![[Feedback]](/icons/banner/feedbackACT.gif)
![[For Subscribers]](/icons/banner/subscriberACT.gif)
![[Archive]](/icons/banner/archiveACT.gif)
![[Search]](/icons/banner/searchACT.gif)
![[Contents]](/icons/banner/tocACT.gif)
Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, October 1999, p. 2389-2394, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Effects of Antibiotic Therapy on Pseudomonas
aeruginosa-Induced Lung Injury in a Rat Model
Erika J.
Ernst,1,*
Satoru
Hashimoto,2
Joseph
Guglielmo,3
Teiji
Sawa,4
Jean-Francois
Pittet,4
Helmut
Kropp,6
Jesse J.
Jackson,6 and
Jeanine
P.
Wiener-Kronish4,7
College of Pharmacy, University of Iowa, Iowa
City, Iowa 522421; Department of
Anesthesiology and Intensive Care Unit, Kyoto Prefectural University of
Medicine, Kyoto, Japan 6022; Department
of Clinical Pharmacy,3 Department of
Anesthesia and Perioperative Care,4 and
Department of Medicine and Cardiovascular Research
Institute,7 University of California, San
Francisco, California 94143; and Merck Research
Laboratories, Rahway, New Jersey, 070656
Received 2 April 1999/Returned for modification 4 May 1999/Accepted 26 July 1999
 |
ABSTRACT |
The effect of antibiotics on the acute lung injury induced by
virulent Pseudomonas aeruginosa PA103 was quantitatively
analyzed in a rat model. Lung injury was induced by the instillation of PA103 directly into the right lower lobes of the lungs of anesthetized rats. The alveolar epithelial injury, extravascular lung water, and
total plasma equivalents were measured as separate, independent parameters of acute lung injury. Four hours after the instillation of
PA103, all the parameters were increased linearly depending on the dose
of P. aeruginosa. Next, we examined the effects of intravenously administered antibiotics on the parameters of acute lung
injury in D-galactosamine-sensitized rats. One hour after the rats received 107 CFU of PA103, an intravenous bolus
injection of aztreonam (60 mg/kg) or imipenem-cilastatin (30 mg/kg) was
administered. Despite an MIC indicating resistance, imipenem-cilastatin
improved all the measurements of lung injury; in contrast, aztreonam,
which had an MIC indicating sensitivity, did not improve any of the lung injury parameters. The antibiotics did not generate different quantities of plasma endotoxin; therefore, endotoxin did not appear to
explain the differences in lung injury. This in vivo model is useful to
quantitatively compare the efficacies of parenteral antibiotic
administration on Pseudomonas airspace infections.
| |
INTRODUCTION |
Pseudomonas aeruginosa is
a major cause of lung infections, particularly nosocomial pneumonia
(9, 13, 23, 28). Mortality rates of patients with P. aeruginosa pneumonia are higher than the mortality rates of
patients with pneumonia caused by other pathogens (14)
because P. aeruginosa pneumonia frequently disseminates to
cause bacteremia and sepsis (6, 22, 27). This rapid dissemination is associated with the generation of acute lung epithelial injury by some strains of P. aeruginosa (29,
30). To protect patients who have P. aeruginosa
pneumonia from bacteremia, sepsis, and death, the effective utilization
of antibiotics is important. However, most of the strains of P. aeruginosa are inherently resistant to many antibiotics
(10).
The hypothesis tested by this study was that acute lung injury may be
decreased by a single bolus of antibiotics if the antibiotics decrease
the number of bacteria instilled in the lungs of rats. We also sought
to determine whether the amount of lung injury was related to the
change in endotoxin concentration over the experimental period. In this
investigation, we quantitated the acute lung injury caused by the
airspace instillation of a virulent strain of P. aeruginosa,
PA103, in anesthetized rats. The effects of different inoculums of the
same strain, PA103, on multiple, independent parameters of lung injury
were determined. We then investigated the effect of antibiotic
treatment on these parameters of bacterially induced lung injury. We
chose two antibiotics, aztreonam and imipenem-cilastatin, and compared
their effects on the parameters of acute lung injury in the rat model.
Both aztreonam (1, 5, 11) and imipenem (3, 4, 26)
are utilized clinically to treat infections caused by this organism.
The MIC in vitro bacterial sensitivity test is utilized routinely to
choose an antibiotic that can effectively kill a bacterial pathogen.
