In vitro antibacterial activities of the fluoroquinolones PD 117596, PD 124816, and PD 127391

The susceptibilities of 123 clinically isolated strains of Xanthomonas maltophilia to six fluoroquinolones (clinafloxacin, PD 131628, PD 138312, PD 140248, ciprofloxacin, and ofloxacin) were examined by microdilution MIC methodology. Clinafloxacin and PD 131628 were the most active compounds tested (MICs for 50% of the strains tested [MIC50s] of 0.5 and 1.0 ,ug/ml and MIC90s of 2.0 and 4.0 ,ug/ml, respectively). PD 138312, PD 140248, ciprofloxacin, and ofloxacin were less active, with MIC50s ranging from 4.0 to 8.0 ,ug/ml and MIC90s of 16.0 ,ug/ml for all four compounds. Only clinafloxacin and PD 131628 were active against ciprofloxacinresistant strains, with MIC50s of 0.5 and 1.0 ,ug/ml and MIC90s of 2.0 and 4.0 ,ug/ml, respectively.Infections caused by Xanthomonas maltophilia are increasingly encountered, especially in patients with compromised host defense mechanisms (10,11,17). The problem is further complicated by the inherently resistant nature of this species, which is due to a combination of permeability defects and ,B-lactamase production (3,10,11,13,17). Of commonly used antimicrobial agents, only trimethoprim-sulfamethoxazole has been found to be consistently active in vitro against this organism (10,17). Available quinolones such as ciprofloxacin and ofloxacin are marginally active, with MICs for susceptible isolates clustering around the breakpoint (1,4,9,(12)(13)(14). Clinafloxacin (CI-960, PD 127391) and PD 131628 (the active component of the prodrug CI-990) are two new fluoroquinolones with improved activity against gram-positive cocci, gramnegative nonfermenters, and anaerobes (5,6,8,9,12,16). This study compared the activities of clinafloxacin, PD 131628, two other experimental broad-spectrum fluoroquinolones (PD 138312 and PD 140248) (2, 7), ciprofloxacin, and ofloxacin against 123 clinical isolates of X maltophilia.Most clinical isolates (85%) were from different patients at Hershey Medical Center and University Hospitals of Cleveland and were collected over a 3-year period. The remainder were obtained from sources listed in the Acknowledgments and were isolated over a 6-year period. All strains were reidentified and MIC studies performed at Hershey Medical Center. Strains were identified by standard methods (10) Suscep-tibility breakpoints for ciprofloxacin (2.0 ,ug/ml) and ofloxacin (4.0 ,ug/ml) were those recommended by the National Committee for Clinical Laboratory Standards for members of the family Enterobacteriaceae (15). Breakpoints for the other four compounds were all 2.0 pug/ml, on the basis of preliminary data for members of the family Enterobacteriaceae (2). It should be noted, however, that no definitive quinolone susceptibility breakpoints are available for X maltophilia.The results of MIC testing are presented in Tables 1 and 2. Clinafloxacin and PD 131628 were the most active agents against all X. maltophilia strains, with 94 and 80% of the strains susceptible to the respective compounds at the preliminary breakpoints. MIC ranges of 0.06 to 8.0 and 0.125 to 16.0 iig/ml, MI...

supporting

confidence: 80%

mentioning

confidence: 99%

Susceptibilities of 123 Xanthomonas maltophilia strains to clinafloxacin, PD 131628, PD 138312, PD 140248, ciprofloxacin, and ofloxacin

Pankuch

Jacobs

Appelbaum

1994

“…PD 127391 was also tested against clinical isolates of E. faecium which can cause serious infections and present difficult therapeutic dilemmas (10,11). Our susceptibility results for PD 127391 and sparfloxacin are in agreement with other reports and indicate that these compounds are highly active agents against clinically significant isolates of grampositive cocci (3,7,8,18). Furthermore, no decrease in activity of either PD 127391 or sparfloxacin was noted for isolates of highly gentamicin-resistant and ,B-lactamase-producing E. faecalis or isolates of methicillin-resistant S. aureus.…”

supporting

confidence: 79%

“…Members of this drug class possess a high degree of activity against aerobic gram-negative organisms but are generally less active against aerobic gram-positive cocci, particularly streptococci and enterococci (19). The recently developed quinolones tosufloxacin (1), sparfloxacin (12), CI-934 (2,8), PD 117596 (3,15), WIN 57273 (5), and PD 127391 (CI-960) (7,8,14,15,18), however, have good antimicrobial activity against these organisms. PD 127391 appears to be one of the most active of these agents.…”

mentioning

confidence: 99%

Comparative in vitro activity of PD 127391, a new fluoroquinolone agent, against susceptible and resistant clinical isolates of gram-positive cocci

