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Antimicrobial Agents and Chemotherapy, March 1999, p. 672-677, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Pharmacodynamic Comparisons of Levofloxacin,
Ciprofloxacin, and Ampicillin against Streptococcus
pneumoniae in an In Vitro Model of Infection
Melinda K.
Lacy,1,*
Wen
Lu,2
Xiaowei
Xu,2
Pamela R.
Tessier,2
David P.
Nicolau,2,3
Richard
Quintiliani,4 and
Charles H.
Nightingale4
Department of Pharmacy Practice, The
University of Kansas Medical Center, Kansas City, Kansas
66160-7231,1 and Department of Pharmacy
Research,2 Division of Infectious
Diseases,3 and Office of Research
Administration,4 Hartford Hospital,
Hartford, Connecticut 06102-5037
Received 23 January 1998/Returned for modification 7 June
1998/Accepted 8 December 1998
 |
ABSTRACT |
The increasing frequency of penicillin-resistant pneumococcus
continues to be of concern throughout the world. Newer fluoroquinolone antibiotics, such as levofloxacin, have shown enhanced in vitro activity against Streptococcus pneumoniae. In this study,
the bactericidal characteristics and pharmacodynamic profiles of
levofloxacin, ciprofloxacin, and ampicillin against four isolates of
S. pneumoniae were compared by using an in vitro model of
infection. Standard antibiotic dosing regimens which simulated the
pharmacokinetic profile observed in humans were used. Control and
treatment models were sampled for bacterial CFU per milliliter over the
duration of each 24- or 48-h experiment. In addition, treatment models were sampled for MIC determinations and drug concentration. Regrowth of
all isolates as well as an increase in MICs throughout the study period
was observed in the ciprofloxacin experiments. A limited amount of
regrowth was noted during levofloxacin therapy for one isolate;
however, no change in MIC was detected for any isolate. Ampicillin
showed rapid and sustained bactericidal activity against all isolates.
In this study, ratios of effective fluoroquinolone area under the
concentration-time curve (AUC):MIC values ranged from 30 to 55. Levofloxacin, owing to its larger AUC0-24 values, has
excellent and sustained activity against different pneumococcal strains
superior to that of ciprofloxacin.
| |
INTRODUCTION |
Streptococcus pneumoniae
continues to be the leading cause of community-acquired pneumonia,
acute sinusitis, and bacterial meningitis worldwide (1, 10, 15,
30). Penicillin resistance for pneumococcus has been reported to
be widespread since it was first noted in 1967 (17),
especially over the last 6 years (6, 14, 31). Recent
surveillance studies have shown that the frequency of S. pneumoniae with reduced susceptibility to penicillin (intermediate and resistant strains) in the United States is currently around 24 to
34% (6, 32). Therefore, the continuing trend toward penicillin resistance for S. pneumoniae is leading
clinicians to consider non-
-lactam alternatives for coverage of this
important community-acquired pathogen.
It is well established that fluoroquinolone (FQ) antibiotics have good
activity against gram-negative and atypical pathogens. However, a
review of the literature shows that treatment failures have been
reported for older FQ agents when used in patients infected with
S. pneumoniae (3, 5, 12, 18, 20, 28, 33). Since
those reports appeared, newer agents, such as levofloxacin, have been
approved for use in the United States. To further investigate the
activity of FQ antibiotics against S. pneumoniae, we
evaluated the bactericidal and pharmacodynamic profiles of levofloxacin and ciprofloxacin against four isolates with various susceptibilities. For comparative purposes, the -lactam ampicillin was also tested.
(This work was presented in part at the 20th International Congress of
Chemotherapy, Sydney, Australia, 29 June 1997 to 3 July 1997.)
| |
MATERIALS AND METHODS |
Bacterial strains and susceptibility testing.
Thirty-five
S. pneumoniae clinical isolates from Hartford Hospital were
screened for susceptibility to penicillin, ciprofloxacin, and
levofloxacin. MICs and minimum bactericidal concentrations (MBC) were
determined according to method of the National Committee for Clinical
Laboratory Standards by using a microdilution technique (23). Four isolates which displayed a range of
susceptibility profiles for penicillin, ciprofloxacin, and levofloxacin
were selected.
Antibiotics.
