Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, January 1999, p. 90-95, Vol. 43, No. 1
Departments of Pathology and Laboratory
Medicine1 and
Medicine,2 University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283
Received 30 June 1998/Returned for modification 8 September
1998/Accepted 26 October 1998
The activities of HMR 3647, HMR 3004, erythromycin, clarithromycin,
and levofloxacin for 97 Legionella spp. isolates were determined by microbroth dilution susceptibility testing. Growth inhibition of two Legionella pneumophila strains grown in
guinea pig alveolar macrophages was also determined. The concentrations required to inhibit 50% of strains tested were 0.06, 0.02, 0.25, 0.03, and 0.02 µg/ml for HMR 3647, HMR 3004, erythromycin, clarithromycin, and levofloxacin, respectively. BYE HMR 3647 (RU 6647) and HMR 3004 (RU
004 and RU 64004) are novel macrolide compounds in the ketolide class.
Ketolides are semisynthetic derivatives of erythromycin A which differ
from erythromycin A by substitution of a 3-keto group for
L-cladinose. Both HMR 3004 and HMR 3647 have a C11-C12 side
chain. HMR 3004 has a C11-C12 carbazate on which a quinoline group is
attached through a propyl chain and has been withdrawn from clinical
development. In contrast, HMR 3647 has a carbamate group on which
amidazolyl and pyridyl moieties are fixed through a propyl chain
(1, 2, 6). HMR 3647 has potent activity against many
gram-positive bacteria, including erythromycin-resistant
Streptococcus pneumoniae. It is also known to be active
against Haemophilus influenzae, many anaerobic bacteria, and
Toxoplasma gondii (3, 22, 26) and to accumulate
in polymorphonuclear neutrophils and macrophages in a nonsaturable
fashion (23, 33). HMR 3004 is also known to have excellent
activity against the same bacteria and to accumulate within human
polymorphonuclear neutrophils (1-4, 18, 19, 22, 26, 31,
32). HMR 3004 has been reported to be active against
Legionella bacteria in vitro (5). This study was
designed to determine the in vitro activities of HMR 3647 and HMR 3004 against a large number of Legionella spp. bacteria as well
as the in vivo activity of HMR 3647 for the treatment of a guinea pig
model of Legionnaires' disease. We demonstrate that HMR 3647 is at
least as active as erythromycin against Legionella spp. bacteria in vitro, in Legionella pneumophila-infected
alveolar macrophages, and in a guinea pig model of L. pneumophila pneumonia.
Bacterial strains and growth conditions.
All legionellae
studied were low-passage clinical isolates, if possible, and were
isolated by us or obtained from the American Type Culture Collection
(Table 1). Included were all known
serogroups of each Legionella species. Among the 46 L. pneumophila strains tested were 24 strains belonging
to serogroup 1. 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%
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
In Vitro Activity of the Ketolide HMR 3647 (RU
6647) for Legionella spp., Its Pharmacokinetics in Guinea
Pigs, and Use of the Drug To Treat Guinea Pigs with
Legionella pneumophila Pneumonia
ABSTRACT
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
broth did not significantly inhibit the activities of the drugs tested, as judged by the
susceptibility of the control Staphylococcus aureus strain;
however, when Escherichia coli was used as the test strain,
levofloxacin activity tested in BYE broth was fourfold lower. HMR
3647, HMR 3004, erythromycin, and clarithromycin (0.25 and 1 µg/ml)
reduced bacterial counts of two L. pneumophila strains
grown in guinea pig alveolar macrophages by 0.5 to 1 log10,
but regrowth occurred over a 2-day period. HMR 3647, erythromycin, and
clarithromycin appeared to have equivalent intracellular activities
which were solely static in nature. HMR 3004 was more active than all
drugs tested except levofloxacin. In contrast, levofloxacin (1 µg/ml)
was bactericidal against intracellular L. pneumophila
and significantly more active than the other drugs tested. Therapy
studies with HMR 3647 and erythromycin were performed in guinea pigs
with L. pneumophila pneumonia. When HMR 3647 was given
(10 mg/kg of body weight) by the intraperitoneal route to infected
guinea pigs, mean peak plasma levels were 1.4 µg/ml at 0.5 h and
1.0 µg/ml at 1 h postinjection. The terminal half-life phase of
elimination from plasma was 1.4 h. All 16 L. pneumophila-infected guinea pigs treated with HMR 3647 (10 mg/kg/dose given intraperitoneally once daily) for 5 days survived for
9 days after antimicrobial therapy, as did all 16 guinea pigs treated
with the same dose of HMR 3647 given twice daily. Fourteen of 16 erythromycin-treated (30 mg/kg/dose given intraperitoneally twice
daily) animals survived, whereas 0 of 12 animals treated with saline
survived. HMR 3647 is effective against L. pneumophila
in vitro, in infected macrophages, and in a guinea pig model of
Legionnaires' disease. HMR 3647 given once daily should be evaluated
as a treatment for Legionnaires' disease in humans.
