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Antimicrobial Agents and Chemotherapy, August 2001, p. 2204-2209, Vol. 45, No. 8
Departments of Pathology and Laboratory
Medicine1 and
Medicine,2 University of Pennsylvania
School of Medicine, Philadelphia, Pennsylvania 19104-4283, and
Department of Drug Metabolism and Pharmacokinetics,
SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn Herts AL6 9AR,
United Kingdom3
Received 29 November 2000/Returned for modification 27 March
2001/Accepted 27 April 2001
The activity of gemifloxacin against intracellular
Legionella pneumophila and for the treatment of guinea
pigs with L. pneumophila pneumonia was studied.
Gemifloxacin, azithromycin, and levofloxacin (1 µg/ml) reduced
bacterial counts of two L. pneumophila strains grown in
guinea pig alveolar macrophages by 2 to 3 log10 units. Gemifloxacin and levofloxacin had roughly equivalent intracellular activities. In contrast, erythromycin had static activity only. Therapy
studies of gemifloxacin, azithromycin, and levofloxacin were performed
in guinea pigs with L. pneumophila pneumonia. When gemifloxacin (10 mg/kg) was given by the intraperitoneal (i.p.) route
to infected guinea pigs, mean peak levels in plasma were 1.3 µg/ml at
0.5 h and 1.2 µg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 1.3 h, and the area
under the concentration-time curve from 0 to 24 h
(AUC0-24) was 2.1 µg · h/ml. For the same drug
dose, mean levels in lungs were 3.4 µg/g at both 0.5 and 1 h,
with a half-life of 1.5 h and an AUC0-24 of 6.0 µg · h/ml. All 15 L. pneumophila-infected guinea pigs treated with gemifloxacin (10 mg/kg/dose given i.p. once
daily) for 2 days survived for 9 days after antimicrobial therapy, as
did 13 of 14 guinea pigs treated with the same dose of gemifloxacin
given for 5 days. All 12 azithromycin-treated animals (15 mg/kg/dose
given i.p. once daily for 2 days) survived, as did 11 of 12 animals
treated with levofloxacin (10 mg/kg/dose given i.p. once daily for 5 days). None of 12 animals treated with saline survived. Gemifloxacin is
effective against L. pneumophila in infected macrophages
and in a guinea pig model of Legionnaires' disease, even with an
abbreviated course of therapy. These data support studies of the
clinical effectiveness of gemifloxacin for the treatment of
Legionnaires' disease.
Gemifloxacin (SB-265805, LB20304a)
is a novel pyrrolidine-type quinolone antimicrobial agent with
broad-spectrum activity against gram-negative and gram-positive
pathogens (1a). Previous studies have shown that the drug
has good in vitro activity against Legionella bacteria in
vitro (3, 20) and in human macrophages (I. A. Critchley, J. Broskey, and K. Coleman, Abstr. 38th Intersci. Conf.
Antimicrob. Agents Chemother., abstr. F-100, 1998). This study
was designed to further define the intracellular activity of
gemifloxacin against Legionella pneumophila, as well as to determine the in vivo activity of the drug for the treatment of a
guinea pig model of Legionnaires' disease. We demonstrate that gemifloxacin is as active as levofloxacin or azithromycin in these two
models of L. pneumophila infection.
Bacterial strains and growth conditions.
Both L. pneumophila strains studied, F889 and F2111, were low-passage
clinical isolates which have been extensively studied in a cell model
of L. pneumophila infection. Strain F889 has also been used
extensively by us in a well-validated guinea pig model of L. pneumophila pneumonia (4-7, 13, 16).
Staphylococcus aureus ATCC 29213 and Escherichia
coli ATCC 25922 were used as control organisms for susceptibility
testing. To obtain inocula for susceptibility testing, legionellae were
grown on MOPS (morpholinepropanesulfonic acid)-buffered charcoal-yeast
extract medium supplemented with 0.1% Antimicrobials.
Gemifloxacin standard powder was obtained
from SmithKline Beecham Pharmaceuticals, Worthing, United Kingdom.
