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Antimicrobial Agents and Chemotherapy, March 1999, p. 667-671, Vol. 43, No. 3
The R. W. Johnson Pharmaceutical
Research Institute, Raritan, New Jersey 08869
Received 10 February 1998/Returned for modification 25 May
1998/Accepted 23 December 1998
Oral levofloxacin was compared to oral ciprofloxacin in a
Staphylococcus aureus subcutaneous abscess model in
rabbits. Rabbits were surgically prepared with subcutaneous wiffle
balls (43 mm in diameter) and allowed to recover for 4 to 6 weeks.
Rabbits were infected by direct injection into the capsule with
S. aureus ATCC 29213 (5 × 105 CFU) and
were allowed to remain infected for 8 days before the initiation of
anti-infective treatment. Efficacy was determined by assessing the
bacterial load within the capsule over a 10-day treatment period. In
single-dose pharmacokinetic studies in infected rabbits, similar area
under the concentration-time curve/MIC ratios were obtained in the
plasma and abscess fluid for levofloxacin at 45 mg/kg of body weight
and ciprofloxacin at 200 mg/kg of body weight. Similar efficacies were
seen with levofloxacin at 45 mg/kg/day and ciprofloxacin 400 mg/kg/day
by day 10. In this model, levofloxacin was significantly more
efficacious than ciprofloxacin (P < 0.01).
Treatment of deep, nondraining
abscesses clinically is often met with difficulty and sometimes with
clinical failure. Some of the reasons for treatment failure are low
concentrations of anti-infective agents at the infection site, large
numbers of bacteria in the stationary phase, low pH, and high protein
content within the abscess (12). It has been shown in an
uninfected peritoneal capsule model that drug penetration rate,
extravascular drug elimination rate, and free (not protein bound) drug
molecules are related to the agent's ability to penetrate into
capsular fluid (9). Also, slow capsule kinetics (penetration
and elimination) have been shown to be important factors contributing
to the drug's ability to cure an abscess infection (7). In
effect, if the drug can penetrate the abscess, its efficacy will be
aided by the slower elimination kinetics.
In an acute subcutaneous rabbit abscess model, ciprofloxacin was shown
to be effective against gram-negative bacilli (4). More
recently, Bamberger et al. have shown that ciprofloxacin (1)
was not effective, while cefazolin (1), cefmetazole (1), and ofloxacin (2) were moderately effective,
and azithromycin (3) and combinations of ciprofloxacin plus
rifampin (1) and ofloxacin plus rifampin (2) were
highly effictive in killing Staphylococcus aureus in a
peritoneal abscess model. To date, there has been no report of a
fluoroquinolone alone being highly effective in curing a staphylococcal
infection in a rabbit abscess model.
Levofloxacin, the active L-isomer of the racemate ofloxacin, has
broad-spectrum activity against both gram-positive and gram-negative bacteria (6). Because levofloxacin is nearly 100% orally
bioavailable (5), it has an advantage over other
fluoroquinolones that have a broad spectrum of activity but limited
oral bioavailability. In this study, we compared the in vivo efficacies
of orally administered levofloxacin and ciprofloxacin in a rabbit model
of a subcutaneous staphylococcal abscess.
(This paper was presented in part at the 37th Interscience Conference
on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 28 September to 1 October 1997 [abstr. B-105].)
Surgical preparation and animal care.
Female New Zealand
White rabbits (Covance, Inc., Denver, Pa.), weighing between 3.0 and
4.1 kg, were anesthetized, and a single, sterile golf practice wiffle
ball (43 mm in diameter; Wilson Sporting Goods, Chicago, Ill.) was
surgically implanted in the dorsal cervical area. The rabbits were
given a single 0.1-mg/kg (body weight) dose of butorphanol (Torbugesic;
Fort Dodge Laboratories, Fort Dodge, Iowa) intravenously for the
reduction of pain and also a single 84,000-IU/kg dose of penicillin
G-procaine-benzathine (PenG; Phoenix Pharmaceutical, Inc., St. Joseph,
Mo.) subcutaneously for the prevention of infection following surgery.
The rabbits were given a 4- to 6-week recovery period before the
initiation of any studies. During this recovery period, the rabbits
were observed daily, and the Wiffle ball (capsule) became walled off and filled with sterile fluid. All protocols for animal use were approved by the R. W. Johnson Pharmaceutical Research Institute Institutional Animal Care and Use Committee, and the animals were housed in accordance with the Guide for the Care and Use of
Laboratory Animals (11).
