Comparison of difloxacin, enoxacin, and
cefoperazone for treatment of experimental
Enterobacter aerogenes endocarditis.
J A Boscia, W D Kobasa and D Kaye
Antimicrob. Agents Chemother. 1987, 31(3):458. DOI:
10.1128/AAC.31.3.458.
These include:
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Vol. 31, No. 3
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1987, p. 458-460
0066-4804/87/030458-03$02.00/0
Copyright © 1987, American Society for Microbiology
Comparison of Difloxacin, Enoxacin, and Cefoperazone for
Treatment of Experimental Enterobacter aerogenes Endocarditis
JEROME A. BOSCIA,* WILLIAM D. KOBASA, AND DONALD KAYE
Department of Medicine, Division of Infectious Diseases, The Medical College of Pennsylvania, Philadelphia,
Pennsylvania 19129
Received 18 September 1986/Accepted 15 December 1986
enoxacin at 100 mg/kg administered orally and 0.25, 0.5, 1, 2,
and 4 h after one dose of cefoperazone at 60 mg/kg adnministered intramuscularly. Concentrations of difloxacin, enoxacin, and cefoperazone in serum were measured by a paper
disk agar diffusion method (1). The half-lives of the antimicrobial agents in serum were calculated by the method of
least squares (7).
The development of oral antimicrobial agents with activity
against resistant aerobic gram-negative bacilli will represent
a major breakthrough in the treatment of deep-seated infections caused by these bacteria. The endocarditis model in
rabbits is a severe test of the efficacy of antimicrobial agents
for deep-seated infections. The purpose of this study was to
compare the therapeutic efficacies of difloxacin administered
orally, enoxacin administered orally, and cefoperazone administered intramuscularly for the treatment of experimental
Enterobacter aerogenes endocarditis.
The E. aerogenes strain used in this study was a clinical
isolate which has been previously studied (2). The MICs and
MBCs of difloxacin, enoxacin, and cefoperazone were determined with an inoculum of 106 CFU of E. aerogenes per
ml as previously described (6). The survival of a large
inoculum (3 x 107 CFU/ml) of E. aerogenes was studied in
flasks with Mueller-Hinton broth (MHB) containing
difloxacin at 12 ,ug/ml, enoxacin at 6 ,ug/ml, or cefoperazone
at 170 jxg/ml or with MHB alone as previously described (2).
These concentrations of difloxacin, enoxacin, and cefoperazone were similar to peak levels achieved in serum in rabbits
after a single dose of difloxacin or enoxacin at 100 mg/kg
administered orally and after one dose of cefoperazone at 60
mg/kg administered intramuscularly.
Female New Zealand White rabbits ranging from 2 to 2.7
kg in weight were anesthetized, and the right carotid artery
of each was cannulated with advancement of the catheter
across the aortic valve (4). Each rabbit was inoculated 24 h
later through an ear vein with 109 CFU of E. aerogenes in 1
ml of normal saline. Five days after inoculation, rabbits were
randomly separated into an untreated control group and
groups that were started on treatment with difloxacin or
enoxacin at 100 mg/kg administered orally by syringe every
12 h or cefoperazone at 60 mg/kg administered intramuscularly every 6 h. Surviving rabbits were randomly sacrificed
after 5 or 10 days of therapy 12 h after the last dose of
antimicrobial agent. All aortic valve vegetations from each
sacrificed rabbit were excised, pooled, and titrated as previously described (3). In sterile vegetations, the number of
CFU was calculated as 2 log10 CFU/g because the smallest
amount of vegetations plated was 10 mg.
Blood was taken from the ear veins of uninfected rabbits
0.5, 1, 2, 4, and 6 h after a single dose of difloxacin or
*
10987-
6
5
J-l
-4
0
24
Time (h)
FIG. 1.
kate of decrease in numbers of E. aerogenes in MHB
containing difloxacin at 12 ,ug/ml, enoxacin at 6 jIg/ml, or cefoper-
Corresponding author.
azone at 170
458
.g/mnl.
Downloaded from http://aac.asm.org/ on September 9, 2014 by guest
This study compared difloxacin administered orally, enoxacin administered orally, and cefoperazone
administered intramuscularly for the treatment of experimental Enterobacter aerogenes endocarditis.