However, the concentration of antibiotics at the site of infection,
which is affected by various pharmacokinetic factors, including the
rate of penetration into the specific tissues and the speed of
metabolism of the drugs, may be more important in the efficacy of
antibiotics in vivo. Therefore, we utilized this animal model to
compare two antibiotics that had different MICs to determine which of
the antibiotics was more efficacious in improving the parameters of
bacterially induced lung injury.
| |
MATERIALS AND METHODS |
Surgical preparation and ventilation.
Male Sprague-Dawley
rats (300 to 350 g; Simonsen, Gilroy, Calif.), certified pathogen
free, were anesthetized with 30 mg of pentobarbital given
intraperitoneally; anesthesia was maintained with 12 mg of
intraperitoneally administered pentobarbital every 2 h. All rats
remained anesthetized, intubated, and ventilated throughout the entire
experiment. The right carotid artery was cannulated with a polyethylene
tube (PE50; Clay Adams, Parsippany, N.J.), for monitoring arterial
blood pressure and for blood sampling. The right jugular vein was
cannulated with a PE50 tube, and the drugs were administered
intravenously. Pancuronium bromide (0.3 mg/kg of body weight) was given
intravenously every 2 h for neuromuscular blockade. An
endotracheal tube (PE240; Clay Adams) was inserted into the trachea via
a tracheostomy. The rats were ventilated with a constant-volume animal
respirator (Harvard Apparatus, South Natick, Mass.) with an
O2 fraction of 1.0 and 3-cm positive end-expiratory pressure. The respiratory rate was adjusted to maintain an arterial PCO2 between 35 and 45 mm Hg. All animal experiments were
conducted in compliance with the guidelines of the Animal Care
Committee of the University of California at San Francisco.
Culture conditions, bacterial strains, and instillate
preparation.
P. aeruginosa PA103 was instilled to induce
lung injury, as it has been shown to significantly increase the
measurements of lung injury (20). The strain was stored as
a bacterial stock at 
70°C in a 10% sterile skim milk
solution. The bacteria were streaked onto a Vogel-Bonner minimal medium
plate for 36 h at 37°C, and then the bacteria were cultured in
tryptic soy broth for 13 h at 32°C in a shaking incubator.
The instillate consisted of a 1-ml iso-osmolar albumin solution
prepared from Ringer's lactate, 2 mg of Evans blue dye, and 3 µCi of
125I-labeled albumin. P. aeruginosa at a
concentration of 106, 107, or 108
CFU, determined spectrophotometrically, was added to the instillate just prior to airspace instillation. A sample of the instillate was
saved for measurement of radioactivity, protein concentration, and
quantitative bacterial cultures to assure accurate inoculations.
Treatments.
The MICs of the antibiotics were determined by
the standard microdilution technique, according to the methods of the
National Committee for Clinical Laboratory Standards (21).
Aztreonam (Squibb Inc., Princeton, N.J.) at 60 mg/kg or
imipenem-cilastatin (Merck, Inc., Rahway, N.J.) at 30 mg/kg was
administered as an intravenous bolus dose 1 h after the airspace
bacterial instillation. Control rats received an equal volume of normal
saline (Baxter, Roundlake, Ill.) as a bolus. The investigator was
blinded to whether a drug was administered. Due to the length of
surgery, only two rats were studied in 1 day to maintain
reproducibility of the model; a control rat was always one of the
experimental animals.
Endotoxin measurements.
Serum samples for measurements of
endotoxin were obtained just prior to and 4 h after the bacterial
instillation. The samples were allowed to clot for 20 min and then were
centrifuged and immediately frozen at 70°C until they were
analyzed. The serum samples were measured for free endotoxin with the
Limulus amebocyte lysate assay (Chromogenic-Limulus
Amebocyte; Wittaker M. A. Bioproducts, Walkersville, Md.).
General experimental protocol.
In all experiments, after the
surgical preparation, 3 µCi of 131I-albumin
(Merck-Frosst, Kirkland, Quebec, Canada) was injected intravenously.
The rats were then placed in a right lateral decubitus position. With
the use of 1-ml syringes and PE50 tubes, the instillates were delivered
to the right lungs (primarily the right lower lobes) over a 30-min
interval. The rats were injected with 500 mg of D-galactosamine/kg intraperitoneally during the bacterial
instillation in order to sensitize them to the effects of endotoxin
(2, 15, 16). Systemic arterial and airway pressures were
measured at 1-h intervals. Blood samples were obtained for
131I-albumin and 125I-albumin measurement every
hour after the instillation for 6 h.
