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International multicenter investigation of LB203W. a new fluoronaphthyridone

1998; Elsevier BV; Volume: 4; Issue: 5 Linguagem: Inglês

10.1111/j.1469-0691.1998.tb00057.x

1469-0691

Annik F. Hohl, Reno Frei, Verena Pünter, Alexander von Graevenitz, C C Knapp, John A. Washington, David M. Johnson, Ronald N. Jones,

Synthesis of β-Lactam Compounds

Because of increasing bacterial resistance worldwide, the search for new antibacterial agents is more pressing than ever. Advances achieved with the extended broad-spectrum β-lactams and the quinolones against a large number of pathogens have been compromised over the last few years by bacteria carrying novel β-lactamases and/or chromosomal mutations of penicillin-binding proteins and/or the DNA gyrase A and/or other forms of resistance affecting these agents. However, researchers from Korea (LG Chemical Ltd, Tae Jon) have described a novel fluoronaphthyridone with a vicinal substitution (3-aminomethyl;4-methyloxyimino) at the 7-pyrrolidine ring that enhances potency against some resistant pathogens [1Kim Y-K Choi H Kim S-H et al.Synthesis and antibacterial activities of LB20304: a new fluoronaphthyridone antibiotic containing novel oxime functionalized pyrrolidine.in: Proceedings of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, DC1995: 148Google Scholar,2Oh J-I Ahn M-H Paek K-S et al.In vitro and in vivo evaluations of LB20304, a new fluoronaphthyridone.Antimicrob Agents Chemother. 1996; 40: 1564-1568PubMed Google Scholar]. The novel agent has demonstrated improved activity primarily against Gram-positive cocci in expanded studies [3Cormican MG Jones RN Antimicrobial activity and spectrum of LB20304, a novel fluoronaphthyridone.Antimicrob Agents Chemother. 1997; 41: 204-211PubMed Google Scholar]. In light of the evolving international antimicrobial resistance problems, we evaluated this promising compound in four large medical centers (two in the USA, and two in Switzerland) against a broad range of routinely isolated, non-fastidious pathogens. A total of 379 aerobic bacterial strains (mostly recent single-patient clinical isolates from university medical centers) were tested in Basel (N=75), Cleveland (N=100), Iowa City (N=104) and Zürich (N=104). Representative members of species that pose antimicrobial resistance problems were selected from among the most commonly encountered bacteria in each laboratory. Of these, 260 isolates were Gram-negative, and 119 were Gram-positive. They were identified by standard methods [4American Society for MicrobiologyManual of clinical microbiology. 6th edn. American Society for Microbiology, Washington, DC1996Google Scholar]. Prefabricated 96-well microtiter plates with serial two-fold decreasing antimicrobial concentrations in cation-adjusted Mueller—Hinton broth (Becton-Dickinson, Cockeysville, MD, USA) were obtained from a commercial manufacturer (PML Microbiologicals, Tualatin, OR, USA) and distributed at −70°C to the participating laboratories. The minimum inhibitory concentrations (MIC) were determined as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) [5National Committee for Clinical Laboratory StandardsMethods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. NCCLS, Villanova, PA1997Google Scholar]. The compounds were provided by their respective manufacturers: LB20304 from LG Chemical Ltd, ciprofloxacin from Miles Pharmaceuticals (West Haven, CT, USA), clinafloxacin (formerly CI-960) from Parke-Davis, Inc. (Ann Arbor, MI, USA), fleroxacin from F. Hoffmann-LaRoche AG (Basel, Switzerland), ofloxacin from Ortho-McNeil Pharmaceuticals (Raritan, NJ, USA), sparfloxacin from Rhone-Poulenc Rorer (Collegeville, PA, USA), and trovafloxacin (formerly CP99,219) from Pfizer, Inc. (Central Research, Groton, CT, USA). The tested range of serial two-fold dilutions (11 dilutions) extended from ≤0.008 mg/L to 8 mg/L and was equal for all drugs tested. The MIC was defined as the lowest concentration which yielded no visible growth. Faint hazes were disregarded. The MIC breakpoints applied for susceptible and resistant categories were taken from the current NCCLS guidelines [5National Committee for Clinical Laboratory StandardsMethods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. NCCLS, Villanova, PA1997Google Scholar]. For compounds without published criteria, we determined the percentage of susceptible strains at two potential, commonly used breakpoint concentrations (1 mg/L; 2 mg/L) for fluoroquinolones [5National Committee for Clinical Laboratory StandardsMethods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. NCCLS, Villanova, PA1997Google Scholar]. Standard quality control, American Type Culture Collection (ATCC) strains included Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, and Pseudomonas aeruginosa ATCC 27853. Because all testing was performed with the same lot of prefabricated trays, all quality control values were found within the recommended ranges, and the susceptibility ranges and potencies of the tested bacteria from the different centers for each group of isolates were not significantly different, we pooled the antimicrobial susceptibility test data of the four participant laboratories. The percentage of non-fastidious aerobically growing Gram-positive cocci susceptible to LB20304 was most similar to that of trovafloxacin and clinafloxacin, but higher than that of sparfloxacin, ofloxacin, ciprofloxacin and fleroxacin (Table 1). The activity of all compounds was substantially lower against oxacillin-resistant than against oxacillin-susceptible staphylococci, particularly Staphylococcus aureus (e.g. 93% versus 13% for ciprofloxacin). Coagulase-negative staphylococci exhibited this difference only when the MIC90 results for the oxacillin-resistant strains were compared. Whereas LB20304, clinafloxacin and trovafloxacin showed activity against a majority of oxacillin-resistant Staphylococcus aureus strains, the older marketed fluoroquinolones (ciprofloxacin, ofloxacin, sparfloxacin, and fleroxacin) were at least modestly active against some of these strains. At 2 mg/L clinafloxacin, trovafloxacin, and LB20304 inhibited at least 60% of Enterococcus faecium strains, while fleroxacin was least active. Against the more common Enterococcus faecalis strains, only LB20304, clinafloxacin, sparfloxacin and trovafloxacin inhibited nearly 90% of strains at 1 mg/L.Table 1In vitro activity of LB20304 compared to six other quinolones tested against 119 strains of Gram-positive cocci and 260 strains of Gram-negative bacilliMIC (mg/L)% at MIC (mg/L)aPercentages in parentheses indicates the NCCLS [5] breakpoint for the susceptible interpretation.Organism (no. tested)Quinolone50%90%Range≤1≤2Staphylococcus aureusOxacillin susceptible (29)LB203040.0150.03≤0.008-0.5100100Ciprofloxacin0.2510.12-2(93)100Clinafloxacin0.0150.03≤0.008-0.5100100Fleroxacin0.510.25-493(93)Ofloxacin0.2510.25-293(97)Sparfloxacin0.120.250.015-0.5(100)100Trovafloxacin0.0150.06≤0.008-0.5100100Oxacillin