Miranda¹,

Wanger²,

Singh³

et al. 1992

We examined the in vitro activity of PD 127391, an investigational fluoroquinolone antibacterial agent, against staphylococci (including methicillin-resistant Staphylococcus aureus), enterococci (including beta-lactamase-producing and highly gentamicin-resistant isolates), and streptococci. The compound was active against all organisms tested and compared favorably with antimicrobial agents routinely used to treat infections with these organisms. On the basis of MICs for 90% of the strains tested, PD 127391 was 32-fold more active against all staphylococci, 16-fold more active against methicillin-resistant S. aureus, 8-fold more active against all streptococci, and 4-fold more active against all enterococci than ciprofloxacin. PD 127391 was shown to be more active than sparfloxacin, which in turn was shown to be more active than ciprofloxacin, against these gram-positive cocci. PD 127391 shows promise for the treatment of infections with gram-positive cocci, including organisms which are resistant to other commonly used antimicrobial agents.

“…DU-6859a (DU) is a new fluoroquinolone antimicrobial agent with the chemical structure 7-[(7S)-7-amino-5-azaspiro [2,4]heptan-5-yl]-8-chloro-6-fluoro-1-[(lR,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate (25). Since the presently available fluoroquinolone agents possess only moderate activities against many gram-positive bacteria, recent efforts have been directed toward the synthesis of compounds which have greater activities against these organisms, such as tosufloxacin (1), sparfloxacin (1,3,9), CI-934 (4), WIN 57273 (7,15,17), PD 117596 (5), PD 127391 (CI-960) (5,9,20), PD 131628 (9), T-3761 (10), OPC-17116 (14), AM-1155 (13), E-4497 (11), CP-74667 (16), and CP-99219 (6). DU appears to be one of the most active of these agents (25).…”

mentioning

confidence: 99%

Comparative in vitro activity of DU-6859a, a new fluoroquinolone agent, against gram-positive cocci

Korten¹,

Tomayko²,

Murray³

1994

The in vitro activity of DU-6859a (DU), a new fluoroquinolone agent, was evaluated against 233 gram-positive cocci and was compared with those of ciprofloxacin, vancomycin, nafcillin, and ampicillin. The MICs of DU for 90% of the staphylococci tested were <0.06 ,ug/ml. All of the groups A and B and viridans group streptococci were inhibited by sO.125 ,ug of DU per ml, which was 32-fold more active than ciprofloxacin. On T-3761 (10), OPC-17116 (14), AM-1155 (13), E-4497 (11), CP-74667 (16), and CP-99219 (6). DU appears to be one of the most active of these agents (25). In the present study, the antibacterial activity of DU was investigated and compared with the activities of ciprofloxacin, vancomycin, nafcillin, and ampicillin against gram-positive cocci representing a broad range of antimicrobial resistance patterns. DU in powder form was provided by Daiichi Pharmaceutical Co., Tokyo, Japan; ciprofloxacin was provided by Miles Pharmaceuticals, West Haven, Conn.; and vancomycin, nafcillin, and ampicillin were purchased from Sigma Chemical Co., St. Louis, Mo. All staphylococci and streptococci were collected from hospitals in Houston, Tex., between 1989 and The bactericidal activity of DU against 7 E. faecalis and 3 E. faecium isolates was determined. Overnight cultures were diluted to yield a final inoculum of _107 CFU/ml in flasks containing brain heart infusion broth. The concentration of DU (2 ,ug/ml) used in the time-kill assays was recommended by the manufacturer to represent levels achievable in human serum. Samples (100 ,ul each) were withdrawn from flasks following 0, 4, and 24 h of incubation at 37°C with agitation. Undiluted and serially diluted samples were plated onto brain heart infusion agar plates. The lowest detectable number of organisms was 10 CFU/ml. The agar plates were incubated at 37°C for 24 h before CFU were counted. Bactericidal activity was defined as a reduction in CFU of >3 loglo. A drug carryover effect was excluded by showing that there was less than 5% difference in colony counts when 100 ,ul of 103 to 104 CFU/ml was plated onto antibiotic-free plates in the absence or presence of DU (2 ,ug/ml).The results of susceptibility testing with DU and a comparison of these results with the results of testing with other antibiotics are shown in Table 1. Fifty percent of the staphylococcal isolates tested were inhibited by .0.03 ,ug of DU per ml, and 90% were inhibited by .0.06 ,ug/ml (Table 1). The MICs for 90% of strains tested (MIC90s) were higher for the methicillin-resistant subgroups of S. aureus and coagulasenegative staphylococci than for the methicillin-susceptible sub-