After 6 h, the rats were deeply anesthetized, their abdomens were
opened, and they were exsanguinated. Samples of blood, urine, right
pleural fluid, and liver were obtained for bacterial cultures and
radioactivity counts. The lungs were removed, and any remaining instillate was aspirated with a 3-ml syringe and a PE50 tube passed into the right lower lobes. The total protein and radioactivity of the
alveolar samples were measured. The right and left lungs were
homogenized separately for water-to-dry-weight ratio measurements and
for culture. Measurements of the total protein concentrations of
plasma, pleural fluid, and initial and final instillate samples were
performed by the Biruet method.
Measurements of lung injury.
Lung injury was quantified in
four ways, as previously described (29, 30). The first
method quantified the movement of the alveolar protein tracer,
125I-albumin, from the lung into the blood by measuring the
amount of residual 125I-albumin in the lung as well as the
accumulation of the tracer in the plasma over the 6-h course of the
experiment. Total 125I-albumin instilled into the lung was
determined by measuring duplicate samples of the instillate for total
radioactivity (counts per minute per gram) and multiplying this amount
by the total volume instilled into the lung. To calculate the residual
125I-albumin in the lung after 6 h, the average of two
0.5-g samples obtained from the lung homogenate was multiplied by the
total volume of the lung homogenate. The radioactivities in the lung homogenates were added to the recovered radioactive counts in the
aspirated fluid from the lungs. Circulating plasma
125I-albumin was measured from a sample of plasma obtained
at the end of 6 h. The plasma fraction was accounted for by
multiplying the counts per milliliter by the plasma volume [body
weight × 0.07 (1 hematocrit)].
The second method required the measurement of 131I-albumin
(the vascular protein tracer) in the airspace compartment of the lung at the end of the experiment. This was accomplished by measuring the
131I-albumin counts in the final airspace sample. Plasma
131I-albumin counts were averaged over the course of the
experiment, and the 131I-albumin counts in the airspaces
were expressed as a ratio to the plasma counts. This ratio provides a
good index of equilibration of the vascular protein tracer into the
alveolar compartment, as had been shown previously (30).
Third, extravascular lung water was determined for each separate lung
by calculating the water-to-dry-weight ratio. The excess water in the
experimental lung was calculated with the same equation described
previously (30). Briefly, the volume of excess lung water
(ELW; in ml) of the serum-instilled experimental lung was calculated as
follows: ELW = [We/(De P) Wc/Dc](De P), where W and D are extravascular lung
water and blood-free dry weights, respectively, of the experimental
lung (e) and the control lung (c) and
P is the blood-free dry weight of the initial alveolar fluid
multiplied by the fraction of 125I-albumin remaining in the lung.
Finally, the accumulation of the vascular protein tracer into the
extravascular space of the lung was calculated by determining the total
extravascular count of 131I-albumin in the lung divided by
the average counts in the plasma over the 6-h study period and was
expressed as total plasma equivalents in milliliters.
Statistics.
All data presented are means ± standard
errors. The data were analyzed by one-way analysis of variance followed
by Dunnet's multiple-comparison test. A P value of <0.05
was accepted as statistically significant.
| |
RESULTS |
Acute lung injury induced by the airspace instillation of P. aeruginosa.
First, we quantified the acute lung injury in rats
receiving the airspace instillation of P. aeruginosa. Rats
receiving three different doses (106, 107, and
108 CFU/rat) of P. aeruginosa were compared with
the control rats that received vehicle without bacteria. The
measurements of alveolar epithelial injury (the alveolar protein tracer
in blood) and two measurements of lung edema (extravascular lung water
and total plasma equivalents) were calculated in the 4-h experiments.
The alveolar epithelial injury quantified by the movement of the
radiolabeled alveolar protein tracer was increased linearly with
increasing doses of P. aeruginosa or by increasing the
duration of bacterial exposure in the lung from 2 to 4 h (Fig.
1). Both parameters of lung edema, the
extravascular lung water (Fig. 2) and the
total plasma equivalents (Fig. 3), were
also increased linearly with increasing doses of P. aeruginosa. Therefore, in this rat model, increasing quantities of
acute lung injury can be consistently produced by modifying the dose of
bacteria and/or the interval of bacterial exposure.
View larger version (25K):
[in this window]
[in a new window]
|
FIG. 1.
