Vol. 35, No. 1
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1991, p. 141-146
0066-4804/91/010141-06$02.00/0 Copyright © 1991, American Society for Microbiology
In Vitro Antibacterial Activities of PD 131628, 1,8-Naphthyridine Anti-Infective Agent
a
New
MICHAEL A. COHEN,'* MICHAEL D. HUBAND,1 GAIL B. MAILLOUX,1 STEVEN L. YODER,' GREGORY E. ROLAND,' JOHN M. DOMAGALA,2 AND CARL L. HEIFETZ' Departments of Experimental Therapy' and Chemistry,2 Parke-Davis Pharmaceutical Research Division, 2800 Plymouth Road, Ann Arbor, Michigan 48105 Received 13 August 1990/Accepted 18 October 1990
PD 131628 is a new aminopyrrolidine-substituted fluorocyclopropyl naphthyridine quinolone which possesses high in vitro activity against a wide spectrum of bacterial species. The MICs for .90% of strains were 0.125 to 0.25 ,ug/ml for staphylococci, Streptococcus pyogenes, and S. pneumoniae; 0.5 ,ug/ml for S. agalactiae and Enterococcus faecalis; 0.125 jug/ml for members of the family Enterobacteriaceae and Acinetobacter spp.; 0.5 ,Lg/mI for Pseudomonas aeruginosa; and 128
0.125 1 0.125 1 2 4 0.06
0.125-0.25 0.25-1 0.004-0.008
0.25 0.5 0.004 0.008 0.125 0.125 0.06
0.25 0.5 0.008 0.015 0.25 0.5 0.125
0.5
0.03-0.06 0.125-0.25 0.125-32 0.03-4
0.5 1 0.015 0.06 0.125 16 0.06
0.125-0.5
0.25
Methicillin-resistant Staphylococcus spp. (15)b
PD 131628
.0.03-0.125
Ciprofloxacin Imipenem Oxacillin Amikacin Vancomycin
0.125-1 0.06-128 16->128 0.5-32 0.5-4
Methicillin-susceptible Staphylococcus spp. (11)C
PD 131628
.0.03-0.125
Ciprofloxacin Imipenem Cefazolin Oxacillin Amikacin Vancomycin
0.125-0.5
PD131628 Ciprofloxacin Imipenem Penicillin G Cefazolin Doxycycline
Streptococcus pneumoniae (20)
Erythromycin Streptococcus pyogenes, group A (20)
Streptococcus agalactiae, group B (20)
PD131628
Ciprofloxacin Imipenem Penicillin G Cefazolin Doxycycline Erythromycin PD 131628
Ciprofloxacin Imipenem Penicillin G Cefazolin Doxycycline Erythromycin
MIC (,ugtml)
90%o 0.125 0.5 128 >128 32 2
Range
0.004-2 0.125-0.25 0.06-0.5 0.03->128 0.25-1 0.5-2
0.008-0.03
50%o
0.25 1 0.5 8 16 16 >128
1 0.015 0.06 0.25 16 1
0.5 1 1 2 4
Enterococcus faecalis (20)
PD 131628
Ciprofloxacin Imipenem Ampicillin Vancomycin
0.25-1 0.5-2 0.5-2 1-4
1 1 1 2
Other streptococci (6)d
PD131628
0.25-0.5
0.5 2 2 1 8 16 4 s0.03 s0.03 2 128 16 0.125 1
Ciprofloxacin Imipenem Penicillin G
0.008-2 0.03-1
Cefazolin Doxycycline
0.06-8 0.03-16 0.015-4
0.25 1 0.06 0.06 1 0.5 0.03
.0.03
.0.03
Erythromycin Haemophilus influenzae (10)
PD 131628
Ciproftoxacin Imipenem Ampicillin Cefazolin Ceftazidime Doxycycline
Moraxella catarrhalis (20)
PD 131628
Ciprofloxacin Imipenem Amoxicillinclavulanic acide
1-2
s0.03 0.03-2 0.125-128 4-16
0.015-0.125 0.5-1
s0.03 s0.03 0.015-4
.0.002-0.03
s0.03 0.5
0.5 8 0.03 0.5 s0.03 c0.03 0.03 0.008
.0.03 s0.03 0.06 0.03
Continued on following page
VOL. 35, 1991
IN VITRO ANTIBACTERIAL ACTIVITY OF PD 131628
143
TABLE 1-Continued Organism (no. of strains)
Neisseria gonorrhoeae (12)
Acinetobacter spp. (14)
Citrobacter spp. (10)f
