In vivo evaluation of NM441, a new thiazeto-quinoline derivative

Ozaki, Masakuni; Matsuda, Masato; Tomii, Yoshifumi; Kimura, Kiyoshi; Segawa, Jun; Kitano, Masahiko; Kise, Masahiro; Shibata, Kazuo; Otsuki, Masako; Nishino, Takeshi

doi:10.1128/aac.35.12.2496

Cited by 38 publications

(17 citation statements)

References 8 publications

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“…Time-kill experiments using selected isolates confirmed that the bactericidal activity of AF 3013 was at least similar to that of ciprofloxacin. Altogether, the excellent inhibitory and bactericidal activities exhibited by AF 3013 in vitro, in addition to the favorable characteristics shown by its prodrug (prulifloxacin) in preliminary in vivo studies-experimental infections in mice (8), pharmacokinetic investigations with mice and dogs (8), and pharmacokinetic and safety studies with healthy human volunteers (5)-warrant further in vitro and in vivo studies and appropriate clinical trials addressing in particular the treatment of urinary infections. …”

Section: Discussionmentioning

confidence: 99%

“…AF 3013, a fluoroquinolone formerly called NM394 (5,8,11), is the active compound derived from the transformation of the prodrug prulifloxacin (also called NM441 or AF 3012) after its oral administration and intestinal absorption. Prulifloxacin and AF 3013 were developed in the late 1980s in Japan.…”

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confidence: 99%

“…Other fluoroquinolones, which had further-enhanced activity against gram-positive bacteria and were also variably active against anaerobes, were developed in the 1990s (10). However, several of these newer quinolones ended up being limited in their clinical use due to various, unexpected toxicity problems (1).AF 3013, a fluoroquinolone formerly called NM394 (5,8,11), is the active compound derived from the transformation of the prodrug prulifloxacin (also called NM441 or AF 3012) after its oral administration and intestinal absorption. Prulifloxacin and AF 3013 were developed in the late 1980s in Japan.…”

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confidence: 99%

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In Vitro Antibacterial Activities of AF 3013, the Active Metabolite of Prulifloxacin, against Nosocomial and Community Italian Isolates

Montanari

Mingoia

Varaldo

2001

Antimicrob Agents Chemother

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AF 3013, the active metabolite of prulifloxacin, was tested to determine its inhibitory and bactericidal activities against 396 nosocomial and 258 community Italian isolates. Compared with that of ciprofloxacin, its activity (assessed in MIC and minimal bactericidal concentration tests) was generally similar or greater against gram-positive bacteria and greater against gram-negative bacteria. In time-kill assays using selected isolates, its bactericidal activity was comparable to that of ciprofloxacin.Nonfluorinated quinolones, developed in the 1960s and 1970s, had a spectrum limited to aerobic gram-negative bacteria; they had a poor systemic distribution but reached high concentrations in urine; their use was therefore confined to the treatment of urinary tract infections. The introduction of fluoroquinolones (i.e., molecules fluorinated in the C-6 position) marked a dramatic improvement (2). The earlier drugs of this group, developed in the late 1970s and in the 1980s, were suitable for a far wider clinical use by virtue of a broader spectrum, encompassing gram-positive bacteria, and a good systemic distribution. Other fluoroquinolones, which had further-enhanced activity against gram-positive bacteria and were also variably active against anaerobes, were developed in the 1990s (10). However, several of these newer quinolones ended up being limited in their clinical use due to various, unexpected toxicity problems (1).AF 3013, a fluoroquinolone formerly called NM394 (5,8,11), is the active compound derived from the transformation of the prodrug prulifloxacin (also called NM441 or AF 3012) after its oral administration and intestinal absorption. Prulifloxacin and AF 3013 were developed in the late 1980s in Japan. The in vitro activity of AF 3013 has so far been investigated only in that country, against strains mostly isolated in the 1980s (11). At present, prulifloxacin is being considered for marketing in Italy and other European countries. This prompted us to investigate the in vitro activity of its active form, AF 3013, against a variety of nosocomial and community bacterial strains recently isolated in Italy. AF 3013 was obtained from Angelini ACRAF, Pomezia, Italy. Of six additional fluoroquinolone molecules tested as comparators, two (ciprofloxacin and ofloxacin) were purchased from Sigma Chemical Co. (St. Louis, Mo.), and four (levofloxacin, sparfloxacin, trovafloxacin, and moxifloxacin) were from their respective manufacturers. Bacteria.A total of 654 cultures of aerobic bacteria were examined, all freshly isolated (in 1998 to 2000) from clinical material in several Italian laboratories. Multiple isolates from the same patient were avoided. Most of these cultures (151 gram-positive strains and 245 gram-negative strains), isolated from inpatients Ͼ48 h after hospital admission, were regarded as being associated with nosocomial infections. The remaining (102 gram-positive and 156 gram-negative) strains, isolated from outpatients, were regarded as being associated with community infections. Most strains w...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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In Vitro Antibacterial Activities of AF 3013, the Active Metabolite of Prulifloxacin, against Nosocomial and Community Italian Isolates