Alveolar epithelial injury in rats instilled with three
different doses of P. aeruginosa. The rats received an
instillate that included the alveolar protein tracer
125I-albumin without bacteria (control) or with P. aeruginosa PA103 (106, 107, or
108 CFU) in their lungs. The percentage of the alveolar
protein tracer in the blood at 2, 3, or 4 h after the instillation
was calculated. The data are means + standard errors. *,
P < 0.05. P values are by comparison with the results
for the control group that did not receive bacteria (analysis of
variance followed by Dunnet's test). The control (no-bacteria) and
106-, 107-, and 108-CFU groups had
seven, six, nine, and five rats, respectively.
|
|
View larger version (16K):
[in this window]
[in a new window]
|
FIG. 2.
Extravascular lung water measurements in rats instilled
with three different doses of P. aeruginosa. The rats
received an instillate without bacteria (control) or with P. aeruginosa PA103 (106, 107, or
108 CFU) in their lungs. The amount of extravascular lung
water was calculated 4 h after the instillation. The data are
means + standard errors. *, P < 0.05. P values
are by comparison with the results for the control group that did not
receive bacteria. The control (no-bacteria) and 106-,
107-, and 108-CFU groups had seven, six, nine,
and five rats, respectively.
|
|
View larger version (17K):
[in this window]
[in a new window]
|
FIG. 3.
Total plasma equivalents in rats instilled with three
different doses of P. aeruginosa. The rats received an
instillate without bacteria (control) or with P. aeruginosa
PA103 (106, 107, or 108 CFU) in
their lungs. The total plasma equivalent was calculated 4 h after
the instillation. The data are means + standard errors. *,
P < 0.05. P values are by comparison with the results
for the control group that did not receive bacteria. The control
(no-bacteria) and 106-, 107-, and
108-CFU groups had seven, six, nine, and five rats,
respectively.
|
|
Effects of antibiotics on acute lung injury caused by P. aeruginosa.
Based on the results described above, we evaluated
the effects of two antibiotics, aztreonam and imipenem-cilastatin, on
acute lung injury. A dose (107 CFU) of P. aeruginosa was administered to each rat to produce a moderate
quantity of lung injury that might be modified by the administration of
antibiotics. We observed the animals for 6 h in this series
to evaluate the effect of antibiotics. In addition to the parameters
of acute lung injury, we measured the number of bacteria in the
instilled lung 6 h after the tracheal instillation of P. aeruginosa.
The MIC of imipenem-cilastatin was 16 µg/ml, considered to be
resistant by the National Committee for Clinical Laboratory Standards
(20). In contrast, the MIC of aztreonam was 0.5 µg/ml, considered sensitive by the same standards. Nonetheless, among the rats
that received imipenem-cilastatin after the instillation of bacteria
there was a trend toward fewer bacteria remaining in the lungs
(3.0 × 105 ± 2.0 × 105
CFU/ml) than among the rats that had received aztreonam (3.2 × 106 ± 1.7 × 106 CFU/ml) or the rats
that had not received antibiotics (6.0 × 106 ± 4.0 × 106 CFU/ml) (Fig.
4). The blood culture results from all
rats at the end of the experimental period were negative. The culture results from a liver sample taken at the end of the experiment were
positive for all rats. Imipenem-cilastatin significantly improved all
the parameters of lung injury measured compared to the control,
untreated rats or to the aztreonam-treated rats. The administration of
imipenem-cilastatin resulted in significantly less alveolar epithelial
injury (Fig. 5), significantly less
extravascular lung edema (Fig. 6), and
significantly fewer total plasma equivalents (Fig.
7). The baseline blood pressure
measurements of the groups were not different (P > 0.05). Treatment with aztreonam resulted in greater reduction in
systolic and diastolic blood pressure 5 h after instillation
compared to treatment with imipenem-cilastatin and the control (Table
1). At 6 h, systolic blood pressure
was significantly reduced in the aztreonam-treated group (P = 0.026), and there was a trend toward statistical significance
for reduction in diastolic blood pressure in the aztreonam-treated
group (P = 0.052) at this time point. The reduction in
lung injury and hypotension in the imipenem-cilastatin-treated rats was
not explained by the serum endotoxin levels 4 h after the tracheal
instillation of P. aeruginosa; the levels were not different
in the antibiotic-treated rats and the control animals (Table
2).
View larger version (15K):
[in this window]
[in a new window]
|
FIG. 4.
