Vol. 34, No. 4
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1990, p. 568-575
0066-4804/90/040568-08$02.00/0 Copyright © 1990, American Society for Microbiology
In Vitro and In Vivo Activities of a New Quinolone, WIN 57273, Possessing Potent Activity against Gram-Positive Bacteria DAVID M. SEDLOCK,l* RICHARD A. DOBSON,' DIANNE M. DEUEL,1 GEORGE Y. LESHER,2 AND JAMES B. RAKE' Departments of Microbiology' and Medicinal Chemistry,2 Sterling Research Group, Columbia Turnpike, Rensselaer, New York 12144 Received 6 October 1989/Accepted 8 January 1990
The antibacterial activity of a new 7-dimethylpyridinyl quinolone, WIN 57273, was assessed by using in vitro and in vivo models. Agar inclusion and broth dilution in vitro tests revealed broad-spectrum activity against gram-positive and selected gram-negative organisms, with the greatest potency observed against the staphylococci. The MIC for 90% of coagulase-positive strains tested (MIC90) was 32 >32 0.5->32
0.5 2 >32 4
WIN 57273 Ciprofloxacin Ofloxacin Amifloxacin Gentamicin Ampicillin Cefotaxime
0.125-8 0.008-0.125 0.06-1 0.125-0.5 0.5-2 >32 0.25->32
0.5 0.03 0.25 0.25 0.5 >32 2
Proteus mirabilis (35)
WIN 57273 Ciprofloxacin Ofloxacin Amifloxacin Gentamicin
0.125-1 0.06-0.5 0.125-1 0.125-1 1-4
0.5 0.006 0.25 0.25 4
1 0.125 0.5 0.5 4
Salmonella species (20)
WIN 57273
0.03-0.5 0.03-0.06 0.06-0.5 0.125-0.25 0.5-4
0.125 0.06 0.25 0.25 1
0.25 0.06 0.25 0.25 4
0.125-1 0.03-2 0.125-2 0.125-4 0.25-4
0.25 0.125 0.5 0.25 1
0.5 0.25 1 2 2
1->32 0.125-2 0.5-8 0.5-8 2-32 1-32 1-32
2 0.25 2 2 4 2 8
8 1
8 4 16 8 32
0.06-1 0.125-2 0.25-8 0.5-4 4->32 0.125-2 1->32
0.125 0.5 0.5 1 16 0.25 16
0.25 1 2 2 >32 0.5 >32
0.004-0.125 0.016-0.06 0.03-0.25 0.03-0.25 0.25->32 4-16
0.008 0.03 0.06 0.06 0.5 8
0.06 0.03 0.06 0.125 4 16
0.004 0.03 0.06 0.06 0.25
0.016 0.06 0.06 0.125 >32 2
Citrobacterfreundii (27)
Ciprofloxacin Ofloxacin Amifloxacin Gentamicin
Klebsiella pneumoniae (29)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Gentamicin Pseudomonas aeruginosa (32)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Ceftazidime Imipenem Gentamicin
Acinetobacter species (23)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Ceftazidime
Imipenem Gentamicin
Haemophilus species (22)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Ampicillin Erythromycin Neisseria gonorrhoeae (30)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Ampicillin Erythromycin
C0.002-0.06 0.008-0.25 0.008-0.5 0.03-4 0.03->32 0.03-4
4 4 >32 32
4 0.06 0.5
0.5 2 >32 >32
0.5 Continued on following page
VOL. 34, 1990
IN VITRO AND IN VIVO ACTIVITIES OF WIN 57273
573
TABLE 1-Continued
Organism (no. of strains tested)
Listeria monocytogenes (2)
MIC
Compound WIN 57273
Range
Ofloxacin
2, 4 22
Amifloxacin Penicillin G
0-52
WIN 57273
Clindamycin
0.03 0.5 1 1 0.5 0.5 0.5
4 32 2 1 16
WIN 57273
0.016-0.25
Ciprofloxacin
0.125-16 0.25-32 1->32 0.5-8 0.125-1 0.03-1
0.03 1 1 8 1 0.25 0.06
0.125 4 8 32 2 1 0.5
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Difloxacin
Metronidazole
Ofloxacin Amifloxacin Difloxacin
Metronidazole Clindamycin b
0.5 32 16 >32 8 0.5
0.004-0.5 0.25-16 0.25-16 0.5->32 0.25-8 0.03-2 0.03-16
Clindamycin
a
82
0.25 16 8 >32 4 0.5 1
Ofloxacin Amifloxacin Difloxacin Metronidazole
Peptostreptococcus species (14)
90%
0.125-0.5 4->32 2-32 16->32 1-16 0.25-1 0.25-4
Ciprofloxacin
Clostridium species (21)
50%
0.1252b
Ciprofloxacin
Bacteroides species (29)
(I.Lg/ml)a
4
0.25 4
50o and 90%, MIC for 50 and 90%o of strains tested, respectively. The inferior number is the number of isolates with the indicated MIC.