Levofloxacin, erythromycin, and azithromycin powders were obtained from
Daiichi Pharmaceutical Co. (Tokyo, Japan), Aventis Pharmaceuticals
(Romainville, France), and Pfizer Pharmaceuticals (New York,
N.Y.), respectively. Gemifloxacin was dissolved in sterile water
for injection, USP. Levofloxacin standard powder was dissolved in
sterile water for injection, USP. Erythromycin standard powder was
first dissolved in 95% ethanol and then diluted in tissue culture
medium M199. Azithromycin standard powder was dissolved in 95% ethanol
and then in tissue culture medium or water, as appropriate. The final concentrations of ethanol in the dissolved compounds were 0.05 to
0.0004%, which were sufficient to remove the possibility of antimicrobial activity of the ethanol (P. Edelstein, unpublished data).
Levofloxacin and azithromycin preparations for intravenous administration were prepared according to the manufacturer's
instructions and were diluted so that the volume administered was 1 ml.
The gemifloxacin concentrations used for the pharmacokinetic and
treatment studies were 4 and 3 mg/ml, respectively, and these were
prepared within 1 h of injection.
Antimicrobial susceptibility testing.
Broth microdilution
susceptibility testing was performed using
N-(2-acetamido)-2-aminoethanesulfonic acid (ACES)-buffered yeast extract broth supplemented with 0.1% Growth inhibition in alveolar macrophages.
Guinea pig
pulmonary alveolar macrophages were harvested and purified as described
previously (9). The final concentration of macrophages was
approximately 105 cells per well. Incubation
conditions for all macrophage studies were 5%
CO2 in air at 37°C.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.8.2204-2209.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
In Vitro Activity of Gemifloxacin (SB-265805,
LB20304a) against Legionella pneumophila and Its
Pharmacokinetics in Guinea Pigs with L.
pneumophila Pneumonia
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-ketoglutarate (BCYE) that
was made in our laboratory, and nonlegionellae were grown on commercial
tryptic soy agar containing 5% sheep blood (12).
Incubation of all media was at 35°C in humidified air for 24 to
48 h, depending on the organism and growth rate.
-ketoglutarate (BYE) (for Legionella) or Mueller-Hinton broth (for
non-Legionella bacteria), with a final volume of 100 µl
and a final bacterial concentration of 5 × 105 CFU/ml (15). The BYE broth
was made in our laboratory. All testing was done in duplicate, with
average results calculated using the geometric mean calculation.
agar were used to infect the macrophages. Approximately
104 bacteria were added to each well. Bacteria
were incubated with macrophages for 1 h in a shaking incubator and
then for 1 day in stationary culture, as described previously
(9). One set of replicate wells was washed (500 µl)
three times with tissue culture medium and then sonicated at low energy
to release intracellular bacteria, which were quantified using BCYE
agar. Antimicrobials were then added to the washed nonsonicated wells;
several wells had no antimicrobial added to serve as growth controls.
The infected tissue cultures were then incubated for 2 days, after
which supernatant samples were taken for quantitative culture. The
antimicrobials were then removed by washing, and the experiment was
continued for five more days, with daily quantification of L. pneumophila in well supernatants. All experiments were carried out
in duplicate or triplicate, and quantitative plating was done in
duplicate. All wells were observed microscopically daily to detect
macrophage infection and to roughly quantify numbers of macrophages in
the wells. To exclude gemifloxacin macrophage toxicity, control wells were set up that contained macrophages, tissue culture medium, and
antimicrobial agents but no bacteria. These control wells were
monitored daily by microscopy for evidence of cell death or loss from
the monolayer. Prior studies have demonstrated no macrophage toxicity
caused by levofloxacin, erythromycin, or azithromycin (10,
15). In this system there is no extracellular growth of L. pneumophila, so all increases in supernatant bacterial
concentration are the result of intracellular growth.
Guinea pig pneumonia model.
Hartley strain male guinea pigs,
300 g in weight, were used for the pneumonia model, as previously
described (5, 6). Animals were observed for illness 1 week
prior to infection; in the case of the animals used for the treatment
study, temperatures and weights were obtained during the preinfection
period. The guinea pigs were infected with L. pneumophila
serogroup 1 strain F889, which was administered by the intratracheal
route as previously described (6). About 7.3 × 106 and 3.5 × 106 CFU
were administered for the pharmacokinetic and treatment studies, respectively.
Pharmacokinetic study.