Effect of administration of aztreonam or
imipenem-cilastatin on the number of bacteria in the right lung 6 h after the instillation of P. aeruginosa PA103. One hour
after the airspace instillation of PA103 (107 CFU), an
intravenous bolus dose of aztreonam (AZT; 60 mg/kg) or
imipenem-cilastatin (IPM/CST; 30 mg/kg) was administered. Control rats
(Control) received an equal volume of normal saline intravenously
1 h after the airspace instillation of PA103 (107
CFU). The data are means + standard errors (there were no
statistically significant differences among groups by one-way analysis
of variance). The control, AZT, and IPM/CST groups had seven, four, and
four rats, respectively.
|
|
View larger version (18K):
[in this window]
[in a new window]
|
FIG. 5.
Alveolar epithelial injury in rats instilled with
P. aeruginosa and then treated with aztreonam or
imipenem-cilastatin. One hour after the airspace instillation of PA103
(107 CFU) with the alveolar protein tracer
125I-albumin, an intravenous bolus dose of aztreonam (AZT;
60 mg/kg) or imipenem-cilastatin (IPM/CST; 30 mg/kg) was administered.
The percentage of the alveolar protein tracer in the blood 6 h
after the instillation was calculated. The data are means + standard errors.  , P < 0.05. P values are by
comparison with the results for the AZT group (one-way analysis of
variance followed by Dunnet's test). The control, AZT, and IPM/CST
groups had seven, four, and four rats, respectively.
|
|
View larger version (17K):
[in this window]
[in a new window]
|
FIG. 6.
Extravascular lung water measurements in rats instilled
with P. aeruginosa and then treated with aztreonam
or imipenem-cilastatin. One hour after the airspace instillation of
PA103 (107 CFU) with the alveolar protein tracer
125I-albumin, an intravenous bolus dose of aztreonam (AZT;
60 mg/kg) or imipenem-cilastatin (IPM/CST; 30 mg/kg) was administered.
The extravascular lung water 6 h after the instillation was
calculated. Data are means + standard errors. , P < 0.05. P values are by comparison with the results for the AZT
group (one-way analysis of variance followed by Dunnet's test). The
control, AZT, and IPM/CST groups had seven, four, and four rats,
respectively.
|
|
View larger version (15K):
[in this window]
[in a new window]
|
FIG. 7.
Total plasma equivalents in rats instilled with P. aeruginosa and then treated with aztreonam or imipenem-cilastatin.
One hour after an airspace instillation of PA103 (107 CFU),
an intravenous bolus dose of aztreonam (AZT; 60 mg/kg) or
imipenem-cilastatin (IPM/CST; 30 mg/kg) was administered. The total
plasma equivalents 6 h after the instillation of antibiotic were
calculated. Data are means + standard errors. *, P < 0.05. P values are by comparison with the results for the control
group (one-way analysis of variance followed by Dunnet's test). The
control, AZT, and IPM/CST groups had seven, four, and four rats,
respectively.
|
|
| |
DISCUSSION |
A model that produces a consistent quantity of bacterially-induced
lung injury is a useful tool for comparing the effects of various
antibiotic treatments on markers of lung injury. In the development of
such a model we have shown that the administration of small doses
(106 CFU) of P. aeruginosa for longer intervals
(4 h) consistently led to moderate quantities of lung injury. The
administration of larger doses (108 CFU) of P. aeruginosa for longer intervals produced larger quantities of lung
injury with very small standard deviations in the measurements. Therefore, the airspace administration of P. aeruginosa can
be utilized to produce a consistent quantity of lung injury that can be
increased or decreased by modifying the dose or the interval. These
results allowed us to choose a dose of P. aeruginosa,
107 CFU, and an interval, 6 h, to produce a moderate
amount of lung injury. While this model has some limitations, such as
the short evaluation period of 6 h, it also has advantages, such
as reproducible, quantifiable lung injury measurements. Because of
these advantages, we elected to use this model to test the hypothesis
that acute lung injury may be decreased by a single bolus of
antibiotics if the antibiotics decrease the number of bacteria
instilled in the lungs of rats. We also sought to determine whether the
amount of lung injury was related to the change in serum endotoxin
concentration over the experimental period. In fact, we were able to
document that one bolus of imipenem-cilastatin, but not aztreonam,
significantly improved all parameters of the bacterially induced lung
injury as evidenced by the extravascular lung water and total plasma equivalents. The extravascular lung water is an overall measurement of
lung edema. Total plasma equivalents is also a measure of lung edema
but is more specific for the movement of plasma into the lung. We were
not able to correlate these parameters of lung injury with plasma
endotoxin concentration.