Difloxacin significantly reduced bacterial counts of vegetations, as compared with enoxacin and cefoperazone.
Enoxacin and cefoperazone did not differ significantly. This study demonstrated that difloxacin Was
significantly more effective than enoxacin and cefoperazone for the treatment of E. aerogenes endocarditis in
rabbits.
VOL. 31, 1987
NOTES
459
TABLE 1. Counts of E. aerogenes in vegetations
Mean ± SE log10 CFU/g of vegetation (no. sterile/total no.) with:
Duration of therapy
(days)
Difloxacin
Enoxacin
Cefoperazone
No treatment
5
10
2.8 ± 0.4 (4/9)
2.0 ± 0.0 (8/9)
5.4 ± 0.6 (2/11)
5.7 ± 0.9 (1/9)
5.9 ± 1.1 (1/6)
6.6 ± 1.0 (0/6)
7.9 ± 0.1 (0/3)
8.8 ± 0.8 (0/3)
in other animals and humans of difloxacin administered
orally than of many of the other quinolones administered
orally (Abbott Laboratories, unpublished data).
Enoxacin significantly reduced bacterial counts of vegetations, as compared with no treatment, but enoxacin and
cefoperazone did not differ significantly. In a previous study
of endocarditis in rabbits with the same strain of E. aerogenes, enoxacin at 100 mg/kg administered orally every 6 h
significantly reduced bacterial counts of vegetations, as
compared with cefoperazone at 60 mg/kg administered intramuscularly every 6 h and no therapy (2). The reason that
enoxacin was significantly better than cefoperazone in the
previous study (2) but not in the present study is probably
the different dosage intervals in the two studies (every 6 h
versus every 12 h, respectively). In the present study and in
the previous study (2), cefoperazone reduced bacterial
counts of vegetations, as compared with no therapy, but not
significantly.
In other studies, ciprofloxacin (another new quinolone
antimicrobial agent) administered parenterally was effective
for the treatment of experimental Pseudomonas aeruginosa
endocarditis and chronic osteomyelitis (5, 8, 9). The unique
aspect of the present study was the demonstration that the
oral administration of quinolone antimicrobial agents
(difloxacin and enoxacin) was effective in reducing bacterial
counts of vegetations in E. aerogenes endocarditis in rabbits. Difloxacin was significantly more effective than
enoxacin in equivalent doses. Therefore, the oral administration of quinolone antimicrobial agents may prove useful
for the treatment of deep-seated infections caused by resistant aerobic gram-negative bacilli.
This study was supported in part by a grant from Abbott Laboratories.
We are grateful to Adele Kaplan for her statistical consultation
and to Mary E. Imming for her secretarial assistance.
LITERATURE CITED
1. Anhalt, J. P. 1985. Assays for antimicrobial agents in body fluids,
p. 1009-1014. In E. H. Lennette, A. Balows, W. J. Hausler, Jr.,
and H. J. Shadomy (ed.), Manual of clinical microbiology, 4th ed.
Amican Society for Microbiology, Washington, D.C.
2. Boscia, J. A., W. D. Kobasa, and D. Kaye. 1985. Enoxacin
compared with cefoperazone for the treatment of experimental
Enterobacter aerogenes endocarditis. Antimicrob. Agents Chemother. 27:708-711.
3. Carrizosa, J., and D. Kaye. 1976. Antibiotic synergism in
enterococcal endocarditis. J. Lab. Clin. Med. 88:132-141.
4. Durack, D. T., and R. G. Petersdorf. 1973. Chemotherapy of
experimental streptococcal endocarditis. I. Comparison of commonly recommended prophylactic regimens. J. Clin. Invest. 52:
592-598.
5. Ingerman, M. J., P. G. Pitsakis, A. F. Rosenberg, and M. E.
Levison. 1986. The importance of pharmacodynamics in determining the dosing interval in therapy for experimental Pseudomonas endocarditis in the rat. J. Infect. Dis. 153:707-714.
6. Jones, R. N., A. L. Barry, T. L. Gavan, and J. A. Washington II.
1985. Susceptibility tests: microdilution and macrodilution broth
procedures, p. 972-977. In E. H. Lennette, A. Balows, W. J.