Plasma and lung specimens were
obtained from gemifloxacin-treated guinea pigs with L. pneumophila pneumonia as described previously (17).
The drug was given in a single intraperitoneal dose (10 mg/kg [4.0
mg/ml], with the injection volume dependent on individual animal
weight) to guinea pigs 1 day after infection; the mean guinea pig
weight was 332 g. At timed intervals after drug injection, anesthetized animals in groups of two or three were exsanguinated by
removal of heart blood under direct vision, followed by lung removal.
Heart blood was collected with a syringe and needle, transferred
immediately to K-EDTA tubes (Vacutainer; Becton-Dickinson, Rutherford,
N.J.), and refrigerated (5°C) immediately. Within 1 h, the
plasma was separated from the cellular blood components by
centrifugation at 5,000 × g at 5°C for 10 min and
then stored frozen at 
70°C until shipped to England on dry ice.
Gemifloxacin is stable in plasma stored at 20°C for up to 6 months
(2). Following removal the lungs were rinsed in
phosphate-buffered saline, drained on sterile cotton gauze, weighed,
and ground in a known amount of high-pressure liquid chromatography
(HPLC)-grade water; the final volume of the homogenate was measured to
determine the lung weight per volume of final homogenate. Negative
controls included guinea pig lung homogenate and plasma that had been
collected identically from normal guinea pigs given identical
anesthesia but no antimicrobial.
Drug assay. Gemifloxacin in plasma and lung homogenates was assayed by HPLC tandem mass spectrometry by SmithKline Beecham, Welwyn, England (2). The samples were prepared for direct injection onto the HPLC column by diluting them 1:6 (vol/vol) in acetonitrile containing [13C2H3]gemifloxacin (internal standard). The mobile phase was composed of 70% ammonium acetate buffer (0.01 M, pH 2.5 with trifluoroacetic acid) and 30% acetonitrile. HPLC was performed using a PLPR-S column (100 Å, 5 µm, 500 by 4.6 mm [internal diameter]; Polymer Laboratories Ltd., Shropshire, England), with a mobile-phase flow rate of 1 ml per min. Gemifloxacin and the internal standard were detected by a tandem mass spectrometer operated in positive-ion mode with multiple reaction monitoring, and quantification was achieved by comparison of the chromatographic peak areas for gemifloxacin (nominal positive ion, 390; nominal product ion, 313) and the internal standard (nominal positive ion, 394; nominal product ion, 313). Standardization curves were constructed for gemifloxacin contained in normal guinea pig plasma and lung homogenate and were found to be linear over the concentration range of 10 to 5,000 ng/ml. There was insufficient guinea pig plasma for a full validation of the method, but based on the assay of human plasma, the average within-run and between-run coefficients of variation were <11% at concentrations of 10 ng/ml and greater. The average accuracy was generally within 7% of the nominal concentration.
Animal treatment study. Guinea pigs surviving surgery were randomized into five treatment groups 1 day after infection. Starting on that day, treatment was given once daily (9 a.m.) for 2 to 5 days. All injections were given by the intraperitoneal route in a 1.0-ml volume. One group of 15 animals received gemifloxacin (10 mg/kg) given once daily for 2 days; another 14 animals received the same dosage of gemifloxacin for 5 days. A third group of 12 animals received azithromycin once daily for 2 days (15 mg/kg). The fourth and fifth groups consisted of 12 animals each and received levofloxacin (10 mg/kg) or saline (1 ml), respectively, for 5 days. Dosing of the antimicrobial agents was designed to roughly emulate expected peak levels in serum in humans as determined by pharmacokinetic studies with the animals and published studies with humans, without regard to differing drug clearances in the two different species (1, 6, 8, 15, 31). Animal weights and rectal temperatures were taken periodically during the 14-day postinfection observation period; the measurements were taken about 2 h after drug administration on all treatment days. Necropsies and quantitative lung cultures were performed on all animals that died. All animals surviving for 14 days postinfection were killed with pentobarbital. Necropsies, lung histopathology, and quantitative lung cultures were performed on half of the lowest-weight survivors from each treatment group (6). A histologic score was assigned to each lung examined, based on the percentage of consolidated lung, as previously described (6). The lower limit of detection of L. pneumophila in the lung was about 100 CFU/g. All animal studies were approved by the University of Pennsylvania Institutional Animal Care and Use Committee.
