Antibiotikatherapie der Sepsis
Tobias Welte
Klinik für Pneumologie
Medizinische Hochschule Hannover
Outline
• 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
MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia
Welte – Bremen 20.02.2014
Outline
• 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
MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia
Welte – Bremen 20.02.2014
Adequate vs inadequate antibiotic therapy
Hospital mortality (%)
p<0.001
p<0.001
88/169
71/169
114/486
52.1%
23.5%
42.0%
17.7%
86/486
Mortality type
Hospital mortality and infection-related mortality rates for infected patients from all causes (n=655)
receiving either initially inadequate or adequate antimicrobial treatment
Prospective US cohort study evaluating 2000 consecutive patients
Kollef et al. Chest 1999;115:462-74
Welte – Bremen 20.02.2014
Adequate versus inadequate initial antibiotic
treatment and mortality
p<0.001
Hospital mortality (%)
70
60
91/14
7
50
40
30
20
98/34
5
10
0
Adequate
Inadequate
Initial antimicrobial treatment
Prospective US study in ICUs (492 bloodstream infections)
ICU, intensive care unit
Welte – Bremen 20.02.2014
Ibrahim et al. Chest 2000;118:146-55
Outline
• 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
MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia
Welte – Bremen 20.02.2014
Changes in vancomycin MIC have been
observed in the clinical setting
•
•
TEST programme = international surveillance with standardised BMD methodology
Looking for progression of vancomycin ‘creep’ into vancomycin resistance
Phenotype
Year
Isolates
S. aureus
MRSA
MSSA
2004-2009
All (n)
Vancomycin MIC ≥2 µg/mL, n (%)
20,004
797 (4.0)
8249
439 (5.3)
11,755
358 (3.0)
2004
All (n)
Vancomycin MIC ≥2 µg/mL, n (%)
2525
101 (4.0)
1158
65 (5.6)
1367
36 (2.6)
2005
All (n)
Vancomycin MIC ≥2 µg/mL, n (%)
2930
62 (2.1)
1411
39 (2.8)
1519
23 (1.5)
2006
All (n)
Vancomycin MIC ≥2 µg/mL, n (%)
3612
94 (2.6)
1531
50 (3.3)
2081
44 (2.1)
2007
All (n)
Vancomycin MIC ≥2 µg/mL, n (%)
4944
160 (3.2)
2028
78 (3.8)
2916
82 (2.8)
2008
All (n)
Vancomycin MIC ≥2 µg/mL, n (%)
4348
253 (5.8)
1481
136 (9.2)
2867
117 (4.1)
2009
All (n)
Vancomycin MIC ≥2 µg/mL, n (%)
1645
127 (7.7)
640
71 (11.1)
1005
56 (5.6)
p<0.001
Welte – Bremen 20.02.2014
Hawser et al. Int J Antimicrob Agents 2011;37:219-24
Vancomycin treatment failures increase with MIC
60
51
Failure rate (%)
50
40
30
22
20
31
27
10
0
0.0
0.5
1.0
1.5
2.0
MIC (μg/mL)
Relationship between MIC and vancomycin treatment
MIC, minimum inhibitory concentration
Stevens. Clin Infect Dis 2006;42 Suppl 1:S51-7
Welte – Bremen 20.02.2014
Outline
• 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
MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia
Welte – Bremen 20.02.2014
Importance of PK-PD parameters for
optimal treatment of MRSA infection
• For
vancomycin
and linezolid
Antibiotic (C)
– 24-hour AUC
appears to be
the most
important PKPD
parameter1,2
Peak
AUC, area under the curve; MIC, minimum inhibitory concentration;
MRSA, methicillin-resistant S. aureus;
PD, pharmacodynamic; PK, pharmacokinetic
Welte – Bremen 20.02.2014
24-hour AUC
MIC
Time (h)
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.
