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Antimicrobial Agents and Chemotherapy, May 1999, p. 1189-1191, Vol. 43, No. 5
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Activities of Several Novel Oxazolidinones against
Mycobacterium tuberculosis in a Murine Model
M. H.
Cynamon,*
S. P.
Klemens,
C. A.
Sharpe, and
S.
Chase
Veteran Affairs Medical Center and State
University of New York Health Science Center, Syracuse, New York 13210
Received 20 October 1998/Returned for modification 29 December
1998/Accepted 25 February 1999
 |
ABSTRACT |
The activities of linezolid, eperezolid, and PNU-100480 were
evaluated in a murine model of tuberculosis. Approximately
107 viable Mycobacterium tuberculosis ATCC
35801 organisms were given intravenously to 4-week-old outbred CD-1
mice. In the first study, treatment was started 1 day postinfection and
was given by gavage for 4 weeks. Viable cell counts were determined
from homogenates of spleens and lungs. PNU-100480 was as active as
isoniazid. Linezolid was somewhat less active than PNU-100480 and
isoniazid. Eperezolid had little activity in this model. In the next
two studies, treatment was started 1 week postinfection. A
dose-response study was performed with PNU-100480 and linezolid (both
at 25, 50, and 100 mg/kg of body weight). PNU-100480 was more active
than linezolid, and its efficacy increased with an escalation of the
dose. Subsequently, the activity of PNU-100480 alone and in combination
with rifampin or isoniazid was evaluated and was compared to that of
isoniazid-rifampin. The activity of PNU-100480 was similar to that of
isoniazid and/or rifampin in the various combinations tested. Further
evaluation of these oxazolidinones in the murine test system would be
useful prior to the development of clinical studies with humans.
| |
INTRODUCTION |
Oxazolidinones are a new class of
antibacterial protein synthesis inhibitors. The activities of selected
oxazolidinones in vitro against gram-positive organisms, including
methicillin-resistant Staphylococcus aureus,
penicillin-resistant Streptococcus pneumoniae, and multiple
drug-resistant enterococci have been reported previously (2, 4, 8,
15). The oxazolidinones have also been demonstrated to have
activity in murine models of systemic infections caused by these
organisms (6).
The activities of selected oxazolidinones in vitro have been observed
against susceptible and resistant Mycobacterium tuberculosis (1, 3, 15). Ashtekar et al. (1) reported on the
activity of DuP-721, an oxazolidinone, administered orally to mice
infected with M. tuberculosis H37Rv (strain B-216)
(1). A dose-dependent prolongation in the survival time of
infected mice was observed. DuP-721 was not as active as isoniazid
(INH) or rifampin (RIF) in the murine model.
Newly synthesized oxazolidinones were evaluated for their in vitro
activities against M. tuberculosis, and subsequently, a murine model was used to evaluate the in vivo activities of the most
active compounds. We report on the promising antituberculosis activities of two novel oxazolidinones.
| |
MATERIALS AND METHODS |
Drugs.
Linezolid (PNU-100766; formerly U-100766), eperezolid
(PNU-100592; formerly U-100592), and PNU-100480 (formerly U-100480) were provided by Pharmacia & Upjohn, Inc., Kalamazoo, Mich. INH and RIF
were purchased from Sigma Chemical Co., St. Louis, Mo. The
oxazolidinones and RIF were dissolved in dimethyl sulfoxide and were
subsequently diluted in distilled water. INH was dissolved in distilled
water. The drugs were prepared each morning, prior to administration.
Isolate.
M. tuberculosis ATCC 35801 (strain Erdman)
was obtained from the American Type Culture Collection (ATCC),
Rockville, Md. The MICs of all antimicrobial agents were determined in
modified 7H10 broth (7H10 agar formulation with agar and malachite
green omitted; pH 6.6) supplemented with 10% Middlebrook oleic
acid-albumin-dextrose-catalase (OADC) enrichment (Difco Laboratories,
Detroit, Mich.) and 0.05% Tween 80 (13). The MICs of
PNU-100480, linezolid, eperezolid, INH, and RIF were determined by a
broth dilution method (14) and were 1, 0.5, 0.25, 0.03, and
0.06 µg/ml, respectively.
Medium.
The organism was grown in modified 7H10 broth with
10% OADC enrichment and 0.05% Tween 80 on a rotary shaker for 5 days.
The culture suspension was diluted in modified 7H10 broth to yield 100 Klett units/ml (Klett-Summerson colorimeter; Klett Manufacturing, Brooklyn, N.Y.) or approximately 5 × 107 CFU/ml. The
size of the inoculum was determined by titration and counting from
triplicate 7H10 agar plates (BBL Microbiology Systems, Cockeysville,
Md.) supplemented with 10% OADC enrichment. The plates were incubated
at 37°C in ambient air for 4 weeks before counting of the colonies.
Infection study.
Four-week-old female outbred CD-1 mice
(Charles River, Wilmington, Mass.) were infected intravenously through
a caudal vein. Each mouse received approximately 107 viable
organisms suspended in 0.2 ml of modified 7H10 broth. There were eight
mice per group.
Treatment for the initial study was started 1 day after infection. In
the other studies, treatment began 1 week after infection. Therapy was
given 5 days per week for 4 weeks. All agents were administered by
gavage: the oxazolidinones were dosed at 100 mg/kg of body weight, INH
was dosed at 25 mg/kg of body weight, and RIF was dosed at 20 mg/kg of
body weight. Control groups of infected but untreated mice were killed
at the initiation of therapy (early controls) or at the end of the
treatment period (late controls). Mice were killed by cervical
dislocation 3 to 5 days after administration of the last dose of drug.