The following antibiotics were used: sterile
ampicillin sodium, 500 mg of powder for injection (lot F5V04A;
expiration date, June 1999; Apothecon); ciprofloxacin for intravenous
injection, 40 mg/ml (lot 5GFC; expiration date, July 1998; Bayer
Corporation); and levofloxacin standard powder (RWJ-02513-097-AQ;
potency, 969.5 mg/g; lot CRO38; expiration date 19 January 1997;
R. W. Johnson).
Bacterial growth media.
Cation-adjusted Mueller-Hinton broth
(CAMHB) (Becton Dickinson, Cockeysville, Md.) supplemented with 2.5 to
5% lysed horse blood (LHB) (Remel, Lenexa, Kans.) was used as the
bacterial growth medium in all in vitro model experiments and
susceptibility determinations. Trypticase soy agar plates (100-mm
diameter) with 5% sheep blood and Mueller-Hinton agar plates (150-mm
diameter) with 5% sheep blood (Becton Dickinson) were used for the
quantitative determinations.
In vitro model.
The in vitro model used in this study has
previously been described (13). By using a central
compartment model, bacteria were exposed to changing concentrations of
antibiotics to simulate human pharmacokinetic parameters. Each
experiment consisted of three independent models (two
antibiotic-treated models and one growth control model) which were run
simultaneously for all organisms and treatment regimens. The models
were placed in a 37°C temperature-controlled circulating water bath
for optimal temperature control, and magnetic stir bars were used in
each model to ensure adequate mixing of all contents. Fresh CAMHB
supplemented with LHB was continuously pumped into each of the models
by a peristaltic pump at rates which simulated the elimination
half-lives of the test antibiotics (for ampicillin, ciprofloxacin, and
levofloxacin the half-lives are 1, 4, and 7 h, respectively).
A starting inoculum of 106 CFU/ml was prepared from an
overnight culture of the test isolate for all model experiments. To ensure that bacteria were in logarithmic growth phase prior to antimicrobial exposure, experiments were started 1 h after
inoculation of bacteria into the models.
Twenty-four-hour studies were initially conducted for each antibiotic
against all
S. pneumoniae isolates. In the cases where
bacterial regrowth was detected at 24 h, separate 48-h experiments
were performed to further characterize antibiotic activity over
time.
Bacterial regrowth was assessed with quantitative cultures
as outlined
below. Additionally, since MIC and MBC tests were
performed on samples
obtained throughout the duration of each
experiment, any bacteria
present at the 24- or 48-h time point
were therefore
detected.
Antibiotics were added to the models to simulate intravenous (IV) bolus
dosing for the following regimens: for ampicillin,
500 mg (with test
isolate SP4) or 1,000 mg (with test isolates
SP28, SP34, and SP12) IV
every 6 h (q6h), with peak concentrations
of 50 and 25 µg/ml,
respectively; for ciprofloxacin, 400 mg IV
q12h, with a peak
concentration of 4.6 µg/ml; and for levofloxacin,
500 mg IV q24h,
with a peak concentration of 6.4 µg/ml. To confirm
the simulation of
human pharmacokinetic parameters, samples were
taken throughout the
entire duration of the model experiment and
samples were stored at
80°C until they were assayed for drug
concentration.
To assess bacterial density over time, samples were obtained from each
model and serially diluted in saline. Aliquots of each
diluted sample
were plated in triplicate for quantitative culture.
To minimize any
effect of antibiotic carryover on the less-diluted
samples, larger
plates (150-mm-diameter agar plates) were used
for detection of
bacterial growth. After 24-h incubation at 37°C,
the change in
log
10 CFU/ml at 24-h intervals was calculated and
time-kill
curves were constructed by plotting log
10 CFU/ml against
time. In addition, preliminary experiments were conducted to assess
the
influence of antibiotic carryover with each of the test agents.
As a
result of these data, the limit of quantification for ampicillin
was
determined to be 10
2 CFU/ml. No antibiotic carryover was
observed for the FQ; thus,
the limit of quantification was
10
1 CFU/ml.
Development of resistance was assessed by performing MIC and MBC
determinations on
S. pneumoniae recovered from experimental
models at 0, 6, 12, and 24 h (and at 36 and 48 h when longer
experiments
were
performed).
Antibiotic concentration determinations.