INTRODUCTION
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
-ketoglutarate that was made in our laboratory (BCYE) and nonlegionellae were grown on commercial tryptic soy agar containing 5%
sheep blood (13). All media were incubated at 35°C in
humidified air for 24 to 48 h, depending on organism and growth
rate.
TABLE 1.
Broth dilution MICs (µg/ml) for 46 L. pneumophila strainsa
Antimicrobial agents. Standard powders of HMR 3647, HMR 3004, and levofloxacin were obtained from Hoechst Marion Roussel, Romainville, France. Clarithromycin and erythromycin standard powders were obtained from Abbott Laboratories, North Chicago, Ill. Both ketolide compounds were solubilized by acidification in glacial acetic acid (13 mM final concentration) and then diluted in sterile water for injection, USP. Levofloxacin standard powder was dissolved in sterile water for injection, USP. Erythromycin and clarithromycin standard powders were first dissolved in methanol and then diluted in water and phosphate buffer, respectively. Subsequent dilutions of the dissolved compounds were sufficient to remove the possibility of antimicrobial activity of the solubilizing agents. Erythromycin lactobionate (Abbott Laboratories) was used for the treatment study and dissolved in lactated Ringer's solution for injection, USP, to a final concentration of 9.7 mg/ml. The HMR 3647 concentrations used for the pharmacokinetic and treatment studies were 2.9 and 3.2 mg/ml, respectively, and were made within 1 h before each injection.
Antimicrobial susceptibility testing.
Microbroth dilution
susceptibility testing was performed with
n-(2-acetamido)-2-aminoethanesulfonic acid (ACES)-buffered
yeast extract broth supplemented with 0.1% -ketoglutarate (BYE)
(Legionella) or Mueller-Hinton broth
(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 by the
geometric mean calculation.
Growth inhibition in alveolar macrophages. Guinea pig pulmonary alveolar macrophages were harvested and purified as described previously (11). 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.
L. pneumophila F889 and F2111 grown overnight on BCYE 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
(11). 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 with BCYE
agar. Antimicrobial agents were then added to the washed nonsonicated
wells; several wells with no antimicrobial agent added served as growth
controls. The infected tissue cultures were then incubated for 2 days,
after which supernatant samples were taken for quantitative culture. The antimicrobial agents were then removed by washing, and the experiment continued for 5 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 ketolide or clarithromycin macrophage toxicity, control wells, containing macrophages, tissue culture medium, and antimicrobial agents, but no bacteria, were set up.
Prior studies have demonstrated no macrophage toxicity caused by
levofloxacin or erythromycin (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, 
320 g in weight, were used for the pneumonia model, as
previously described (10). Animals were observed for illness
1 week prior to infection; for the animals used in the
treatment study, temperatures and weights were obtained during the
preinfection period. The guinea pigs were infected with L. pneumophila serogroup 1, strain F889, administered by the
intratracheal route. About 6 × 106 and 4 × 106 CFU were administered for the pharmacokinetic and
treatment studies, respectively.
Pharmacokinetic study.
HMR 3647 plasma concentrations were
measured in guinea pigs with L. pneumophila pneumonia
as described previously (17). The drug was given in a single
intraperitoneal dose (10 mg/kg of body weight, 2.9 mg/ml, 1.0-ml
injection) to guinea pigs 1 day after infection; the mean guinea pig
weight was 290 g. At timed intervals after drug injection,
anesthetized animals in groups of two to three were exsanguinated by
the removal of heart blood under direct vision. Heart blood was
collected with a syringe and needle and then transferred immediately to
heparinized tubes (Vacutainer; Becton Dickinson, Rutherford, N.J.). The
heparinized blood was refrigerated immediately afterwards at 5°C.
Within 2 to 12 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 it was shipped to
France on dry ice. HMR 3647 is stable in plasma stored at 20°C for
up to a year (8). The plasma specimens were analyzed for HMR
3647 by high-pressure liquid chromatography (HPLC). Negative controls
included guinea pig plasma that had been collected from both
L. pneumophila-infected and normal guinea pigs given
identical anesthesia but no antimicrobial agent.
Drug assay.
