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Antimicrobial Agents and Chemotherapy, September 1998, p. 2336-2341, Vol. 42, No. 9
Division of Special Pathogen and Immunologic
Drug Products (HFD-590)1 and
Division of
Antiviral Drug Products (HFD-530),2 Food and
Drug Administration, Rockville, Maryland 20857
Received 26 March 1998/Returned for modification 27 April
1998/Accepted 29 June 1998
Increased production of tumor necrosis factor alpha (TNF- In human immunodeficiency virus
(HIV) disease, overproduction of tumor necrosis factor alpha (TNF- Mycobacterium avium complex (MAC) is a common opportunistic
infection in AIDS patients. It is well established that TNF- The purpose of this study was to evaluate the effect of TNF- Mice.
Female C57BL/6 bg/+ mice, 5 to 6 weeks of
age, were used in all studies. Additionally, female C57BL/6 +/+ and
C57BL/6 bg/bg mice (5 to 6 weeks old) were used in
experiments which compared disease progression and serum TNF- Infection of mice.
MAC strain 101 (MAC 101) was cultured on
Middlebrook 7H11 agar plates (Remel, Lenexa, Kan.). After 2 to 3 weeks
of incubation, transparent colonies of MAC 101 were picked from the
plates, suspended in sterile Middlebrook 7H9 broth (Difco Laboratories,
Detroit, Mich.), aliquoted, and frozen at Microbial burden.
Weighed sections of tissues (liver, lung,
and spleen) were homogenized in Middlebrook 7H9 medium (Difco), and
aliquots from different dilutions were plated onto Middlebrook 7H11
agar plates (Remel) in triplicate. The cultures were incubated for 3 weeks at 37°C in 7% CO2.
TNF- Treatment with TNF- Statistical analysis.
A Kaplan-Meier curve was used to
demonstrate survival rates over time. Time to death among three
different strains of mice was analyzed by the log rank test. The
pairwise comparison was used after the overall P value was
found to be less than 0.05; therefore, no adjustment was imposed on the
pairwise comparison of P values.
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Inhibition of Tumor Necrosis Factor Alpha Alters
Resistance to Mycobacterium avium Complex Infection in
Mice
and
ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
)
appears to play an important role in the progression of human immunodeficiency virus disease. One treatment strategy being explored is the use of TNF- inhibitors. TNF- also appears to be important in conferring resistance to infections, and the inhibition of this
cytokine may exacerbate the emergence of opportunistic pathogens, such as Mycobacterium avium complex (MAC). The
present study examines the possibility that inhibition of TNF- will
increase the progression of disease in mice infected with MAC. C57BL/6
beige (bg/bg) mice have been shown to be highly susceptible
to infection with MAC and are routinely used for testing of
antimycobacterial drugs. However, bg/bg mice are known to
exhibit impaired phagocyte and natural killer cell function. Since
these cell types are important sources of TNF-, the susceptibility
of the bg/bg strain to infection with MAC was compared with
those of the heterozygous (bg/+) and wild-type (+/+)
strains of C57BL/6 mice. The susceptibilities of the bg/bg
and bg/+ strains of mice infected with MAC were found to be
comparable. The +/+ strain was the least susceptible. Mycobacterial burden and serum TNF- levels increased over time in all the strains of mice tested. The bg/+ strain of C57BL/6 mice was then
chosen to measure the activity of TNF- antagonists. Treatment
with dexamethasone decreased serum TNF- levels and increased
mycobacterial burden. Treatment with anti-TNF- antibody or
pentoxifylline did not significantly alter serum TNF-
levels but increased mycobacterial burden. Treatment with thalidomide
neither consistently altered mycobacterial burden in the
spleens or livers of infected mice nor affected serum TNF- levels.
INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
)
is associated with increased viral replication in vitro (9,
23) and a wasting syndrome in humans (17,
21). One of the focuses of HIV treatment research has been
to reduce TNF- levels by using drug therapy. However, the impact of
therapeutic reduction of TNF- levels on the susceptibility of
patients with AIDS to opportunistic infections and the progression of
disease is not known.
is
produced in response to Mycobacterium infections and is
important in their control. Addition of TNF- to cultures or animals
infected with a Mycobacterium sp. has been associated with
increased resistance to the infection, and inhibition of TNF- has
been reported to decrease resistance. In vitro addition of TNF- to
human or murine macrophages infected with M. avium resulted
in increased intracellular killing of mycobacteria (4, 10,
19). Similarly, treatment of infected mice with TNF-, with or
without interleukin 2 (IL-2), resulted in a decrease in the
mycobacterial burden in the spleens and livers of the animals (6,
8). In another study, however, an additive decrease in resistance
as measured by an increase in mycobacterial CFU was observed in mice
treated with a combination of antibodies to TNF- and gamma
interferon (IFN-
) compared to that observed after administration
of either antibody alone (1). The addition of
pentoxifylline, a chemical inhibitor of TNF-, to M. avium-infected human monocyte-derived macrophages also resulted in
increased numbers of intracellular mycobacteria (32).
inhibitors on MAC disease progression in vivo. Several substances, including dexamethasone, antibody to TNF-, pentoxifylline, and thalidomide, which have different mechanisms of action and effects on
production and secretion of TNF-, were evaluated in C57BL/6 bg/+ immunocompetent mice infected with M. avium. Although C57BL/6 beige (bg/bg) mice have been
reported to be more susceptible to infection with MAC than wild-type
(+/+) C57BL/6 mice (12, 14, 15, 18), bg/bg
mice exhibit impaired phagocytic (13), NK (3, 29,
30), and T (2, 33)-cell functions, which constitute important mechanisms of immunoregulation and sources of TNF-. The
current study also evaluated the utility of C57BL/6 bg/+
littermates as a model for assessment of the effects of modulation of
TNF- on MAC infections.
MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
production among the different strains of mice. All animals (Jackson
Laboratories, Bar Harbor, Maine) were randomized and housed in groups
of no more than five in microisolator cages and were fed ad libitum.
70°C as the stock culture
(5 × 108 to 1 × 109 CFU/ml) for all
infection studies. The mice were infected intravenously with 5 to
6 × 107 CFU of MAC 101 in 7H9 broth. Control mice
were sham infected with broth. Groups of five animals were sacrificed
at weeks 1, 3, 5, and 8 following infection and evaluated for body
weight, organ weight (spleen, liver, and lung), and microbial burden in the weighed subsections of these organs. Blood was collected for measurement of TNF- levels in the serum. A separate group of each
strain of mice, infected (n = 20) and uninfected
(n = 10), was set aside for a survival study.
levels.
TNF- levels in the sera were measured by
an enzyme-linked immunosorbent assay with kits obtained from Genzyme
Diagnostics (Cambridge, Mass.).
inhibitors and measurement of disease
progression.
C57BL/6 bg/+ mice were infected with
MAC 101 as described above. Sufficient animals were randomized to each
treatment group in every study to compensate for the expected death
rate due to mycobacterial infection. The mice were treated with various
doses of dexamethasone, anti-TNF- antibody, pentoxifylline,
thalidomide, or the vehicle beginning at the time of initiation of
infection. All treatments were administered by the intraperitoneal
route for a period of up to 8 weeks. Dexamethasone 21-phosphate (Sigma Chemical Co., St. Louis, Mo.) was administered on alternate days. Pentoxifylline (Sigma Chemical Co.) was administered daily. Thalidomide (courtesy of John Reepmeyer, Division of Drug Analysis, Food and Drug
Administration [FDA], St. Louis, Mo.) was prepared daily in
acidified, tissue culture grade water (pH 5.0) immediately prior to
injection to minimize the potential for hydrolysis. Anti-TNF- antibody and the isotype control (XT-11-22 and GL113, respectively; DNAX, Palo Alto, Calif.) were administered once a week. Dexamethasone, pentoxifylline, and anti-TNF- antibodies were dissolved or diluted in phosphate-buffered saline (PBS), pH 7.2, and thalidomide was diluted
in acidified water. PBS and acidified water, respectively, were used as
vehicle controls in each experiment. Untreated (i.e., naive) mice,
infected and uninfected, were also included in the study. Five mice
from each treatment group were sacrificed at different time points, and
the spleens and livers were processed for measurement of microbial
burden. TNF- levels were measured in the sera as described above.