Samples of CAMHB
supplemented with LHB taken from each of the treatment models were
assayed for ampicillin, levofloxacin, and ciprofloxacin. Samples
containing the FQ were analyzed by an ion-paired validated
high-performance liquid chromatography method as previously described
(21), with modifications. CAMHB with LHB was used to prepare
standards, check samples, and dilute samples as required. Briefly, 50 µl of pipemidic acid (Sigma Chemical Co., St. Louis, Mo.) used as an
internal standard was added to 200 µl of sample or standard and
mixed. After the addition of 3.5 ml of methylene chloride (Mallinckrodt
Baker, Paris, Ky.) for ciprofloxacin-containing samples or chloroform
(Mallinckrodt Baker) for levofloxacin-containing samples, all samples
were shaken for 10 min and then centrifuged at 3,000 × g for 10 min. To the organic layer, 200 µl of 0.1-mol/liter
sodium hydroxide (Sigma Chemical Co.) was added, and all tubes were
shaken for 20 min and then centrifuged at 3,000 × g
for 15 min. Twenty microliters of the aqueous layer was injected onto a
10-µm-particle-diameter C18 column (4.6 mm [outside
diameter] by 250 mm [height]) (Nucleosil; Alltech Associates, Inc.,
Deerfield, Ill.), and fluorescence was monitored at excitation
wavelengths of 278 nm for ciprofloxacin and 282 nm for levofloxacin by
using a fluorescence detector (model 980; Applied Biosystems Inc.,
Foster City, Calif.) with a filter with an emission cutoff of 418 nm.
The mobile phase consisted of 0.01 M phosphate buffer (pH 2.5) (Sigma
Chemical Co.) with 0.01 M tetrabutylammonium hydrogen sulfate (Sigma
Chemical Co.) and acetonitrile (Mallinckrodt Baker) in an 87:13 ratio
(vol/vol) pumped at flow rates of 1.8 ml/min for ciprofloxacin and 1.4 ml/min for levofloxacin by an isocratic pump (model 510; Waters
Associates, Milford, Mass.). The assay of ciprofloxacin was linear over
the range from 0.1 to 6 µg/ml. Intrarun coefficients of variation (CVs) were 1.98% (n = 10) and 2.40% (n = 10) for the check samples with low (1 µg/ml) and high (5 µg/ml) concentrations, and interrun CVs were 2.56% (n = 9), 2.17% (n = 16), and 1.92% (n = 25) for the check samples with low (0.5 and 1 µg/ml) and high (5 µg/ml) concentrations, respectively. The assay of levofloxacin was
linear over the range from 0.1 to 10 µg/ml. Intrarun CVs were 1.24%
(n = 10) and 0.57% (n = 10), and
interrun CVs were 1.90% (n = 17) and 1.19%
(n = 17), for the low (1 µg/ml) and high (8 µg/ml)
check samples, respectively. The limit of sensitivity for both assays was 0.1 µg/ml.
Ampicillin concentrations in CAMHB with LHB were determined by a
validated bioassay method. CAMHB supplemented with LHB was
used to
prepare standards and check samples and was used to dilute
samples as
required. Antibiotic medium 11 (Difco Laboratories,
Detroit, Mich.) was
seeded with a spore suspension of
Bacillus subtilis ATCC
6633 (Difco) and poured into sterile, square petri
dishes (245 mm by
245 mm; 20-mm depth; Nalge Nunc International,
Rochester, N.Y.). After
the agar cooled and hardened, four 1/4-inch
paper discs (Schleicher and
Schuell, Inc., Keene, N.H.) spotted
with 20 µl of each standard or
sample were placed on the agar
in a random, Latin square pattern. The
bioassay plates were incubated
for 16 to 18 h at 37°C in ambient
air. Zones of inhibition around
the paper discs were measured and
concentrations in samples were
extrapolated by using the line equation
from the standard curve.
The limit of sensitivity of the ampicillin
assay was 0.5 µg/ml,
and the assay was linear over the range from 0.5 to 10 µg/ml.
Intrarun CVs were 5.40% (
n = 9) and
3.63% (
n = 9) for the check
samples with low (1.0 µg/ml) and high (7.5 µg/ml) concentrations,
respectively. Interrun
CVs were 5.7% (
n = 29) and 5.6% (
n = 29)
for the check samples with low and high concentrations,
respectively.
