In vitro antibacterial activities of PD 138312 and PD 140248, new fluoronaphthyridines with outstanding gram-positive potency

Huband, Michael D.; Cohen, Michael; Meservey, Mark A.; Roland, Gregory E.; Yoder, Steven L.; Dazer, M E; Domagala, John M.

doi:10.1128/aac.37.12.2563

Cited by 11 publications

(7 citation statements)

References 12 publications

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“…In vitro studies with PD 138312 and PD 140248 have shown similar MICs at which 90% of vancomycin-resistant and vancomycin-susceptible strains of Enterococcus faecalis and Enterococcus faecium are inhibited (9). Recent in vivo studies with PD 138312 with a mouse E. faecalis sepsis model reveals good protective efficacy against a vancomycin-resistant strain (4).…”

Section: Discussionmentioning

confidence: 98%

“…Two new 7-pyrrolidinyl naphthyridines, PD 138312 and PD 140248, have been shown to possess excellent broad-spectrum activity in vitro, most notably against gram-positive organisms and anaerobes (8,9). The structures of PD 138312-(R) Given their promising in vitro potencies, the objective of the study described here was to evaluate these compounds with respect to their in vivo chemotherapeutic activities and bioavailabilities in acute, systemic infections in mice.…”

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confidence: 99%

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In vivo therapeutic efficacies of PD 138312 and PD 140248, two novel fluoronaphthyridines with outstanding gram-positive potency

Shapiro¹,

Dever²,

Joannides³

et al. 1995

Antimicrob Agents Chemother

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PD 138312 and PD 140248 are novel broad-spectrum 7-pyrrolidinyl fluoronaphthyridines with a cyclopropyl or a difluorophenyl substitution at the 1 positions, respectively. They have been demonstrated to have excellent in vitro activity against gram-positive organisms. These compounds were evaluated for their in vivo potencies against acute systemic infections in mice and in a mouse pneumococcal pneumonia model. They were very effective by both the oral and subcutaneous routes of administration. Most remarkable were their comparative median protective values against methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. In general, these compounds were 28-to 100-fold more active than ciprofloxacin against these clinically significant organisms when the drugs were given orally and 10-to 38-fold more active when the drugs were given parenterally. Average ratios of drug concentrations in mice after drug administration by the oral route to that after administration by the subcutaneous route indicate 34 to 44% greater bioavailabilities of PD 138312 and PD 140248 compared with that of ciprofloxacin. In a multidose pneumococcal mouse pneumonia model these new quinolones were extremely effective, with median curative doses of 2 to 2.8 mg/kg of body weight per dose. Ciprofloxacin was ineffective (median curative dose, >100 mg/kg per dose) in this model. Comparative pharmacokinetic studies in mice revealed a relative superiority of PD 140248. Peak levels of PD 140248 in blood after the administration of a single oral 50-mg/kg dose were twice those of PD 138312 and ciprofloxacin, with PD 140248 having a substantially longer half-life. These results indicate that PD 138312 and PD 140248 have excellent therapeutic potential against clinically important gram-positive pathogens when the drugs are administered both orally and parenterally.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

In vivo therapeutic efficacies of PD 138312 and PD 140248, two novel fluoronaphthyridines with outstanding gram-positive potency

Shapiro¹,

Dever²,

Joannides³

et al. 1995

Antimicrob Agents Chemother

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“…Although strains of E. faecalis and E. faecium resistant to these newer quinolones are encountered (300,400), several investigations have included strains resistant to other nonquinolone antimicrobial agents and obtained similar results (105,208,255,289,300,425); in one case, gentamicin-resistant strains were significantly more resistant to the quinolone CP 99219 than gentamicin-susceptible strains (105). Temafloxacin has been withdrawn from clinical development because of unexpected toxicity, and tosufloxacin is not being developed further (193). Sparfloxacin and clinafloxacin have given promising results in vitro against glycopeptide-resistant E. faecium (61) and in the rabbit endocarditis model against E. faecalis and E. faecium (386).…”