level) were determined by analysis
of variance. Results of the microbial burden (in CFU) were analyzed
after log transformation of the data. All P values reported
are the results of two-tailed tests, with no adjustment for multiple
comparisons.
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RESULTS |
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Materials & Methods
Results
Discussion
References
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Susceptibility of C57BL/6 (bg/+) mice to MAC 101. C57BL/6 mice heterozygous for the beige allele (bg/+) were susceptible to infection with MAC 101. Mortality rates for bg/+ mice were intermediate to the rates observed for beige (bg/bg) mice and C57BL/6 wild-type (+/+) mice (Fig. 1). Following infection, initial deaths among the bg/+ mice occurred earlier (week 3) than among the bg/bg and +/+ mice (week 5). However, by week 6, the mortality rates for bg/+ mice were comparable to those for the bg/bg mice. Mortality in bg/bg mice continued to increase throughout the observation period, whereas the mortality rates stabilized at week 8 for both bg/+ and +/+ strains.
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Serum TNF- levels following infection.
No consistent
differences in serum TNF- levels among the three strains of mice
were observed following infection. TNF- was detectable in the sera
at week 1 of infection with MAC 101 (Fig. 3), and the levels of TNF- increased
over time in all infected animals. The uninfected animals demonstrated
no detectable TNF- in their sera at any of the time points when they
were tested.
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Effect of dexamethasone on disease progression.
C57BL/6
bg/+ mice were treated with dexamethasone at doses of 10 or
20 mg/kg of body weight every other day up to 8 weeks. Treatment with
10 or 20 mg of dexamethasone/kg suppressed the serum TNF- levels by
two- to threefold after 3 and 8 weeks of treatment (Fig.
4). The typical mycobacterial
infection-induced splenomegaly and hepatomegaly were decreased by two-
to threefold in the infected mice (data not shown). In contrast,
microbial burden was increased by 1 and 2 log units in the livers and
spleens of mice treated with dexamethasone (Fig.
5).
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Effect of anti-TNF- antibody on disease progression.
Previous studies (1) have demonstrated that administration
of anti-TNF- antibody results in an increase in mycobacterial CFU in
the livers and spleens of BALB/c mice. To confirm the role of TNF-
in mycobacterial resistance in the present model, C57BL/6 bg/+ mice were treated with anti-TNF- antibody at doses
of 0.75 to 7.5 mg/kg once weekly for 3 weeks. Treatment with
anti-TNF- antibody for a period of 3 weeks increased the microbial
burden in the spleen over the isotype control group at all doses
tested. Splenic CFU ranged from 2.0 × 108 to
3.1 × 108 per g of tissue in the isotype control
groups and were increased to 8.7 × 108 to
11.2 × 108 per g of tissue in the anti-TNF-
antibody-treated group. The microbial burden in the liver showed a
similar trend; however, the changes observed were not statistically
different (1.6 × 108 to 2.1 × 108
CFU per g of liver in the control group to 2.2 × 108
to 3.3 × 108 CFU per g of liver in the treatment
group). Neither the weight of the spleen, liver, or lung nor serum
TNF- levels (as measured by enzyme-linked immunosorbent assay) were
altered by treatment with anti-TNF- antibody.
Effect of pentoxifylline on disease progression.