MIC90s ranging from 0.03 to 0.125 ,ug/ml. WIN 57273 was 32-fold more active against the enterococci than any of the reference agents tested. Testing of WIN 57273 against members of the family Enterobacteriaceae revealed, in general, that it had lower activity than it did against the gram-positive cocci; however, low MIC90s (3.1 2.7 (2.0-3.6) >100 7.3 (4.2-9.6)
S.C. p.o. S.C. S.C.
0.25 (0.18-0.35) 0.66 (0.46-0.97) >100 14.5 (11.4-17.1)
S.C. P.O.
Ciprofloxacin
per dose PDo[95%(mg/kg confidence
SEDLOCK ET AL.
574
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 3. Comparative in vivo efficacy of WIN 57273 against streptococcal infections in mice Route Of PD" (mg/kg per dose addrug [95% confidence Culture Compound mirnistrainterval]) tion
Streptococcus pneumoniae ATCC 10813
WIN 57273
Ciprofloxacin
Ofloxacin
Penicillin G Streptococcus
WIN 57273
pyogenes
C203
Ciprofloxacin Ofloxacin Penicillin G
s.c. p.o. s.c. p.o. s.c. p.o. s.c.
9.5 (7.2-12.8) 10.3 (7.5-13.0) 85.3 (70.3-118.3) >250 59.8 (41.4-86.7) 89.2 (79.3-100.9) 1.8 (1.3-2.4)
s.c. p.O s.c. s.c. s.c.
2.2 (1.8-2.6) 2.4 (1.8-3.1) 4.4 (3.5-5.7) 9.7 (7.2-11.9) 0.05 (0.04-0.07)
routes of drug administration were compared. Treatment of animals in this and all other models by either the p.o. or s.c. route yielded very similar results, implying that WIN 57273 has close to 100% bioavailability, at least in the murine
model. Other gram-positive cocci tested included Streptococcus pneumoniae and Streptococcus pyogenes. Animals infected with these organisms were also effectively treated with WIN 57273 (Table 3). While the efficacy of WIN 57273 was not on a par with that of the penicillin G reference agent, comparison with other quinolone compounds indicated that WIN 57273 had a severalfold superior activity. Activity against the gram-negative bacterial infections was demonstrated in the Escherichia coli and Klebsiella pneumoniae models but not in the Pseudomonas aeruginosa model (Table 4). The PD50s, which ranged from 3 to 4 mg/kg against Escherichia coli and Klebsiella pneumoniae, revealed that WIN 57273 has a lower efficacy than those of the reference compounds, although its activity was comparable to that of amifloxacin. Very weak activity was measured against a Pseudomonas infection, showing a clear distinction between WIN 57273 and, for example, ciprofloxacin. In testing its efficacy against a Listeria monocytogenes TABLE 4. Comparative in vivo efficacy of WIN 57273 against gram-negative infections in mice Route of
Culture
Compound
dRug
of ministra-
PD50 (mg/kg
per
dose
[95% confidence interval])
dion
Escherichia coli Vogel
Klebsiella
WIN 57273
Ciprofloxacin
s.c.
Gentamicin
s.c.
Pseudomonas aeruginosa MGH-2
3.1 (2.4-4.2) 3.8 (2.8-5.2) 0.09 (0.06-0.14) 0.50 (0.37-0.61)
Gentamicin
s.c. s.c.
4.4 (2.8-6.4) 3.2 (1.0-5.7) 0.15 (0.09-0.28) 0.84 (0.52-1.21) 0.35 (0.25-0.49)
WIN 57273 Ciprofioxacin Ofioxacin Gentamicin
s.c. s.c. s.c. s.c.
160 (114-406) 0.59 (0.45-0.77) 3.9 (2.9-5.4) 6.9 (5.3-9.8)
WIN 57273
pneumo-
niae 39645
s.c. p.o.
s.c. p.o.
Ciprofloxacin Ofloxacin
s.c.