Statistical analysis.
All data analysis was performed with
the use of either Prism (version 3.02) or InStat (version 2.01)
software (GraphPad, San Diego, Calif.). Prism software was also used to
calculate pharmacokinetic parameters. A P value of 
0.05
was predefined as significant. Lung histologic scores were transformed
by a logarithmic transformation of the score plus 1 to make the
distributions Gaussian and then were analyzed by using a
repeated-measures one-way analysis of variance, with Tukey's
multiple-comparison test for post-hoc analysis. Body weight and
temperature comparisons were analyzed using one-way analysis of
variance, with Tukey's multiple comparison test for post-hoc analysis.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Broth dilution susceptibility.
The gemifloxacin MIC for
L. pneumophila strains F889 and F2111 was 0.008 µg/ml.
Azithromycin and levofloxacin MICs for the same strains were 0.06 and
0.016 µg/ml, respectively. Previous work in this laboratory showed
that the erythromycin MICs for strains F889 and F2111 were consistently
0.25 and 0.50 µg/ml, respectively (7). Gemifloxacin and
levofloxacin activities against the control S. aureus and
E. coli strains, respectively, were about twofold greater in
Mueller-Hinton broth than in BYE broth. Azithromycin activity
against the control S. aureus strain was about fourfold
greater in Mueller-Hinton broth than in BYE broth.
Antimicrobial inhibition of intracellular growth.
Both
L. pneumophila strains grown in guinea pig alveolar
macrophages were significantly inhibited by all four drugs tested (Fig.
1). Gemifloxacin was at least as active
as levofloxacin or azithromycin; all three of these drugs slowed, or
completely inhibited, bacterial regrowth after drug washout, in
comparison with erythromycin. The activities of erythromycin and
levofloxacin against both bacterial strains were similar, whereas
gemifloxacin and azithromycin demonstrated improved activity against
strain F889 in terms of either increased bacterial killing
(azithromycin) or bacterial regrowth after drug washout (gemifloxacin
and azithromycin). Interestingly, azithromycin demonstrated generally
weaker activity against strain F2111 than did either of the quinolone
antimicrobials. Gemifloxacin showed no evidence of microscopically
visible toxicity for macrophages in drug-only control wells.
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,
no-drug control; 
, gemifloxacin; 
, azithromycin; 
,
levofloxacin; 
, erythromycin.
Pharmacokinetic study.
Gemifloxacin administration (10 mg/kg)
to L. pneumophila-infected guinea pigs gave the highest
measured plasma drug concentrations of 1.3 and 1.2 µg/ml at 0.5 and
1.0 h, respectively (Fig. 2). The
highest measured lung gemifloxacin concentrations were 3.4 µg/g,
measured at both 0.5 and 1 h. A one-phase exponential-decay model
gave the best fit for the data and was used to calculate half-life. The
plasma and lung terminal-phase (
-phase) half-lives of elimination
were calculated to be 1.3 h (95% confidence interval = 0.9 to 2.0 h) and 1.5 h (95% confidence interval = 1.0 to
2.7 h), respectively. The area under the concentration-time curve from 0 to 24 h (AUC0-24) for plasma was
calculated to be 2.14 µg · h/ml, and that for the lung was
5.96 µg · h/ml. We have previously determined in the same
animal model that a single dose of levofloxacin (10 mg/kg, given
intraperitoneally) results in mean plasma and lung drug concentrations
of 2.6 µg/ml and 0.6 µg/g, respectively, at 1 h postinjection.
The half-life for levofloxacin is 1.0 h for both lung and plasma,
and the plasma AUC0-24 is 4.4 µg · h/ml
(15). Values for azithromycin (15 mg/kg, given intraperitoneally) are 0.58 µg/ml and 11.6 µg/g for serum and lung,
respectively, at 1 h postinjection. The azithromycin serum half-life is 4.7 h; the lung half-life could not be calculated because of steady to increasing concentrations over time. The azithromycin serum AUC0-24 is 7 µg · h/ml (31). Further details of the pharmacokinetics of
azithromycin and levofloxacin in guinea pigs can be found in the
references cited above.
|
) and lung (
) gemifloxacin
concentrations in guinea pigs with L. pneumophila
pneumonia. Animals were given a single 10-mg/kg dose administered by
the intraperitoneal route at time zero. Three animals were sampled at
each time point, except for two being sampled for the 3-h point. The
vertical bars represent the ranges for each time point, which unless
shown were smaller than the height of the symbol representing the mean.