C57BL/6 bg/+ mice were treated with pentoxifylline
daily at doses of 30, 100, or 300 mg/kg for up to 8 weeks. Treatment
with pentoxifylline up to a dose of 100 mg/kg did not significantly alter the organ weights or serum TNF- levels in infected or
uninfected mice (data not shown). Mycobacterial burden, however,
was increased significantly in the spleen after 3 and 5 weeks
of treatment, and in the liver after 5 weeks of treatment, with 100 mg
of pentoxifylline/kg (Fig. 6). These
differences were not observed at 8 weeks postinfection. The lowest dose
(30 mg/kg) had no significant effect on disease progression. The
highest dose of pentoxifylline tested (300 mg/kg) was found to be toxic
(all the mice died within a few hours of drug administration).
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Effect of thalidomide on disease progression.
C57BL/6
bg/+ mice were treated with thalidomide at doses of 10, 30, or 100 mg/kg daily for up to 8 weeks. Thalidomide was prepared daily in
acidified water to reduce the potential for hydrolysis. Serum TNF-
levels, microbial burden, and weights of spleens and livers were not
altered consistently by treatment with thalidomide. Treatment with
thalidomide had no appreciable effect on mycobacterial burden
following 3 weeks of infection and treatment. At 5 weeks, splenic CFU
were modestly increased in the thalidomide-treated groups; the
increase was statistically significant only in the 30 mg/kg/day
group (Fig. 7). By 8 weeks, the treatment
effect was abrogated. No changes in CFU were observed in the livers at
any time point when they were tested.
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DISCUSSION |
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Abstract
Introduction
Materials & Methods
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Discussion
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One of the strategies for treatment of HIV disease has been the
use of TNF- antagonists, which have been shown to inhibit TNF--induced HIV replication in vitro (11, 22, 27).
However, cytokines play an important role in resistance to
infections. Thus, therapy that produces an imbalance or defect in one
of the cytokines may produce an alteration in susceptibility to
infection. TNF- is an important cytokine in conferring protection,
either directly or indirectly, against opportunistic infections
due to agents such as M. avium. In this regard,
stimulation or activation of human monocyte-derived macrophages
in vitro with TNF- was associated with increased intracellular
killing of M. avium (4, 36). Pourshafie and
Sonnenfeld (28) and Gomez-Flores et al. (16)
demonstrated an increased in vitro killing of M. avium by murine macrophages in the presence of exogenous TNF-.
Mycobacterial killing by macrophages was enhanced if the cells were
activated with IFN- before infection (compared to killing by
resident macrophages) and was correlated with a fivefold-increased
production of TNF- (16). Finally, treatment of mice with
TNF-, IL-2, or a combination of TNF- and IL-2 1 week after
infection with M. avium resulted in decreased CFU in the
spleen and liver (6), and treatment with anti-TNF-
antibody resulted in increased CFU in the spleens and livers of
infected mice (1).
In the present study, we examined the impact of treatment with TNF-
antagonists on the susceptibility of C57BL/6 bg/+ mice to MAC infection. Treatment with dexamethasone at the time of infection
significantly increased mycobacterial burden in the spleen and liver.
Such an effect was observed within 3 weeks of infection and persisted
at 8 weeks of infection. Treatment with anti-TNF- antibody and
pentoxifylline also resulted in significant increases in splenic
CFU but not dependably in liver CFU. Treatment with thalidomide did not
consistently alter mycobacterial burden in either the spleens or the
livers of infected mice, but a trend towards an increase in splenic CFU
was observed at 5 weeks postinfection. Increases in microbial burden
following treatment did not result in any overt decrease in the
survival of infected mice compared to that of the infected control
groups; however, specific survival studies of treated mice were not
conducted.
The results presented here are compatible with those of several other
studies which demonstrate that inhibition of TNF- can dysregulate
the cytokine cascade, leading to a reduction in resistance to MAC
infections. Treatment of M. avium-infected SCID and BALB/c mice with anti-TNF- antibody was shown to increase mycobacterial CFU
in the spleens and livers (1, 8) and reduce the protective effect of immunization with BCG (1). Antibody to TNF-
inhibited in vitro killing of MAC in human monocyte-derived macrophages activated with vitamin D (5), and treatment of ex vivo- or in vitro-infected human monocyte-derived macrophages with
pentoxifylline or dexamethasone enhanced MAC growth (31,
32). Similarly, treatment of MAC-infected murine peritoneal
macrophages with pentoxifylline or anti-TNF- antibody suppressed the
anti-mycobacterial response induced by activation of the macrophages
with IFN- and TNF- (16).
