In vitro activity of T-3761, a new fluoroquinolone

Muratani, Tetsuro; Inoue, Matsuhisa; Mitsuhashi, Susumu

doi:10.1128/aac.36.10.2293

Cited by 32 publications

(16 citation statements)

References 9 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Levofloxacin appears to be more active than ciprofloxacin (95). Temofloxacin (32), T-3761 (221), and sparfloxacin (257) appear to be comparable to ciprofloxacin. Importantly, resistance to sparfloxacin appeared to emerge less rapidly following exposure to increasing concentrations than that to ciprofloxacin (284).…”

Section: Conventional Methodsmentioning

confidence: 99%

Update on clinical significance of coagulase-negative staphylococci

1994

View full text Add to dashboard Cite

The clinical significance of coagulase-negative Staphylococcus species (CNS) continues to increase as strategies in medical practice lead to more invasive procedures. Hospitalized patients that are immunocompromised and/or suffering from chronic diseases are the most vulnerable to infection. Since CNS are widespread on the human body and are capable of producing very large populations, distinguishing the etiologic agent(s) from contaminating flora is a serious challenge. For this reason, culture identification should proceed to the species and strain levels. A much stronger case can be made for the identification of a CNS etiologic agent if the same strain is repeatedly isolated from a series of specimens as opposed to the isolation of different strains of one or more species. Strain identity initially can be based on colony morphology, and then one or more molecular approaches can be used to gain information on the genotype. Many of the CNS species are commonly resistant to antibiotics that are being indicated for staphylococcal infections, with the exception of vancomycin. The widespread use of antibiotics in hospitals has provided a reservoir of antibiotic-resistant genes. The main focus on mechanisms of pathogenesis has been with foreign body infections and the role of specific adhesins and slime produced by Staphylococcus epidermidis. Slime can reduce the immune response and opsonophagocytosis, thereby interfering with host defense mechanisms. As we become more aware of the various strategies used by CNS, we will be in a better position to compromise their defense mechanisms and improve treatment.

show abstract

Section: Conventional Methodsmentioning

confidence: 99%

Update on clinical significance of coagulase-negative staphylococci

1994

View full text Add to dashboard Cite

show abstract

“…This quinolone has a unique 1-aminocyclopropyl group at the C7 position (shown in Fig. 6), whose nature steers away from the traditional piperazine and pyrrolidine derivatives (13,29). The antibacterial activity of T-3761…”

Section: Materuils and Methodsmentioning

confidence: 99%

In vitro anti-Mycobacterium avium activities of quinolones: predicted active structures and mechanistic considerations

Klopman

Wang

et al. 1994

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The relationship between the structures of quinolones and their anti-Mycobacterium avium activities has been previously derived by using the Multiple Computer-Automated Structure Evaluation program. A number of substructural constraints required to overcome the resistance of most of the strains have been identified. Nineteen new quinolones which qualify under these substructural requirements were identified by the program and subsequently tested. The results show that the substructural attributes identified by the program produced a successful a priori prediction of the anti-M. avium activities of the new quinolones. All 19 quinolones were found to be active, and 4 of them are as active or better than ciprofloxacin. With these new quinolones, the updated multiple computer-automated structure evaluation program structure-activity relationship analysis has helped to uncover additional information about the nature of the substituents at the C5 and C7 positions needed for optimal inhibitory activity. A possible explanation of drug resistance based on the observation of suicide inactivation of bacterial cytochrome P-450 by the cyclopropylamine moiety has also been proposed and is discussed in this report. Furthermore, we confirm the view that the amount of the uncharged form present in a neutral pH solution plays a crucial role in the drug's penetration ability.Quinolones, more specifically, fluoroquinolones, have shown great potential in treating Mycobacterium avium-M intracellulare complex (MAI) infection, the most common bacterial infection complicating AIDS (6, 18). Although a large number of quinolone analogs have been made and their activities against some groups of bacteria, such as gram positive, gram negative, tuberculosis causing, etc., have been tested (36), only a limited number of quinolones have been tested for activity against MAI (25,42).To discover quinolones more potent against drug-resistant MAI organisms, we have previously tested 88 quinolones against a spectrum of M avium strains and identified relevant quantitative structure-activity relationships by Multiple Computer-Automated Structure Evaluation (MULTICASE) analysis (22, 23). From the activity spectrum of the 88 quinolones, we found variable and progressive resistance of the selected M avium strains. On the basis of susceptibility to quinolones, the strains used in our tests have been classified into a continuum between the most susceptible and the most resistant strains. In our previous analysis, we found that quinolones active against susceptible strains are not always active against resistant strains while those effective against resistant strains always exhibit good activities against susceptible strains. Furthermore, our previous studies have shown that as the susceptibility of the strains decreases, the identified substructures of quinolones required for the inhibitory activity become more restrictive. However, whether this progressive resistance is due to more selective penetration of the bacterial cell membrane or more restrictive bi...