TABLE 5. Comparative in vivo efficacy of WIN 57273 administered s.c. against a Listeria monocytogenes infection in mice Compound
Dose se
WIN 57273
6.25 12.5 6.25 12.5
Ampicillin
Mean log1o
spleen count ± SEM
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1990, p. 568-575
0066-4804/90/040568-08$02.00/0 Copyright © 1990, American Society for Microbiology
In Vitro and In Vivo Activities of a New Quinolone, WIN 57273, Possessing Potent Activity against Gram-Positive Bacteria DAVID M. SEDLOCK,l* RICHARD A. DOBSON,' DIANNE M. DEUEL,1 GEORGE Y. LESHER,2 AND JAMES B. RAKE' Departments of Microbiology' and Medicinal Chemistry,2 Sterling Research Group, Columbia Turnpike, Rensselaer, New York 12144 Received 6 October 1989/Accepted 8 January 1990
The antibacterial activity of a new 7-dimethylpyridinyl quinolone, WIN 57273, was assessed by using in vitro and in vivo models. Agar inclusion and broth dilution in vitro tests revealed broad-spectrum activity against gram-positive and selected gram-negative organisms, with the greatest potency observed against the staphylococci. The MIC for 90% of coagulase-positive strains tested (MIC90) was 32 >32 0.5->32
0.5 2 >32 4
WIN 57273 Ciprofloxacin Ofloxacin Amifloxacin Gentamicin Ampicillin Cefotaxime
0.125-8 0.008-0.125 0.06-1 0.125-0.5 0.5-2 >32 0.25->32
0.5 0.03 0.25 0.25 0.5 >32 2
Proteus mirabilis (35)
WIN 57273 Ciprofloxacin Ofloxacin Amifloxacin Gentamicin
0.125-1 0.06-0.5 0.125-1 0.125-1 1-4
0.5 0.006 0.25 0.25 4
1 0.125 0.5 0.5 4
Salmonella species (20)
WIN 57273
0.03-0.5 0.03-0.06 0.06-0.5 0.125-0.25 0.5-4
0.125 0.06 0.25 0.25 1
0.25 0.06 0.25 0.25 4
0.125-1 0.03-2 0.125-2 0.125-4 0.25-4
0.25 0.125 0.5 0.25 1
0.5 0.25 1 2 2
1->32 0.125-2 0.5-8 0.5-8 2-32 1-32 1-32
2 0.25 2 2 4 2 8
8 1
8 4 16 8 32
0.06-1 0.125-2 0.25-8 0.5-4 4->32 0.125-2 1->32
0.125 0.5 0.5 1 16 0.25 16
0.25 1 2 2 >32 0.5 >32
0.004-0.125 0.016-0.06 0.03-0.25 0.03-0.25 0.25->32 4-16
0.008 0.03 0.06 0.06 0.5 8
0.06 0.03 0.06 0.125 4 16
0.004 0.03 0.06 0.06 0.25
0.016 0.06 0.06 0.125 >32 2
Citrobacterfreundii (27)
Ciprofloxacin Ofloxacin Amifloxacin Gentamicin
Klebsiella pneumoniae (29)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Gentamicin Pseudomonas aeruginosa (32)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Ceftazidime Imipenem Gentamicin
Acinetobacter species (23)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Ceftazidime
Imipenem Gentamicin
Haemophilus species (22)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Ampicillin Erythromycin Neisseria gonorrhoeae (30)
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Ampicillin Erythromycin
C0.002-0.06 0.008-0.25 0.008-0.5 0.03-4 0.03->32 0.03-4
4 4 >32 32
4 0.06 0.5
0.5 2 >32 >32
0.5 Continued on following page
VOL. 34, 1990
IN VITRO AND IN VIVO ACTIVITIES OF WIN 57273
573
TABLE 1-Continued
Organism (no. of strains tested)
Listeria monocytogenes (2)
MIC
Compound WIN 57273
Range
Ofloxacin
2, 4 22
Amifloxacin Penicillin G
0-52
WIN 57273
Clindamycin
0.03 0.5 1 1 0.5 0.5 0.5
4 32 2 1 16
WIN 57273
0.016-0.25
Ciprofloxacin
0.125-16 0.25-32 1->32 0.5-8 0.125-1 0.03-1
0.03 1 1 8 1 0.25 0.06
0.125 4 8 32 2 1 0.5
WIN 57273
Ciprofloxacin Ofloxacin Amifloxacin Difloxacin
Metronidazole
Ofloxacin Amifloxacin Difloxacin
Metronidazole Clindamycin b
0.5 32 16 >32 8 0.5
0.004-0.5 0.25-16 0.25-16 0.5->32 0.25-8 0.03-2 0.03-16
Clindamycin
a
82
0.25 16 8 >32 4 0.5 1
Ofloxacin Amifloxacin Difloxacin Metronidazole
Peptostreptococcus species (14)
90%
0.125-0.5 4->32 2-32 16->32 1-16 0.25-1 0.25-4
Ciprofloxacin
Clostridium species (21)
50%
0.1252b
Ciprofloxacin
Bacteroides species (29)
(I.Lg/ml)a
4
0.25 4
50o and 90%, MIC for 50 and 90%o of strains tested, respectively. The inferior number is the number of isolates with the indicated MIC.
