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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, March 2000, p. 633-639, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Activities and Postantibiotic Effects of
Gemifloxacin Compared to Those of 11 Other Agents against
Haemophilus influenzae and Moraxella
catarrhalis
Todd A.
Davies,1
Linda M.
Kelly,1
Dianne B.
Hoellman,1
Lois M.
Ednie,1
Catherine L.
Clark,1
Saralee
Bajaksouzian,2
Michael R.
Jacobs,2 and
Peter C.
Appelbaum1,*
Department of Pathology, Hershey Medical
Center, Hershey, Pennsylvania 17033,1 and
Department of Pathology, Case Western Reserve University,
Cleveland, Ohio 441062
Received 29 July 1999/Returned for modification 23 November
1999/Accepted 8 December 1999
 |
ABSTRACT |
The activity of gemifloxacin against Haemophilus
influenzae and Moraxella catarrhalis was compared to
those of 11 other agents. All quinolones were very active (MICs,
0.125 µg/ml) against 248 quinolone-susceptible H. influenzae isolates (40.7% of which were 
-lactamase
positive); cefixime (MICs, 0.125 µg/ml) and amoxicillin-clavulanate (MICs 4.0 µg/ml) were active, followed by cefuroxime (MICs, 16.0 µg/ml); azithromycin MICs were 4.0 µg/ml. For nine H. influenzae isolates with reduced quinolone susceptibilities, the
MICs at which 50% of isolates are inhibited (MIC50s) were
0.25 µg/ml for gemifloxacin and 1.0 µg/ml for the other quinolones
tested. All strains had mutations in GyrA (Ser84, Asp88); most also had
mutations in ParC (Asp83, Ser84, Glu88) and ParE (Asp420, Ser458), and
only one had a mutation in GyrB (Gln468). All quinolones tested were equally active (MICs, 0.06 µg/ml) against 50 M. catarrhalis strains; amoxicillin-clavulanate, cefixime,
cefuroxime, and azithromycin were very active. Against 10 H. influenzae strains gemifloxacin, levofloxacin, sparfloxacin, and
trovafloxacin at 2× the MIC and ciprofloxacin at 4× the MIC were
uniformly bactericidal after 24 h, and against 9 of 10 strains
grepafloxacin at 2× the MIC was bactericidal after 24 h. After
24 h bactericidal activity was seen with amoxicillin-clavulanate
at 2× the MIC for all strains, cefixime at 2× the MIC for 9 of 10 strains, cefuroxime at 4× the MIC for all strains, and azithromycin at
2× the MIC for all strains. All quinolones except grepafloxacin (which
was bactericidal against four of five strains) and all ß-lactams at
2× to 4× the MIC were bactericidal against five M. catarrhalis strains after 24 h; azithromycin at the MIC was
bactericidal against all strains after 24 h. The postantibiotic
effects (PAEs) against four quinolone-susceptible H. influenzae strains were as follows: gemifloxacin, 0.3 to 2.3 h; ciprofloxacin, 1.3 to 4.2 h; levofloxacin, 2.8 to 6.2 h;
sparfloxacin, 0.6 to 3.0 h; grepafloxacin, 0 to 2.1 h;
trovafloxacin, 0.8 to 2.8 h. At 10× the MIC, no quinolone PAEs
were found against the strain for which quinolone MICs were increased.
Azithromycin PAEs were 3.7 to 7.3 h.
| |
INTRODUCTION |
Although the development of an
effective vaccine against Haemophilus influenzae type b has
led to the disappearance of this organism from many parts of the world,
untypeable H. influenzae strains, followed by
Streptococcus pneumoniae and Moraxella
catarrhalis, are now considered the leading cause of acute
exacerbations of chronic bronchitis and an important cause, together
with S. pneumoniae and M. catarrhalis, of acute
otitis media, sinusitis, and community-acquired respiratory tract
infections (4, 6, 8, 18).
Current recommendations by the National Committee for Clinical
Laboratory Standards (NCCLS) for the use of Haemophilus test medium (HTM) for Haemophilus susceptibility testing have
been complicated by difficulty with the commercial manufacture of this medium and its short shelf-life when it is made in-house
(8).
