Expert Opinion on Pharmacotherapy

Monthly Focus: Anti-infectives

Norrby
Linezolid

Linezolid - a review of the first

oxazolidinone
Ragnar Norrby
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http://www.ashley-pub.com

The Swedish Institute for Infectious Disease Control, Solna, Sweden

Drug Evaluation
1.

Overview of the market

2.

Introduction to linezolid

3.

Chemistry

4.

Antibacterial activity

5.

Pharmacokinetics

6.

Clinical efficacy in Phase

II/III studies

7.

Safety and tolerability

8.

Regulatory affairs

9.

Conclusions

10.

Expert opinion
Bibliography

Linezolid is the first of a truly new class of antibiotics, the oxazolidinones. It

acts as an inhibitor of bacterial protein synthesis by blocking the formation
of the 70S ribosomal initiation complex. Its activity is bacteriostatic against
some species (e.g., enterococci) and bactericidal against others (e.g.,
pneumococci). The antibacterial spectrum of linezolid includes
Gram-positive pathogens and some Gram-negative anaerobic species but
not Gram-negative aerobes. Importantly, multi-drug resistant organisms
such as methicillin-resistant staphylococci, staphylococci with reduced
susceptibility to vancomycin, penicillin- and macrolide-resistant pneumococci and vancomycin-resistant enterococci are fully susceptible to
linezolid. Linezolid has almost 100% bioavailability and the area under the
plasma concentration curve is identical after oral and iv. administration.
This enables initial oral administration of linezolid in those patients who
can absorb the drug normally and also an early step-down therapy from iv.
to oral. Controlled, randomised clinical studies have documented efficacy
and safety of linezolid in hospital- and community-acquired pneumonia,
uncomplicated and complicated skin and soft tissue infections and
infections caused by vancomycin-resistant enterococci. The safety and
tolerability of linezolid are advantageous. Linezolid is a weak and reversible
monoamine oxidase (MAO) inhibitor and although no increased frequency
of adrenergic or serotonergic adverse events has been reported, it is
recommended that linezolid is used with caution in patients treated with
other MAO inhibitors.
Keywords: enterococci, Gram-positive bacteria, linezolid,
methicillin-resistant, penicillin-resistant, pneumococci, staphylococci,
vancomycin-resistant
Exp. Opin. Pharmacother. (2001) 2(2):293-302

1. Overview of the market

During the last 10 years, the development of new antibiotics has concentrated mainly on drugs active against Gram-positive organisms (Table 1). In
most cases, the new agents have been chemical modifications within old
classes of antibiotics. For example, telithromycin is chemically similar to the
macrolides. Despite that, it is often active against macrolide-resistant
Gram-positive organisms, particularly Streptococcus pneumoniae, but
cross-resistance may exist. The new fluoroquinolones, like gatifloxacin,
levofloxacin and moxifloxacin, have markedly improved Gram-positive
activity but compared to ciprofloxacin they are less active against Pseudomonas aeruginosa.
293
2001 Ashley Publications Ltd. ISSN 1465-6566

294 Linezolid
Table 1: New antibiotics.

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Antibiotic

Class

Daptomycin
Gatifloxacin
Levofloxacin

Glycopeptide
Fluoroquinolone
Fluoroquinolone

Linezolid
Moxifloxacin
Quinpristin + dalfopristine and VRE
Telithromycin

Oxazolidinone
Fluoroquinolone
Streptogramines
Ketolide

Antibacterial spectrum
Gram-positive including MRSA, MRSE and PRP
Gram-negative and Gram- positive, including PRP and VRE
Gram-negative and Gram- positive, including PRP, VISA and
VRE but excluding MRSA and MRSE
Gram-positive including MRSA, MRSE, PRP, VISA and VRE
Gram-negative and Gram-positive, including PRP and VRE
Gram-positive including MRSA, MRSE, PRP, VISA
Gram-positive including MRSA, MRSE, PRP, VISA and VRE

Not active against Enterococcus faecalis.

MRSA: Methicillin-resistant Staphylococcus aureus; MRSE: Methicllin-resistant Staphylococcus epidermidis (and other coagulase
negative staphylococci); PRP: Penicillin-resistant Streptococcus pneumoniae); VISA: Vancomycin-resistant S. aureus;
VRE: Vancomycin-resistant enterococci.