Pharmacokinetic and pharmacodynamic analysis.
Target human
pharmacokinetic parameters were selected prior to initiation of the
study. By using actual drug concentration data from each set of
experiments, the following parameters were determined for each
antibiotic by noncompartmental methods: peak concentration (peak),
elimination rate constant, half-life, and area under the curve (AUC).
The AUC values were calculated by the trapezoidal method. By using
experimental pharmacokinetic and screening MIC data the following
pharmacodynamic parameters were determined: peak:MIC ratio,
AUC0-24:MIC ratio (for ciprofloxacin and levofloxacin),
and time above the MIC (for ampicillin). The higher screening MIC was
used for these calculations when the MICs were one dilution apart.
| |
RESULTS |
Susceptibility testing.
Table 1
shows the preexperimental MICs of ampicillin, ciprofloxacin, and
levofloxacin against the four clinical isolates utilized in this study.
The screening MICs of penicillin for each isolate were as follows: for
SP28, 0.06 µg/ml; for SP34, 4 µg/ml; for SP12, 0.06 µg/ml; and
for SP4, 0.125 µg/ml.
Pharmacokinetic analysis.
Target pharmacokinetic parameters
and experimental pharmacokinetic data are summarized in Table
2. The FQ pharmacokinetic profiles
observed in the model were similar to that of the target values. In
addition, the variation of these profiles over the several months
required to conduct all studies of drug-isolate combinations was
minimal. While more variability was observed with the pharmacokinetic
data for ampicillin relative to targeted values, the elimination
half-life values were very similar and thus produced similar values for
time above the MIC, the important correlate related to -lactam
activity.
We are unsure why the peaks for ampicillin in the SP4 experiments were
much lower than the target values. Although unlikely,
it is possible
that these samples might have been drawn late.
In spite of the lower
peaks, the resultant AUCs and elimination
half-lives were close to the
target values. Therefore, since time
above the MIC and not magnitude of
peak concentrations is the
important pharmacodynamic parameter for
ampicillin, the effect
of the low measured peak values in this set of
experiments on
the results is not thought to be of extreme
importance.
Bactericidal activity.
The starting inocula were all within
one dilution of the target (106 CFU/ml) except for the two
cases noted below. Against SP12, the starting inoculum for levofloxacin
was slightly smaller than projected, and for ampicillin against SP4, a
slightly larger starting inoculum was used. However, neither change
appeared to have a profound influence on the bactericidal profiles of
these agents.
Figures
1 and
2 summarize the resultant kill curves for
two of the test isolates, SP34 and SP4. Plotted data are the means
for
the two treatment models and the growth control model for
each
experiment. Rapid bactericidal effect was observed for ampicillin
against all isolates; the concentrations declined to the limit
of
detection (10
2 CFU/ml) during the initial 6 h, and
regrowth was not observed
over the remaining 18 h, of the
experiments with ampicillin. Furthermore,
this was also evident in the
experiment that used 500-mg doses
of ampicillin against the isolate
with intermediate response to
penicillin, SP4.
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FIG. 1.
Bactericidal activity for SP34. AMP, ampicillin; CIP,
ciprofloxacin; CTL, control; LEV, levofloxacin.
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FIG. 2.
Bactericidal activity for SP4. AMP, ampicillin; CIP,
ciprofloxacin; CTL, control; LEV, levofloxacin.
|
|
Rapid and sustained bactericidal activity was observed for levofloxacin
against all isolates except SP4, which showed regrowth
at the end of
each dosing interval. The rates of kill for levofloxacin,
as shown by
the slopes of the resultant kill curves, were comparable
to those of
ampicillin against SP34 and
SP12.
In contrast, the rate and extent of ciprofloxacin bactericidal activity
against all isolates tested were related to in vitro
susceptibilities
over the first 24 h. However, when experiments
were continued for
an additional 24-h period, diminished bactericidal
activity was noted
for subsequent doses and regrowth was evident
for all isolates at the
conclusion of the 48-h
experiment.
Detection of resistance.
Table 1 shows the MIC values observed
throughout the study in the treatment models, indicating that
penicillin susceptibility had no impact on FQ susceptibility. Between a
1- to 2- and an 8- to 16-fold increase in ciprofloxacin MIC was
observed for all experiments, as shown in Table 1. The resultant kill
curves clearly reflect the observed changes in MIC since regrowth was
noted for each isolate. The regrowth was more pronounced during the 24- to 48-h period.