Time to MRSA eradication with vancomycin
Culture-positive patients (%)
AUC/MIC<400 (n=16)
AUC/MIC≥400 (n=18)
100
80
60
40
20
p=0.04
0
0
10
20
Days of therapy until bacterial eradication
30
AUIC, area under the inhibitory curve; MIC, minimum inhibitory concentration;
MRSA, methicillin-resistant S. aureus
Moise-Broder et al. Clin Pharmacokinet 2004;43:925-42
Welte – Bremen 20.02.2014
Percent
Probability of achieving AUIC/MIC ≥400
for vancomycin regimens of varying intensity
when Cmin was between 15 and 20 mg/L
MIC value (mg/L)
AUIC, area under the inhibitory curve; Cmin, trough concentration; q12h, every 12
hours; MIC, minimum inhibitory concentration
Welte – Bremen 20.02.2014
Patel et al. Clin Infect Dis 2011;52:969-74
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
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
Welte – Bremen 20.02.2014
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
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
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
Welte – Bremen 20.02.2014
1. Conte Jr et al. Antimicrob Agents Chemother 2002;46:1475-80;
2. Boselli et al. Crit Care Med 2005;33:1529-33;
Linezolid: high bioavailability in ELF
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%
Serum
ELF
20
Linezolid concentration (mg/L)
•
16
12
8
4
0
−1 0
2
4
6
Time (hours)
8
10
12
No relationship between clinical outcomes and pharmacokinetics has been established
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 deviations
BAL, bronchoalveolar lavage; ELF, epithelial lining fluid; MRSA, methicillin-resistant S. aureus;
MSSA, methicillin-sensitive S. aureus; VAP, ventilator-associated pneumonia
Boselli et al. Crit Care Med 2005;33:1529-33
Welte – Bremen 20.02.2014
Continuous vs intermittent infusion
vancomycin
•
•
•
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
60
Intermittent infusion (n=58)
Continuous infusion (n=61)
50
Patients (%)
•
40
30
20
10
n=30
n=28
n=15
n=13
n=7
n=5
0
No pathogen
(day 5)
Treatment failure
(day 10)
Infection-related deaths
(day 10)
Adapted from Wysocki et al. Antimicrob Agents Chemother 2001;45:2460-7
Welte – Bremen 20.02.2014
Outline
• 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
MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia
Welte – Bremen 20.02.2014
Nephrotoxicity (%)
Renal effects related to vancomycin concentration
p=0.002
70
60
50
40
30
20
10
0
Renal toxicity was
defined as increased
creatinine by
0.5 mg/dL or
doubling of baseline
value
<15
15-20
>20
Maximum vancomycin steady-state
trough concentrations (mg/mL)a
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 study
HCAP, healthcare-associated pneumonia; MRSA, methicillin-resistant S. aureus
Adapted from Jeffres et al. Clin Ther 2007;29:1107-15
Welte – Bremen 20.02.2014
Vancomycin relationships:
toxicity and target attainment
AUC/MIC ratio ≥400
MIC value
Nephrotoxic event
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
AUC, area under the curve; ICU, intensive care unit;
MIC, minimum inhibitory concentration
Patel et al. Clin Infect Dis 2011;52:969-74
Welte – Bremen 20.02.2014
Vancomycin concentration-time profile
Lodise et al. Clin Infect Dis 2009;49:507-14
•
•
Retrospective US study
correlating the vancomycin
nephrotoxicity with its
pharmacokinetics in
166 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
Logistic regression-derived
nephrotoxicity probability functions
ICU patients
ICU
patients
Probability of Nephrotoxicity
•
Non-ICU
patients
Non-ICU
patients
1.00
0.80
0.60
0.40
0.20
0.00
0
5
10
15
20
25
Initial Vancomycin Trough Value, mg/L
ICU, intensive care unit
Welte – Bremen 20.02.2014
30
Outline
• 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
MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia
Welte – Bremen 20.02.2014
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
HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia;
MRSA, methicillin-resistant S. aureus; VAP, ventilator-associated pneumonia
Welte – Bremen 20.02.2014
Wunderink et al. Clin Infect Dis 2012;54:621-9
ZEPHyR study: randomisation and
interventions
Linezolid IV
600 mg q12h
1:1
randomisation
7-14 days
EOT
visit
EOS
visit
Within 5 days 7-30 days after EOT
of EOT
Follow-up
call:
survival
status at
day 60
Vancomycin IV
15 mg/kg q12h

Vancomycin dose adjusted by unblinded pharmacist per local protocols