2. Introduction to linezolid
Figure 1: Chemical structure of linezolid.

O
O

N
F

O
N
H

Four developments during the last 20 years have lead

to the markedly increased interest in antibiotics with
activity against Gram-positive bacteria. The frequency
of methicillin-resistant strains of Staphylococcus
aureus and coagulase-negative staphylococci has
increased markedly and methicillin-resistant S. aureus
(MRSA) has now started to occur in the community
when previously it was almost exclusively a hospital
pathogen [1]. In a low frequency, strains of MRSA with
intermediate susceptibility of vancomycin and other
glycopeptides (VISA or GISA) have been identified [2].
The third important event is the increase of penicillinresistance in S. pneumoniae. In some areas, e.g.,
Korea and Hong Kong, > 50% of the pneumococcal
isolates are today highly resistant to penicillin [3].
Fourthly, enterococci (both Enterococcus faecalis and
Enterococcus faecium) resistant to vancomycin and
other glycopeptide antibiotics, so-called VRE, are now
relatively frequent in the hospitals of some countries,
especially the USA [4].
From a marketing point of view, development of the
new antibiotics has focused on their use for treatment
of respiratory tract infections.
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Linezolid is the first compound in the first new class of

antibiotics for more than 30 years, the oxazolidinones.
The high degree of activity of this group of antibiotics
was first realised by scientists at DuPont de Nemours
and Co. [5]. Later, scientists at the Upjohn Company
(today Pharmacia) continued the development and
several clinical candidates were synthesised with the
goal of finding an antibiotic active against all common
Gram-positive pathogens, irrespective of their susceptibility to other antibiotics.

3. Chemistry
Linezolid (U 100 766, PNU 100766, Zyvox) is
(S)-N-[{3-fluoro-4-(4-morphinyl)phenyl}-2-oxo-5-oxazolidinyl] methyl acetamine (Figure 1). Its
synthesis is described in several publications [6,7]. The
molecular weight is 337.35 Da.

4. Antibacterial activity
4.1

Mode of action

The oxazolidinones act by inhibiting protein synthesis

and seem to do so on the bacterial ribosomal level by
preventing formation of the 70S initiation complex
(Figure 2) [8-11]. Against most susceptible bacterial
species, linezolid is bacteriostatic in its mode of
action; the killing rate for most species is about 1
log/24 h [12-14].
Exp. Opin. Pharmacother. (2001) 2(2)

Norrby 295
Figure 2: Mode of action of antibiotics which inhibit bacterial protein synthesis on the ribosomal level. Reproduced with permission
from Pharmacia Corp.

The Ribosome Cycle

Oxazolidinones
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Inititation factors
30S &
mRNA
fMet tRNA

30S

mRNA

70S
Initiation
complex

50S

Termination

Elongation
Cycle

Peptide product

Elongation
factors

Puromycin
Lincosamides
Macrolides
Tetracyclines
Chloramphenicol
Aminoglycosides
Pristinamycin

Fusidic acid

Table 2 summarises the antibacterial spectrum of

linezolid, which covers important Gram-positive
pathogens such as S. aureus, coagulase-negative
staphylococci, pneumococci, enterococci, group A
-haemolytic streptococci and some anaerobes.
Importantly, the activity of linezolid against all species
tested is the same irrespective of whether or not the
strains have been resistant to one or more other antibiotics. Thus, there seems to be no cross-resistance
between linezolid and other classes of antibiotics.

As mentioned above, the activity of linezolid is mostly

bacteriostatic if such activity is defined as 1 log
reduction of the viable count of bacteria following
exposure for 24 h to an antibiotic. Such activity is
generally seen with linezolid against enterococci and
staphylococci [21]. However, pneumococci, group A
-haemolytic streptococci and anaerobes (Bacteroides fragilis, Clostridium per fringens and
Peptostreptococcus spp.) are killed much more rapidly
with 2 log reduction of viable counts per 24 h (6 h
for S. pneumoniae) of exposure to linezolid [21].

Mycobacterium tuberculosis is susceptible to linezolid

and was inhibited in vitro by 0.5 - 2 mg/l [21]. Species
that are not susceptible to linezolid include all
Gram-negative aerobic bacteria e.g., Escherichia coli
and Klebsiella spp. Mycoplasma spp. and Chlamydia
spp. are probably resistant [23].

Resistance to linezolid is difficult to select. Kaatz and

Seo [24] failed to select stable resistant mutants of
Staphylococcus epidermidis but managed to induce
resistance in one strain of MRSA. In clinical trials of
linezolid, selection of resistance has been reported in
several patients with infections caused by E. faecium.

4.2

Antibacterial spectrum in vitro

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Exp. Opin. Pharmacother. (2001) 2(2)

296 Linezolid
Table 2: In vitro activity of linezolid against common bacterial pathogens.

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Bacterial species
Bacillus cereus
Bacteroides fragilis
Clostridium difficile
Corynebacterium jeikeium
Enterococcus faecalis
Enterococcus faecalis, vancomycin-resistant
Enterococcus faecium
Enterococcus faecium, vancomycin-resistant
Enterococcus gallium
Fusobacterium spp.
Legionella spp.
Haemophilus influenzae
Moraxella catarrhalis
Pasteurella multocida
Peptostreptococcus spp.
Rhodococcus equi
MSSA
MRSA
Staphylococcus spp., coagulase-neg. and methicillin-susceptible
Staphylococcus spp., coagulase-neg. and methicillin-resistant
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pneumoniae, penicillin-resistant
Streptococcus pyogenes
Streptococcus spp., group C, G

MIC90 (mg/l)

Ref.