HMR 3647 was quantified in plasma by HPLC
(Hoechst Marion Roussel) (7). The bacteria in the plasma
specimens were first inactivated by beta-irradiation of the frozen
specimens at a dose of 50 kGy, which did not cause thawing of the
samples. The samples were diluted 1:10 in normal human plasma, after
which protein was precipitated by acetonitrile addition. The
supernatant was dried under nitrogen gas and then dissolved in ammonium
acetate (0.05 M), methanol/acetonitrile (29/24) in a 60:40 volume
ratio. An internal standard (RU 66260) was added to the sample. The
mobile phase was composed of ammonium acetate (0.05 M), methanol, and acetonitrile in a 52:29:24 volume ratio. HPLC was performed with a
Purospher RP-18e 125 by 4.0 mm, 5-µm particle size column (Merck) with a mobile phase flow rate of 1 ml per min. HMR 3647 and the internal standard were detected with a fluorescence detector, with
excitation and emission wavelengths of 263 and 460 nm, respectively. HMR 3647 was quantified by the peak height ratio method in comparison with the internal standard. A standardization curve for HMR 3647 contained in normal human plasma was constructed and was found to be
linear over the concentration range of 0.005 to 1.000 µg/ml; this
result correlates with a detectable range in the original samples of
0.05 to 10 µg/ml (because of 1:10 dilution). Positive controls tested
included spiked human and guinea pig plasma. Several different tests of
the extraction and detection efficiencies of the method were performed,
including the use of spiked guinea pig plasma that was then irradiated.
These quality control tests showed combined extraction and detection
errors that ranged from 9 to +13%.
Animal treatment study. Guinea pigs surviving surgery were randomized into four treatment groups 1 day after infection. Starting on that day, treatment was given once or twice daily (9 a.m. and 4 p.m.) for 5 days. All injections were given by the intraperitoneal route, in a 1.0-ml volume. One group of 16 animals received HMR 3647 (10 mg/kg) given once daily, another 16 animals received the same dose of HMR 3647 twice daily (total daily dose, 20 mg/kg). The third group of 16 animals received erythromycin twice daily (30 mg/kg/dose, or a total daily dose of 60 mg/kg), and the last group of 12 animals received normal saline. Dosing of the antimicrobial agents was designed to roughly emulate expected peak concentrations in serum in humans, as determined by pharmacokinetic studies in the animals and published and unpublished studies in humans, without regard to difference in drug clearances between the two different species (10, 28). Animal weights and temperatures were taken periodically during the 14-day postinfection observation period. 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 the eight survivors from each treatment group with the lowest weights (10). 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 2.01) 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.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
|
|---|
Broth dilution susceptibility.
All 99 Legionella
strains tested by the agar dilution method were susceptible to low
concentrations of all five antimicrobial agents tested (Tables 1 and
2). Both HMR 3004 and levofloxacin were
equally and highly active against the bacteria tested and more active
than the other drugs tested. HMR 3647 was more active than erythromycin
but less active than clarithromycin, HMR 3004, and levofloxacin.
Notably, of the Legionella species, L. pneumophila was the most susceptible to the antimicrobial
agents tested except for HMR 3647 (Table
3). HMR 3647, HMR 3004, erythromycin,
clarithromycin, and levofloxacin MICs for L. pneumophila F889 were 0.12, 0.03, 0.25, 0.04, and 0.02 µg/ml,
respectively; respective values for strain F2111 were 0.18, 0.03, 0.50, 0.03, and 0.02 µg/ml. There were no significant differences in the
MICs of all five drugs tested for the control S. aureus
strain in BYE and Mueller-Hinton broths. However, the levofloxacin
MICs for E. coli were 2 twofold dilutions lower in
Mueller-Hinton broth than in BYE broth. Since the other agents
tested are not active against E. coli, they could not be
successfully tested with this organism.
|
|
Antimicrobial inhibition of intracellular growth. Both L. pneumophila serogroup 1 strains grown in guinea pig alveolar macrophages were significantly inhibited by all five drugs tested (Fig. 1). HMR 3647 was about as active as erythromycin and clarithromycin, while HMR 3004 and levofloxacin were significantly more inhibitory than the other drugs tested. Levofloxacin (0.25 µg/ml) was much more active than were HMR 3647, erythromycin, and clarithromycin (all 1.0 µg/ml). HMR 3004 (0.25 µg/ml) was about as active as the two macrolides and HMR 3647 (all 1.0 µg/ml). Levofloxacin was more active than HMR 3004 at an equivalent concentration. Thus, HMR 3004 and levofloxacin were the most active drugs tested in this assay, with levofloxacin the more active of the two. HMR 3647, erythromycin, and clarithromycin allowed rapid regrowth of L. pneumophila after drug washout, whereas HMR 3004 slowed regrowth. Levofloxacin did not allow any regrowth of F889 and significantly slowed the regrowth of F2111 by several days in comparison to erythromycin. No evidence of drug toxicity for macrophages was observed in drug-only control wells.
|
, no drug control; 
, clarithromycin, 1 µg/ml; 
(dotted
line), HMR 3647, 1 µg/ml; 
, levofloxacin, 0.25 µg/ml; 
,
levofloxacin, 1 µg/ml. (B) 
, erythromycin,
1 µg/ml; 
, HMR
3004, 0.25 µg/ml; 
(dotted line), HMR 3004, 1 µg/ml; Pharmacokinetic study.