Imipenem-cilastatin, but not aztreonam, was able to significantly
improve lung injury. P. aeruginosa PA103 is sensitive to aztreonam, as the MIC for it was 0.5 µg/ml; therefore the lack of
improved killing compared to untreated controls was not due to
antibiotic resistance. In contrast, there was a trend for increased killing by imipenem-cilastatin despite a MIC of imipenem (16 µg/ml) higher than the MIC of aztreonam (0.5 µg/ml). This result suggests that measurement of the in vitro killing of bacteria does not correlate
with antibiotic-induced killing in an airspace infection in vivo. The
pharmacokinetics of aztreonam and imipenem-cilastatin have been
described previously in rats (17, 19). The penetrations of
these antibiotics into the lung tissue are comparable, measuring approximately 50% of that in the serum. The protein binding of aztreonam is nearly 50 to 60%, whereas that of imipenem-cilastatin is
only 10 to 20% (7, 8). In order to account for this
difference in protein binding in the model, we elected to give a higher
dose of aztreonam (60 mg/kg) than of imipenem-cilastatin (30 mg/kg). Aztreonam displays an effect of inoculum on the MIC at 107
to 108 CFU/ml, whereas impenem does not show an inoculum
effect on the MIC until 108 CFU/ml (7, 8). It is
possible that the inoculum selected for study, 107 CFU/ml,
favored the activity of imipenem-cilastatin. However, the MIC of
aztreonam was five times lower that that of imipenem-cilastatin, which
would favor the activity of aztreonam.
This model of lung injury also resulted in bacteremia, as evidenced by
the positive liver cultures. Administration of imipenem-cilastatin, but
not aztreonam, resulted in a reduction of systemic hypotension over the
experimental period, which may have contributed to the increased lung
injury observed in the aztreonam-treated rats.
It has been demonstrated that antibiotics which target PBP-2, such as
imipenem, liberate less endotoxin than antibiotics which bind PBP-3,
such as aztreonam (12, 18, 25). Aztreonam may cause
endotoxin release due to filamentation, which appears to be secondary
to the properties of the penicillin binding protein. In fact, we
previously documented that the airspace instillation of aztreonam along
with P. aeruginosa caused endotoxin release and increased
acute lung injury (24). However, in this model, there were
no differences in the serum levels of endotoxin between the groups.
Therefore, antibiotic-induced release of serum endotoxin did not appear
to explain the differences in the lung injury measurements between the
aztreonam-treated rats and the imipenem-cilastatin-treated rats. It is
possible that lung endotoxin levels were different in the treatment
groups; however, we were unable to measure lung endotoxin levels using
this model.
In conclusion, a virulent strain of P. aeruginosa, PA103,
can be utilized to create a consistent quantity of lung injury for comparisons of antibiotic effectiveness in airspace infections. Imipenem-cilastatin administration led to significant improvement in
all the measured parameters of lung injury. In contrast, aztreonam, which was effective in killing this bacterium in vitro, did not improve
any of the parameters of lung injury compared to nontreated animals.
These results suggest that the evaluation of antibiotic effects in vivo
may be important in airspace infections. Our animal model for
Pseudomonas pneumonia is useful for evaluation of the comparative effects of antibiotics.
| |
ACKNOWLEDGMENTS |
We thank Richard Shanks for his technical support.
This work was supported by National Heart and Lung Institute grants
HL49810 and HL59239 (J.P.W.-K.).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: College of
Pharmacy, S428 PHAR, University of Iowa, Iowa City, IA 52242-1112. Phone: (319) 335-8785. Fax: (319) 353-5646. E-mail:
erika-ernst{at}uiowa.edu.
| |
REFERENCES |
| 1.
|
Allen, K. D., and H. T. Green.
1989.
Aztreonam in infections due to aerobic gram-negative bacteria.
J. Antimicrob. Chemother.
23:290-291[Free Full Text].
|
| 2.
|
Bahrami, S.,
H. Redl,
W. A. Buurman, and G. Schlag.
1992.
Influence of the xanthine derivative HWA 138 on endotoxin-related coagulation disturbances: effects in non-sensitized vs. D-galactosamine sensitized rats.
Thromb. Haemost.
68:418-423[Medline].
|
| 3.
|
Barza, M.
1985.
Imipenem: first of a new class of beta-lactam antibiotics.
Ann. Intern. Med.
103:552-560.
|
| 4.
|
Birnbaum, J. F.,
M. Kahan,
H. Kropp, and J. S. MacDonald.
1987.
Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin.
Am. J. Med.