Gemifloxacin (SB 265805; LB 20304a) is a new broad-spectrum
fluoronaphthyridone carboxylic acid with a novel pyrrolidone
substituent. Preliminary studies have shown that this compound is very
active against H. influenzae and M. catarrhalis (2, 7, 11). This study examined the
activity of gemifloxacin against these species by (i) the NCCLS
microdilution MIC methodology to test the activities of
gemifloxacin, ciprofloxacin, levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin, ampicillin, amoxicillin, amoxicillin-clavulanate, cefixime, cefuroxime, and azithromycin against 257 H. influenzae and 50 M. catarrhalis strains; (ii) testing
the MICs for and the resistance mechanisms of 9 H. influenzae strains with reduced fluoroquinolone susceptibilities;
(iii) testing the killing kinetics of the compounds listed above
against 10 H. influenzae and 5 M. catarrhalis
strains; and (iv) testing the postantibiotic effects (PAEs) of the
compounds listed above against 5 H. influenzae strains.
| |
MATERIALS AND METHODS |
Bacteria and antimicrobial agents.
Strains (248 quinolone-susceptible H. influenzae strains, 9 H. influenzae strains with reduced quinolone susceptibility, and 50 M. catarrhalis strains) were isolated from clinical
specimens within the past 2 years and were stored at 
70°C in
double-strength skim milk (Difco Laboratories, Detroit, Mich.) prior to
use. H. influenzae strains with reduced fluoroquinolone
susceptibilities compared to those of strains usually encountered (see
Table 1) were recovered from patients in Western Europe and were
obtained from David Felmingham (GR Micro, London, United Kingdom).
Gemifloxacin powder for susceptibility testing was obtained from
SmithKline Beecham Laboratories, Harlow, United Kingdom. The other
drugs were obtained from their respective manufacturers.
MIC determination.
ß-Lactamase production was tested by the
nitrocefin disk method (Cefinase; BBL Microbiology Systems, Sparks,
Md.). MICs were determined by the NCCLS microdilution method
(10) with HTM in frozen 96-well trays (Medical Specialties,
Inc., Cleveland, Ohio). The HTM used in the trays was freshly prepared,
and its growth properties were confirmed. The quinolone-susceptible
H. influenzae strains comprised 50 type b strains and 198 untypeable strains. Inocula were prepared from chocolate agar plates
incubated for a full 24 h by the direct colony suspension method,
as follows. In a tube of Mueller-Hinton broth (Difco), an organism
suspension was made to a density of a 0.5 McFarland standard
(108 CFU/ml). The latter inoculum was diluted in sterile
saline such that the final organism suspensions in the trays yielded
colony counts of 3 × 105 to 8 × 105
CFU/ml. Inoculum checks were performed for all strains, and testing was
repeated if the inocula were not in the correct range.
Wells were inoculated by use of disposable inoculators, and the trays
were incubated in ambient air at 35°C for 20 to 24 h. The lowest
drug concentration at which no growth occurred was read as the MIC.
Clavulanate was added to amoxicillin at a ratio of 1:2. Standard
quality control strains, including H. influenzae ATCC 49766, H. influenzae ATCC 49247, Staphylococcus aureus
ATCC 29213, and Escherichia coli ATCC 25922, were included
with each run.
Time-kill studies.
Ten H. influenzae strains
(five ß-lactamase positive strains), including one strain for which
quinolone MICs were increased, and five ß-lactamase-positive M. catarrhalis strains were tested. Glass tubes containing 5 ml of
HTM with doubling antibiotic concentrations were inoculated with
approximately 5 × 105 of organism per ml (5 × 105 to 5 × 106 CFU/ml) and were incubated
at 35°C in a shaking water bath. Antibiotic concentrations were
chosen to comprise three doubling dilutions above and three dilutions
below the MIC determined by the broth microdilution method. Freshly
made batches of HTM were used for all tests. The dilutions required to
obtain the correct inoculum (approximately 5 × 105
CFU/ml) were determined by prior viability studies with each strain
(12, 13).