2
4
8
2
1-2
1-4
2
2-4
2
0.5
4-8
8
4-8
2
1
2
1-4
1-4
0.5 - 2
1-2
2
1-2
1
1-4
2

[12]
[17,21]
[17]
[12]
[12-14,17]
[12,15,17]
[12,14,15]
[12,15]
[14]
[16]
[18]
[21]
[16,21]
[16]
[16]
[20]
[12,13,17]
[12,13,17]
[12,13,16]
[11,12,17]
[12,17]
[12,17,19]
[19]
[12,17]
[22]

MIC90: Minimal inhibitory concentration for 90% of isolates tested; MRSA: Methicillin-resistant Staphylococcus aureus:
MSSA: Methicillin-susceptible Staphylococcus aureus.
4.3

Efficacy in animal infections

The in vivo efficacy of linezolid in animal models has

been reviewed and summarised by Clemett and
Markham [25]. Against ip. S. aureus infections and
experimental endocarditis in both rats and rabbits,
linezolid was as effective as vancomycin. Against
Streptococcus pyogenes and pneumococci, linezolid
had comparable activity to that of clindamycin and
amoxicillin, respectively. In an uncontrolled study,
linezolid eradicated amoxicillin- and erythromycinresistant pneumococci from the middle ear of
chinchillas and the concentrations of linezolid in the
middle ear exudate was found to be 81% of that in
plasma. In a rabbit model of experimental meningitis,
linezolid reduced the viable counts of S. pneumoniae
in cerebrospinal fluid but was considerably less
effective than ceftriaxon. Linezolid was found the
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effective against enterococcal infections in a neutropenic mouse model. Finally, in a murine model,
linezolid reduced the viable counts of M. tuberculosis
in lung and spleen [26].
5. Pharmacokinetics
Linezolid can be assayed by reverse phase
high-performance liquid chromatography (HPLC)
[27]. The technique has a high degree of accuracy and
the inter- and intra-assay variability is low with full
linearity between 0.04 and 47 mg/l.
The pharmacokinetic parameters of linezolid
following oral or iv. administration are given in Table
3 [28,29]. The absorption after oral administration is
close to 100%. The plasma protein binding is 31% and
the volume of distribution at steady-state is 40 - 50 l.
Exp. Opin. Pharmacother. (2001) 2(2)

Norrby 297
Table 3: Pharmacokinetic parameters for linezolid. Data from the US package insert.

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Linezolid regimen
dose (mg)
400 SD tablet
400 MD tablet
600 SD tablet
600 MD tablet
600 SD suspension
600 SD iv.
600 MD iv.

Cmax
(mg/l)

Cmin
(mg/l)

Tmax
(h)

AUC
(mg.h/l)

T
(h)

8.1
11.1
12.7
21
11.0
12.9
15.1

1.5
3.1
1.3
6.2
1.0
0.5
3.7

55
1.1
91
1.0
81
80
0.5

5.2
73
4.3
138
4.6
4.4
90

146
4.7
127
5.4
141
138
4.8

Cl
(ml/min)
110
80

123

AUC: Area under the plasma concentration-time curve; Cl: Systemic clearance; Cmax: Maximal plasma concentration; Cmin: Plasma
concentration before new dose (12 h after dosing); MD: Multiple dose (every 12 h); SD: Single dose; T: Plasma half-life; Tmax: Time
to Cmax.

The single-dose pharmacokinetics are not affected by

gender or age [30]. In patients with renal failure, the
elimination rate constant or the linezolid plasma
clearance did not change as a function of the
glomerular filtration rate. On the other hand the
clearance rate increased by about 80% in patients on
haemodialysis in conjunction with the linezolid dose
[31]. In a small study, no significant effects of hepatic
failure on the pharmacokinetics of linezolid were
found [32].
As shown in Figure 3, virtually identical areas under
the plasma-time concentration curves and plasma
concentrations of linezolid (from 2 h after administration) were obtained after oral and iv. administration of
the same dose. Obviously, that facilitates step-down
therapy in patients who are started on an iv. regimen.
Also, it allows initial oral treatment in those patients
who have normal absorption capacity.
The distribution of linezolid to various lung compartments was studied by Conte Jr. et al. [33]. Using
bronchoalveolar lavage they could estimate the
epithelial lining fluid (ELF) concentrations of linezolid
following 5 doses of 600 mg every 12 h. The
ELF:plasma ratios ( SD) at 4 and 12 h after the 5th
dose were 2.2 0.6 and 1.4 1.3, respectively,
indicating a high degree of penetration to this
extravascular compartment.
In vitro, linezolid or its main metabolites (see below)
show little or no induction or inhibition of the
cytochrome P450 system [34]. Studies of the metabolism and excretion of linezolid in man have shown
that it is excreted mainly in the urine as a parent
compound (approximately 30% of the dose) or as
carboxylic acid metabolites (PNU-142586, 38 - 40% of
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the dose and PNU-142300, 9 - 10% of the dose) [35].