78:3-21.
|
| 5.
|
Boccazzi, A.,
M. Langer,
M. Mandeli,
A. M. Ranzi, and R. Urso.
1989.
The pharmacokinetics of aztreonam and penetration into the bronchial secretions of critically ill patients.
J. Antimicrob. Chemother.
23:401-407[Abstract/Free Full Text].
|
| 6.
|
Brewer, S. C.,
R. G. Wunderink,
C. B. Jones, and K. V. Leeper, Jr.
1996.
Ventilator-associated pneumonia due to Pseudomonas aeruginosa.
Chest
109:1019-1029[Abstract/Free Full Text].
|
| 7.
|
Brogden, R. N., and R. C. Heel.
1986.
Aztreonam, a review of its antibacterial activity, pharmacokinetic properties and therapeutic use.
Drugs
31:96-130[Medline].
|
| 8.
|
Buckley, M. M.,
R. N. Brogden,
L. B. Barradell, and K. L. Goa.
1992.
Imipenem/cilastatin, a reappraisal of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy.
Drugs
44:408-444[Medline].
|
| 9.
|
Craven, D. E., and K. Steger.
1996.
Nosocomial pneumonia in mechanically ventilated adult patients: epidemiology and prevention in 1996.
Semin. Respir. Infect.
11:32-53[Medline].
|
| 10.
|
Cullmann, W.,
K. H. Buscher, and W. Dick.
1987.
Selection and properties of Pseudomonas aeruginosa variants resistant to beta-lactam antibiotics.
Eur. J. Clin. Microbiol.
6:467-473[Medline].
|
| 11.
|
Demaria, A.,
T. L. Treadwell,
C. A. Saunders,
R. Porat, and W. R. McCabe.
1989.
Randomized clinical trial of aztreonam and aminoglycoside antibiotics in the treatment of serious infections caused by gram-negative bacilli.
Antimicrob. Agents Chemother.
33:1137-1143[Abstract/Free Full Text].
|
| 12.
|
Dofferhoff, A. S. M.,
J. H. Nijland,
H. G. de Vries-Hispers,
P. O. M. Mulder,
J. Veits, and V. J. Bom.
1991.
Effects of different types and combinations of antimicrobial agents on endotoxin release from gram-negative bacteria: an in-vitro and in-vivo study.
Scand. J. Infect. Dis.
23:745-754[Medline].
|
| 13.
|
Fabregas, N.,
A. Torres,
M. El-Ebiary,
J. Ramfrez,
C. Hernandez,
J. Gonzalez,
J. P. de la Bellacasa,
J. de Anta, and R. Rodoriguez-Roisin.
1996.
Histopathologic and microbiologic aspects of ventilator-associated pneumonia.
Anesthesiology
84:760-771[Medline].
|
| 14.
|
Fagon, J. Y.,
J. Chastre,
A. J. Hance,
P. Montravers,
A. Novara, and C. Gilbert.
1993.
Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay.
Am. J. Med.
94:281-288[Medline].
|
| 15.
|
Galanos, C., and M. A. Freudenberg.
1993.
Mechanisms of endotoxin shock and endotoxin hypersensitivity.
Immunobiology
187:346-356[Medline].
|
| 16.
|
Galanos, C.,
M. A. Freudenberg, and W. Reutter.
1979.
Galactosamine-induced sensitization to the lethal effects of endotoxin.
Proc. Natl. Acad. Sci. USA
76:5939-5943[Abstract/Free Full Text].
|
| 17.
|
Hashimoto, S.,
E. Wolfe,
B. Guglielmo,
R. Shanks,
J. Sundelof,
J. F. Pittet,
E. Thomas, and J. Wiener-Kronish.
1996.
Aerosolization of imipenem/cilastatin prevents pseudomonas-induced acute lung injury.
J. Antimicrob. Chemother.
38:809-818[Abstract/Free Full Text].
|
| 18.
|
Jackson, J. J., and H. Kropp.
1992.
 -Lactam antibiotic-induced release of free endotoxin: in vitro comparison of penicillin-binding protein (PBP) 2-specific imipenem and PBP-3-specific ceftazidime.
J. Infect. Dis.
165:1033-1041[Medline].
|
| 19.
|
Kripilani, K. J.,
S. M. Singhvi,
S. H. Weinstein,
D. W. Everett,
M. S. Bathala,
A. V. Dean,
C. E. Ita,
L. Lawrence,
F. S. Meeker, Jr.,
J. M. Shaw,
B. D. Walker, and B. H. Migdalof.
1984.
