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New
Antistaphylococcal
Agents:
Linezolid, Daptomycin, and
Tigecycline
Cary Engleberg, M.D.
Division of Infectious Diseases,
University of Michigan Medical School
Linezolid
(Zyvox®)
Linezolid (Zyvox®)
Pharmacodynamics of linezolid
• Peak concentration of 18µg/ml in 1 -2h
•
•
post-dose
Elimination half-life = 4.5 - 5.5 hours
Parameter predicting successful
therapy:
– Time above MIC
– Target = >40% of dosing interval
Mean plasma linezolid levels following
equivalent (375mg) oral and IV doses
p.o. (Fasted) (n=12)
10
Plasma
linezolid
conc.
(µg/mL)
IV (n=12)
Bioavailability = 100%
8
6
4
2
0
0
2
4
6
8
10
12
14
16
Hours After Administration
Source: Pharmacia & Upjohn.
18
20
22
24
Linezolid concentrations after 14 days
of steady state, bid dosing
(Stalker, et al. ICAAC, Toronto, Ontario. 1997)
375 mg BID (n=12)
20
625 mg BID (n=12)
16
MIC-90 S. aureus
MIC-90 enterococci
Linezolid 12
Conc.
(µg/mL) 8
MIC-90 pneumococcus
4
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Hours After Last Dose
3
Linezolid vs. vancomycin in MRSA infections
(Stevens et al. Clin Infect Dis 2002; 34:1481-90)
Cure rate (%) of evaluable MRSA
Infection
Linezolid 600mg bid
Skin/soft tissue 27/34 (79.4)
Pneumonia
9/12 (75)
UTI
0/1 (0)
Other sites
3/6 (50)
Bacteremia
9/15 (60)
All
48/68 (70.6)
Vanco 1gm BID
22/30 (73.3)
12/16 (75)
1/1 (100)
2/3 (66.7)
7/10 (70)
44/60 (73.3)
Linezolid concentrations in joints
and bone
(Rana et al. 2002)
Sub-MIC effect of linezolid on
bacterial virulence
• Decreased hemolysin and coagulase
•
•
expression in S. aureus at 1/2, 1/4, and 1/8
MIC
Decreased streptolysin O and DNAse
production in group A streptococcus
Concentrations below the MIC potentiate
the opsonophagocytosis of S. aureus and
S. pyogenes
Resistance to linezolid
• Originally thought to be unlikely given chemical
•
origin and mode of action of the drug
2 of 169 patients treated on a compassionate
use protocol developed resistant strains
– rRNA mutation (G2576U)
– Both involved prolonged indwelling lines
• Induction of resistance in the laboratory by
prolonged passage:
– in staphylococci, frequency is 10-9 - 10-11
– among enterococci, E. faecalis is more likely to
develop resistance (G2576U) than E. faecium
Linezolid dosing and use
• 600mg IV or po q 12 h for serious
•
•
•
infections
No adjustment necessary for renal
dysfunction
Adverse effects: most common is GI
disturbance; thrombocytopenia after 17
days
MAO inhibitor activity: may enhance
pressor responses with adrenergic drugs
Daptomycin
(Cubicin®)
Daptomycin
Fermentation product of
Streptomyces roseosporus
Mechanism of action:
Interacts with the bacterial
plasma membrane via the
lipid portion to form a pore.
Metabolic death occurs by
leakage of electrolytes
without lysis of the bacteria
Cyclic
peptide
Lipid
(acyl)
chain
Features of daptomycin kinetics
• Linear kinetics
• Half life = 8.5 hrs.
• 87-94% plasma protein bound
• Urine excretion - 80% (66% active)
• Limited metabolism; No significant
•
CyP450 interactions
Requires physiologic concentrations of
calcium to be active in vitro
Daptomycin in the lung
• When distributed into the lung,
•
•
daptomycin partitions into the surfactant
layer via its lipid moeity.
This is a disadvantage, in that little free
drug is available to interact with bacteria.