To inoculate each tube of serially diluted antibiotic, 30 µl of
diluted inoculum was delivered beneath the surface of the broth with a
pipette. The tube was then vortexed and the contents were plated for
viability counts (0 h). Only tubes containing an initial inoculum
within the range of 5 × 105 to 5 × 106 CFU/ml were acceptable.
The viability counts of the antibiotic-containing suspensions were
determined at 0, 3, 6, 12, and 24 h by plating 10-fold dilutions
of 0.1-ml aliquots from each tube in Mueller-Hinton broth (BBL) onto
chocolate agar plates. Recovery plates were incubated for up to 48 h. Colony counts were determined for plates that yielded 30 to 300 colonies (12, 13).
The lower limit of sensitivity of the colony count determinations was
300 CFU/ml. Time-kill data were analyzed by determining the number of
strains which yielded changes of 1 2, and 3 log10 CFU/ml at 0, 3, 6, 12, and 24 h compared to the counts at time zero. Antimicrobial agents were considered bactericidal if they reduced
the original inoculum by 
3 log10 CFU/ml (99.9%) at each of the time periods and bacteriostatic if they reduced the inoculum by
0 to <3 log10 CFU/ml. With the sensitivity threshold and
inocula used in these studies, no problems were encountered in
delineating 99.9% killing, when it was present. The problem of
antibiotic carryover was addressed as described previously (12,
13). Amoxicillin and ampicillin were not tested against
ß-lactamase-positive H. influenzae and M. catarrhalis strains.
Measurement of PAE.
The PAE (3) was determined by
the viable plate count method with freshly made HTM. The bacterial
inoculum was prepared by suspending growth from an overnight chocolate
agar plate in broth. The suspension was diluted in Mueller-Hinton broth
until the turbidity matched that of a no. 1 McFarland standard
(approximately 5 × 108 CFU/ml) (3, 14,
15).
For PAE experiments, tubes with 5 ml of broth and the antibiotic to be
tested at 10× the MIC were inoculated with 50 µl of inoculum to
provide 5 × 106 CFU/ml. The tubes were then vortexed,
and the contents were plated for viability count determinations. Growth
controls with inoculum but no antibiotic were included with each
experiment. The inoculated test tubes were then placed in a shaking
water bath at 35°C for 1 h. At the end of the 1-h period,
cultures were diluted 1:1,000 in prewarmed HTM broth to remove the
antibiotic. An additional control culture containing bacteria and
antibiotic at a concentration of 0.01× the MIC was prepared to confirm
that after dilution the antibiotic is no longer bacteriostatic (3,
14, 15).
Viability counts were determined before exposure and immediately after
dilution (0 h) and then every 2 h until the turbidity of the tube
reached that of a no. 1 McFarland standard. Viability counts studies
were performed by preparing 10-fold dilutions of 0.1-ml aliquots from
each tube in Mueller-Hinton broth and plating 0.1-ml volumes onto
chocolate agar plates. Recovery plates were incubated for 24 h,
and colony counts were determined for plates that yielded 30 to 300 colonies (3, 14, 15).
The PAE was defined as described by Craig and Gudmundsson as
T C, where T is the time
required for viability counts of an antibiotic-exposed culture to
increase by 1 log10 above the counts observed immediately
after dilution and C is the corresponding time for the
growth control. For each experiment, viability counts, expressed as
log10 CFU per milliliter, were plotted against time. Results were expressed as the means of two separate assays
(3).
PCR and DNA sequencing of quinolone resistance-determining
regions of parC, parE, gyrA, and
gyrB.