Pharmacodynamic analysis.
The pharmacodynamic results are
summarized in Table 3. All FQ peak to MIC
ratios were less than 10. Bacterial regrowth was noted when the FQ
AUC:MIC ratios were 28 or less. In the ampicillin experiments, the
proportion of the time that the drug concentrations exceeded the MIC
for the organism during the dosing interval was less than 50% only for
the penicillin-resistant isolate, SP34. However, complete bactericidal
activity against this isolate was noted, as shown by the lack of
bacterial growth in the 6-h sample after 24-h incubation.
| |
DISCUSSION |
The pharmacodynamics of the FQ are well described. It has
previously been shown that these antibiotics display
concentration-dependent bactericidal effect (4, 7, 8, 25). A
correlation of clinical and microbiologic outcomes to the AUC:MIC ratio
indicated that values of 125 or higher were predictive of clinical
cures against nosocomial pathogens when ciprofloxacin was used in
hospitalized patients (11). While peak:MIC ratios of 10:1 or
greater appear to be associated with optimal bactericidal activity, the
AUC:MIC ratio may better correlate with microbiologic effects when the peak:MIC ratio cannot be optimized (25).
The optimal AUC:MIC ratio for FQ against S. pneumoniae has
not previously been determined. In this study we showed, using a wide
range of MIC values, that the lower threshold of the AUC:MIC ratio for
this pathogen appears to be around 30, as demonstrated by a lack of
regrowth when values higher than this were achieved. Raddatz and
colleagues evaluated the pharmacodynamics of trovafloxacin and
ciprofloxacin against four penicillin-resistant isolates over 24 h
in an in vitro model of infection (26). These investigators showed that AUC:MIC values of 187.1 for trovafloxacin resulted in
superior bactericidal activity as compared with ciprofloxacin, which
resulted in regrowth at 24 h for all isolates. Resultant values
for ciprofloxacin AUC:MIC ratios were either 30.4 or 60.8. However, as
only one ciprofloxacin dose was administered over the 24-h evaluation
period in this study, the condition does not simulate actual human
pharmacokinetics when dosing q12h is utilized in patients with normal
renal function.
In this study, the development of resistance to ciprofloxacin for all
study isolates was apparent, especially after 24 h. The induction
of resistance of S. pneumoniae to FQ in vitro has been
previously reported (19). After repeated transfer in
ciprofloxacin, temafloxacin, and norfloxacin there was an 8- to 16-fold
decrease in susceptibility, while after transfer in levofloxacin only
minimal decreases in susceptibility were observed. Additionally, active efflux has been demonstrated as a mechanism of resistance to
ciprofloxacin for pneumococcus (34). In our study, the
actual mechanism of resistance to ciprofloxacin was not evaluated.
Our results seem to correlate well with published reports of
levofloxacin clinical efficacy against S. pneumoniae
(9). In summary, we have shown that complete bactericidal
activity and decreased regrowth or resistance of pneumococcus was noted when FQ AUC:MIC values were around 30.
| |
ACKNOWLEDGMENTS |
This work was supported by a grant from Ortho-McNeil Pharmaceuticals.
We thank Christina Turley for technical support and Matthew Charnas for
development of a diagram of the in vitro model of infection.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pharmacy Practice, The University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7231. Phone: (913) 588-5314. Fax: (913) 588-2355. E-mail: mlacy{at}kumc.edu.
| |
REFERENCES |
| 1.
|
Bartlett, J. G., and L. M. Mundy.
1995.
Community-acquired pneumonia.
N. Engl. J. Med.
333:1618-1624[Free Full Text].
|
| 2.
|
Bayer Corporation.
1997.
Cipro package insert.
Bayer Corporation, West Haven, Conn.
|
| 3.
|
Cooper, B., and M. Lawlor.
1989.
Pneumococcal bacteremia during ciprofloxacin therapy for pneumococcal pneumonia.
Am. J. Med.
87:475[Medline]. (Letter.)
|
| 4.
|
Craig, W. A., and S. C. Ebert.
1991.
Killing and regrowth of bacteria in vitro: a review.