HMR 3647 administration (10 mg/kg) to
L. pneumophila-infected guinea pigs gave the highest
measured plasma concentrations of 1.4 and 1.0 µg/ml at 0.5 and
1.0 h, respectively (Fig. 2). A
single-compartment exponential decay model gave the best fit for the
data and was used to calculate half-life. The plasma terminal phase
(
phase) half-life of elimination was calculated to be 1.4 h
(95% confidence interval [CI] = 1.1 to 1.9 h), based on the
single-compartment exponential decay model.
|
Therapy in guinea pigs. All guinea pigs treated with HMR 3647 given once or twice daily (10 mg/kg/dose, n = 16 in each group) survived, as opposed to 100% deaths in the 12 guinea pigs receiving saline alone (Fig. 3). Fourteen of 16 guinea pigs given erythromycin treatment twice daily (30 mg/kg/dose) survived. The two erythromycin treatment group animals that died did so on days 5 and 6 postinfection and had necropsy, lung histology, and culture findings consistent with antibiotic-associated colitis, not with fatal pneumonia. Lung culture and necropsy results of all saline-treated animals were diagnostic of fatal L. pneumophila pneumonia; the mean concentration of L. pneumophila was log10 9.2 CFU/g of lung, with a range of log10 7.6 to 9.7 CFU/g. Five of the seven lungs examined from the erythromycin treatment group survivors were positive for L. pneumophila; these contained an average of log10 3.8 CFU/g, with a range of log10 3.1 to 4.2 CFU/g. Three of the eight lungs examined from the once daily HMR 3647 treatment group contained L. pneumophila; these contained log10 3.0, 3.4, and 3.4 CFU/g. Seven of eight lungs examined from the twice daily HMR 3647 treatment group contained L. pneumophila, with an average concentration of log10 3.6 CFU/g and a range of log10 2.7 to 4.2 CFU/g. There were no significant differences between the three active groups in the proportion of culture-negative survivors (P > 0.1 by chi-square test). Animal weights and temperatures were indistinguishable for all three active treatment groups (data not shown). No significant differences in lung histopathology were observed between those examined from the erythromycin and ketolide treatment groups or between those in the once and twice daily ketolide treatment groups.
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
|
|---|
Both HMR 3647 and HMR 3004 were more active than erythromycin against Legionella species in vitro, with HMR 3004 being the most active of the two ketolides tested. Because of the intracellular residence of L. pneumophila in human infection, antimicrobial agents used to treat Legionnaires' disease need to be effective at limiting growth of the intracellular bacterium, which was demonstrated for both ketolide compounds. HMR 3647 given once or twice daily was quite effective for the treatment of a guinea pig model of L. pneumophila pneumonia, confirming its intracellular and extracellular activity.
Since the 14-OH metabolite of clarithromycin was not included in our in vitro testing, we may have underestimated the extracellular activity of clarithromycin (29). Also, the extracellular activity of one or more drugs may have been underestimated because of medium inhibition of drug activity, as evidenced by the differences in the E. coli susceptibility to levofloxacin depending on the test medium used. Greater resistance to antimicrobial agents of Legionella species other than L. pneumophila has not been reported. The large number and variety of non-L. pneumophila strains studied, greater than previously published, may account for this result. The greater apparent resistance of Legionella spp. other than L. pneumophila to several antimicrobial agents may account in part for the poorer outcome of patients with infections caused by such species (20).
HMR 3647 and clarithromycin were about as active as erythromycin for intracellular L. pneumophila. All three of these drugs were solely inhibitory for the intracellular bacterium, based on rapid regrowth of the bacterium after drug washout from the wells. Prior studies by us and others have shown that erythromycin is purely inhibitory in this and other macrophage systems, even at concentrations as high as 5 µg/ml (12, 25, 34). In contrast, HMR 3004 and levofloxacin were bactericidal against L. pneumophila in macrophages at concentrations of 1 µg/ml. Many fluoroquinolone drugs possess this bactericidal activity against intracellular L. pneumophila (11, 12, 17, 24, 27, 34). A prolonged postantibiotic effect, as observed in this study for levofloxacin and HMR 3004, has been regularly observed for fluoroquinolone antimicrobial agents tested by these methods (11, 17, 30).
The pharmacokinetic profile of plasma HMR 3647 in the guinea pig is
different from that measured in humans (28). In addition, the plasma concentrations achieved in our animal treatment study are
lower than those achieved in humans. The HMR 3647 serum half-life of
terminal elimination ( phase) in humans is about 10 to 13 h, in
contrast to the 1.4-h half-life measured in our study. Peak serum
levels in humans after chronic daily oral administration of 800 mg are
about 1.8 ± 1.1 µg/ml and occur about 2 h after administration. In contrast, the maximum plasma level we observed in
the guinea pig was 1.3 µg/ml and occurred 0.5 h after
intraperitoneal administration. The implication of these
pharmacokinetic differences for HMR 3647 treatment of Legionnaires'
disease in humans is unclear but favors at least equivalent efficacy
based on pharmacokinetic considerations alone.