Hausler, Jr., and H. J. Shadomy (ed.), Manual of clinical
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A two-factor analysis of variance, followed by the TukeyA post hoc procedure with the harmonic mean cell size, was
used to determine significant differences in bacterial counts
of vegetations. The independent variables were therapeutic
agents and duration of therapy. The dependent variable was
CFU per gram of vegetation.
The MICs and MBCs in micrograms per milliliter of each
antimicrobial agent for an inoculum of 106 CFU of the E.
aerogenes strain used in this study per ml were 0.8 and 3.1
for difloxacin and enoxacin and 6.3 and 6.3 for cefoperazone,
respectively. Figure 1 shows the rate of decrease in numbers
of E. aerogenes in MHB containing difloxacin at 12 ,ug/ml,
enoxacin at 6 ,ug/ml, or cefoperazone at 170 p.g/ml with an
inoculum of 3 x 107 CFU/ml. Enoxacin and cefoperazone
resulted in similar decreases in numbers of E. aerogenes in
MHB, but the effect was greatest with difloxacin.
Table 1 shows the mean (+ standard error) counts of E.
aerogenes in log1o CFU per gram of vegetation for the
untreated control group and the three treatment groups of
rabbits after 5 and 10 days of therapy. A two-facter analysis
of variance revealed a significant main effect of antimicrobial
agents on reducing bacterial counts of vegetations (P <
0.001). The main effect of duration of therapy, i.e., 5 versus
10 days, and the two-factor interaction of treatment and
duration of therapy were not significant. The Tukey-A post
hoc procedure with the harmonic mean cell size performed
on the main effect of antimicrobial agents revealed that
difloxacin significantly reduced bacterial counts of vegetations, as compared with enoxacin, cefoperazone, and no
therapy (P < 0.01). Enoxacin significantly reduced bacterial
counts of vegetations, as compared with no treatment (P <
0.01). Enoxacin and cefoperazone did not differ significantly,
and cefoperazone and no therapy did not differ significantly.
Mortality during the treatment period (1 to 2 rabbits per
group) did not differ among the four groups (difloxacin,
enoxacin, cefoperazone, and no therapy).
The mean (± standard error) peak concentrations and
elimination half-lives in serum after a single dose of
difloxacin or enoxacin at 100 mg/kg administered orally and
after one dose of cefoperazone at 60 mg/kg administered
intramuscularly were 11.8 ± 1.8 Fg/ml and 3.6 ± 0.5 h for
difloxacin (four rabbits), 5.9 ± 0.5 ,ug/ml and 2.3 ± 0.3 h for
enoxacin (three rabbits), and 171.5 ± 8.8 ,ug/ml and 0.6 ± 0.0
h for cefoperazone (four rabbits), respectively.
In the treatment of E. aerogenes endocarditis in rabbits,
difloxacin significantly reduced bacterial counts of vegetations, as compared with enoxacin, cefoperazone, and no
therapy. These in vivo results were predictable on the basis
of the results of the in vitro time kill studies, which demonstrated the greater bactericidal activity against the E. aerogenes strain of difloxacin than of enoxacin and cefoperazone
(when concentrations similar to peak levels in serum were
used). Also, the superior in vivo results of difloxacin as
compared with enoxacin were in part predictable on the
basis of the better pharmacokinetic profile of difloxacin. The
superior pharmacokinetic parameters of difloxacin administered orally compared with those of enoxacin administered
orally are consistent with the better pharmacokinetic profile
460
NOTES
microbiology, 4th ed. American Society for Microbiology, Washington, D.C.
7. Levison, M. E., S. P. Levison, K. Ries, and D. Kaye. 1973.
Pharmacology of cefazolin in patients with normal and abnormal
renal function. J. Infect. Dis. 128(Suppl.):354-357.
8. Norden, C. W., and E. Shinners. 1985. Ciprofloxacin as therapy
ANTIMICROB. AGENTS CHEMOTHER.
for experimental osteomyelitis caused by Pseudomonas aeruginosa. J. Infect. Dis. 151:291-294.
9. Strunk, R. W., J. C. Gratz, R. Maserati, and W. M. Scheld. 1985.
Comparison of ciprofloxacin with azlocillin plus tobramycin in
the therapy of experimental Pseudomonas aeruginosa endocarditis. Antimicrob. Agents Chemother. 28:428-432.
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