In the present study, dexamethasone was more potent than either
pentoxifylline or thalidomide in reducing serum TNF- levels and
enhancing mycobacterial burden in infected mice. The increase in
mycobacterial burden following dexamethasone treatment may be
attributable to the substantive reduction of systemic TNF- levels.
Alternatively, general corticosteroid effects on multiple immune or
inflammatory effector mechanisms, including neutrophil migration,
phagocytosis, lymphocyte apoptosis and function, and the disruption or
inhibition of several cytokines in addition to TNF-, may contribute
substantially to the mechanism of inhibition.
Clearly, TNF- is somewhat involved in resistance to MAC infections
in the present model. Anti-TNF- antibody, unlike dexamethasone, is a neutralizing antibody which specifically inhibits the function of
TNF-. In our study, immunoreactive TNF- levels were not reduced in the serum following administration of anti-TNF- antibody; however, mycobacterial CFU were significantly increased in the spleen
and were higher (although the increase was not statistically significant) in the liver. These effects on CFU levels are consistent with the increase in mycobacterial levels in BALB/c mice following anti-TNF- antibody treatment reported by Appleberg et al.
(1). The lack of a reduction in detectable serum TNF-
levels does not preclude the possibility that TNF- function was
altered following antibody treatment (10) or that localized
production of TNF- was reduced. Moreover, the lack of a measurable
effect on serum TNF- levels, as detected by immunoassay, may simply
be a limitation of the methodology resulting from competition between
the antibodies used for neutralization in vivo and detection in vitro.
Alternatively, mycobacterial infections are potent inducers of TNF-,
and doses of anti-TNF- antibody substantially higher than those used
in the present study may have been needed to alter serum TNF- levels and to further reduce CFU in the spleen and liver. The modest increase
in CFU observed following administration of anti-TNF- antibody may
reflect the fact that TNF- is not the only cytokine or immunologic
mechanism contributing to overall resistance to M. avium
infections.
The effect of pentoxifylline appears to be more modest than that of
dexamethasone or antibody to TNF- on host resistance to MAC
infections. Pentoxifylline (100 mg/kg/day) increased splenic CFU at
weeks 3 and 5 postinfection and increased liver CFU at week 5 postinfection. Higher doses of pentoxifylline were toxic and could not
be evaluated. Although a trend towards increased splenic CFU was
observed at 5 weeks postinfection in the present study, thalidomide
treatment had no consistent effect on mycobacterial burden or TNF-
levels. While thalidomide has been reported to be a selective inhibitor
of TNF- production (22, 24) in vitro, demonstration of in
vivo inhibition of TNF- has been inconsistent. Thalidomide has been
shown not to inhibit endotoxin-induced TNF- production in mice, but
it did reduce TNF- plasma levels in nonneutropenic mice after
injection with Candida albicans (26). This may be a reflection of the potency of thalidomide with respect to inhibition of TNF- production in murine models: TNF- levels induced by endotoxin were 5- to 10-fold greater than the levels induced by C. albicans. In the present study, MAC infections are strong
inducers of TNF- production; thus, thalidomide may not be a
sufficient inhibitor of TNF- in this system to alter resistance. It
should also be noted that by week 8, approximately 30% of the animals had died irrespective of treatment, and the effect on CFU may be
abrogated. The abrogation of the effect may have been the result of
censoring of data as the result of the level of mortality at week 8 or
simply that TNF- inhibitors were less effective at reducing TNF-
levels in this model.