Scand. J. Infect. Dis. Suppl.
74:63-70.
|
| 5.
|
Davies, B. I.,
F. P. V. Maesen, and C. Baur.
1986.
Ciprofloxacin in the treatment of acute exacerbations of chronic bronchitis.
Eur. J. Clin. Microbiol.
5:226-231[Medline].
|
| 6.
|
Doern, G. V.,
A. Brueggemann,
H. P. Holley, Jr., and A. M. Rauch.
1996.
Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.
Antimicrob. Agents Chemother.
40:1208-1213[Abstract].
|
| 7.
|
Drusano, G. L.,
D. E. Johnson,
M. Rosen, and H. C. Standiford.
1993.
Pharmacodynamics of a fluoroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas sepsis.
Antimicrob. Agents Chemother.
37:483-490[Abstract/Free Full Text].
|
| 8.
|
Dudley, M. N.
1991.
Pharmacodynamics and pharmacokinetics of antibiotics with special reference to the fluoroquinolones.
Am. J. Med.
91(Suppl. 6A):45S-50S[Medline].
|
| 9.
|
File, T. M., Jr.,
J. Segreti,
L. Dunbar,
R. Player,
R. Kohler,
R. R. Williams,
C. Kojak, and A. Rubin.
1997.
A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia.
Antimicrob. Agents Chemother.
41:1965-1972[Abstract].
|
| 10.
|
Fine, M. J.,
M. A. Smith,
C. A. Carson,
S. S. Mutha,
S. S. Sankey,
L. A. Weissfeld, and W. N. Kapoor.
1996.
Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis.
JAMA
275:134-141[Abstract/Free Full Text].
|
| 11.
|
Forrest, A.,
D. E. Nix,
C. H. Ballow,
T. F. Gross,
M. C. Birmingham, and J. J. Schentag.
1993.
Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients.
Antimicrob. Agents Chemother.
37:1073-1081[Abstract/Free Full Text].
|
| 12.
|
Frieden, T. R., and R. J. Mangi.
1990.
Inappropriate use of oral ciprofloxacin.
JAMA
264:1438-1440[Abstract/Free Full Text].
|
| 13.
|
Garrison, M. W.,
K. Vance-Bryan,
T. A. Larson,
J. P. Toscano, and J. C. Rotschafer.
1990.
Assessment of effects of protein binding on daptomycin and vancomycin killing of Staphylococcus aureus by using an in vitro pharmacodynamic model.
Antimicrob. Agents Chemother.
34:1925-1931[Abstract/Free Full Text].
|
| 14.
|
Goldstein, F. W.,
J. F. Acar, and The Alexander Project Collaborative Group.
1996.
Antimicrobial resistance among lower respiratory tract isolates of Streptococcus pneumoniae: results of a 1992-93 Western Europe and USA collaborative surveillance study.
J. Antimicrob. Chemother.
38(Suppl. A):71-84.
|
| 15.
|
Gwaltney, J. M., Jr.
1996.
Acute community-acquired sinusitis.
Clin. Infect. Dis.
23:1209-1223[Medline].
|
| 16.
|
Hampel, B.,
H. Lode,
G. Bruckner, and P. Koeppe.
1988.
Comparative pharmacokinetics of sulbactam/ampicillin and clavulanic acid/amoxicillin in human volunteers.
Drugs
35(Suppl. 7):29-33.
|
| 17.
|
Hansman, D., and M. M. Bullen.
1967.
A resistant pneumococcus.
Lancet
i:264-265.
|
| 18.
|
Kimbrough, R. C., III,
W. B. Gerecht,
F. C. Husted, and J. E. Wolfe.
1991.
The failure of ciprofloxacin to prevent the progression of Streptococcus pneumoniae infections to meningitis.
Mo. Med.
88:635-637[Medline].
|
| 19.
|
Lafredo, S. C.,
B. D. Foleno, and K. P. Fu.
1993.
Induction of resistance of Streptococcus pneumoniae to quinolones in vitro.
Chemotherapy (Basel)
39:36-39.
|
| 20.
|
Lee, B. L.,
A. M. Padula,
R. C. Kimbrough,
S. R. Jones,
R. E. Chaisson,
J. Mills, and M. A. Sande.
1991.
Infectious complications with respiratory pathogens despite ciprofloxacin therapy.