The faecal excretion in this study was 7 - 12% of the
dose, mainly as metabolites. The metabolites had little
or no antibacterial activity.
Using a rat model of pneumococcal pneumonia,
Olese et al. could demonstrate that the pharmacokinetic parameter which best predicted the outcome of
treatment with linezolid was time above MIC. Specifically, efficacy was favoured when concentrations
above MIC were maintained for 45% of the dose
interval [36]. This is important since with a 600 mg
dose every 12 h of linezolid, concentrations above an
MIC of 4 mg/l are maintained for > 75% of the dose
interval in steady-state and concentrations above 2
mg/l are maintained for an entire 12 h dose interval.

6. Clinical efficacy in Phase II/III studies

6.1

Clinical and microbiological efficacy

Most of the large Phase II and III studies comprising

the new drug application for registration of linezolid
are still not published in peer-reviewed scientific
journals. However, there are numerous abstracts from
recent scientific meetings presenting results from
these studies. Table 4 summarises the clinical
outcomes in some of the more important studies,
showing that linezolid is at least as effective as the
antibiotics used as comparators.
The microbiological efficacy of linezolid agrees with
the clinical results. In community-acquired
pneumonia, the eradication rates for Haemophilus
influenzae, S. aureus and pneumococci in patients
treated with linezolid were 89% (16/18), 90% (36/40)
and 92% (138/150) [41], respectively. The eradication
Exp. Opin. Pharmacother. (2001) 2(2)

298 Linezolid
Figure 3: Plasma concentrations after single oral or iv. doses of 375 mg linezolid.

12
Linezolid conc. (g/ml)

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11
10
9
8
7

Oral tablets (fasted)

iv. infusion

5
4
3
2
1
0

10

12

14

16

18

20

22

24

Time after dose (h)

rates achieved with cephalosporin comparators were

89%, 83% and 90%, respectively. Notably, despite
poor in vitro activity (Table 2) H. influenzae was as
effectively eradicated with linezolid as with the
cephalosporins.
6.2

Outcome studies

As mentioned above, the pharmacokinetics of

linezolid allow primary oral treatment also of serious
infections and, above all, early step-down from iv. to
oral treatment. From a pharmacokinetic point of view
this offers a possibility to reduce length of hospitalisation and/or reduction of costs for intensive home care.
Two studies have demonstrated that the hospitalisation time was significantly shorter in patients treated
with linezolid (iv. and/or orally) for infections caused
by S. aureus than in those who were randomised to
receive comparators (vancomycin or cloxacillin iv.
followed by optional oral dicloxacillin) [42,43].

7. Safety and tolerability

Table 5 gives frequencies of the most common
adverse events reports in Phase II-III clinical trials.
These frequencies are in agreement with published
data [44]. Diarrhoea was the most common event
reported. However, colitis, pseudomembraneous
colitis or diarrhoea caused by Clostridium difficile
was reported in only one patient of 2046 randomised
to linezolid while seven patients of 2001 randomised
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to comparators had such events (four colitis, one

pseudomebraneous colitis and two diarrhoea) [45].
Linezolid administered iv. was well-tolerated with a
low incidence of thrombophlebitis [46].
The laboratory adverse event profile of linezolid did
not differ from that of its comparators [44]. However, it
has been used for treatment times above 4 weeks in
only a few patients and in some of those there have
been indications of a low risk of haematological side
effects e.g., thrombocytopaenia. In a study by Forrest
et al. [47], a correlation was found between duration
and area under the plasma-time concentration curve
and risk of thrombocytopaenia.
Linezolid is a weak reversible inhibitor of MAO.
However, adrenergic and serotonergic adverse events
have not been reported in a high frequency in Phase
III trials [48]. Nevertheless, the US package insert
warns that excessive intake of food or beverage with a
high tyramine content should be avoided in patients
treated with linezolid. Examples of such products are
sun dried ham and tap beer.
Drug-drug interactions have not been reported with
linezolid. It does not interact with warfarin. However,
it seems proper to consider the possible risk of
potentiation of the MAO inhibitory capacity of
linezolid when it is co-administered with other MAO
inhibitors.
Exp. Opin. Pharmacother. (2001) 2(2)

Norrby 299
Table 4: Results of Phase III trials of linezolid.

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Type of infection
Streptococcal skin and soft
tissue infections
Staphylococcal skin and soft
tissue infections
MRSA skin and soft tissue
infections
Community-acquired
pneumonia (hospitalised)
VRE infections

Treatment
Linezolid 400 mg or 600 mg b.i.d. vs.
clarithromycxin or oxacillin
Linezolid 400 mg or 600 mg b.i.d. vs.
clarithromycin or oxacillin
Linezolid 600 mg iv. vs. vancomycin
Linezolid 600 mg b.i.d. iv. or orally vs.
ceftriaxone/cefpodoxime
Linezolid 600 mg vs. 200 mg b.i.d.