Disposition of [14C]aztreonam in rats, dogs, and monkeys.
Antimicrob. Agents Chemother.
26:119-126[Abstract/Free Full Text].
|
| 20.
|
Kudoh, I.,
J. P. Wiener-Kronish,
S. Hashimoto,
J.-F. Pittet, and D. Frank.
1994.
Exoproduct secretions of Pseudomonas aeruginosa strains influence severity of alveolar injury.
Am. J. Physiol.
267:L511-L516.
|
| 21.
|
National Committee for Clinical Laboratory Standards.
1997.
Methods for determining dilution antimicrobial susceptibility tests for bacteria that grow aerobically. M7-A4.
National Committee for Clinical Laboratory Standards, Wayne, Pa.
|
| 22.
|
Parrillo, J. E.,
M. M. Parker,
C. Nathanson,
A. F. Suffredini,
R. L. Danner,
R. E. Cunnion, and F. P. Ognibene.
1990.
Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction and therapy.
Ann. Intern. Med.
113:227-237.
|
| 23.
|
Rouby, J. J.
1996.
Nosocomial infection in the critically ill. The lung as a target organ.
Anesthesiology
84:757-758[Medline].
|
| 24.
|
Sawa, T.,
K. Kurahashi,
M. Ohara,
M. A. Gropper,
V. Doshi,
J. W. Larrick, and J. P. Wiener-Kronish.
1998.
Evaluation of antimicrobial and lipopolysaccharide-neutralizing effects of a synthetic CAP18 fragment against Pseudomonas aeruginosa in a mouse model.
Antimicrob. Agents Chemother.
42:3269-3275[Abstract/Free Full Text].
|
| 25.
|
Shenep, J. L.,
R. P. Barton, and K. A. Mogan.
1985.
Role of antibiotic class in the rate of liberation of endotoxin during therapy for experimental gram-negative bacterial sepsis.
J. Infect. Dis.
151:1012-1018[Medline].
|
| 26.
|
Stradvik, G.,
A. S. Malmborg,
T. Bergan,
H. Michalsen,
O. T. Storrosten, and B. Wretlind.
1988.
Imipenem/cilastatin, an alternative treatment of Pseudomonas infection in cystic fibrosis.
J. Antimicrob. Chemother.
21:471-480[Abstract/Free Full Text].
|
| 27.
|
Taylor, G. D.,
M. Buchanan-Chell,
T. Kirkland,
M. McKenzie, and R. Wiens.
1994.
Bacteremic nosocomial pneumonia. A 7-year experience in one institution.
Chest
108:786-788[Abstract/Free Full Text].
|
| 28.
|
Torres, A.,
R. Aznar,
J. M. Gatell,
P. Jimenez,
J. Gonzalez,
A. Ferrer,
R. Celis, and R. Rodriguez-Roisin.
1990.
Incidence, risk, and prognosis factors of nosocomial pneumonia in mechanically ventilated patients.
Am. Rev. Respir. Dis.
142:523-528[Medline].
|
| 29.
|
Wiener-Kronish, J. P.,
K. H. Albertine, and M. A. Matthay.
1991.
Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin.
J. Clin. Investig.
88:864-875.
|
| 30.
|
Wiener-Kronish, J. P.,
T. Sakuma,
I. Kudoh,
J.-F. Pittet,
D. Frank,
L. Dobbs,
M. L. Vasil, and M. Matthay.
1993.
Alveolar epithelial injury and pleural empyema in acute P. aeruginosa pneumonia in anesthetized rabbits.
J. Appl. Physiol.
75:1661-1669[Abstract/Free Full Text].
|
Antimicrobial Agents and Chemotherapy, October 1999, p. 2389-2394, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Allmond, L. R., Ajayi, T., Moriyama, K., Wiener-Kronish, J. P., Sawa, T.
(2004). V-Antigen Genotype and Phenotype Analyses of Clinical Isolates of Pseudomonas aeruginosa. J. Clin. Microbiol.
42: 3857-3860
[Abstract]
[Full Text]
-
Bellais, S., Mimoz, O., Leotard, S., Jacolot, A., Petitjean, O., Nordmann, P.
(2002). Efficacy of {beta}-Lactams for Treating Experimentally Induced Pneumonia Due to a Carbapenem-Hydrolyzing Metallo-{beta}-Lactamase-Producing Strain of Pseudomonas aeruginosa. Antimicrob. Agents Chemother.
46: 2032-2034
[Abstract]
[Full Text]
Top
Abstract
Introduction