N. Engl. J. Med.
325:520-521[Medline]. (Letter.)
|
| 21.
|
Marangos, M. N.,
A. T. Skoutelis,
C. H. Nightingale,
Z. Zhu,
A. G. Psyrogiannis,
D. P. Nicolau,
H. P. Bassaris, and R. Quintiliani.
1995.
Absorption of ciprofloxacin in patients with diabetic gastroparesis.
Antimicrob. Agents Chemother.
39:2161-2163[Abstract].
|
| 22.
|
Meyers, B. R.,
P. Wilkinson,
M. H. Mendelson,
S. Walsh,
C. Bournazos, and S. Z. Hirschman.
1991.
Pharmacokinetics of ampicillin-sulbactam in healthy elderly and young volunteers.
Antimicrob. Agents Chemother.
35:2098-2101[Abstract/Free Full Text].
|
| 23.
|
National Committee for Clinical Laboratory Standards.
1997.
Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed.
Approved standard. NCCLS document M7-A4. 17(2):10-13. National Committee for Clinical Laboratory Standards, Wayne, Pa.
|
| 24.
|
Ortho Pharmaceutical Corporation.
1996.
Levaquin package insert.
Ortho Pharmaceutical Corporation, Raritan, N.J.
|
| 25.
|
Preston, S. L.,
G. L. Drusano,
A. L. Berman,
C. L. Fowler,
A. T. Chow,
B. Dornseif, et al.
1998.
Pharmacodynamics of levofloxacin, a new paradigm for early clinical trials.
JAMA
279:125-129[Abstract/Free Full Text].
|
| 26.
|
Raddatz, J. K.,
L. B. Hovde, and J. C. Rotschafer.
1996.
An in vitro pharmacodynamic (PD) evaluation of trovafloxacin (T) against four strains of penicillin (P) resistant Streptococcus pneumoniae (SP), abstr. A61, p. 12.
In
Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 27.
|
Rho, J. P.,
A. Jones,
M. Woo,
S. Castle,
K. Smith,
R. E. Bawdon, et al.
1989.
Single-dose pharmacokinetics of intravenous ampicillin plus sulbactam in healthy elderly and young adult subjects.
J. Antimicrob. Chemother.
24:573-580[Abstract/Free Full Text].
|
| 28.
|
Righter, J.
1990.
Pneumococcal meningitis during intravenous ciprofloxacin therapy.
Am. J. Med.
88:548[Medline]. (Letter.)
|
| 29.
|
Ripa, S.,
L. Ferrante, and M. Prenna.
1990.
Pharmacokinetics of sulbactam/ampicillin in humans after intravenous and intramuscular injection.
Chemotherapy (Basel)
36:185-192.
|
| 30.
|
Schuchat, A.,
K. Robinson,
J. D. Wenger,
L. H. Harrison,
M. Farley,
A. L. Reingold, et al.
1997.
Bacterial meningitis in the United States in 1995.
N. Engl. J. Med.
337:970-976[Abstract/Free Full Text].
|
| 31.
|
Simberkoff, M. S.
1994.
Drug-resistant pneumococcal infections in the United States.
JAMA
271:1875-1876[Abstract/Free Full Text]. (Editorial.)
|
| 32.
|
Thornsberry, C.,
P. Ogilvie,
J. Kahn, and Y. Mauriz.
1997.
Surveillance of antimicrobial resistance in S. pneumoniae (Sp), H. influenzae (Hi), and M. catarrhalis (Mc) in the U.S. during the 1996-97 respiratory season.
Clin. Infect. Dis.
25:364. (Abstract 52.)
|
| 33.
|
Thys, J. P.
1988.
Quinolones in the treatment of bronchopulmonary infections.
Rev. Infect. Dis.
10(Suppl. 1):S212-S217.
|
| 34.
|
Zeller, V.,
C. Janoir,
M.-D. Kitzis,
L. Gutmann, and N. J. Moreau.
1997.
Active efflux as a mechanism of resistance to ciprofloxacin in Streptococcus pneumoniae.
Antimicrob. Agents Chemother.
41:1973-1978[Abstract].
|
Antimicrobial Agents and Chemotherapy, March 1999, p. 672-677, Vol. 43, No. 3
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Abstract
Introduction