Range
(ixg/Ml)a 50%o
Cefaclor Doxycycline Erythromycin
0.03-2.5 0.008-0.03 s0.08-0.6
0.6 0.015 0.3
PD131628 Ciprofloxacin Imipenem Penicillin G Doxycycline Erythromycin Spectinomycin
.0.03-0.06
.0.03 .0.03 0.03 0.125 0.25 0.06 16
PD 131628
.0.03-0.25
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
0.06-2 0.06-0.5 1->128 2-32 1-8 0.125-64
s0.03 0.25 0.25 16 32 4 2
0.125 1 0.5 128 32 8 32
PD 131628
s0.03-0.06 s0.03-0.125 0.125-1 8->128 0.03->128 0.06->128 1-4
.0.03 .0.03 0.25 64 0.125 0.25 2
.0.03
s0.03 s0.03-0.06 0.125-2 16->128 0.125->128 0.25-128 2-4
.0.03
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin PD 131628
s0.03-0.125 s0.03-0.125
Antimicrobial agent
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
Enterobacter spp. (10)g
Escherichia coli (11)
PD 131628
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
Klebsiella spp.
(11)h
0.03-1 8->128
0.125-1 4->128 0.06-64 0.125-64 1-8 s0.03-4
Ciprofloxacin Imipenem Ampicillin
.0.03-8
PD 131628
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
Proteus mirabilis (10)
.0.03-0.06 0.015-0.125 0.015->128 0.06-2
PD 131628
Aztreonam Ceftazidime Amikacin
Indole-positive members of the Proteeae (12)M
MIC
PD 131628
Ciprofloxacin Imipenem Ampicillin Aztreonam
Ceftazidime Amikacin
0.125-1 32->128 0.06-0.5 0.125-1 1-2
s0.03-0.125 s0.03-0.25 1-16 4->128 0.004-1 0.03-128 0.5-32
.0.03-0.06 .0.03 4-16 1->128 0.015 0.06 1-8
.0.03 0.5 >128 1 2 2
90%
1.25 0.03 0.3
.0.03 .0.03 0.125 128 2 0.5 >128
.0.03 1 >128 8 8 2
.0.03 .0.03 1 >128 32 64 2
.0.03 .0.03 0.125 8 0.125 0.25 4
.0.03
.0.03 .0.03 0.5 128 0.125 0.25 2
0.06 0.125 0.5 128 0.25 0.5 2
.0.03 .0.03
.0.03 0.25 32 0.25 0.25 4
4
0.125 0.125 8 >128 0.25 2 16
.0.03 0.03
.0.03
4 >128 0.03 0.25
4 2 0.015 0.06 4
0.06
8 2 0.015 0.06 8
Continued on following page
144
COHEN ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1-Continued Organism (no. of strains)
MIC
Antimicrobial agent
(qLg/ml)a
Range
50%o
Ciprofloxacin Imipenem Cefsulodin Ceftazidime Piperacillin Amikacin
s0.03-8 0.06-16 0.5-32 1->128 1-64 2->128 1-64
0.125 0.25 2
Pseudomonas cepacia (10)
PD 131628 Ciprofloxacin Imipenem Piperacillin Ceftazidime Cefsulodin Amikacin
0.5-4 1-16 8->128 8->128 2-32 >128 128->128
Salmonella and Shigella spp. (12Y
PD 131628 Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
.0.03
128 0.03, 0.125 0.125, 0.5 4, 32
0.25 0.5 0.015
MICs for
(idvuml)
0.015, 0.06, 0.25 0.5, 12 0.008, 4, 8 12, 2
1
Penicillin G Cefazolin Doxycycline Erythromycin
Ampicillin Aztreonam Ceftazidime Amikacin Yersinia enterocolitica (1)
22, 4 32 8, 162 0.52, 4
Antimicrobial agent
Penicillin G Cefoxitin Clindamycin Metronidazole
1, 22
0.25, 0.52
Ceftazidime Amikacin Alcailigenes odorans (1)
:rainsa
PD 131628 Ciprofloxacin
Aztreonam
Organism (no. of strains)
MICs foir
(ivdml)
145
8, 16 1, 2 0.5 4 4, 32 0.5
The inferior number is the number of isolates with the MIC indicated. Includes one C. difficile strain and one C. ramosum strain. Includes one F. mortiferum strain and one F. varium strain.