The dashed lines show the one-component exponential-decay regression
curves for the data sets; r2 = 0.96 for
plasma and 0.97 for lung.
Therapy in guinea pigs.
All 15 guinea pigs treated with
gemifloxacin given for 2 days survived, as did 13 of 14 treated for 5 days. Azithromycin- and levofloxacin-treated animals also had high
survival rates. This was in contrast to 100% deaths in the 12 guinea
pigs receiving saline alone (Fig. 3). The
two deaths in the active-treatment groups occurred on the second
treatment day and after 2 days of therapy; necropsies were diagnostic
of acute consolidating pneumonia, but the lung L. pneumophila concentrations were much lower than is usually
observed for fatal acute L. pneumophila pneumonia, i.e.,
log10 4.7 and 5.3 CFU/g. In contrast, the
lung L. pneumophila concentrations for the three
saline-treated animals that died 1 day later were
log10 9.7, 9.8, and 9.9. Lung culture and
necropsy results for all saline-treated animals were diagnostic of
fatal L. pneumophila pneumonia; the mean concentration of
L. pneumophila was log10 9.9 CFU/g of
lung, with a range of log10 8.2 to 10.7 CFU/g.
Eight of the 15 lungs examined from the gemifloxacin treatment group
survivors were negative (<log10 2.0 CFU/g) for
L. pneumophila; the seven culture-positive lungs contained
an average of log10 2.3 CFU/g, with a range of
log10 2.0 to 2.7 CFU/g. There was no significant
difference in L. pneumophila lung counts or positivity rates
between the 2- and 5-day treatment groups (P > 0.2 by
the Student t test and Fisher exact test, respectively).
Three of the six lungs examined from the levofloxacin treatment group
contained L. pneumophila; these contained
log10 2.0, 2.5, and 2.9 CFU/g. Only one of six
lungs examined from the azithromycin treatment group contained L. pneumophila, at a concentration of log10 2.4 CFU/g. There were no significant differences between the four active
groups in the proportion of culture-negative survivors (P > 0.2 by the chi-square test).
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), or levofloxacin (
) or on days 1 and 2 with gemifloxacin (
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Gemifloxacin and levofloxacin were equally active against intracellular L. pneumophila. Both these drugs and azithromycin were substantially more active against the intracellular bacterium than was erythromycin. This effect was concentration dependent, but even a fourfold-higher concentration of erythromycin was less active than the other three drugs tested. Erythromycin allowed rapid regrowth of the bacterium after drug washout from the wells, in contrast to substantially delayed or absent regrowth observed with the two quinolone agents and azithromycin. Prior studies have shown that erythromycin is bacteriostatic in this and other macrophage systems, even at concentrations as high as 5 µg/ml (10, 24, 33). In contrast, gemifloxacin and levofloxacin were bactericidal against L. pneumophila in macrophages at concentrations of 1 µg/ml. Many fluoroquinolone drugs share this bactericidal activity against intracellular L. pneumophila (9, 10, 17, 22, 27, 33). All four drugs studied are concentrated in macrophages, with approximate cellular-to-extracellular ratios of 30, 5, 40 to 300, and 20 for gemifloxacin, levofloxacin, azithromycin, and erythromycin, respectively (19, 21, 25, 30-32; Critchley et al., 38th ICAAC). The approximate ratios of the cellular-to-extracellular ratios to the MICs for L. pneumophila for each drug tested are 900, 300, 3,000, and 80 for gemifloxacin, levofloxacin, azithromycin, and erythromycin, respectively. The ratios of the intracellular concentrations to MICs of these drugs explain in part their good and relative intracellular activities against L. pneumophila but do not correlate with their intracellular activities completely. A prolonged postantibiotic effect in macrophages, as observed in this study for gemifloxacin, has been regularly observed for fluoroquinolone antimicrobial agents and azithromycin tested using these methods (9, 10, 17, 29). Some bacterial strain differences were noted in these experiments, with gemifloxacin and azithromycin appearing more active against intracellular strain F889 in comparison with strain F2111. Azithromycin showed poorer activity against strain F2111 than did either of the quinolone compounds. These data may reflect the increased virulence of strain F2111 in the macrophage model and its decreased responsiveness to intracellular antimicrobials generally (7, 9-11, 15, 16).