Template DNA for PCR was prepared as follows. A colony
from an overnight growth was lysed by incubation for 1 h at 37°C
in lysis buffer (6 mM Tris-HCl [pH 7.4], 1 M NaCl, 10 mM EDTA [pH 8.0], 0.2% deoxycholate, 0.5% sodium lauroyl sarcosine) to which lysozyme (Sigma, St. Louis, Mo.) at 0.5 mg/ml and lysostaphin (Sigma)
at 0.05 mg/ml were added fresh. DNA was isolated from the lysed cells
with a Prep-A-Gene kit (Bio-Rad, Hercules, Calif.) as recommended by
the manufacturer. PCR was carried out in a final volume of 100 µl
containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM
MgCl2, each deoxynucleoside triphosphate at a concentration of 200 µM, 5 pmol of each primer, 5 to 10 ng of DNA template, and 2.5 U of Taq DNA polymerase (Fisher Biotech). Conditions for PCR
were 30 cycles of 94°C for 1 min, annealing at 53°C for 1 min, and
extension at 72°C for 3 min. For parC a 370-bp region encoding residues 41 to 163 was amplified with primers HFPAR CUP (5'-TGGTTTAAAACCCGTTCA-3'; nucleotide positions 120 to 137)
and HFPARCDN (5'-AGCAGGTAAATATTGTGG-3'; positions 473 to
490). For parE a 471-bp region encoding residues 335 to 491 was amplified with primers HFPAREUP (5'-GAACGCTTATCATCACGCCA-3';
positions 1003 to 1022) and HFPAREDN
(5'-AGCATCCGCGAGAATACAGA-3'; positions 1454 to 1473). For
gyrA a 375-bp region encoding residues 47 to 171 was
amplified with primers HFGYRAUP (5'-CCGCCGCGTACTGTTCT-3'; positions 138 to 154) and HFGYRADN (5'-CCATTTGCTAAAAGTGC-3';
positions 496 to 512). For gyrB a 445-bp region
encoding residues 367 to 513 was amplified with primers HFGYRBFOR
(5'-GGAAAATCCTGCAGATGC-3'; positions 1095 to 1113) and
HFGYRBBAC (5'-AAGCAACGTACGGATGTG-3'; positions 1522 to
1539). After amplification the PCR products were purified from excess
primers and nucleotides with a QIAquick PCR purification kit (Qiagen,
Valencia, Calif.) and were sequenced directly by using an Applied
Biosystems model 373A DNA sequencer. The products of independent PCRs
were sequenced twice in the forward and reverse directions.
| |
RESULTS |
The results of microdilution testing of quinolone-susceptible
strains are presented in Table 1. All
quinolones were very active (MICs, 0.125 µg/ml) against 248 quinolone-susceptible H. influenzae (40.9% of which were
ß-lactamase positive); cefixime (MICs, 0.125 µg/ml) and
amoxicillin-clavulanate (MICs, 4.0 µg/ml) were very active,
followed by cefuroxime (MICs, 16.0 µg/ml); azithromycin MICs were
all 4.0 µg/ml. All quinolones were equally active (MICs, 0.06
µg/ml) against 50 M. catarrhalis (all of which were
ß-lactamase positive); amoxicillin-clavulanate, cefixime, cefuroxime,
and azithromycin were also very active.
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TABLE 1.
MICs for 248 H. influenzae and 50 M. catarrhalis (all quinolone susceptible) strains determined by the
broth microdilution method
|
|
For nine H. influenzae strains with reduced fluoroquinolone
susceptibilities, the MICs at which 50% of isolates are inhibited (MIC50s) were 0.25 µg/ml (highest MIC, 1.0 µg/ml) for
gemifloxacin, whereas they were 1.0 µg/ml (highest MIC, 8.0 µg/ml)
for the other quinolones tested (Table
2). The mechanisms of quinolone
resistance in the H. influenzae strains are presented in
Table 3. All nine strains had mutations
at Ser84 in GyrA, with Ser84 to Leu, Phe, or Tyr being observed.
Additional mutations in GyrA at Asp88 to Asn or Tyr and Ala117 to Glu
were also observed in some strains. Most strains also had at least one
mutation in ParC (at Asp83, Ser84, Glu88, Ser133, or Asn138) and ParE
(at Gly405, Asp420, Ser458, or Ser474). Strain 4 had an in-frame
insertion in parE that led to an insertion of a Ser residue
between Ser458 and Thr459. Only one strain had a mutation in GyrB (at
Gln468). The most resistant strain (strain 9) had double mutations in
GyrA, ParC, and ParE.