HMR 3647 was about as effective as erythromycin for the treatment of
experimental Legionnaires' disease, despite the fact that it was given
only once daily and at a low dose. There was no evidence that twice
daily HMR 3647 dosing was more advantageous than once daily dosing by
any outcome measure recorded
animal weight or temperature, survival,
lung histology, or bacterial lung load. Neither HMR 3647 nor
erythromycin treatments resulted in the lung sterilization seen with
some very active fluoroquinolone antimicrobial agents or
azithromycin (14-16, 21). Regardless, HMR 3647 was
very effective in this animal model and has the potential to be as
effective in humans, because the correlation between results for
treatment of Legionnaires' disease in an animal model and humans is
excellent (9).
The apparently equivalent efficacy of once and twice daily dosing of
HMR 3647 stresses the importance of the use of animal models in
assessing the potential utility of antimicrobial agents for the
treatment of Legionnaires' disease. Such equivalence could not have
been predicted based on knowledge of HMR 3647 animal pharmacokinetics,
extracellular MICs, or intracellular infection studies. Once-daily
dosing was effective, despite drug concentrations in plasma that were
below the extracellular MIC for the infecting strain for 
18 h. Drug
persistence and activity in phagosomes may partially explain this
result, as intracellular HMR 3647 is slowly cleared from cells, albeit
completely within 2 to 3 h (23, 33). Another possible
explanation is a greater postantibiotic effect in vivo than we measured
in vitro. In addition, recovery from L. pneumophila
pneumonia occurs in the guinea pig despite the persistence of the
bacterium in the lung, which may also explain why nonbactericidal drugs
can be effective in this disease. The reason more drug was not more
effective is not known but might hinge on some sort of threshold effect
of drug clearance or effectiveness.
Based on the results of our studies, HMR 3647 should be effective for the treatment of Legionnaires' disease. This finding, plus the activity of the drug against penicillin-resistant pneumococci, may warrant human clinical trials of HMR 3647 for community-acquired pneumonia.
| |
ACKNOWLEDGMENTS |
|---|
This study was funded by Hoechst Marion Roussel, Romainville, France.
Jianjun Ren, Thao Truoung, and Masao Tateyama provided expert technical assistance.
| |
FOOTNOTES |
|---|
* 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.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
|
|---|
| 1. | Agouridas, C., A. Bonnefoy, and J. F. Chantot. 1995. In vitro antibacterial activity of RU 004, a novel ketolide highly active against respiratory pathogens, abstr. F158, p. 140. In Program and abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C. |
| 2. |
Agouridas, C.,
A. Bonnefoy, and J. F. Chantot.
1997.
Antibacterial activity of RU 64004 (HMR 3004), a novel ketolide derivative active against respiratory pathogens.
Antimicrob. Agents Chemother.
41:2149-2158 |
| 3. |
Araujo, F. G.,
A. A. Khan,
T. L. Slifer,
A. Bryskier, and J. S. Remington.
1997.
The ketolide antibiotics HMR 3647 and HMR 3004 are active against Toxoplasma gondii in vitro and in murine models of infection.
Antimicrob. Agents Chemother.
41:2137-2140 |
| 4. | Barry, A. L., P. C. Fuchs, and S. D. Brown. 1997. In vitro activity of the new ketolide HMR 3004 compared to an azalide and macrolides against Streptococcus pneumoniae and Haemophilus influenzae. Eur. J. Clin. Microbiol. Infect. Dis. 16:767-769[Medline]. |
| 5. | Bornstein, N., H. Behr, Y. Brun, and J. Fleurette. 1995. In vitro activity of RU 004 on Legionella species, abstr. F166, p. 142. In Program and abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C. |
| 6. | Bryskier, A., C. Agouridas, and J. F. Chantot. 1997. Ketolides: new semisynthetic 14-membered-ring macrolides, p. 39-50. In S. H. Zinner, L. S. Young, J. Acar, and H. C. Neu (ed.), Expanding indications for the new macrolides, azalides, and streptogramins. Marcel Dekker, Inc., New York, N.Y. |
| 7. | Dupront, A., D. Coussediere, and B. Lenfant. 1997. Assay technique of HMR 3647 in human plasma, p. 1-56. Hoechst Marion Roussel, Romainville, France. |
| 8. | Dupront, A., and B. Lenfant. 1997. Assay technique of HMR 3647 in human plasma. Addendum No. 5: 12 months stability of HMR 3647 in frozen plasma, p. 1-2. Hoechst Marion Roussel, Romainville, France. |
| 9. | Edelstein, P. H. 1995. Antimicrobial chemotherapy for Legionnaires' disease: a review. Clin. Infect. Dis. 21:S265-S276. |
| 10. | Edelstein, P. H., K. Calarco, and V. K. Yasui. 1984. Antimicrobial therapy of experimentally induced Legionnaires' disease in guinea pigs. Am. Rev. Respir. Dis. 130:849-856[Medline]. |
| 11. |
Edelstein, P. H., and M. A. C. Edelstein.
1989.