RESULTS
0.03 8 .0.03 128 0.03 0.03 16
c0.03 c0.03 0.5 16 0.25 0.125 2
PD 131628 Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
0.125, 0.5, 1 0.5, 4. 8 128, >1282 >128 128, >1282
PD 131628 Ciprofloxacin Imipenem
0.125, 0.252 0.52,1
-
-
64 82, >1128
0.06
Continued
In vitro antibacterial activity. Details of the in vitro activities of PD 131628 against 349 clinically significant grampositive and gram-negative bacterial isolates are shown in Tables 1 and 2 and compared with those of relevant antimicrobial agents; the MIC range, MIC for 50% of isolates (MIC50), and MIC for 90% of isolates (MIC90) (in micrograms per milliliter) are shown in most cases. Table 3 shows PD 131628 MICs obtained against reference cultures from the American Type Culture Collection. A collection of methicillin-resistant (15 strains) and methicillin-susceptible (11 strains) staphylococci were inhibited by .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1991, p. 141-146
0066-4804/91/010141-06$02.00/0 Copyright © 1991, American Society for Microbiology
In Vitro Antibacterial Activities of PD 131628, 1,8-Naphthyridine Anti-Infective Agent
a
New
MICHAEL A. COHEN,'* MICHAEL D. HUBAND,1 GAIL B. MAILLOUX,1 STEVEN L. YODER,' GREGORY E. ROLAND,' JOHN M. DOMAGALA,2 AND CARL L. HEIFETZ' Departments of Experimental Therapy' and Chemistry,2 Parke-Davis Pharmaceutical Research Division, 2800 Plymouth Road, Ann Arbor, Michigan 48105 Received 13 August 1990/Accepted 18 October 1990
PD 131628 is a new aminopyrrolidine-substituted fluorocyclopropyl naphthyridine quinolone which possesses high in vitro activity against a wide spectrum of bacterial species. The MICs for .90% of strains were 0.125 to 0.25 ,ug/ml for staphylococci, Streptococcus pyogenes, and S. pneumoniae; 0.5 ,ug/ml for S. agalactiae and Enterococcus faecalis; 0.125 jug/ml for members of the family Enterobacteriaceae and Acinetobacter spp.; 0.5 ,Lg/mI for Pseudomonas aeruginosa; and 128
0.125 1 0.125 1 2 4 0.06
0.125-0.25 0.25-1 0.004-0.008
0.25 0.5 0.004 0.008 0.125 0.125 0.06
0.25 0.5 0.008 0.015 0.25 0.5 0.125
0.5
0.03-0.06 0.125-0.25 0.125-32 0.03-4
0.5 1 0.015 0.06 0.125 16 0.06
0.125-0.5
0.25
Methicillin-resistant Staphylococcus spp. (15)b
PD 131628
.0.03-0.125
Ciprofloxacin Imipenem Oxacillin Amikacin Vancomycin
0.125-1 0.06-128 16->128 0.5-32 0.5-4
Methicillin-susceptible Staphylococcus spp. (11)C
