/82)

49.0%(73/149)

48.2%(55/114)

36.1%(35/97)

31.7%(26/82)

51.0%(76/149) 51.8%

(59/114)

58.1%(97/167)

47.1%(82/174)

81.9%(149/182)

60.6%(114/188)

61.4%(35/57)

50.0%(26/52)

82.6%(76/92)

54.1%(59/109)

95% CI 12.3-30.2

CI, confidence interval; EOS, end of study; EOT, end of treatment; PP, per protocol


57.6 55.5

44.450.0

58.8 55.662.5 61.5

51.746.6 44.2

31.640.8

48.643.1

50.0 47.843.1

0

20

40

60

80

100Linezolid Vancomycin

Response differences between linezolid and vancomycin remained across most subgroups in the ZEPHyR study


Clin

ical

su

cces

s ra

te1 (

%)

APACHE, Acute Physiological Assessment and Chronic Health Evaluation; EOS, end of study; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus; MV, mechanical ventilation


No relationship between vancomycin trough level and

outcomes in the ZEPHyR study

Adapted from Niederman et al. Am J Respir Crit Care Med 2011;183:A3932

Clinical

12.2

14.416.0

12.6

14.8

17.8

0

5

10

15

20

25

Vancomycin Day 3

Vancomycin Day 6

Vancomycin Day 9

Clinical success

Clinical failure

Med

ian

vanc

omyc

in t

roug

h co

ncen

trat

ion

(µg/

mL)

Range: 3.4-50.8 2.8-43.2 5.1-45.0 2.7-41.4 2.0-42.6 4.1-46.9

73 82 47 52 23 15

Microbiological

Med

ian

vanc

omyc

in t

roug

h co

ncen

trat

ion

(µg/

mL)

Range: 2.8-50.8 3.3-43.2 5.1-45.0 2.7-36.4 2.9-42.6 3.0-46.9

76 80 50 49 22 16

End of study End of study


Nephrotoxicity was nearly twice as common in vancomycin patients in the ZEPHyR study (mITT population)

Adapted from Wunderink et al. Clin Infect Dis 2012;54:621-9

Pat

ient

s w

ith

neph

roto

xici

ty (

%)

GFR, glomerular filtration rate

Laboratory evidence of nephrotoxicity (0.5 mg/mL increase in serum creatinine if normal at baseline,

or 50% increase if abnormal at baseline)


Linezolid has a comparable tolerability profile with vancomycin in the ZEPHyR

study


aPatient was reported to have ≥1 of the following: renal failure, renal impairment and/or azotaemiaAE, adverse event

AE, n (%)Linezolid(n=597)

Vancomycin(n=587)

Anaemia 30 (5.2) 42 (7.2)

Renal failure/impairment/azotaemiaa 22 (3.7) 43 (7.3)

Cardiac arrest 11 (1.8) 13 (2.2)

Thrombocytopenia 8 (1.3) 13 (2.2)

Pancreatitis 5 (0.8) 1 (0.2)

Polyneuropathy — 1 (0.2)

Pancytopenia/neutropenia 4 (0.6) 2 (0.4)

Paresthesia — 1 (0.2)


Similar 60-day mortality with linezolidand vancomycin: the ZEPHyR study

Comparable all-cause 60-day mortality rates1

– Linezolid arm 15.7%; vancomycin arm 17.0% (ITT population)– Linezolid arm 28.1%; vancomycin arm 26.3% (mITT population)

1. Wunderink et al. Clin Infect Dis 2012;54:621-9;2. Wunderink et al. Clin Infect Dis 2012;55:163-5 [letter]

20

40

60

80

100

Pat

ient

s su

rviv

ing

(%)

00 20 60 80

Time (days)

40 100 120

Linezolid

Vancomycin

Linezolid censored

Vancomycin censored

No pneumonia trialhas ever demonstrated

an overall mortality difference between

antibiotics2

1109070503010ITT, intent-to-treat; mITT, modified intent-to-treat

Kaplan–Meier survival curves for the mITT population


• MRSA NP remains an important healthcare burden• Linezolid demonstrated statistically superior clinical

efficacy versus vancomycin in the treatment of MRSA NP in the ZEPHyR study1

• Overall, linezolid demonstrated an acceptable safety and tolerability profile for the treatment of proven MRSA nosocomial pneumonia1

• Linezolid was associated with lower rates of pneumonia-related rehospitalisation versus vancomycin in a US retrospective study 2

Conclusions

MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia 1 .Wunderink et al. Clin Infect Dis 2012;54:621-92. Mullins et al. Poster PIN56 presented at ISPOR 2012


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Antibiotikatherapie der Sepsis Tobias Welte Klinik für Pneumologie Medizinische Hochschule Hannover