show abstract

“…Pyrrolidines at this position offer great potency against gram-positive bacteria, and piperazines introduce excellent activity against gram-negative bacteria. Furthermore, among the variations described at position 7 (1,2,7,12,16), it has been proven that the presence of an azetidine moiety (3,5,6,8,9) yields a broader spectrum and enhanced activity against gram-positive bacteria. On the other hand, the substituent at position 8 controls in vivo efficacy and is largely responsible for the activity against anaerobic bacteria, with halogens being one of the optimal substitution groups at this site.…”

Section: E-4767 {(؊)-7-[3-(r)-amino-2-(s)-methyl-1-azetidinyl]mentioning

confidence: 99%

Antibacterial Activities and Pharmacokinetics of E-4767 and E-5065, Two New 8-Chlorofluoroquinolones with a 7-Azetidin Ring Substituent

Gargallo-Viola

Ferrer

Tudela

et al. 2001

Antimicrob Agents Chemother

View full text Add to dashboard Cite

E-4767 {(؊)-7-[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-8-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid} and E-5065 [(؊)-7-(3-amino-1-azetidinyl)-8-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid] are two new chlorofluoroquinolones with an azetidine moiety at position 7. Their in vitro activities were evaluated in comparison with those of ciprofloxacin, ofloxacin, fleroxacin, and tosufloxacin, while ciprofloxacin was used as a reference for in vivo studies. Against gram-positive organisms, E-4767 and E-5065 were, in general, eight-and fourfold more active than tosufloxacin, which is the most potent of the reference compounds. E-4767 and E-5065 were also more potent than the reference compounds against all species of enteric bacteria tested. The MICs of E-4767 and E-5065 at which 90% of the isolates tested were inhibited (MIC 90 s) were 0.007 to 0.5 g/ml and 0.03 to 2 g/ml, respectively, for gram-positive organisms and <0.003 to 0.06 g/ml and 0.007 to 0.12 g/ml, respectively, for members of the family Enterobacteriaceae except Serratia marcescens and Providencia spp. (MIC 90 s of E-4767 and E-5065 for these species were <0.5 g/ml and <2 g/ml, respectively). For Pseudomonas aeruginosa both compounds had a MIC 90 of 0.5 g/ml. E-4767 and E-5065 were 356-and 32-fold more potent than ciprofloxacin against Bacteroides spp., and their MIC 90 s for Clostridium spp. were 0.25 and 0.5 g/ml, respectively. Both products showed a remarkable reduction of activity when the pH was below 4.8 and, in general, were less active in the presence of 5 or 10 mM Mg 2؉ . The presence of horse serum or human urine (pH 7.2) decreased the activity of E-4767 and E-5065 only two-to fourfold more than the activity observed in broth. After an oral dose of 50 mg/kg of body weight, the maximum levels in serum (the maximum concentration of drug in serum was reached 30 min postadministration) of E-4767 and E-5065 were approximately threefold higher than that of ciprofloxacin. The area under the concentration-time curve from 0 to 4 h for ciprofloxacin was about two-and fourfold lower than that for E-4767 and E-5065, respectively. These two new chlorofluoroquinolones were as effective as or more effective than ciprofloxacin against all experimental infections evaluated, not only against gram-negative bacteria, such as Escherichia coli or P. aeruginosa, but also against gram-positive pathogens, such as Staphylococcus aureus or Streptococcus pneumoniae. E-4767 was the most effective compound, with a 50% effective dose (ED 50 ) of <17 mg/kg for all strains tested except ciprofloxacin-resistant S. aureus strains. The ED 50 of E-4767 for these strains was <47.5 mg/kg. Against gram-positive experimental infections, the ED 50 values of E-4767 were 3-to 14-fold lower than those of E-5065 and up to 25 times lower than those of ciprofloxacin.Since the discovery of nalidixic and oxolinic acids (10, 13), many modifications have been introduced in the chemical structure of the quinolonic ring, yielding new drug...

show abstract

In vitro activity of T-3761, a new fluoroquinolone

Cited by 32 publications

References 9 publications

Update on clinical significance of coagulase-negative staphylococci

Update on clinical significance of coagulase-negative staphylococci

In vitro anti-Mycobacterium avium activities of quinolones: predicted active structures and mechanistic considerations

Antibacterial Activities and Pharmacokinetics of E-4767 and E-5065, Two New 8-Chlorofluoroquinolones with a 7-Azetidin Ring Substituent

Contact Info

Product

Resources

About