resistant (15)LB20304280.015 to >84753Ciprofloxacin>8>80.25 to >8(13)20Clinafloxacin0.520.015-46093Fleroxacin>8>80.5 to >87(20)Ofloxacin>8>80.25 to >820(20)Sparfloxacin>8>80.06 to >8(20)20Trovafloxacin140.015-86780Coagulase negative staphylococciOxacillin susceptible (14)LB203040.0150.06≤0.008-0.12100100Ciprofloxacin0.2520.12-4(79)86Clinafloxacin0.030.060.015-0.06100100Fleroxacin1>80.5 to >879(86)Ofloxacin0.540.25-486(86)Sparfloxacin0.120.50.06-2(93)100Trovafloxacin0.030.060.015-05100100Oxacillin resistant (26)LB203040.0154≤0.008 to >88185Ciprofloxacin0.25>80.06 to >8(69)69Clinafloxacin0.01510.008 to >89296Fleroxacin1>80.25 to >862(65)Ofloxacin0.5>80.12 to >869(69)Sparfloxacin0.12>80.06 to >8(69)69Trovafloxacin0.03>8≤0.008 to >87781Enterococcus faecalis (25)LB203040.0620.015 to >88896Ciprofloxacin1>80.25 to >8(56)80Clinafloxacin0.1220.03 to >88896Fleroxacin4>81 to >84(16)Ofloxacin2>81 to >812(60Sparfloxacin1>80.12 to >8(88)88Trovafloxacin0.2580.03 to >88888Enterococcus faecium (10)LB203041>80.06 to >86060Ciprofloxacin2>81 to >8(30)60Clinafloxacin0.580.12 to >86070Fleroxacin8>84 to >80(0)Ofloxacin4>82 to >80(20)Sparfloxacin2>80.5 to >8(20)60Trovafloxacin140.25 to >85070Acinetobacter spp. (11)LB20304>8>80.015 to >84545Ciprofloxacin>8>80.03 to >8(36)36Clinafloxacin1>80.008 to >85573Fleroxacin>8>80.12 to >845(45)Ofloxacin>8>80.12 to >836(45)Sparfloxacin>8>8≤0.008 to >8(45)45Trovafloxacin>8>8≤0.008 to >84545Pseudomonas aeruginosa (30)LB203040.25>80.015 to >87780Ciprofloxacin0.128≤0.008 to >8(80)87Clinafloxacin0.122≤0.008 to >88793Fleroxacin1>80.06 to >853(60)Ofloxacin2>80.06 to >847(73)Sparfloxacin1>80.25 to >8(60)70Trovafloxacin0.5>80.12 to >87383Stenotrophomonas maltophilia (11)LB203040.580.25 to >86482Ciprofloxacin140.25 to >8(55)73Clinafloxacin0.120.50.03-1100100Fleroxacin180.5 to >855(73)Ofloxacin1>80.5 to >855(64)Sparfloxacin0.2540.12 to >8(73)82Trovafloxacin0.2540.06 to >87382Citrobacter freundii (17)LB203040.030.5≤0.008 to >89494Ciprofloxacin0.0150.12≤0.008 to >8(94)94Clinafloxacin0.0150.12≤0.008 to 294100Fleroxacin0.120.50.03 to >894(94)Ofloxacin0.250.50.03 to >894(94)Sparfloxacin0.1210.03 to >8(94)94Trovafloxacin0.030.50.015 to >89494Enterobacter aerogenes (15)LB203040.030.250.015-0.25100100Ciprofloxacin0.0150.25≤0.008-8(93)93Clinafloxacin0.0150.12≤0.008-0.25100100Fleroxacin0.1210.06-893(93)Ofloxacin0.1210.06-893(93)Sparfloxacin0.1210.03-2(93)100Trovafloxacin0.060.50.015-0.5100100Enterobacter cloacae (20)LB203040.0150.12≤0.008-0.25100100Ciprofloxacin0.0150.12≤0.008-0.25(100)100Clinafloxacin≤0.0080.06≤0.008-0.06100100Fleroxacin0.060.250.03-0.5100(100)Ofloxacin0.120.50.03-1100100Sparfloxacin0.060.250.015-0.5(100)100Trovafloxacin0.030.12≤0.008-0.25100100Escherichia coli (58)LB203040.0150.06≤0.008 to >89797Ciprofloxacin≤0.0080.06≤0.008 to >8(97)97Clinafloxacin≤0.0080.015≤0.008 to >89798Fleroxacin0.060.250.03 to >897(97)Ofloxacin0.060.250.03 to >895(97)Sparfloxacin0.030.12≤0.008 to >8(97)97Trovafloxacin0.0150.06≤0.008 to >89797Klebsiella pneumoniae (28)LB203040.031≤0.008 to >89696Ciprofloxacin0.031≤0.008 to >8(93)96Clinafloxacin0.0150.5≤0.008-296100Fleroxacin0.1220.06 to >882(93)Ofloxacin0.1240.06 to >882(86)Sparfloxacin0.1220.06 to >8(86)93Trovafloxacin0.0610.03 to >89696Proteus mirabilis (19)LB203040.120.50.06 to >89595Ciprofloxacin0.030.06≤0.008 to >8(95)95Clinafloxacin0.0150.06≤0.008 to >895100Fleroxacin0.120.250.03 