Recently published data show that the human maximum gemifloxacin concentration in plasma (Cmax) is about 1.5 µg/ml following a 320-mg oral dose, which was achieved about 1 h after drug ingestion (1). The Cmax and time to Cmax are similar to what was observed for guinea pigs in this study, although the guinea pigs were dosed differently than the subjects in the human study. The elimination half-life of plasma gemifloxacin in humans was dose independent and had a mean value of 7.4 h. As expected, guinea pigs cleared the drug much more rapidly and had a gemifloxacin plasma elimination half-life of 1.3 h, 18% of the human value. It is very unusual for us to observe a guinea pig serum or plasma elimination half-life of greater than 2 h for any drug, which in some cases can be only 15% of the human half-life of elimination for many antimicrobial agents (9). Use of the AUC0-24/MIC ratio for prediction of drug efficacy for Legionnaires' disease has never been validated, and it may be misleading because of the great dependence of Legionnaires' disease drug efficacy on intracellular concentration. In prior studies, we have observed AUC0-24 values for trovafloxacin, levofloxacin, fleroxacin, and sparfloxacin that were 5, 9, 8, and 24%, respectively, of values for standard therapy in humans; in all of these cases the animals had excellent responses to the drugs for therapy of L. pneumophila pneumonia (P. Edelstein, unpublished data). In the present study, the plasma AUC0-24 for gemifloxacin represents approximately 21% of the human AUC0-24 (320-mg oral dose), in keeping with the values observed for other quinolone antimicrobials.
Gemifloxacin was as clinically effective as levofloxacin or azithromycin for the treatment of experimental Legionnaires' disease, despite being given for only 2 days. There was no evidence that five doses of gemifloxacin gave an advantage over two doses by the outcome measures of animal weight or temperature, survival, or bacterial lung load. Although the rate of bacterial killing in vivo was not monitored in these studies, the limited data from the two active-treatment animals that died during therapy (two doses administered) suggest that the reduction in bacterial numbers is relatively rapid with quinolone antimicrobial therapy. In contrast, treatment with erythromycin in this animal model results in a slow clearance of viable bacteria from the lungs (14-16, 18).
There was a trend for increased lung consolidation in the animal group given 2 days of gemifloxacin therapy; these histologic differences were apparent only in comparison with the azithromycin treatment group and not in comparison with either the 5-day gemifloxacin or 5-day levofloxacin treatment group. This finding may reflect the anti-inflammatory properties proposed for macrolide and azalide antimicrobials, which may also explain the reduced body temperature noted in these experiments for animals dosed with azithromycin (23, 26, 28). Alternatively, it is possible that 2 days of gemifloxacin treatment is not enough to clear all intrapulmonary bacteria, resulting in a more protracted infection and a delay in the resolution of lung consolidation. Further work investigating the in vivo killing kinetics of gemifloxacin against L. pneumophila would be required to investigate these alternative hypotheses. The lack of full weight gain observed in the azithromycin treatment group was most probably due to gastrointestinal toxicity of the drug, which is often accentuated in the guinea pig (6).
There is an excellent correlation between antimicrobial effectiveness in this animal model and antimicrobial effectiveness in humans with Legionnaires' disease (4, 5). Based on these studies, clinical trials of the effectiveness of gemifloxacin for the treatment of Legionnaires' disease are warranted.
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ACKNOWLEDGMENT |
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This work was funded by SmithKline Beecham Pharmaceuticals.
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FOOTNOTES |
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* Corresponding author. Mailing address: Clinical Microbiology Laboratory, 4 Gates, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104-4283. Phone: (215) 662-6651. Fax: (215) 662-6655. E-mail: phe{at}mail.med.upenn.edu.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, August 2001, p. 2204-2209, Vol. 45, No. 8
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.8.2204-2209.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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