Montanari

Mingoia

Varaldo

2001

Antimicrob Agents Chemother

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“…A number of these studies were conducted to investigate the pathogenesis of various uropathogens and for the evaluation of different antibiotics for UTIs in laboratory animals (2,8,11,12,17,23,33,39,40,43,46). However, monitoring the infections in these animal models using conventional methods is cumbersome, laborious, and time consuming.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive Biophotonic Imaging for Monitoring of Catheter-Associated Urinary Tract Infections and Therapy in Mice

Kadurugamuwa¹,

Modi²,

Yu³

et al. 2005

Infect Immun

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Urinary tract infections (UTIs) are among the most common bacterial infections acquired by humans, particularly in catheterized patients. A major problem with catheterization is the formation of bacterial biofilms on catheter material and the risk of developing persistent UTIs that are difficult to monitor and eradicate. To better understand the course of UTIs and allow more accurate studies of in vivo antibiotic efficacy, we developed a catheter-based biofilm infection model with mice, using bioluminescently engineered bacteria. Two important urinary tract pathogens, Pseudomonas aeruginosa and Proteus mirabilis, were made bioluminescent by stable insertion of a complete lux operon. Segments of catheter material (precolonized or postimplant infected) with either pathogen were placed transurethrally in the lumen of the bladder by using a metal stylet without surgical manipulation. The bioluminescent strains were sufficiently bright to be readily monitored from the outside of infected animals, using a low-light optical imaging system, including the ability to trace the ascending pattern of light-emitting bacteria through ureters to the kidneys. Placement of the catheter in the bladder not only resulted in the development of strong cystitis that persisted significantly longer than in mice challenged with bacterial suspensions alone but also required prolonged antibiotic treatment to reduce the level of infection. Treatment of infected mice for 4 days with ciprofloxacin at 30 mg/kg of body weight twice a day cured cystitis and renal infection in noncatheterized mice. Similarly, ciprofloxacin reduced the bacterial burden to undetectable levels in catheterized mice but did not inhibit rebound of the infection upon cessation of antibiotic therapy. This methodology easily allows spatial information to be monitored sequentially throughout the entire disease process, including ascending UTI, treatment efficacy, and relapse, all without exogenous sampling, which is not possible with conventional methods.Urinary tract infections (UTI) are one of the most common bacterial infections in humans (9, 35). The majority of these infections follow instrumentation of the urinary tract, mainly urinary catheterization, with the development of catheter-associated bacteriuria being directly related to the duration of implant (6,18,37,44). Thus, it is commonplace for the incidence of bacteriuria to be as high as 95% in catheterized patients with implants present for 30 days or more (6, 44). Complications with such infections can lead to fever, cystitis, acute pyelonephritis, bacteremia, and death (44). Catheter-associated urinary tract infections are caused by a variety of uropathogens, including Escherichia coli, Klebsiella, Proteus, Enterococcus, Pseudomonas, Enterobacter, Serratia, and Candida (6,44).Typically, the bacterial biofilm growth on urinary catheter and adjacent mucosa accounts for the pathophysiology of catheter-associated UTI (25,26,31). Diseases involving bacterial biofilms are generally chronic and difficult to treat, be...