to >895(95)Ofloxacin0.120.50.06 to >895(95)Sparfloxacin0.520.25 to >8(89)95Trovafloxacin0.250.50.12 to >89595Serratia marcescens (20)LB203040.2580.12 to >87580Ciprofloxacin0.1240.03 to >8(80)80Clinafloxacin0.0610.015-49090Fleroxacin0.2580.06 to >870(75)Ofloxacin0.580.12 to >870(80)Sparfloxacin180.25 to >8(50)75Trovafloxacin0.580.12 to >86575Other (31)bIncludes Citrobacter koseri (two strains), Klebsiella oxytoca (nine strains), Morganella morganii (five strains), Proteus vulgaris (five strains), Providencia spp. (five strains), and Serratia liquefaciens (five strains). EnterobacteriaceaeLB203040.062≤0.008 to >88790Ciprofloxacin0.0150.12≤0.008 to >8(90)94Clinafloxacin≤0.0080.06≤0.008 to >8100100Fleroxacin0.060.25≤0.008 to >890(90)Ofloxacin0.120.50.03 to >890(90)Sparfloxacin0.1240.015 to >8(87)87Trovafloxacin0.0610.008-89497a Percentages in parentheses indicates the NCCLS [5National Committee for Clinical Laboratory StandardsMethods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. NCCLS, Villanova, PA1997Google Scholar] breakpoint for the susceptible interpretation.b Includes Citrobacter koseri (two strains), Klebsiella oxytoca (nine strains), Morganella morganii (five strains), Proteus vulgaris (five strains), Providencia spp. (five strains), and Serratia liquefaciens (five strains). Open table in a new tab The activity of LB20304 against the Enterobacteriaceae was generally two-fold less than that of ciprofloxacin or clinafloxacin, but equal to or two-fold more than that of trovafloxacin (Table 1). Clinafloxacin was slightly more active (MIC50, 1 mg/L) against Acinetobacter spp., but only 36% (ciprofloxacin) to 45% (three drugs) of recent clinical isolates were inhibited by currently available compounds. Pseudomonas aeruginosa was most susceptible to clinafloxacin (87% inhibited at ≤1 mg/L), yet LB20304 inhibited 80% of these strains at ≤2 mg/L, e.g., equal to ciprofloxacin. Among the currently available drugs tested, fleroxacin had the greatest activity (73%) versus Stenotrophomonas maltophilia, followed by ofloxacin and ciprofloxacin (55%). LB20304 inhibited (MIC50, 0.5 mg/L) 82% of these strains at ≤2 mg/L and clinafloxacin had the greatest potency (MIC90, 0.5 mg/L). Overall, against the Gram-negative strains, the seven compounds only varied in spectrum from 83% to 94% at ≤1 mg/L (investigational drugs) or at NCCLS published breakpoints for susceptibility [5National Committee for Clinical Laboratory StandardsMethods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. NCCLS, Villanova, PA1997Google Scholar]. The overall percentage of susceptible strains for LB20304, clinafloxacin and trovafloxacin were consistently higher at 1 mg/L or at 2 mg/L compared to those of the older fluoroquinolones. For the investigational quinolones, the rank order of spectra (% inhibited at ≤ 1 mg/L) was clinafloxacin (92%) > LB20304 and trovafloxacin (87%). The observation that the overall percentage of susceptible strains to ciprofloxacin, ofloxacin, fleroxacin and sparfloxacin did not exceed 80% among species prone to quinolone resistance illustrates that these compounds have lost potency and spectrum in recent years within the study centers and nations monitored. However, the investigational compounds LB20304, clinafloxacin and trovafloxacin demonstrated that improved activity against Gram-positive organisms can be achieved among the quinolone class members without undue sacrifice of potency against important Gram-negative organisms. Clinafloxacin was the most potent of the agents tested [6Domagala JM Structure—activity and structure—side-effect relationship for the quinolone antibacterials.J Antimicrob Chemother. 