Fluoroquinolone concentrations in uninfected rabbits.
Prior
to studies with infected rabbits, the maximum concentration of
fluoroquinolone (Cmax)/MIC ratio and the time to
achieve the maximum concentration (Tmax) were
determined with the plasma and abscess fluid of uninfected rabbits
following a single oral dose of fluoroquinolone. The area under the
concentration-time curve (AUC)/MIC ratio was calculated from
single-dose pharmacokinetic studies over a 24-h period. The time above
the MIC (T>MIC) was also calculated. Uninfected rabbits
were given a single oral dose of levofloxacin (The R. W. Johnson
Pharmaceutical Research Institute, Raritan, N.J.) at 22.5, 45, or 90 mg/kg or ciprofloxacin (Bayer-Pentex, Kankakee, Ill.) at 45, 90, or 200 mg/kg. Three rabbits were used at each dose. At 0, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, and 24 h after administration, blood was
collected via the marginal ear vein into lithium heparin tubes (LH/1.3;
Sarstedt, Newton, N.C.) and centrifuged at 7,400 × g
for 5 min. The supernatant was removed and frozen at
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Comparison of Efficacies of Oral Levofloxacin and
Oral Ciprofloxacin in a Rabbit Model of a Staphylococcal
Abscess
ABSTRACT
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
80°C until
analyzed. A small volume of abscess fluid was removed from the capsule
with a syringe and collected in nontreated tubes at 0, 0.75, 1, 1.5, 2, 3, 4, 6, and 24 h after administration of fluoroquinolone. The
samples were centrifuged at 7,400 × g for 5 min, and
the supernatant was frozen at 80°C until analyzed.
Fluoroquinolone concentrations in infected rabbits. The fluoroquinolone concentrations in infected rabbits were studied to relate efficacy to the concentration of fluoroquinolone in the plasma and abscess fluid. The infection was established according to the method outlined below in the infection studies section. Levofloxacin at 45 mg/kg and ciprofloxacin at 200 mg/kg were given once orally to rabbits with an infection that had been established and maintained for 8 days. Blood and abscess fluid were collected and analyzed as described above in order to determine the fluoroquinolone concentrations in uninfected rabbits. In addition, the T>MIC was calculated. Three rabbits were tested at each dose.
Fluoroquinolone concentrations during the infection study. Blood and abscess fluid were removed two to three times during the second week (days 13 to 18) of the treatment phase to determine the concentration of fluoroquinolone in the plasma or abscess fluid. Blood was removed 1 h after and abscess fluid was removed 4 h after the first dose of the day. During the infection study, all fluoroquinolone-treated groups had peak fluoroquinolone concentrations within the capsule that were greater than the MICs, except for the rabbits dosed with levofloxacin at 22.5 mg/kg (data not shown).
Infection studies. On day 1 of the infection study, a 0.2-ml sample of abscess fluid was removed from the capsule to determine if the abscess fluid was sterile. Rabbits with bacteria present in the abscess fluid before inoculation with S. aureus would be excluded from the study. For this report, no rabbits were excluded due to a prior infection within the capsule. The capsules were infected by injection of S. aureus ATCC 29213 (5 × 105 CFU suspended in 3 ml of 5% mucin [Sigma Chemical Company, St. Louis, Mo.]) directly into the capsule. The MIC of levofloxacin and ciprofloxacin for S. aureus ATCC 29213 was 0.5 µg/ml. The rabbits remained infected without antibiotic treatment for 8 days. On day 9, the rabbits received either oral levofloxacin (22.5, 45, or 90 mg/kg once a day) or oral ciprofloxacin (45, 90, or 200 mg/kg twice a day) for 10 days. All treatments were delivered through a no. 16 French urethral catheter (Davol, Inc., Cranston, R.I.) passed orally into the stomach. Treatment groups were randomized before the start of the study. Each group consisted of three rabbits.