Studies with TNF- inhibitors have shown that TNF- plays a role in
resistance to MAC infections. Multiple mechanisms, however, clearly
operate in conferring susceptibility or resistance to M. avium infection. For example, in immunocompromised C57BL/6 bg/bg mice, in vivo treatment with IFN- (which enhanced
the production of TNF-) did not decrease the mycobacterial burden in
the spleen and liver but showed an inhibitory effect on the
mycobacterial count from peritoneal macrophages (16). These
seemingly contradictory actions on different cell types may be the
result of differences in cell maturation and/or activation in different
tissues or compartments of the lymphoid system. Multiple cytokines are
also important in resistance to MAC infections. Addition of IFN-
(19, 34), granulocyte-macrophage colony-stimulating factor
(19), or anti-transforming growth factor 
antibodies in
vitro (7) and treatment of mice with IL-12 (20)
have been reported to reduce mycobacterial burden. In contrast, IL-3,
IL-6, and macrophage colony-stimulating factor have been reported to
increase mycobacterial burden in vitro (34). It is of
interest to note that dexamethasone and pentoxifylline showed opposite
effects on IL-6 production; dexamethasone was shown to suppress IL-6
production, whereas pentoxifylline enhanced it (31). The
relevance of these findings to in vivo situations is unclear.
Chemical inhibition of TNF- decreases resistance to MAC infections
in vivo and in vitro. However, most inhibitors not only inhibit
different steps in the cytokine biosynthesis pathway (24) but also are not truly specific for TNF-. For example,
pentoxifylline, in addition to inhibiting TNF-, may suppress the
production of IFN-, IL-10, and other immune functions (25,
35). Dexamethasone inhibits multiple cytokines. Thus, suppression
of a specific cytokine may disrupt the cascade effect of the cytokine
network and alter susceptibility to infection. The extent of such an
effect may be influenced by the time of onset of treatment, the
concentration of the inhibitor used, and the immune status of the host.
This could be taken to indicate a difference in cell maturation and/or activation in different tissues or compartments of the lymphoid system.
C57BL/6 bg/bg mice, known to have impaired phagocytic,
NK, and T-cell functions (2, 3, 13, 29, 30, 33), have been
routinely used for testing the activity of antimycobacterial drugs
(14). In our studies, C57BL/6 bg/+ mice were
chosen for measuring the activity of immunomodulatory agents. The
susceptibility to MAC infection of the bg/+ strain was
comparable to that of the bg/bg strain. The wild-type strain
was less susceptible. All three strains of mice tested were shown to
produce substantial amounts of TNF- in response to MAC infection.
C57BL/6 bg/+ mice may provide a useful model for the
assessment of other immunomodulators on the progression of disease
following MAC infection.
In summary, our results suggest that substances which inhibit cytokine production following MAC infection may reduce resistance to M. avium in vivo. The clinical relevance of this finding is unknown. However, it may be worthwhile to consider that treatment of AIDS patients with immunomodulatory drugs may ultimately impact their resistance to opportunistic infections.
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ACKNOWLEDGMENTS |
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We thank Michael Ussery, Laboratory Director, Nicholson Lane Research Center, FDA, for providing support for the research project. We thank Linda Gosey, Division of Special Pathogen and Immunologic Drug Products, FDA, for providing the MAC 101 strain and Mark Seggel, Division of Special Pathogen and Immunologic Drug Products, FDA, for providing chemistry advice with respect to thalidomide. We also thank Debbie Stahler for animal care assistance and Matthew Bacho, Nicholson Lane Research Center, FDA, for technical assistance.
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Special Pathogen and Immunologic Drug Products (HFD-590), 5600 Fishers Ln., Rockville, MD 20857. Phone: (301) 827-2336. Fax: (301) 827-2523. E-mail: balas{at}cder.fda.gov.
Present address: Otsuka America Pharmaceutical, Inc., Maryland
Office of Clinical Research, Rockville, MD 20850.
Present address: Food and Drug Administration, Harrisburg, PA
17108.
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, September 1998, p. 2336-2341, Vol. 42, No. 9
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