Cure rate linezolid

Comparator

Ref.

51/57 (89%)

52/61(85%)

[37]

201/223 (90%)

229/260 (88%)

[38]

27/34 (79%)

22/30 (73%)

[39]

247/272 (91%)

225/254 (89%)

[40]

39/44 (600 mg) (89%) 23/38 (200 mg) (61%) [41]

Cure rates are given as No. clinically cured/No. treated and refers to microbiologically evaluable patients.
b.i.d.: Twice daily; iv.: Intravenously; MRSA: Methicllin-resistant Staphylococcus aureus; VRE: Vancomycin-resistant
Enterococcus spp.

Table 5: Frequencies of adverse events reported in 2% of patients in Phase II/III trials of linezolid. Data from the US package insert
information for Zyvox.
Adverse event

Frequency
Linezolid

Comparators

8.3%
6.5%
6.2%
3.7%
2.5%
2.2%
2.0%
2.0%
1.6%

6.3%
5.5%
4.6%
2.0%
1.7%
2.1%
2.2%
1.9%
2.0%

Diarrhoea
Headache
Nausea
Vomiting
Insomnia
Constipation
Rash
Dizziness
Fever

8. Regulatory affairs
Linezolid (tablet, preparation for iv. use and suspension for oral use) is licensed in USA with the following
indications:
vancomycin-resistant Enterococcus faecium
infections
nosocomial pneumonia caused by methicillinsusceptible strains of S. aureus
complicated skin and skin structure infections
caused by S. pyogenes, Streptoccocus agalactiae or
methicillin-susceptible and -resistant strains of S.
aureus
uncomplicated skin and skin structure infections
caused by S. pyogenes or methicllin-susceptible
strains of S. aureus
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community-acquired pneumonia caused by

penicillin-susceptible strains or S. pneumoniae or
methicillin-susceptible strains of S. aureus.
The fact that indications in some cases are limited to
methicillin-susceptible staphylococci or penicillinsusceptible pneumococci is due to the limited number
of patients with resistant pathogens enrolled in the
clinical trial programme.
Registration of linezolid in Europe is pending.

9. Conclusions
Linezolid is a major new addition to the therapeutic
armamentarium. Since it belongs to a completely new
class of antibiotic with a unique site of action in the
bacterial protein synthesis, resistance to other antibiotics does not affect its activity, a fact that has been
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300 Linezolid
confirmed in extensive surveys. Its spectrum of
activity is relatively narrow and covers mainly
Gram-positive pathogens, including methicillinresistant staphylococci, penicillin- and macrolideresistant pneumococci and glycopeptide-resistant
enterococci i.e., the presently most difficult to treat
bacterial pathogens.

community-acquired pneumonia or skin and soft

tissue infections. Such use of linezolid would lead to
excessive costs and also to an increased likelihood of
emergence of resistance to linezolid.

Linezolid has very favourable pharmacokinetic

profile. It is available for both oral and iv. administration and the bioavailability after oral intake is
approximately 100%. Moreover, the concentrations 2
h after intake, as well as the areas under the plasmatime concentration curves, are virtually identical
which means that as soon as the patient can absorb
linezolid after oral administration nothing is gained by
using the iv. route. This is further emphasised by the
finding in animal studies that the main parameter
determining the efficacy of linezolid is time above
MIC. Thus, the higher peak concentration achieved
after iv. administration should not provide better
antibacterial effect than is achieved with oral
treatment.

Bibliography

The in vitro and animal experimental findings with

linezolid have been confirmed in large clinical trials,
which have documented its efficacy in skin and soft
tissue infections, community acquired pneumonia,
hospital acquired pneumonia (in combination with an
antibiotic active against Gram-negatives) and in
infections caused by VRE.
The possibility to use initial oral treatment or to switch
early on from iv. to oral administration makes
linezolid a cost-effective alternative to other antibiotics such as Synercid or vancomycin.
The safety profile of linezolid has not been different
from what is seen with other antibiotics with a high
degree of safety. The fact that linezolid is a weak MAO
inhibitor seems not to confer increased risks of side
effects. However, it seems proper to recommend
increased awareness when linezolid is given together
with other MAO inhibitors, especially if the patient has
hypertension.

Papers of special note have been highlighted as:

of interest

of considerable interest
1.

2.

3.

4.

5.

6.

10. Expert opinion

Linezolid clearly offers a new safe and effective
treatment option in patients with bacterial infections
caused by multi-drug resistant organisms. It should be
pointed out, however, that it should not be used as a
first-line empirical choice in patients with
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7.