Periodically during the infection (days 1 to 8) and treatment (days 9 to 18) phases of the study, a small volume of abscess fluid was collected to determine the number of bacteria present within the capsule. Abscess fluid was diluted by 10-fold serial dilutions (1:101 to 1:108) in saline, and 100 µl of each dilution was added to plates containing 20 ml of Todd-Hewitt agar according to the pour plate technique. The cultures were incubated at 37°C for 24 h. The lower limit of detection was 1 × 102 CFU/ml.Rate of change of viable bacterial count analysis. The relative efficacies of the two drugs were assessed in the following manner. For each rabbit, the rate at which the log10 CFU/ml decreased over the 10-day dosing period was regarded as its "response" and was estimated as the slope of a linear fit to the plot of log10 CFU/ml versus time. These responses were modeled against dose by using a slope-ratio type of model, i.e., a linear model with three parameters: an intercept term, the dose-response effect for levofloxacin, and the dose-response effect for ciprofloxacin. Statistical significances for the levofloxacin and ciprofloxacin terms were considered indicative of individual drug effects. If the ratio of the levofloxacin and ciprofloxacin dose-response effects was significantly different from 1, this was considered indicative of a difference between drugs.
Susceptibility of recovered organisms. Twenty-four hours following the last dose of each study, abscess fluid was removed to evaluate the susceptibilities of any surviving S. aureus organisms. The MIC of each fluoroquinolone was determined by the broth microdilution method according to the guidelines established by the National Committee for Clinical Laboratory Standards (10).
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RESULTS |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Fluoroquinolone concentrations in uninfected rabbits.
Single-dose plasma and abscess pharmacokinetic values for uninfected
rabbits are summarized in Tables 1 and
2. Single doses of levofloxacin at 22.5, 45, and 90 mg/kg produced Cmax/MIC levels in
plasma of 5.1, 12.4, and 39.9 µg/ml, respectively, in uninfected rabbits. Single doses of ciprofloxacin at 45, 90 and 200 mg/kg achieved
Cmax/MICs in plasma of 6.3, 4.8, and 8.1 µg/ml, respectively. The Tmax in plasma of
both fluoroquinolones was approximately 1 to 2 h. A single dose of
levofloxacin at 22.5, 45, and 90 mg/kg had
Cmax/MICs in abscess fluid of 2.2, 4.7, and 20.2 µg/ml, respectively, in uninfected rabbits. By comparison, a single
dose of ciprofloxacin at 45, 90, and 200 mg/kg achieved a
Cmax/MIC of 2.8, 2.7, and 2.6 µg/ml,
respectively in abscess fluid. The Tmax in
abscess fluid of both fluoroquinolones was approximately 4 to 6 h.
Levofloxacin at 22.5, 45, and 90 mg/kg produced AUC/MICs in plasma and
abscess fluid of 42 and 47, 109 and 89, and 273 and 177 µg · h/ml/MIC, respectively. Ciprofloxacin at 45, 90, and 200 mg/kg produced AUC/MICs in plasma and abscess fluid of 88 and 52, 55 and 60, and 74 and 60 µg · h/ml/MIC, respectively. In uninfected rabbits, the
T>MIC in plasma for levofloxacin ranged from 17.1 to
23.6 h, whereas the T>MIC for ciprofloxacin in plasma
was >24 h for all doses tested. The T>MIC in abscess fluid
for both levofloxacin and ciprofloxacin was >24 h in uninfected
rabbits.
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Fluoroquinolone concentrations in infected rabbits. Single-dose plasma and abscess pharmacokinetic values for infected rabbits are summarized in Tables 1 and 2. A single dose of levofloxacin at 45 mg/kg produced Cmax/MIC levels in plasma and abscess fluid of 28.9 and 5.7 µg/ml, respectively, in infected rabbits. A single dose of ciprofloxacin at 200 mg/kg produced comparable concentrations, with Cmax/MIC levels in plasma and abscess fluid of 45.4 and 8.8 µg/ml, respectively, in infected rabbits. Levofloxacin at 45 mg/kg produced AUC/MICs in plasma and abscess fluid of 268 and 101 µg · h/ml/MIC, respectively. Ciprofloxacin at 200 mg/kg produced comparable ratios of AUC/MICs in plasma and abscess fluid of 236 and 121 µg · h/ml/MIC, respectively. In infected rabbits, the T>MIC in plasma and abscess fluid for ciprofloxacin at 200 mg/kg was >24 h, whereas the T>MIC was >24 h only in the abscess fluid for levofloxacin at 45 mg/kg. In infected rabbits, the T>MIC in plasma for levofloxacin at 45 mg/kg was 22.9 h.
Infection studies. The efficacy of each fluoroquinolone was assessed by evaluating the number of viable bacteria in the abscess over the 10-day dosing period (Fig. 1). The bacterial load within all capsules was between 8 × 107 and 8 × 1010 CFU/ml by the start of treatment. After 10 days of treatment, levofloxacin at 22.5, 45, and 90 mg/kg once a day had reduced the log10 CFU/ml in abscess fluid by 4.5, 7.1, and 10.4, respectively. Ciprofloxacin at 45, 90, and 200 mg/kg twice a day reduced the log10 CFU per milliliter by 0.1, 5.7, and 7.2, respectively, after the same time period.