WIN 57273 is bactericidal for Legionella pneumophila grown in alveolar macrophages.
Antimicrob. Agents Chemother.
33:2132-2136 |
| 12. |
Edelstein, P. H., and M. A. C. Edelstein.
1991.
In vitro activity of azithromycin against clinical isolates of Legionella species.
Antimicrob. Agents Chemother.
35:180-181 |
| 13. |
Edelstein, P. H., and M. A. C. Edelstein.
1993.
Comparison of three buffers used in the formulation of buffered charcoal yeast extract medium.
J. Clin. Microbiol.
31:3329-3330 |
| 14. |
Edelstein, P. H.,
M. A. C. Edelstein, and B. Holzknecht.
1992.
In vitro activities of fleroxacin against clinical isolates of Legionella spp, its pharmacokinetics in guinea pigs, and use to treat guinea pigs with L. pneumophila pneumonia.
Antimicrob. Agents Chemother.
36:2387-2391 |
| 15. |
Edelstein, P. H.,
M. A. C. Edelstein,
K. H. Lehr, and J. Ren.
1996.
In-vitro activity of levofloxacin against clinical isolates of Legionella spp., its pharmacokinetics in guinea pigs, and use in experimental Legionella pneumophila pneumonia.
J. Antimicrob. Chemother.
37:117-126 |
| 16. |
Edelstein, P. H.,
M. A. C. Edelstein,
J. J. Ren,
R. Polzer, and R. P. Gladue.
1996.
Activity of trovafloxacin (CP-99,219) against Legionella isolates: in vitro activity, intracellular accumulation and killing in macrophages, and pharmacokinetics and treatment of guinea pigs with L. pneumophila pneumonia.
Antimicrob. Agents Chemother.
40:314-319 |
| 17. |
Edelstein, P. H.,
M. A. C. Edelstein,
J. Weidenfeld, and M. B. Dorr.
1990.
In vitro activity of sparfloxacin (CI-978; AT-4140) for clinical Legionella isolates, pharmacokinetics in guinea pigs, and use to treat guinea pigs with L. pneumophila pneumonia.
Antimicrob. Agents Chemother.
34:2122-2127 |
| 18. |
Ednie, L. M.,
S. K. Spangler,
M. R. Jacobs, and P. C. Appelbaum.
1997.
Antianaerobic activity of the ketolide RU 64004 compared to activities of four macrolides, five beta-lactams, clindamycin, and metronidazole.
Antimicrob. Agents Chemother.
41:1037-1041 |
| 19. |
Ednie, L. M.,
S. K. Spangler,
M. R. Jacobs, and P. C. Appelbaum.
1997.
Susceptibilities of 228 penicillin- and erythromycin-susceptible and -resistant pneumococci to RU 64004, a new ketolide, compared with susceptibilities to 16 other agents.
Antimicrob. Agents Chemother.
41:1033-1036 |
| 20. | Fang, G.-D., V. L. Yu, and R. M. Vickers. 1989. Disease due to the Legionellaceae (other than Legionella pneumophila). Historical, microbiological, clinical, and epidemiological review. Medicine (Baltimore) 68:116-132[Medline]. |
| 21. | Fitzgeorge, R. B., S. Lever, and A. Baskerville. 1993. A comparison of the efficacy of azithromycin and clarithromycin in oral therapy of experimental airborne Legionnaires' disease. J. Antimicrob. Chemother. 31(Suppl. E):171-176. |
| 22. |
Frean, J. A.,
L. Arntzen,
T. Capper,
A. Bryskier, and K. P. Klugman.
1996.
In vitro activities of 14 antibiotics against 100 human isolates of Yersinia pestis from a southern African plague focus.
Antimicrob. Agents Chemother.
40:2646-2647 |
| 23. | García, I., A. Pascula, S. Ballesta, and E. J. Perea. 1998. Uptake and intracellular activity of HMR 3647 in human phagocytic and nonphagocytic cells, abstr. A-112, p. 35. In Program and abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C. |
| 24. |
Havlichek, D.,
L. Saravolatz, and D. Pohlod.
1987.
Effect of quinolones and other antimicrobial agents on cell-associated Legionella pneumophila.
Antimicrob. Agents Chemother.
31:1529-1534 |
| 25. | Horwitz, M. A., and S. C. Silverstein. 1983. Intracellular multiplication of Legionnaires' disease bacteria (Legionella pneumophila) in human monocytes is reversibly inhibited by erythromycin and rifampin. J. Clin. Investig. 71:15-26. |
| 26. |
Jamjian, C.,
D. J. Biedenbach, and R. N. Jones.
1997.
In vitro evaluation of a novel ketolide antimicrobial agent, RU-64004.
Antimicrob. Agents Chemother.
41:454-459 |
| 27. |
Kitsukawa, K.,
J. Hara, and A. Saito.
1991.
Inhibition of Legionella pneumophila in guinea pig peritoneal macrophages by new quinolone, macrolide and other antimicrobial agents.
