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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
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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%
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
• 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)
2005 All (n)Vancomycin MIC ≥2 µg/mL, n (%)
2930 62 (2.1)
141139 (2.8)
151923 (1.5)
2006 All (n)Vancomycin MIC ≥2 µg/mL, n (%)
361294 (2.6)
153150 (3.3)
208144 (2.1)
2007 All (n)Vancomycin MIC ≥2 µg/mL, n (%)
4944160 (3.2)
202878 (3.8)
291682 (2.8)
2008 All (n)Vancomycin MIC ≥2 µg/mL, n (%)
4348253 (5.8)
1481136 (9.2)
2867117 (4.1)
2009 All (n)Vancomycin MIC ≥2 µg/mL, n (%)
1645127 (7.7)
64071 (11.1)
100556 (5.6)
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
• 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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
*
*
*
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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;
No relationship between clinical outcomes and pharmacokinetics has been established
*
*
*
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
• 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
No relationship between clinical outcomes and pharmacokinetics has been established
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
• 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
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
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
Welte – Bremen 20.02.2014Welte – 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
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
Wunderink et al. Clin Infect Dis 2012;54:621-9
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
Statistically-significant higher rates of microbiological success with linezolid vs vancomycin in the ZEPHyR study
Wunderink et al. Clin Infect Dis 2012;54:621-9
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
Wunderink et al. Clin Infect Dis 2012;54:621-9
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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)
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
Linezolid has a comparable tolerability profile with vancomycin in the ZEPHyR
study
Wunderink et al. Clin Infect Dis 2012;54:621-9
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)
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014
• 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
Welte – Bremen 20.02.2014Welte – Bremen 20.02.2014