based on trough levels and renal impairment

Gram-negative coverage (not MRSA active)
EOT, end of treatment; EOS, end of study; MRSA, methicillin-resistant S. aureus
Welte – Bremen 20.02.2014
Wunderink et al. Clin Infect Dis 2012;54:621-9
Patients with clinical response (%)
Statistically superior clinical efficacy of linezolid vs
vancomycin in MRSA NP in the ZEPHyR study
p=0.042
95% CI 0.5-21.6
95% CI 4.9-22.0
95% CI 0.1-19.8
150/180
161/201
130/186
95/165
95% CI 4.0-20.7
145/214
102/186
81/174
Primary end point
92/205
Secondary end points
Patients with EOS outcome of ‘indeterminate’ were excluded from the efficacy analysis
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
Wunderink et al. Clin Infect Dis 2012;54:621-9
Welte – Bremen 20.02.2014
Statistically-significant higher rates of microbiological success with
linezolid vs vancomycin in the ZEPHyR study
PP population
Patients with respiratory
secretions for culture
Patients with microbiological
response (%)
95% CI 12.3-30.2
95% CI 0.4-21.5
58.1%
(97/167)
47.1%
(82/174)
63.9%
(62/97)
68.3%
(56/82)
36.1%
(35/97)
31.7%
(26/82)
82.6%
(76/92)
81.9%
(149/182)
49.0%
(73/149)
60.6%
(114/188)
61.4%
(35/57)
50.0%
(26/52)
54.1%
(59/109)
48.2%
(55/114)
51.0%
(76/149)
51.8%
(59/114)
Linezolid Vancomycin Linezolid Vancomycin Linezolid Vancomycin Linezolid Vancomycin
EOS
EOT
CI, confidence interval; EOS, end of study; EOT, end of treatment; PP, per protocol
Welte – Bremen 20.02.2014
EOS
EOT
Wunderink et al. Clin Infect Dis 2012;54:621-9
Response differences between linezolid and vancomycin
remained across most subgroups in the ZEPHyR study
Clinical success rate1 (%)
100
Linezolid
Vancomycin
80
60
57.6
46.6
40
62.5
58.8
55.5
44.2
50.0
44.4
55.6
48.6
40.8
61.5
50.0
43.1
47.8
51.7
43.1
31.6
20
0
APACHE, Acute Physiological Assessment and Chronic Health Evaluation;
EOS, end of study; MIC, minimum inhibitory concentration;
MRSA, methicillin-resistant S. aureus; MV, mechanical ventilation
Welte – Bremen 20.02.2014
Wunderink et al. Clin Infect Dis 2012;54:621-9
No relationship between
vancomycin
trough
level
and
Clinical
Microbiological
outcomes in the ZEPHyR study
Clinical success
Clinical failure
20
17.8
16.0
14.4 14.8
15
12.2 12.6
10
5
73
0
Range:
82
3.4-50.8 2.8-43.2
47
52
5.1-45.0 2.7-41.4
23
Median vancomycin trough
concentration (µg/mL)
Median vancomycin trough
concentration (µg/mL)
25
15
2.0-42.6 4.1-46.9
76
Range:
80
2.8-50.8 3.3-43.2
50
49
5.1-45.0 2.7-36.4
22
16
2.9-42.6 3.0-46.9
Vancomycin Vancomycin Vancomycin
Day 3
Day 6
Day 9
End of study
End of study
Adapted from Niederman et al. Am J Respir Crit Care Med 2011;183:A3932
Welte – Bremen 20.02.2014
Nephrotoxicity was nearly twice as common in vancomycin
patients in the ZEPHyR study (mITT population)
Patients with
nephrotoxicity (%)
Laboratory evidence of nephrotoxicity
(0.5 mg/mL increase in serum creatinine if normal at baseline,
or 50% increase if abnormal at baseline)
GFR, glomerular filtration rate
Adapted from Wunderink et al. Clin Infect Dis 2012;54:621-9
Welte – Bremen 20.02.2014
Linezolid has a comparable tolerability
profile with vancomycin in the ZEPHyR
studyLinezolid
Vancomycin
AE, n (%)
(n=597)
(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)
—
1 (0.2)
4 (0.6)
2 (0.4)
—
1 (0.2)
Polyneuropathy
Pancytopenia/neutropenia
Paresthesia
aPatient
was reported to have ≥1 of the following: renal failure, renal impairment and/or azotaemia
AE, adverse event
Wunderink et al. Clin Infect Dis 2012;54:621-9
Welte – Bremen 20.02.2014
Similar 60-day mortality with linezolid
and 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)
No pneumonia trial
has ever demonstrated
an overall mortality
difference between
antibiotics2
1. Wunderink et al. Clin Infect Dis
2012;54:621-9;
2. Wunderink et al. Clin Infect Dis
2012;55:163-5 [letter]
Patients surviving (%)
100
Kaplan–Meier survival curves for the mITT population
80
60
40
Linezolid
Linezolid censored
20
Vancomycin
Vancomycin censored
0
0
ITT, intent-to-treat; mITT, modified intent-to-treat
Welte – Bremen 20.02.2014
10
20
30
40
50 60 70
Time (days)
80
90 100 110 120
Conclusions
• 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
MRSA, methicillin-resistant S. aureus; NP, nosocomial pneumonia
Welte – Bremen 20.02.2014
1 .Wunderink et al. Clin Infect Dis 2012;54:621-9
2. Mullins et al. Poster PIN56 presented at ISPOR 2012
Welte – Bremen 20.02.2014