DIAGN MICROBIOLINFECTDIS 1992;15:531-536
531
NOTES
In vitro Activity of CP-74667 Compared with Four Other Fluoroquinolones Ronald N. Jones and Meridith E. Erwin
CP-74667 is a new, novel C-7 diazabicyclo-fluoroquinolone. Its spectrum of activity includes the Enterobacteriaceae, most nonenteric Gram-negative bacilli, and Gram-positive cocci. Particularly high activity was demonstrated against Xanthomonas maltophilia (MICso, 1 pag/ml), Staphylococcus spp. (MIC5os, 0.06-0.12 lag/ml) and enterococci (MICsos, 0.5-4
~g/ml). Several staphylococci resistant to ciprofloxacin had potentially susceptible range MICs for CP-74667, for example, ~2 i~g/ml. Fluoroquinolones with this C-7 modification appear promising and worthy of continued pharmaceutical investigation.
Compound CP-74667 is a C-7 diazabicyclo-fluoroquinolone (Figure 1). Only the C-7 substitution significantly differs from the ciprofloxacin structure (Hooper and Wolfson, 1991; Wolfson and Hooper, 1989). Structural modifications of the commonly used C-7 piperazine ring moiety (ciprofloxacin, enoxacin, and norfloxacin), such as using a pyrrolidinyl group, improves fluoroquinolone activity against several Gram-positive species (Wolfson and Hooper, 1989). Preliminary information indicates that the C-7 diazabicyclo substitutions expand the fluoroquinolone activity against Gram-positive bacterial species while generally maintaining a Gram-negative spectrum of activity comparable to ciprofloxacin (data on file with Pfizer). In this study, the CP-74667 activity was compared with four clinically available or soon to be
released quinolones--ciprofloxacin, enoxacin, norfloxacin, and ofloxacin. The CP-74667 was obtained from Pfizer Central Research (Groton, CT). The other reference fluoroquinolones were provided by their US manufacturers. Compounds were diluted in cation-adjusted Mueller-Hinton broth (Prepared Media Laboratories, Tualatin, OR) and dispensed into microdilution trays. Trays were stored at -60°C or below until used. Dilution tests were performed by methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS), including those suggested for gonococci, fastidious species, and anaerobic bacteria (NCCLS, 1989 and 1990). The bacteria tested were isolated from patients at the University of Iowa Hospitals and Clinics. Most strains were bloodstream isolates or those taken from normally sterile (nonurinary) body f u i d s in the last 2 years. Table I summarizes the minimum inhibitory concentration (MIC) results for >600 bacterial strains. CP-74667 was generally eightfold (range, 2- to 32fold) less active than ciprofloxacin and comparable in potency to the other fluoroquinolones against the Enterobacteriaceae. Ciprofloxacin was also most potent against Pseudornonas aeruginosa, but CP-74667 was two- to fourfold more active and had the greatest potential spectrum (MICs, -16 4
0.06->8 0.12->4 0.25->8 0.5->16 0.12->8
CP-74667 Ciprofloxacin Enoxacin Norfloxacin Ofloxacin
0.12 0.25 0.5 1 0.5
0.25 0.25
CP-74667 Ciprofloxacin Enoxacin Norfloxacin Ofloxacin
0.5 0.5 4 4 2
2 1
CP-74667 Ciprofloxacin Enoxacin Norfloxacin Ofloxacin
4 4 >8 16 8
4 >4
Organism (No. Tested)
Other coagulase-negative staphylococci (20)a
Enterococcus faecalis (21)
E. faecium (10)
Bacillus cereus (10)
90%
>8
1
1 0.5
8
4 4
>8
Range
4->8
0.03--0.5 0.06--0.5 0.25->8 0.25-4 0.25-1 0.25-4 0.5-2 4-8 2-8 1-8 2-4 4->4 >8
>16
8->16
>8
8->8
CP-74667 Ciprofloxacin Enoxacin Norfloxacin Ofloxacin
0.06 0.03 0.25 0.25 0.25
0.25 0.06 0.5 0.25 0.25
0.06-0.12 0.03-0.05 0.25-0.5 0.25-0.5 0.12-0.5
Group A (20)
CP-74667 Ciprofloxacin
0.25 0.5
0.25 0.5
0.03-0.5 0.25-0.5
Group B (20)
CP-74667 Ciprofloxacin
0.5 0.25
2 0.5
0.25-2 0.12-1
Groups C, F, and G ( 1 4 )
CP-74667 Ciprofloxacin
0.12 0.25
0.5 0.5
~
531
NOTES
In vitro Activity of CP-74667 Compared with Four Other Fluoroquinolones Ronald N. Jones and Meridith E. Erwin
CP-74667 is a new, novel C-7 diazabicyclo-fluoroquinolone. Its spectrum of activity includes the Enterobacteriaceae, most nonenteric Gram-negative bacilli, and Gram-positive cocci. Particularly high activity was demonstrated against Xanthomonas maltophilia (MICso, 1 pag/ml), Staphylococcus spp. (MIC5os, 0.06-0.12 lag/ml) and enterococci (MICsos, 0.5-4
~g/ml). Several staphylococci resistant to ciprofloxacin had potentially susceptible range MICs for CP-74667, for example, ~2 i~g/ml. Fluoroquinolones with this C-7 modification appear promising and worthy of continued pharmaceutical investigation.