MIC90s ranging from 0.03 to 0.125 ,ug/ml. WIN 57273 was 32-fold more active against the enterococci than any of the reference agents tested. Testing of WIN 57273 against members of the family Enterobacteriaceae revealed, in general, that it had lower activity than it did against the gram-positive cocci; however, low MIC90s (3.1 2.7 (2.0-3.6) >100 7.3 (4.2-9.6)
S.C. p.o. S.C. S.C.
0.25 (0.18-0.35) 0.66 (0.46-0.97) >100 14.5 (11.4-17.1)
S.C. P.O.
Ciprofloxacin
per dose PDo[95%(mg/kg confidence
SEDLOCK ET AL.
574
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 3. Comparative in vivo efficacy of WIN 57273 against streptococcal infections in mice Route Of PD" (mg/kg per dose addrug [95% confidence Culture Compound mirnistrainterval]) tion
Streptococcus pneumoniae ATCC 10813
WIN 57273
Ciprofloxacin
Ofloxacin
Penicillin G Streptococcus
WIN 57273
pyogenes
C203
Ciprofloxacin Ofloxacin Penicillin G
s.c. p.o. s.c. p.o. s.c. p.o. s.c.
9.5 (7.2-12.8) 10.3 (7.5-13.0) 85.3 (70.3-118.3) >250 59.8 (41.4-86.7) 89.2 (79.3-100.9) 1.8 (1.3-2.4)
s.c. p.O s.c. s.c. s.c.
2.2 (1.8-2.6) 2.4 (1.8-3.1) 4.4 (3.5-5.7) 9.7 (7.2-11.9) 0.05 (0.04-0.07)
routes of drug administration were compared. Treatment of animals in this and all other models by either the p.o. or s.c. route yielded very similar results, implying that WIN 57273 has close to 100% bioavailability, at least in the murine
model. Other gram-positive cocci tested included Streptococcus pneumoniae and Streptococcus pyogenes. Animals infected with these organisms were also effectively treated with WIN 57273 (Table 3). While the efficacy of WIN 57273 was not on a par with that of the penicillin G reference agent, comparison with other quinolone compounds indicated that WIN 57273 had a severalfold superior activity. Activity against the gram-negative bacterial infections was demonstrated in the Escherichia coli and Klebsiella pneumoniae models but not in the Pseudomonas aeruginosa model (Table 4). The PD50s, which ranged from 3 to 4 mg/kg against Escherichia coli and Klebsiella pneumoniae, revealed that WIN 57273 has a lower efficacy than those of the reference compounds, although its activity was comparable to that of amifloxacin. Very weak activity was measured against a Pseudomonas infection, showing a clear distinction between WIN 57273 and, for example, ciprofloxacin. In testing its efficacy against a Listeria monocytogenes TABLE 4. Comparative in vivo efficacy of WIN 57273 against gram-negative infections in mice Route of
Culture
Compound
dRug
of ministra-
PD50 (mg/kg
per
dose
[95% confidence interval])
dion
Escherichia coli Vogel
Klebsiella
WIN 57273
Ciprofloxacin
s.c.
Gentamicin
s.c.
Pseudomonas aeruginosa MGH-2
3.1 (2.4-4.2) 3.8 (2.8-5.2) 0.09 (0.06-0.14) 0.50 (0.37-0.61)
Gentamicin
s.c. s.c.
4.4 (2.8-6.4) 3.2 (1.0-5.7) 0.15 (0.09-0.28) 0.84 (0.52-1.21) 0.35 (0.25-0.49)
WIN 57273 Ciprofioxacin Ofioxacin Gentamicin
s.c. s.c. s.c. s.c.
160 (114-406) 0.59 (0.45-0.77) 3.9 (2.9-5.4) 6.9 (5.3-9.8)
WIN 57273
pneumo-
niae 39645
s.c. p.o.
s.c. p.o.
Ciprofloxacin Ofloxacin
s.c.
TABLE 5. Comparative in vivo efficacy of WIN 57273 administered s.c. against a Listeria monocytogenes infection in mice Compound
Dose se
WIN 57273
6.25 12.5 6.25 12.5
Ampicillin
Mean log1o
spleen count ± SEM