PD 131628
.0.03-0.125
Ciprofloxacin Imipenem Cefazolin Oxacillin Amikacin Vancomycin
0.125-0.5
PD131628 Ciprofloxacin Imipenem Penicillin G Cefazolin Doxycycline
Streptococcus pneumoniae (20)
Erythromycin Streptococcus pyogenes, group A (20)
Streptococcus agalactiae, group B (20)
PD131628
Ciprofloxacin Imipenem Penicillin G Cefazolin Doxycycline Erythromycin PD 131628
Ciprofloxacin Imipenem Penicillin G Cefazolin Doxycycline Erythromycin
MIC (,ugtml)
90%o 0.125 0.5 128 >128 32 2
Range
0.004-2 0.125-0.25 0.06-0.5 0.03->128 0.25-1 0.5-2
0.008-0.03
50%o
0.25 1 0.5 8 16 16 >128
1 0.015 0.06 0.25 16 1
0.5 1 1 2 4
Enterococcus faecalis (20)
PD 131628
Ciprofloxacin Imipenem Ampicillin Vancomycin
0.25-1 0.5-2 0.5-2 1-4
1 1 1 2
Other streptococci (6)d
PD131628
0.25-0.5
0.5 2 2 1 8 16 4 s0.03 s0.03 2 128 16 0.125 1
Ciprofloxacin Imipenem Penicillin G
0.008-2 0.03-1
Cefazolin Doxycycline
0.06-8 0.03-16 0.015-4
0.25 1 0.06 0.06 1 0.5 0.03
.0.03
.0.03
Erythromycin Haemophilus influenzae (10)
PD 131628
Ciproftoxacin Imipenem Ampicillin Cefazolin Ceftazidime Doxycycline
Moraxella catarrhalis (20)
PD 131628
Ciprofloxacin Imipenem Amoxicillinclavulanic acide
1-2
s0.03 0.03-2 0.125-128 4-16
0.015-0.125 0.5-1
s0.03 s0.03 0.015-4
.0.002-0.03
s0.03 0.5
0.5 8 0.03 0.5 s0.03 c0.03 0.03 0.008
.0.03 s0.03 0.06 0.03
Continued on following page
VOL. 35, 1991
IN VITRO ANTIBACTERIAL ACTIVITY OF PD 131628
143
TABLE 1-Continued Organism (no. of strains)
Neisseria gonorrhoeae (12)
Acinetobacter spp. (14)
Citrobacter spp. (10)f
Range
(ixg/Ml)a 50%o
Cefaclor Doxycycline Erythromycin
0.03-2.5 0.008-0.03 s0.08-0.6
0.6 0.015 0.3
PD131628 Ciprofloxacin Imipenem Penicillin G Doxycycline Erythromycin Spectinomycin
.0.03-0.06
.0.03 .0.03 0.03 0.125 0.25 0.06 16
PD 131628
.0.03-0.25
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
0.06-2 0.06-0.5 1->128 2-32 1-8 0.125-64
s0.03 0.25 0.25 16 32 4 2
0.125 1 0.5 128 32 8 32
PD 131628
s0.03-0.06 s0.03-0.125 0.125-1 8->128 0.03->128 0.06->128 1-4
.0.03 .0.03 0.25 64 0.125 0.25 2
.0.03
s0.03 s0.03-0.06 0.125-2 16->128 0.125->128 0.25-128 2-4
.0.03
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin PD 131628
s0.03-0.125 s0.03-0.125
Antimicrobial agent
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
Enterobacter spp. (10)g
Escherichia coli (11)
PD 131628
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
Klebsiella spp.