The spleens and right lungs were aseptically removed and were ground in
a tissue homogenizer. The number of viable organisms was determined by
titration on 7H10 agar plates. The plates were incubated at 37°C in
ambient air for 4 weeks prior to counting of the colonies.
Statistical evaluations.
The viable cell counts were
converted to logarithms, which were then evaluated by one- or
two-variable analyses of variance. Statistically significant effects
from the analyses of variance were further evaluated by the Tukey
honestly significance difference test (9) to make pairwise
comparisons among means.
| |
RESULTS |
Comparison of PNU-100480, linezolid, and INH.
The inoculum in
this study was 7.0 × 106 viable mycobacteria.
Treatment with PNU-100480, linezolid, and INH reduced the cell counts
in spleens and lungs compared with those in the spleens and lungs of
late controls (P < 0.01 for all agents) (Table
1). Eperezolid had little activity. The
differences in organ cell counts between groups receiving PNU-100480
and INH were not significant (P > 0.05). Although
linezolid was less active than PNU-100480 or INH (P < 0.01 for both), it had considerable activity in the murine system
in this 4-week treatment study.
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|
TABLE 1.
Activities of PNU-100480, linezolid, and eperezolid
compared to that of INH in murine model of tuberculosis
|
|
Dose-response study.
The inoculum in this study was 2.2 × 107 viable mycobacteria. PNU-100480 and linezolid at
doses ranging from 25 to 100 mg/kg were effective against organisms in
the lungs and spleens (P < 0.01 for both) when the
counts were compared to those in the lungs and spleens of the
respective early control groups (Table
2). PNU-100480 at the 100-mg/kg dose was
more active than linezolid against organisms in the spleens and lungs
(P < 0.01). At the two lower doses the activity of
PNU-100480 was not significantly different from that of linezolid
(P > 0.05) except for its activity in the spleens when
it was administered at 50 mg/kg (P < 0.01). At the
25-mg/kg dose, in spite of the similarity in organ cell counts for the
two agents, it is clear that PNU-100480 is more active on the basis of
the four deaths in the linezolid group.
PNU-100480 combination study.
The inoculum in this study was
2.0 × 107 viable mycobacteria. PNU-100480, RIF, and
INH alone and in two-drug combinations had comparable activities
against M. tuberculosis in M. tuberculosis-infected mice (Table
3). There was no significant difference
between the results for these treatment groups; however, the results
for each group were significantly different than those for the early
control group (P < 0.01).
| |
DISCUSSION |
The oxazolidinones represent a novel class of antibacterial agents
whose mechanism of action appears to be inhibition of an early step in
the initiation phase of protein synthesis (5). Lin et al.
(11) concluded that the oxazolidinones inhibit protein synthesis by binding to the 50S ribosomal subunit at a site close to
the site(s) to which chloramphenicol and lincomycin bind but that the
oxazolidinones are mechanistically distinct from these two
antimicrobial agents. These agents have promising in vitro and in vivo
activities against staphylococci, streptococci, enterococci, and
Corynebacterium spp. (6, 15). Linezolid is
currently in clinical trials for the treatment of skin and soft tissue
infections, pneumonia, and bacteremia.
Two oxazolidinones, PNU-100480 and linezolid, have promising
anti-M. tuberculosis activities in the murine test system.
In the murine test system eperezolid was much less active than either PNU-100480 or linezolid. Preliminary pharmacokinetic data for PNU-100480 show that the drug appears to be well absorbed, with a mean
plasma half-life following oral administration of 0.66 h in rats
(7). PNU-100480 is rapidly and substantially converted to
the sulfoxide metabolite and, to a lesser extent, the sulfone metabolite (7). The sulfoxide metabolite, which has potent anti-M. tuberculosis activity (3), achieves a
peak level in the serum of rats of about 7 µg/ml after the
administration of a 50-mg/kg dose (7). Pharmacokinetic and
safety data for linezolid indicate that it is also well absorbed and
appears to be well tolerated in 4-week toxicity studies with rats and
dogs (10). Peak concentrations in the serum of rats of 17.7 and 36.0 µg/ml were observed following the administration of single
oral doses of 50 and 125 mg/kg, respectively (10). CD-1
female mice given a single dose of 50 mg/kg of
[14C]linezolid achieved a plasma radioactivity
concentration of 37.5 µg-eq/g. The levels of radioactivity at 4, 8, and 10 h were 8, 1, and 0.5 µg-eq/g, respectively. Radioactivity in
plasma was primarily composed of parent drug (12).
The activity of PNU-100480 at 100 mg/kg was comparable to that of INH
at 25 mg/kg in the murine test system. Linezolid was somewhat less
active than PNU-100480 and INH. PNU-100480 has sufficient activity in
the murine model to warrant its consideration as a candidate for
clinical evaluation in humans. Linezolid is less active than
PNU-100480; however, it is now undergoing clinical evaluation for the
treatment of bacterial infections. Linezolid should be further studied
with mice alone (at doses higher than 100 mg/kg) and in combination
with other anti-M. tuberculosis agents in the murine system
to better evaluate its potential for clinical development as an
anti-M. tuberculosis agent.
| |
ACKNOWLEDGMENT |
This study was supported by a grant from Pharmacia & Upjohn, Inc.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medicine, Veteran Affairs Medical Center, 800 Irving Ave., Syracuse, NY
13210. Phone: (315) 476-7461, ext. 3324. Fax: (315) 476-5348. E-mail: Cynamon.Michael{at}Syracuse.VA.Gov.
| |
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Antimicrobial Agents and Chemotherapy, May 1999, p. 1189-1191, Vol. 43, No. 5
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