Daptomycin should NOT be used to treat
pneumonia
Comparison of daptomycin activity
with other antimicrobial agents
MIC90 (µg/ml)
Daptomycin Vancomycin Linezolid Synercid®
MSSA (50)
0.13
1.0
4.0
1.0
MRSA (50)
0.13
1.0
4.0
1.0
MSSE (25)
0.5
1.0
4.0
0.5
MRSE (50)
0.25
1.0
4.0
0.25
E. faecalis** (25)
1.0
64.0
4.0
16.0
E. faecium** (25)
4.0
64.0
4.0
4.0
**includes some VRE
(from Rybak et al: Antimicrob Ag Chemother 2000)
Time-kill analysis against MRSA
10
Control
9
8
7
CFU/ml
6
Linezolid
Synercid®
5
4
3
2
0
8
24
hours
Rybak et al: AAC April 2000
Vancomycin
Daptomycin
Time-kill analysis against VRE
9
Control
Vancomycin
8
7
CFU/ml
6
5
Linezolid
Synercid®
Daptomycin
4
3
2
0
8
24
hours
Rybak et al: AAC April 2000
Daptomycin in S. aureus
endocarditis
(Fowler et al. NEJM 2006;355:653-65)
Daptomycin toxicity
• In animal toxicity studies, muscle damage with
increased CPK occurred when the drug was dosed
frequently
• Because daptomycin is rapidly bactericidal, it can be
administered once a day to achieve high peaks
alternating with periods whent the drug is cleared.
• Periods of subtherapeutic levels of daptomycin during
the dosing interval in humans makes the likelihood of
muscle damage every small
• Long term treatment should be followed with weekly
CPK levels
Tigecycline
(Tygacil®)
Drug modifications to avoid resistance
• Tetracyclines and macrolides both inhibit protein
synthesis by binding to the ribosome
• Two major types of resistance occurs against both drug
classes:
– Modification of the ribosomal binding site
– Efflux pumps that expel the drug from the bacterial cytoplasm
• Minocycline and clarithromycin have been chemically
modified by adding side chains to the basic molecule.
This has two effects:
– Increased ribosomal binding, even with modification
– Drug not recognized or mobilized by the efflux system
Drug Modifications
(additions of side chains)
telithromycin
clarithromycin
minocycline
Active against macrolide-resistant S. pneumoniae
tigecycline
Active against many resistant Gram-negatives,
MRSA and VRE
Tigecycline
• Mechanism of action:
–binds to the 30S ribosome and blocks entry of
amino-acyl tRNAs to block protein synthesis
(like all tetracyclines)
–Bacteriostatic, not cidal
• Kinetics:
–T1/2=24-48 hrs
–Distributes to all tissues (large volume of
distribution); including alveolar lining fluid
• Dosing (adult): 100mg loading, then 50mg
q12h
Tigecycline: spectrum of activity
• Staphylococci (including MRSA and MRSE)
• Enterococci (including VRE)
• S. pneumoniae (including pen-resistant)
• Most Gram-negatives (e.g., E. coli, Citrobacter spp,
Klebsiella spp, Serratia spp, Acinetobacter spp,
Stenotrophomonas, Haemophilus)
• Anaerobes (e.g., Bacteroides, Clostridia)
• Chlamydiae, mycoplasmas
• NOT Pseudomonas
Tigecycline: adverse effects
• Nausea (30%); vomiting (20%)
–Most common in older women
–due to serotonin release and modified by
ondansetron
• Dental staining (not used in pregnancy or
•
•
children)
Decreased clearance of warfarin
No significant P450 interactions
Tigecycline: studies of efficacy
• Non-inferior to imipenem in >1000 adults
•
•
with complicated intra-abdominal
infections (2 phase III studies)
Non-inferior to vancomycin+aztreonam in
complicated skin and soft tissue
infections (2 phase III studies)
Tigecycline had more nausea/vomiting in
all studies