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“…NM441 is a new prodrug fluoroquinolone with a sulfur atom at the C-2 position. It is easily absorbed and hydrolyzed to the active form, NM394 (12). In this study, we evaluated in vitro activity of NM394.…”

Section: Discussionmentioning

confidence: 99%

Antibacterial activity of NM394, the active form of prodrug NM441, a new quinolone

Yoshida¹,

Mitsuhashi²

1993

Antimicrob Agents Chemother

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The in vitro antibacterial activity of NM394 was compared with those of other new quinolones. NM394 showed potent and broad-spectrum antibacterial activity against 2,606 recent clinical isolates. The activity of NM394 against gram-positive bacteria was 2-to 16-fold less than that of tosufloxacin and sparfloxacin but was comparable to that of ofioxacin. Only against Streptococcus pyogenes was the activity of NM394 equal to that of sparfloxacin. Against gram-negative bacteria, NM394 showed antibacterial activity equal to that of ciprofloxacin. Against quinolone-resistant Pseudomonas aeruginosa (norfloxacin MIC, >6.25 p,g/ml), the activity of NM394 was greater than those of the other agents tested. NM394 was rapidly bactericidal at concentrations near the MIC. NM394 inhibited supercoiling activities of DNA gyrase purified from Staphylococcus aureus, Escherichia coli, and P. aeruginosa; the 50% inhibitory concentrations were 18.0, 0.41, and 2.05 ,ug/ml, respectively. (7), and OPC-17116 (3, 10), demonstrate more potent activity against gram-positive bacteria.-a]-quinoline-3-carboxylic acid} is the active form of prodrug NM441, a new fluoroquinolone antibacterial agent ( Fig. 1). In a previous report (11), the in vitro antibacterial activity of NM394 was studied in comparison with those of ciprofloxacin, ofloxacin, and enoxacin. Results indicated that NM394 had broad-spectrum antibacterial activity, including activity against gram-positive bacteria. In this study, we evaluated the in vitro activity of NM394 compared with those of other quinolones, including tosufloxacin and sparfloxacin.(Part of this work was presented previously [17]).MATERIALS AND METHODS Antimicrobial agents. NM394 was provided by Nippon Shinyaku Co., Ltd., Kyoto, and Meiji Seika Kaisya, Ltd., Tokyo, Japan. Other antimicrobial agents were provided as follows: norfloxacin, Kyorin Seiyaku Co., Ltd., Tokyo, Japan; ofloxacin, Daiichi Seiyaku Co., Ltd., Tokyo, Japan; ciprofloxacin, Bayer Yakuhin, Ltd., Osaka, Japan; tosufloxacin, Toyama Chemical Co., Ltd., Toyama, Japan; sparfloxacin, Dainippon Seiyaku Co., Ltd., Osaka, Japan; and methicillin and oxacillin, Banyu Seiyaku Co., Ltd., Tokyo, Japan.Test strains. The bacterial strains used in this study were collected between 1984 and 1991 from various hospitals in Japan and were maintained in our laboratory at -80°C in glycerol.Determination

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In vivo evaluation of NM441, a new thiazeto-quinoline derivative

Cited by 38 publications

References 8 publications

In Vitro Antibacterial Activities of AF 3013, the Active Metabolite of Prulifloxacin, against Nosocomial and Community Italian Isolates

In Vitro Antibacterial Activities of AF 3013, the Active Metabolite of Prulifloxacin, against Nosocomial and Community Italian Isolates

Noninvasive Biophotonic Imaging for Monitoring of Catheter-Associated Urinary Tract Infections and Therapy in Mice

Antibacterial activity of NM394, the active form of prodrug NM441, a new quinolone

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