SHOPSIN B, MATHEMA B, MARTINES J et al.: Prevalence

of methicillin-resistant and methicillin-susceptible
Staphylococcus aureus in the community. J. Infect. Dis.
(2000) 182(1):12-18.
Important article pointing out the alarmingly increasing
frequency of MRSA in the community.
PEARL TM: The threat of vancomycin resistance. Am. J.
Med. (1999) 106(5A):26S-37S.
Review of the problem of glycopeptide-resistance.
CHANG SC, HSIEH WC, LIU CY: High prevalence of
antibiotic resistance of common pathogenic bacteria
in Taiwan. The Antibiotic Resistance Study Group of
the Infectious Disease Society of the Republic of China.
Diagn. Microbiol. Infect. Dis. (2000) 36(2):107-112.
Important study showing the negative effects of overuse of
antibiotics.
CARMELI Y, SAMORE HM, HUSKINS C: The association
between antecedent vancomycin treatment and
hospital-acquired vancomycin-resistant enterococci:
a m e ta - a n a l y s i s . A r c h . I n t e r n . M e d . ( 1 9 9 9 )
159(20):2461-2468.
Valuable analysis demonstrating a clear correlation between
hospital use of glycopeptides and emergence of VRE.
SLEE AM, WUONOLA MA, MCRIPLEY RJ et al.: Oxazolidinones, a new class synthetic antibacterial agents: in
vitro and in vivo activities of DuP 105 and DuP 721.
Antimicrob. Agents Chemother. (1987) 31(11):1791-1797.
Early description of the oxazolidinone group.
BRICKNER SJ, HUTCHINSON DK, BARBACHYN MR et al.:
Synthesis and antibacterial activity of U-100592 and
U-100766, two oxazolidinone antibacterial agents for
the potential treatment of multi-drug resistant
Gram-positive bacterial infections. J. Med. Chem. (1996)
1966(3):673-679.
Description of the synthesis of linezolid and related
compounds.
BARNAZIN MR, BRICKNER SJ, GADWOOD RC et al.:
Design, synthesis and evaluation of novel oxazolidinone antibacterial agents active against multidrugresistant bacteria. In: Resolving the Antibiotic Paradox.
Rosen & Mobashery (Eds.), Kluwer Academic/Plenum
Publishers, New York, USA (1998):219-238.
Description of the synthesis of linezolid and related
compounds.
Exp. Opin. Pharmacother. (2001) 2(2)

Norrby 301
8.

SHINABARGER DL, MAROTTI KR, MURRAY RW et al.:

Mechanism of action of the oxazolidinones: effects of
linezolid and eperezolid on translation reactions.
Antimicrob. Agents Chemother. (1997) 41(10):2132-2136.
Report describing the mode of action of linezolid.

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BURGHARDT H, SCHIMZ KL, MLLER M: On the target of

a novel class of antibiotics, oxazolidinones, active
against multidrug-resistant Gram-positive bacteria.
FEBS Letters (1998) 425(1):40-44.
Report describing the mode of action of linezolid.

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MATASSOVA NB, RODNINA MV, ENDERMANN R et al.:

Ribosomal RNA is the target for oxazolidinones, a
novel class of translational inhibitors. RNA (1999)
5:939-946.
Report describing the mode of action of linezolid.
KLOSS P, XIONG L, SHINABARGER DL, MANKIN AS:
Resistance mutations in the 23 S rRNA identify the site
of action of the protein synthesis inhibitor linezolid in
the ribosomal peptidyl transferase center. J. Mol. Biol.
(1999) 294(1):93-101.
Critical article demonstrating the site of action of linezolid.
JONES RN, JOHSON DM, ERWIN ME: In vitro antimicrobial activities and spectra of U-100592 and U-100766m
two novel fluorinated oxazolidinones. Antimicrob.
Agents Chemother. (1996) 40(3):720-726.
Very good in vitro evaluation of linezolid.
JORGENSEN JH, MCELMEEL ML, TRIPPY CW: In vitro
activities of the oxazolidinones U-100592 and
U-100766 against Staphylococcus aureus and
coagulase-negative Staphylococcus species. Antimicrob. Agents Chemother. (1997) 41(2):465-467.
Very good in vitro evaluation of linezolid.
BOSTIC GD, PERRI MB, THAL LA, ZERVOS MJ: Comparative in vitro and bactericidal activity of oxazolidinone
antibiotics against multidrug-resistant enterococci.
Diagn. Microbiol. Infect. Dis. (1998) 30(1):109-112.
Good in vitro evaluation of linezolid.
ELIOPULOS GM, WENNERSTEN CB, GOLD HS,
MOELLERING RC, Jr.: In vitro activities of new oxazolidinones antimicrobial agents against enterococci.
Antimicrob. Agents Chemother. (1996) 40(7):1745-1747.
Very good in vitro evaluation of linezolid.
GOLDTSEIN EJC, CITRON DM, MEERIAM CV: Linezolid
activity compared to those of selected macrolides and
other agents against aerobic and anaerobic pathogens
isolated from soft tissue bite infections in humans.
Antimicrob. Agents Chemother. (1999) 43(6):1469-1474.
Good in vitro evaluation of linezolid.