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, control; 
, levofloxacin at 90 mg/kg once a day; , levofloxacin at 45 mg/kg once a day; 
,
levofloxacin at 22.5 mg/kg once a day; 
, ciprofloxacin at 200 mg/kg
twice a day; 
, ciprofloxacin at 90 mg/kg twice a day; 
,
ciprofloxacin at 45 mg/kg twice a day.
Rate of change of viable bacterial counts.
Levofloxacin at
22.5, 45, and 90 mg/kg once a day affected the rate of change of viable
S. aureus by 0.44, 0.69, and 1.04 log10
CFU/ml/day, respectively (Fig. 2). The
rates of change of viable S. aureus cells treated with
ciprofloxacin at 45, 90, and 200 mg/kg twice a day were 0.03, 0.54,
and 0.71 log10 CFU/ml/day, respectively. The bacteria in
the control group had a rate of change of viable bacteria of 0.09 log10 CFU/ml/day. The results shown in Fig. 2 indicate that
each drug had a statistically significant dose-response effect
(P < 0.01), indicating that the rates of decrease of
log10 CFU per milliliter over time increased with increasing dose for both drugs. Levofloxacin, having a statistically significant higher rate of decrease, was superior to ciprofloxacin (P < 0.01).
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Bacterial eradication within the capsule. The proportions of rabbits having eradication of bacteria (<1 × 102 CFU/ml) increased significantly (P < 0.01; Cochran-Armitage dose-response trend test) with increasing levofloxacin dose (0 of 3 for nontreated controls, 0 of 3 for 22.5 mg/kg, 2 of 3 for 45 mg/kg, and 3 of 3 for 90 mg/kg). All ciprofloxacin-treated rabbits, except for one rabbit treated with 200 mg/kg twice a day, had bacteria remaining within the capsule at the end of the study. The concentrations of the remaining bacteria ranged from 2 × 102 to 1.1 × 107 CFU/ml and correlated with dose.
Susceptibility of recovered organisms. All of the bacteria remained susceptible (±1 twofold dilution) to the fluoroquinolone that was used for the treatment of that group, except for the isolates from one of the ciprofloxacin-treated rabbits. In one rabbit treated with 90 mg of ciprofloxacin per kg for 10 days, the MIC increased from 0.5 µg/ml to 2 µg/ml for the S. aureus recovered. When tested against levofloxacin, the MIC was 1 µg/ml, compared to a levofloxacin MIC of 0.5 µg/ml for the infecting strain.
Pharmacokinetics and pharmacodynamics. The pharmacokinetic and pharmacodynamic results are shown in Fig. 3. There was a linear and proportional dose response with levofloxacin with respect to AUC/MIC and bacterial growth rate. No dose response was seen with ciprofloxacin with respect to AUC/MIC and Cmax; however, a dose response was seen with respect to growth rate. Further pharmacokinetic and pharmacodynamic studies with this dose need to be performed with this model. Toxic side effects were seen with a single 400-mg/kg oral dose of ciprofloxacin which prevented us from studying doses higher than 200 mg/kg. The dose-response relationship that was observed with ciprofloxacin with respect to bacterial killing was due to the better pharmacokinetic parameter (AUC/MIC and Cmax) values in infected rabbits. In fact, both fluoroquinolones had higher pharmacokinetic parameter (AUC/MIC and Cmax) values in infected rabbits. Levofloxacin plasma pharmacokinetic parameter (AUC/MIC and Cmax) values were 2.3 to 2.4 times higher in infected rabbits than in noninfected rabbits. In infected rabbits, ciprofloxacin showed increases in plasma pharmacokinetic parameters (AUC/MIC and Cmax) of 3.2 to 5.6 times greater than the plasma pharmacokinetics attained in uninfected rabbits. In infected rabbits dosed with levofloxacin, there was an approximately twofold increase in the abscess pharmacokinetic parameter (AUC/MIC and Cmax) values compared to those in uninfected rabbits. Ciprofloxacin abscess pharmacokinetic parameters (AUC/MIC and Cmax) were 2 to 3.4 times higher in the infected rabbits.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Levofloxacin and ciprofloxacin are similar with respect to their pharmacodynamic properties in this infection model. In infected rabbits, we have shown that similar AUC/MICs for the levofloxacin 45-mg/kg and the ciprofloxacin 200-mg/kg treatment regimens (Fig. 3, open symbols) result in similar declines in bacterial growth rate. This also occurs in vitro with equal MICs of both drugs for the S. aureus strain used in this study. As shown by the comparable killing of S. aureus with levofloxacin at 45 mg/kg once a day and ciprofloxacin at 200 mg/kg twice a day, it is obvious that levofloxacin had a pharmacokinetic advantage over ciprofloxacin in this model. The differences are probably due to bioavailability, but drug elimination may be a contributing factor. Levofloxacin also had a pharmacoeconomic advantage in this model, achieving the same result (efficacy) with far less drug administered.