Compound CP-74667 is a C-7 diazabicyclo-fluoroquinolone (Figure 1). Only the C-7 substitution significantly differs from the ciprofloxacin structure (Hooper and Wolfson, 1991; Wolfson and Hooper, 1989). Structural modifications of the commonly used C-7 piperazine ring moiety (ciprofloxacin, enoxacin, and norfloxacin), such as using a pyrrolidinyl group, improves fluoroquinolone activity against several Gram-positive species (Wolfson and Hooper, 1989). Preliminary information indicates that the C-7 diazabicyclo substitutions expand the fluoroquinolone activity against Gram-positive bacterial species while generally maintaining a Gram-negative spectrum of activity comparable to ciprofloxacin (data on file with Pfizer). In this study, the CP-74667 activity was compared with four clinically available or soon to be
released quinolones--ciprofloxacin, enoxacin, norfloxacin, and ofloxacin. The CP-74667 was obtained from Pfizer Central Research (Groton, CT). The other reference fluoroquinolones were provided by their US manufacturers. Compounds were diluted in cation-adjusted Mueller-Hinton broth (Prepared Media Laboratories, Tualatin, OR) and dispensed into microdilution trays. Trays were stored at -60°C or below until used. Dilution tests were performed by methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS), including those suggested for gonococci, fastidious species, and anaerobic bacteria (NCCLS, 1989 and 1990). The bacteria tested were isolated from patients at the University of Iowa Hospitals and Clinics. Most strains were bloodstream isolates or those taken from normally sterile (nonurinary) body f u i d s in the last 2 years. Table I summarizes the minimum inhibitory concentration (MIC) results for >600 bacterial strains. CP-74667 was generally eightfold (range, 2- to 32fold) less active than ciprofloxacin and comparable in potency to the other fluoroquinolones against the Enterobacteriaceae. Ciprofloxacin was also most potent against Pseudornonas aeruginosa, but CP-74667 was two- to fourfold more active and had the greatest potential spectrum (MICs, -16 4
0.06->8 0.12->4 0.25->8 0.5->16 0.12->8
CP-74667 Ciprofloxacin Enoxacin Norfloxacin Ofloxacin
0.12 0.25 0.5 1 0.5
0.25 0.25
CP-74667 Ciprofloxacin Enoxacin Norfloxacin Ofloxacin
0.5 0.5 4 4 2
2 1
CP-74667 Ciprofloxacin Enoxacin Norfloxacin Ofloxacin
4 4 >8 16 8
4 >4
Organism (No. Tested)
Other coagulase-negative staphylococci (20)a
Enterococcus faecalis (21)
E. faecium (10)
Bacillus cereus (10)
90%
>8
1
1 0.5
8
4 4
>8
Range
4->8
0.03--0.5 0.06--0.5 0.25->8 0.25-4 0.25-1 0.25-4 0.5-2 4-8 2-8 1-8 2-4 4->4 >8
>16
8->16
>8
8->8
CP-74667 Ciprofloxacin Enoxacin Norfloxacin Ofloxacin
0.06 0.03 0.25 0.25 0.25
0.25 0.06 0.5 0.25 0.25
0.06-0.12 0.03-0.05 0.25-0.5 0.25-0.5 0.12-0.5
Group A (20)
CP-74667 Ciprofloxacin
0.25 0.5
0.25 0.5
0.03-0.5 0.25-0.5
Group B (20)
CP-74667 Ciprofloxacin
0.5 0.25
2 0.5
0.25-2 0.12-1
Groups C, F, and G ( 1 4 )
CP-74667 Ciprofloxacin
0.12 0.25
0.5 0.5
~