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WISE R, ANDREWS JM, BOSWELL FJ, ASHBY JP: The

in-vitro activity of linezolid and tentative breakpoints.
J. Antimicrob. Chemother. (1998) 42(4):721-728.
Good in vitro evaluation of linezolid.
SCHLIN T, WENERSTEN CB, FERRARO MJ, MOELLERING
RC, Jr., ELIOPOULOS GM: Susceptibilities of Legionella
spp. to newer antimicrobial in vitro. Antimicrob. Agents
Chemother. (1998) 42(6):1520-1523.
Good in vitro evaluation of linezolid.

Ashley Publications Ltd. All rights reserved.

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MASON EO, Jr., LAMBERTH LB, KAPLAN SL: In vitro

activities of oxazolidinones U-100592 and U-100766
against penicillin-resistant and cephalosporinresistant strains of Streptococcus pneumoniae. Antimicrob. Agents Chemother. (1996) 40(4):1039-1040.
Good in vitro evaluation of linezolid.
BOWERSTOCK TL, SALMON SA, PORTIS ES et al.: MICs of
oxazolidinones for Rhodococcus equi strains isolated
from human and animals. Antimicrob. Agents
Chemother. (2000) 44(5):1367-1369.
Good in vitro evaluation of linezolid.
ZURENKO GE, YAGI BH, SCHAADT RD et al.: In vitro
activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob. Agents
Chemother. (1966) 40(4):839-845.
Good in vitro evaluation of linezolid.
JOHNSON AP, WARNER M, LIVERMORE DM: activity of
linezolid against multi-resistant Gram-positive
bacteria from diverse hospitals in the United
Kingdom. J. Antimirob. Chemother. (2000) 45(2):225-230.
Good in vitro evaluation of linezolid.
DIEKEMA DJ, JONES RN: Oxazolidinones. A review.
Drugs (2000) 49(1):7-16.
General overview of the oxazolidinones.
KAATZ GW, SEO SM: In vitro activities of oxazolidinone
compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis.
Antimicrob. Agents Chemother. (1996) 40(3):799-801.
Important study of emergence of resistance to linezolid.
CLEMETT D, MARKHAM A: Linezolid. Drugs (2000)
59(4):815-827.
High quality review of linezolid.
CYNAMON MH, KLEMENS SP, SHARPE CA, CHASE S:
Activities of several novel oxazolidinones against
Mycobacterium tuberculosis in a murine model.
Antimicrob. Agents Chemother. (1999) 43(5):1189-1191.
Interesting study showing an activity of linezolid against M.
tuberculosis.
PENG GW, STRYD RP, MURATA S et al.: Determination of
linezolid in plasma by reverse-phase high- performance liquid chromatography. J. Pharm. Biomed. Anal.
(1999) 20(1):65-73.
Description and evaluation of linezolid assay method.
STALKER DJ, WAJSZCZUK CP, BATTS DH. Linezolid
safety, tolerance and pharmacokinetics following oral
dosing twice daily for 14.5 days. The 37th ICAAC. San
Francisco, USA (1997). A-116.
Basic pharmacokinetic information.
STALKER DJ, WAJSZCZUK CP, BATTS DH: Linezolid
safety, tolerance and pharmacokinetics following
intravenous dosing twice daily for 7.5 days. The 37th
ICAAC. San Francisco, USA (1997). A-117.
Basic pharmacokinetic information.
LASHER SISSON T, JUNGBLUTH GL, STALKER DJ,
HOPKINS NK: Effects of age and gender on the singledose pharmacokinetics of linezolid. The 38th ICAAC.
San Francisco, USA (1999). Abstract 1194.
Basic pharmacokinetic information.
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BRIER ME, STALKER DJ, ARONOFF GR et al.: Pharmacokinetics of linezolid in subjects with various degrees of
renal failure. The 38th ICAAC. San Diego, USA (1998).
A-54.
Basic pharmacokinetic information.

HERNDERSHOF PE, JUNGBLUTH GL, CAMMARATA SK,

HOPKINS NK: Pharmacokinetics of linezolid in
patients with liver disease. J. Antimicrob. Chemother.
(1999) 44(Suppl. A):55. Abstract.
Basic pharmacokinetic information.

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CONTE JE Jr, GOLDEN JA, KIPPS JE, ZURLINED E:

Intrapulmonary pharmacokinetics of linezolid. The
40th ICAAC. Toronto, Canada (2000). Abstract No. 659.
Basic pharmacokinetic information.
WIENKERS LC, WYANALDA MA, FEENSTRA KL, GAO P,
SLATTER JG: In vitro metabolism of linezolid
(PNU-100766): lack of induction or inhibition of
cytochrome P450 enzymes and studies on mechanism
of formation of the major human metabolite,
PNU-142586. The 38th ICAAC. San Francisco, CA, USA
(1999). Abstract 11.
Basic pharmacokinetic information.
FEENSTRA KL, SLATTER JG, STALKER DJ et al.: Metabolism and excretion of the oxazolidinone antibiotic
linezolid (PNU 100766) following oral administration
of [14C]PNU 100766 to healthy human volunteers. The
38th ICAAC. San Diego, LA, USA (1998). A-53.
Basic pharmacokinetic information.
OLSEN KM, PREHEIM LC, GENTRY-NIELSEN MJ: The
pharmacodynamic activity and efficacy of linezolid in
a rat model of pneumococcal pneumonia. The 40th
ICAAC. Toronto, Canada (2000). Abstract No. 659.
Basic and very important pharmacodynamic information.
MOLINARI M, MANGANO R, GOUGH M, DECIAN W,
BASSARIS D: Linezolid in the treatment of streptococcal
skin and soft tissue infections: combined results from
three Phase III trials. Clin. Microbiol. Infect.(2000)
6(Suppl. 1):64. Abstract.
Summary of Phase III studies.
DUVALL S, BRUSS J, TODD W, HAFKIN B: Linezolid in the
treatment of staphylococcal skin and soft tissue
infections: combined results from three Phase III
trials. Clin. Microbiol. Infect. (2000) 6(Suppl. 1):64.
Abstract.
Summary of Phase III studies.
LEACH TS, SCHASER RJ, TODD WM, HAFKIN B, KAJA RW:
Clinical efficacy of linezolid (LZD) for complicated
skin and soft tissue infections caused by MRSA. IDSA
38th Annual Meeting. Philadelphia, PA, USA (2000).
Abstract No. 60.
Important clinical data.
CAMMARATA SK, SAN PEDRO GS, TIMM JA et al.:
Com p ar is o n o f l i n e z o l i d v e r s u s ce f tr iaxone/cefpodoxime in the treatment of hospitalized
patients with community acquired pneumonia:

Ashley Publications Ltd. All rights reserved.

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European results. Clin. Microbiol. Infect. (2000) 6(Suppl.

1):136. Abstract.
Summary of Phase III studies.
CAMMARATA SK, STANDFORD H, TODD WM, OLIPHANT
TH, HAFKIN B: Linezolid eradicates common
pathogens in community-acquired pneumonia. Clin.
Microbiol. Infect. (2000) 6(Suppl. 1):136. Abstract.
Summary of microbiological results in Phase III studies.
WILLKE RJ, LI ZJ, RITTENHOUSE BE et al.: Linezolids
effects on early hospital discharge in hospitalized
patients with complicated skin and soft tissue
infections (cSSTI) under varying rates of methicillinresistant staphylococcus (MRS) infection: analysis of
results from two randomized clinical trials (RCTs). The
40th ICAAC. Toronto, Canada (2000). Abstract 112.
Pharmacoeconomic analysis of Phase III results.
RITTENHOUSE BE, LI Z, WILLKE RJ, PINTO L, GLICK HA,
HAFKIN B: Re-examining hospital length of stay (LOS)
reduction potential in a randomized, multi-center
clinical trials of methicillin-resistant staphylococci
species: linezolid vs. vancomycin. The 40th ICAAC.
Toronto, Canada (2000). Abstract 2132.
Pharmacoeconomic analysis of Phase III results.
DUVALL SE: Safety and tolerance of linezolid: adverse
events reported in Phase III trials. IDSA 38th Annual
Meeting. Philadelphia, PA, USA (2000). Abstract 67.
Summary of safety data.
CAMMARATA SK, LE V, OLIPHANT TH, TODD WM,
HAFKIN B: Incidence of Clostridium difficile related
complications during clinical trials of linezolid, an
oxazolidinone. The 40th ICAAC. Toronto, Canada (2000).
Abstract 2132.
Analysis of C. difficile complications.
CAMMARATA SK, LE V, HEMPSALL KA, OLIPHANT TH,
HAFKIN B: Incidence of intravenous catheter-related
complications during clinical trials of linezolid, an
oxazolidinone. IDSA 38th Annual Meeting. Philadelphia,
PA, USA (2000). Abstract 69.
Tolerability report.
FORREST A, RAYNER CR, EAGHER AK, BIRMINGHAM MC,
SCHENTAG JJ: Pharmacostatitistical modelling of
hematological effects of linezolid in seriously ill
patients. The 40th ICAAC. Toronto, Canada (2000). Abstract
2132.
Analysis of risks of haematological adverse reactions.
LEACH TS, LOBECK FG, TODD WM, HAFKIN B: Lack of
serotonin syndrome in Phase III patients receiving
linezolid and a selective serotonin reuptake inhibitor
(SSRI). IDSA 38th Annual Meeting. Philadelphia, PA, USA
(2000). Abstract 64.
Important safety and interaction data.

Ragnar Norrby
The Swedish Institute for Infectious Disease Control, SE17182
Solna, Sweden
Tel.: +46 8 457 2310; Fax: +46 8 303 668;
E-mail: Ragnar.Norrby@smi.ki.se

Exp. Opin. Pharmacother. (2001) 2(2)