Section: Enterococcal Infectionsmentioning

confidence: 99%

“…Characteristic results of in vitro testing of several of these newly introduced quinolones are given in Table 6, which indicates that clinafloxacin (PD 127391, CI 960, and AM-1091) is the most active agent. Other compounds showing promise include PD 138312 and PD 140248 (193). Although strains of E. faecalis and E. faecium resistant to these newer quinolones are encountered (300,400), several investigations have included strains resistant to other nonquinolone antimicrobial agents and obtained similar results (105,208,255,289,300,425); in one case, gentamicin-resistant strains were significantly more resistant to the quinolone CP 99219 than gentamicin-susceptible strains (105).…”

Section: Enterococcal Infectionsmentioning

confidence: 99%

Current perspectives on glycopeptide resistance

et al. 1995

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In the last 5 years, clinical isolates of gram-positive bacteria with intrinsic or acquired resistance to glycopeptide antibiotics have been encountered increasingly. In many of these isolates, resistance arises from an alteration of the antibiotic target site, with the terminal D-alanyl-D-alanine moiety of peptidoglycan precursors being replaced by groups that do not bind glycopeptides. Although the criteria for defining resistance have been revised frequently, the reliable detection of low-level glycopeptide resistance remains problematic and is influenced by the method chosen. Glycopeptide-resistant enterococci have emerged as a particular problem in hospitals, where in addition to sporadic cases, clusters of infections with evidence of interpatient spread have occurred. Studies using molecular typing methods have implicated colonization of patients, staff carriage, and environmental contamination in the dissemination of these bacteria. Choice of antimicrobial therapy for infections caused by glycopeptide-resistant bacteria may be complicated by resistance to other antibiotics. Severe therapeutic difficulties are being encountered among patients infected with enterococci, with some infections being untreatable with currently available antibiotics.

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“…In our consequent approach to new quinolones, the usual fluorine atom at the C-6 position was excluded, while a methyl group was instead included at the C-8 position as a potential enhancer of antibacterial activity, especially against Gram-positive bacteria. , This property is of particular interest since the currently available quinolone agents exhibit only moderate activities against many Gram-positive bacteria. Indeed, recent efforts have been directed toward synthesizing compounds which show greater activity against these organisms ), differ from their slightly active and surpassed predecessors such as nalidixic acid, pipemidic acid, or piromidic acid, in that they maintain the arrangement of the functional groups that SAR studies indicated as optimal to warrant the highest activity levels.…”

Section: Introductionmentioning

confidence: 99%

Potent 6-Desfluoro-8-methylquinolones as New Lead Compounds in Antibacterial Chemotherapy

et al. 1996

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In a furtherance of our SAR study on the C-6 position of quinolone antibacterials, a series of 6-desfluoro-8-methylquinolones were synthesized and evaluated for their in vitro antimicrobial activity. As a result of this study, compounds with strong activity against Gram-positive bacteria, including ciprofloxacin-resistant and methicillin-resistant Staphylococcus aureus, were identified. The best Gram-positive antibacterial activity was exhibited by piperidinyl derivative 6c, which was 17 times more potent than ciprofloxacin and displayed extremely high activity against Streptococcus pneumoniae with an MIC value of <0.016 microg/mL. Thus, we have shown that substituent combinations in the quinolone ring, excluding the C-6 fluorine atom, might produce powerful antibacterial agents.

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In vitro antibacterial activities of PD 138312 and PD 140248, new fluoronaphthyridines with outstanding gram-positive potency

Cited by 11 publications

References 12 publications

In vivo therapeutic efficacies of PD 138312 and PD 140248, two novel fluoronaphthyridines with outstanding gram-positive potency

In vivo therapeutic efficacies of PD 138312 and PD 140248, two novel fluoronaphthyridines with outstanding gram-positive potency

Current perspectives on glycopeptide resistance

Potent 6-Desfluoro-8-methylquinolones as New Lead Compounds in Antibacterial Chemotherapy

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