Levofloxacin, orally administered at 45 and 90 mg/kg once a day, was highly efficacious, achieving at least a 6-log10 decrease in CFU per milliliter. In contrast, only the highest dose of ciprofloxacin had comparable efficacy in this model. Ciprofloxacin at 90 mg/kg twice a day and levofloxacin at 22.5 mg/kg once a day decreased the bacterial load 4 to 5 log10 CFU/ml, whereas ciprofloxacin at 45 mg/kg twice a day was not effective. It is not obvious why the 45-mg/kg ciprofloxacin dose was not efficacious in the infection model, given that the drug exposure in plasma and abscess fluid was above the MIC for the entire dosing interval. Similar reductions in log10 CFU per milliliter were observed at day 10 for levofloxacin at 45 mg/kg once a day and ciprofloxacin at 200 mg/kg twice a day, even though the levofloxacin-treated rabbits received approximately nine times less fluoroquinolone. The decreases in the rate of bacterial growth (inhibition or death of bacteria) for these two treatment groups were also similar. The AUC/MICs of levofloxacin at 45 mg/kg and ciprofloxacin at 200 mg/kg in the plasma and abscess fluid of infected rabbits were similar. The drug penetration into the abscess fluid [(AUCabscess/AUCplasma) ×100%] was slightly higher for ciprofloxacin at 200 mg/kg (51%) than for levofloxacin at 45 mg/kg (37%) in infected rabbits. In light of the fact that ciprofloxacin has increased penetration into the capsule, the AUC/MICs are roughly the same for both fluoroquinolones, and the T>MIC is greater than 24 h for both drugs, further studies examining the capsule elimination kinetics to fully understand the efficacy of levofloxacin in this model are warranted. In pharmacokinetic studies with infected rabbits at 24 h, the fluoroquinolone concentration in abscess fluid was higher with levofloxacin (2.9 µg/ml) than with ciprofloxacin (1.9 µg/ml), suggesting that levofloxacin may have slower capsule elimination kinetics and therefore appears more efficacious. Pharmacokinetic studies covering a range of doses in infected rabbits are necessary to further elucidate the elimination kinetics of both fluoroquinolones. Despite the fact that was delivered more ciprofloxacin than levofloxacin was delivered (200 mg/kg twice a day versus 45 mg/kg once a day), the drug concentrations (AUC/MIC) in plasma and abscess fluid and efficacies were similar. The data from this study are consistent with human data showing that levofloxacin has enhanced oral bioavailability (nearly 100% [5] versus 78% for ciprofloxacin [8]). Levofloxacin was more efficacious than ciprofloxacin in eradicating S. aureus in this model.
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ACKNOWLEDGMENTS |
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We thank James Hastings, Robert DeWire, Jane Folden, Leslie Chalecki, Barbara Foleno, Marie Grant, and Robert Schuster for their technical assistance. We thank Elizabeth Dodemaide and Audrey Stewart for their veterinary assistance. We also thank Karen Bush for her advice and comments during the completion of these studies for publication.
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FOOTNOTES |
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* Corresponding author. Mailing address: The R. W. Johnson Pharmaceutical Research Institute, 1000 Rt. 202 South, Raritan, NJ 08869. Phone: (908) 704-4203. Fax: (908) 526-3047. E-mail: jfernand{at}prius.jnj.com.
This paper is dedicated to the memory of our friend Richard
"Rick" Schwalbe, who offered many valuable suggestions throughout this project.
Present address: Bristol-Myers Squibb Pharmaceutical Research
Institute, Wallingford, CT 06492.
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REFERENCES |
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Abstract
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Materials and methods
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Discussion
References
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Antimicrobial Agents and Chemotherapy, March 1999, p. 667-671, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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