J. Antimicrob. Chemother.
27:343-353 |
| 28. | Lenfant, B., E. Sultan, C. Wable, M. H. Pascual, and B. H. Meyer. 1998. Pharmacokinetics of 800-mg once-daily oral dosing of the ketolide, HMR 3647, in healthy young volunteers, abstr. A-49, p. 16. In Program and abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C. |
| 29. | Martin, S. J., S. L. Pendland, C. Chen, P. C. Schreckenberger, and L. H. Danziger. 1997. In vitro activity of clarithromycin alone and in combination with ciprofloxacin or levofloxacin against Legionella spp.: enhanced effect by the addition of the metabolite 14-hydroxy clarithromycin. Diagn. Microbiol. Infect. Dis. 29:167-171[Medline]. |
| 30. |
Rajagopalan-Levasseur, P.,
E. Dournon,
G. Dameron,
J.-L. Vilde, and J.-J. Pocidalo.
1990.
Comparative postantibacterial activities of pefloxacin, ciprofloxacin, and ofloxacin against intracellular multiplication of Legionella pneumophila serogroup 1.
Antimicrob. Agents Chemother.
34:1733-1738 |
| 31. |
Schulin, T.,
C. B. Wennersten,
R. C. J. Moellering, and G. M. Eliopoulos.
1997.
In vitro activity of RU 64004, a new ketolide antibiotic, against gram-positive bacteria.
Antimicrob. Agents Chemother.
41:1196-1202 |
| 32. |
Vazifeh, D.,
H. Abdelghaffar, and M. T. Labro.
1997.
Cellular accumulation of the new ketolide RU 64004 by human neutrophils: comparison with that of azithromycin and roxithromycin.
Antimicrob. Agents Chemother.
41:2099-2107 |
| 33. |
Vazifeh, D.,
A. Preira,
A. Bryskier, and M. T. Labro.
1998.
Interactions between HMR 3647, a new ketolide, and human polymorphonuclear neutrophils.
Antimicrob. Agents Chemother.
42:1944-1951 |
| 34. |
Vildé, J. L.,
E. Dournon, and P. Rajagopalan.
1986.
Inhibition of Legionella pneumophila multiplication within human macrophages by antimicrobial agents.
Antimicrob. Agents Chemother.
30:743-748 |
Antimicrobial Agents and Chemotherapy, January 1999, p. 90-95, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Lee, J. H., Cho, Y. K., Jung, Y. S., Kim, Y. C., Lee, M. G.
(2008). Effects of Escherichia coli Lipopolysaccharide on Telithromycin Pharmacokinetics in Rats: Inhibition of Metabolism via CYP3A. Antimicrob. Agents Chemother.
52: 1046-1051
[Abstract] [Full Text] -
Sabria, M., Pedro-Botet, M. L., Gomez, J., Roig, J., Vilaseca, B., Sopena, N., Banos, V., for the Legionnaires Disease Therapy Group,
(2005). Fluoroquinolones vs Macrolides in the Treatment of Legionnaires Disease. Chest
128: 1401-1405
[Abstract] [Full Text] -
Lippert, C., Gbenado, S., Qiu, C., Lavin, B., Kovacs, S. J.
(2005). The Bioequivalence of Telithromycin Administered Orally as Crushed Tablets Versus Tablets Swallowed Whole. J Clin Pharmacol
45: 1025-1031
[Abstract] [Full Text] -
Gattringer, R., Urbauer, E., Traunmuller, F., Zeitlinger, M., Dehghanyar, P., Zeleny, P., Graninger, W., Muller, M., Joukhadar, C.
(2004). Pharmacokinetics of Telithromycin in Plasma and Soft Tissues after Single-Dose Administration to Healthy Volunteers. Antimicrob. Agents Chemother.
48: 4650-4653
[Abstract] [Full Text] -
Muller-Serieys, C., Andrews, J., Vacheron, F., Cantalloube, C.
(2004). Tissue kinetics of telithromycin, the first ketolide antibacterial. J Antimicrob Chemother
53: 149-157
[Abstract] [Full Text] -
Roig, J., Rello, J.
(2003). Legionnaires' disease: a rational approach to therapy. J Antimicrob Chemother
51: 1119-1129
[Abstract] [Full Text] -
Ackermann, G., Rodloff, A. C.
(2003). Drugs of the 21st century: telithromycin (HMR 3647)--the first ketolide. J Antimicrob Chemother
51: 497-511
[Abstract] [Full Text] -
Edelstein, P. H., Weiss, W. J., Edelstein, M. A. C.
(2003). Activities of Tigecycline (GAR-936) against Legionella pneumophila In Vitro and in Guinea Pigs with L. pneumophila Pneumonia. Antimicrob. Agents Chemother.
47: 533-540
[Abstract] [Full Text] -
Maurin, M., Bryskier, A., Raoult, D.