Killing kinetic results for the 10 H. influenzae strains for
which killing kinetics were tested are presented in Fig.
1, and those for the 5 M. catarrhalis strains are presented in Fig.
2. Of the quinolones
tested, gemifloxacin, levofloxacin, sparfloxacin, and trovafloxacin at
2× the MIC and ciprofloxacin at 4× the MIC were bactericidal against
all 10 H. influenzae strains after 24 h, and
grepafloxacin at 2× the MIC was bactericidal against 9 of 10 strains
after 24 h. Gemifloxacin at 2× the MIC was bactericidal against 9 of 10 strains after 12 h and showed killing at earlier time
periods. The killing kinetics of the other quinolones tested were
similar to those of gemifloxacin except for the slightly more rapid
killing of levofloxacin, especially at earlier time periods. Of the
other compounds tested, bactericidal activity after 24 h was found
with amoxicillin-clavulanate at 2× the MIC for all 10 strains,
cefixime at 2× the MIC for 9 of 10 strains, cefuroxime at 4× the MIC
for all 10 strains, and azithromycin at 2× the MIC for all strains.
For the five M. catarrhalis strains, all quinolones except
grepafloxacin (which was bactericidal against four of five strains) and
all ß-lactams were uniformly bactericidal at 2× to 4× the MIC after
24 h, with slower but significant killing at earlier time periods;
azithromycin at the MIC was bactericidal against all five strains after
24 h.
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FIG. 1.
Results of time-kill studies for 10 H. influenzae strains that exhibited decreases of 1 ( ), 2 ( ),
or 3 ( )
log 10 CFU/ml compared to the numbers at time zero. *, the lowest
multiple of the MIC that resulted in the observed killing for the most
strains is indicated above each bar. Only five ß-lactamase-negative
strains were tested with ampicillin and amoxicillin.
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FIG. 2.
Results of time-kill studies for five M. catarrhalis strains that exhibited decreases of 1 (), 2 (),
or 3 (),
log10 CFU/ml compared to the numbers at time zero. *, the
lowest multiple of the MIC that resulted in the observed killing for
the most strains is indicated above each bar. Because all strains were
ß-lactamase positive, amoxicillin and ampicillin were not tested.
|
|
PAEs were tested against five H. influenzae strains; four
were quinolone susceptible and the quinolone MICs were increased for
one strain. Three strains (including the strain for which the quinolone
MICs were increased) were ß-lactamase positive. The PAEs of the
antibiotics against the four quinolone-susceptible strains were as
follows: gemifloxacin, 0.3 to 2.3 h; ciprofloxacin, 1.3 to
4.2 h; levofloxacin, 2.8 to 6.2; sparfloxacin, 0.6 to 3.0 h;
grepafloxacin, 0 to 2.1 h; and trovafloxacin, 0.8 to 2.8 h. The PAEs of azithromycin against the five strains were 3.7 to 7.3 h. ß-Lactams had no PAEs against four strains, and PAEs of 0.2 to
1.7 h were detected against one ß-lactamase-negative strain. At
10× the MIC, no PAEs of the quinolones were found against the strain
for which the quinolone MICs were increased.
| |
DISCUSSION |
Previous studies have shown that gemifloxacin is 32- to 64-fold
more active than ciprofloxacin, ofloxacin, sparfloxacin, and trovafloxacin against S. pneumoniae, methicillin-susceptible
and -resistant S. aureus, and methicillin-resistant
Staphylococcus epidermidis. Gemifloxacin was also highly
active against most members of the family
Enterobacteriaceae, with gemifloxacin having activity more
potent than those of sparfloxacin and ofloxacin and activity comparable
to that of ciprofloxacin. Gemifloxacin was the most active agent
against gram-positive species resistant to other quinolones and
glycopeptides. Gemifloxacin has variable activity against anaerobes
(2, 7, 11).