1994; 33: 685-706Crossref PubMed Scopus (646) Google Scholar]. Pharmacokinetic publications favor an interpretive breakpoint of 1 mg/L or lower for this drug, a breakpoint recently accepted by the NCCLS for sparfloxacin [5National Committee for Clinical Laboratory StandardsMethods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. NCCLS, Villanova, PA1997Google Scholar,7Ritz M Lode L Fassbender M Borner K Koeppe P Nord CE Multiple-dose pharmacokinetics of sparfloxacin and its influence on fecal flora.Antimicrob Agents Chemother. 1994; 38: 455-459Crossref PubMed Scopus (28) Google Scholar]. Trovafloxacin's breakpoint for susceptibility is more likely to be at 1 or 2 mg/L, depending on the final recommended dosage and Clinical tolerability [8Teng R Liston TE Harris SC Multiple-dose pharmacokinetics and safety of trovafloxacin in healthy volunteers.J Antimicrob Chemother. 1996; 37: 955-963Crossref PubMed Scopus (68) Google Scholar]. To date, limited human pharmacokinetic information has been published for LB20304, and therefore its activity relative to its comparators must remain an open question. The difference in possible MIC breakpoints (≤1 or ≤2 mg/L) between the latter two compounds has only minor repercussions on the percentage of susceptible isolates. Indeed, the higher (≤2 mg/L) trovafloxacin and LB20304 breakpoints improved their spectra by only 3.2% and 2.4%, respectively. Other promising aspects of LB20304, clinafloxacin and trovafloxacin are their excellent activities against some fastidious species such as pneumococci, Haemophilus spp., and Moraxella catarrhalis [1Kim Y-K Choi H Kim S-H et al.Synthesis and antibacterial activities of LB20304: a new fluoronaphthyridone antibiotic containing novel oxime functionalized pyrrolidine.in: Proceedings of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, DC1995: 148Google Scholar, 2Oh J-I Ahn M-H Paek K-S et al.In vitro and in vivo evaluations of LB20304, a new fluoronaphthyridone.Antimicrob Agents Chemother. 1996; 40: 1564-1568PubMed Google Scholar, 3Cormican MG Jones RN Antimicrobial activity and spectrum of LB20304, a novel fluoronaphthyridone.Antimicrob Agents Chemother. 1997; 41: 204-211PubMed Google Scholar]; (not evaluated here). Therefore, these compounds should be very useful for the treatment of common bacterial respiratory infections. Lastly, it may be speculated that LB20304—which is devoid of a halogen at the C-8 position—would probably have lower rates of photo-toxicity in clinical trials than have been observed for sparfloxacin and clinafloxacin [6Domagala JM Structure—activity and structure—side-effect relationship for the quinolone antibacterials.J Antimicrob Chemother. 1994; 33: 685-706Crossref PubMed Scopus (646) Google Scholar]. Accordingly, we await further clinical development of LB20304 and the other novel congeners utilized as comparison agents in this investigation. This study was funded in part by a grant from LB Chemical Ltd and additional research funds from the Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine. LB20304 will be jointly developed with SmithKline Beecham. Parts of this study were presented at the 8th European Congress of Clinical Microbiology and Infectious Diseases, Lausanne, Switzerland, 25-28 May 1997.