(2002). Antibiotic Susceptibilities of Parachlamydia acanthamoeba in Amoebae. Antimicrob. Agents Chemother.
46: 3065-3067
[Abstract] [Full Text] -
Kadota, J.-I., Ishimatsu, Y., Iwashita, T., Matsubara, Y., Tomono, K., Tateno, M., Ishihara, R., Muller-Serieys, C., Kohno, S.
(2002). Intrapulmonary Pharmacokinetics of Telithromycin, a New Ketolide, in Healthy Japanese Volunteers. Antimicrob. Agents Chemother.
46: 917-921
[Abstract] [Full Text] -
Edelstein, P. H., Shinzato, T., Edelstein, M. A. C.
(2001). BMS-284756 (T-3811ME) a new fluoroquinolone: in vitro activity against Legionella, efficacy in a guinea pig model of L. pneumophila pneumonia and pharmacokinetics in guinea pigs. J Antimicrob Chemother
48: 667-675
[Abstract] [Full Text] -
Muller-Serieys, C., Soler, P., Cantalloube, C., Lemaitre, F., Gia, H. P., Brunner, F., Andremont, A.
(2001). Bronchopulmonary Disposition of the Ketolide Telithromycin (HMR 3647). Antimicrob. Agents Chemother.
45: 3104-3108
[Abstract] [Full Text] -
Edelstein, P. H., Higa, F., Edelstein, M. A. C.
(2001). In Vitro Activity of ABT-773 against Legionella pneumophila, Its Pharmacokinetics in Guinea Pigs, and Its Use to Treat Guinea Pigs with L. pneumophila Pneumonia. Antimicrob. Agents Chemother.
45: 2685-2690
[Abstract] [Full Text] -
Edelstein, P. H., Shinzato, T., Doyle, E., Edelstein, M. A. C.
(2001). In Vitro Activity of Gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and Its Pharmacokinetics in Guinea Pigs with L. pneumophila Pneumonia. Antimicrob. Agents Chemother.
45: 2204-2209
[Abstract] [Full Text] -
Bermudez, L. E., Inderlied, C. B., Kolonoski, P., Wu, M., Aralar, P., Young, L. S.
(2001). Telithromycin Is Active against Mycobacterium avium in Mice despite Lacking Significant Activity in Standard In Vitro and Macrophage Assays and Is Associated with Low Frequency of Resistance during Treatment. Antimicrob. Agents Chemother.
45: 2210-2214
[Abstract] [Full Text] -
Jonas, D., Engels, I., Friedhoff, C., Spitzmuller, B., Daschner, F. D., Frank, U.
(2001). Efficacy of moxifloxacin, trovafloxacin, clinafloxacin and levofloxacin against intracellular Legionella pneumophila. J Antimicrob Chemother
47: 147-152
[Abstract] [Full Text] -
Namour, F., Wessels, D. H., Pascual, M. H., Reynolds, D., Sultan, E., Lenfant, B.
(2001). Pharmacokinetics of the New Ketolide Telithromycin (HMR 3647) Administered in Ascending Single and Multiple Doses. Antimicrob. Agents Chemother.
45: 170-175
[Abstract] [Full Text] -
Maurin, M., Mersali, N. F., Raoult, D.
(2000). Bactericidal Activities of Antibiotics against Intracellular Francisella tularensis. Antimicrob. Agents Chemother.
44: 3428-3431
[Abstract] [Full Text] -
Singh, K. V., Zscheck, K. K., Murray, B. E.
(2000). Efficacy of Telithromycin (HMR 3647) against Enterococci in a Mouse Peritonitis Model. Antimicrob. Agents Chemother.
44: 3434-3437
[Abstract] [Full Text] -
Rastogi, N., Goh, K. S., Berchel, M., Bryskier, A.
(2000). In Vitro Activities of the Ketolides Telithromycin (HMR 3647) and HMR 3004 Compared to Those of Clarithromycin against Slowly Growing Mycobacteria at pHs 6.8 and 7.4. Antimicrob. Agents Chemother.
44: 2848-2852
[Abstract] [Full Text] -
Yamaguchi, T., Hirakata, Y., Izumikawa, K., Miyazaki, Y., Maesaki, S., Tomono, K., Yamada, Y., Kamihira, S., Kohno, S.
(2000). In Vitro Activity of Telithromycin (HMR3647), a New Ketolide, against Clinical Isolates of Mycoplasma pneumoniae in Japan. Antimicrob. Agents Chemother.
44: 1381-1382
[Abstract] [Full Text] -
Strigl, S., Roblin, P. M., Reznik, T., Hammerschlag, M. R.
(2000). In Vitro Activity of ABT 773, a New Ketolide Antibiotic, against Chlamydia pneumoniae. Antimicrob. Agents Chemother.
44: 1112-1113
[Abstract] [Full Text] -
Dedicoat, M., Venkatesan, P.
(1999). The treatment of Legionnaires' disease. J Antimicrob Chemother
43: 747-752
[Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2010 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»