(11)h
0.03-1 8->128
0.125-1 4->128 0.06-64 0.125-64 1-8 s0.03-4
Ciprofloxacin Imipenem Ampicillin
.0.03-8
PD 131628
Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
Proteus mirabilis (10)
.0.03-0.06 0.015-0.125 0.015->128 0.06-2
PD 131628
Aztreonam Ceftazidime Amikacin
Indole-positive members of the Proteeae (12)M
MIC
PD 131628
Ciprofloxacin Imipenem Ampicillin Aztreonam
Ceftazidime Amikacin
0.125-1 32->128 0.06-0.5 0.125-1 1-2
s0.03-0.125 s0.03-0.25 1-16 4->128 0.004-1 0.03-128 0.5-32
.0.03-0.06 .0.03 4-16 1->128 0.015 0.06 1-8
.0.03 0.5 >128 1 2 2
90%
1.25 0.03 0.3
.0.03 .0.03 0.125 128 2 0.5 >128
.0.03 1 >128 8 8 2
.0.03 .0.03 1 >128 32 64 2
.0.03 .0.03 0.125 8 0.125 0.25 4
.0.03
.0.03 .0.03 0.5 128 0.125 0.25 2
0.06 0.125 0.5 128 0.25 0.5 2
.0.03 .0.03
.0.03 0.25 32 0.25 0.25 4
4
0.125 0.125 8 >128 0.25 2 16
.0.03 0.03
.0.03
4 >128 0.03 0.25
4 2 0.015 0.06 4
0.06
8 2 0.015 0.06 8
Continued on following page
144
COHEN ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1-Continued Organism (no. of strains)
MIC
Antimicrobial agent
(qLg/ml)a
Range
50%o
Ciprofloxacin Imipenem Cefsulodin Ceftazidime Piperacillin Amikacin
s0.03-8 0.06-16 0.5-32 1->128 1-64 2->128 1-64
0.125 0.25 2
Pseudomonas cepacia (10)
PD 131628 Ciprofloxacin Imipenem Piperacillin Ceftazidime Cefsulodin Amikacin
0.5-4 1-16 8->128 8->128 2-32 >128 128->128
Salmonella and Shigella spp. (12Y
PD 131628 Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
.0.03
128 0.03, 0.125 0.125, 0.5 4, 32
0.25 0.5 0.015
MICs for
(idvuml)
0.015, 0.06, 0.25 0.5, 12 0.008, 4, 8 12, 2
1
Penicillin G Cefazolin Doxycycline Erythromycin
Ampicillin Aztreonam Ceftazidime Amikacin Yersinia enterocolitica (1)
22, 4 32 8, 162 0.52, 4
Antimicrobial agent
Penicillin G Cefoxitin Clindamycin Metronidazole
1, 22
0.25, 0.52
Ceftazidime Amikacin Alcailigenes odorans (1)
:rainsa
PD 131628 Ciprofloxacin
Aztreonam
Organism (no. of strains)
MICs foir
(ivdml)
145
8, 16 1, 2 0.5 4 4, 32 0.5
The inferior number is the number of isolates with the MIC indicated. Includes one C. difficile strain and one C. ramosum strain. Includes one F. mortiferum strain and one F. varium strain.
RESULTS
0.03 8 .0.03 128 0.03 0.03 16
c0.03 c0.03 0.5 16 0.25 0.125 2
PD 131628 Ciprofloxacin Imipenem Ampicillin Aztreonam Ceftazidime Amikacin
0.125, 0.5, 1 0.5, 4. 8 128, >1282 >128 128, >1282
PD 131628 Ciprofloxacin Imipenem
0.125, 0.252 0.52,1
-
-
64 82, >1128
0.06
Continued
In vitro antibacterial activity. Details of the in vitro activities of PD 131628 against 349 clinically significant grampositive and gram-negative bacterial isolates are shown in Tables 1 and 2 and compared with those of relevant antimicrobial agents; the MIC range, MIC for 50% of isolates (MIC50), and MIC for 90% of isolates (MIC90) (in micrograms per milliliter) are shown in most cases. Table 3 shows PD 131628 MICs obtained against reference cultures from the American Type Culture Collection. A collection of methicillin-resistant (15 strains) and methicillin-susceptible (11 strains) staphylococci were inhibited by .