In our study, all quinolones were very active against
quinolone-susceptible strains of H. influenzae and M. catarrhalis. However, only gemifloxacin had MICs of 1.0 µg/ml
for the rare strains of H. influenzae for which quinolone
MICs were increased. Previous studies (1, 5, 16) have shown
that the primary target of quinolones in H. influenzae is
GyrA; low-level resistance is associated with a mutation in GyrA (Ser84
or Asp88), and high-level resistance is associated with an additional
mutation in ParC (Asp83, Ser84, or Glu88). Sequencing results from our
study were in agreement with those reports, as all nine strains had at
least one mutation in GyrA and the most resistant strains
(ciprofloxacin MICs, 1.0 µg/ml) had an additional mutation in ParC.
In addition, mutations were found in GyrA (Ala117) and ParC (Ser133,
Asn138), which have not been previously reported. This is also the
first study of which we are aware that examined mutations in GyrB and
ParE in H. influenzae: most strains had mutations in ParE,
but only one strain had a mutation in GyrB. Of particular interest was
insertion of a serine between the serine at position 458 and the
threonine at position 459 of ParE in one strain. It therefore appears
that ParE may be more important than GyrB in quinolone resistance in H. influenzae.
All quinolone and nonquinolone compounds tested had good killing
activities relative to their MICs for the H. influenzae and M. catarrhalis strains tested, with azithromycin having the
slowest killing kinetics. At an MIC of 0.5 µg/ml, gemifloxacin also
showed good killing of the one H. influenzae strain for
which quinolone MICs were increased. A slightly improved killing
activity of levofloxacin at earlier time periods compared to those of
the other quinolones tested and a uniform bactericidal activity of
azithromycin at the MIC or 2× the MIC against H. influenzae
after 24 h have been described (12, 17).
All quinolones had PAEs against all quinolone-susceptible strains
tested, and azithromycin had PAEs against all strains. A lack of
significant PAEs of ß-lactams against gram-negative rods has been
described before (3). The PAEs of the quinolones and azithromycin against H. influenzae detected in the present
study are similar to those previously reported for other organisms
(9, 14, 15).
Although strains of H. influenzae with decreased
fluoroquinolone susceptibilities are extremely rare at present,
isolated reports of such strains have appeared in the literature
(1, 16). For an isolate from one patient (16), an
increase in quinolone MICs occurred while the patient was receiving
ofloxacin therapy. If the broad-spectrum quinolones are overused, and
particularly if their use is extended to the pediatric population, the
likelihood of an increase in the numbers of quinolone-resistant
H. influenzae isolates (and perhaps M. catarrhalis isolates) is great.
The results of this study indicate that gemifloxacin has good activity
(comparable to those of other quinolones) against quinolone-susceptible H. influenzae and M. catarrhalis strains
according to MIC determinations and time-kill studies and also that
gemifloxacin had PAEs (albeit slightly shorter than those of the other
quinolones tested) against quinolone-susceptible H. influenzae strains. Because of the wide spectrum of activity of
gemifloxacin against other respiratory pathogens, such as pneumococci
(including quinolone-resistant strains), Legionella,
mycoplasmas, and chlamydia, this compound represents an attractive
addition to other quinolone and nonquinolone agents for empiric
treatment of community-acquired respiratory tract infections,
particularly community-acquired pneumonia. Clinical studies will be
necessary to validate this hypothesis.
| |
ACKNOWLEDGMENTS |
This study was supported by a grant from SmithKline Beecham
Laboratories, Collegeville, Md.
We thank D. Felmingham (London, United Kingdom) for provision of
H. influenzae strains for which quinolone MICs were increased.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail:
pappelbaum{at}psghs.edu.
| |
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Activity of HMR 3647 compared to those of five agents against Haemophilus influenzae and Moraxella catarrhalis by MIC determination and time-kill assay.
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MIC and time-kill study of activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem, and vancomycin against nine penicillin-susceptible and -resistant pneumococci.
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Antimicrobial Agents and Chemotherapy, March 2000, p. 633-639, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
