RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. I. Antibacterial activity in vitro.

The aminothiazolyl-cephalosporin RU 29 246 is the active metabolite of the prodrug-pivaloyl-oxyethyl-ester HR 916. RU 29 246 in vitro activity includes a wide range of clinically relevant bacterial pathogens. Against methicillin-sensitive Staphylococci RU 29 246 (MIC90 of 0.25 approximately 2 micrograms/ml) was clearly more active than cefaclor, cefuroxime, cefpodoxime, cefixime and ceftibuten, but slightly less active than cefdinir. RU 29 246 inhibited hemolytic Streptococci of the serogroups A, B, C and G as well as penicillin-sensitive Streptococcus pneumoniae at concentrations similar to cefdinir, cefpodoxime and cefuroxime (MIC90 less than or equal to 0.13 micrograms/ml), but less than the other oral cephalosporins investigated (cefixime, cefaclor and ceftibuten). MIC90s of RU 29 246 against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Salmonella spp., Shigella spp., Proteus mirabilis and Haemophilus influenzae were less than or equal to 0.5 micrograms/ml. Only RU 29 246 and cefdinir demonstrated moderate activity against Acinetobacter baumannii (MIC90 greater than or equal to 4 micrograms/ml). Most strains of Pseudomonas spp., Serratia marcescens, Enterobacter spp., Hafnia alvei and Bacteroides spp. were resistant to RU 29 246. RU 29 246 killed Escherichia coli and Staphylococcus aureus at a rate of 99% to 99.9% at concentrations of two times MIC. The pH value of the medium (range 5.5 to 8.5) and the inoculum size (range 10(5) to 10(7) cfu/ml) had no or only low influence on the antibacterial activity of RU 29 246. RU 29 246 is a broad spectrum cephalosporin including in its activity both Gram-positive and Gram-negative pathogens and therefore--depending on the bioavailability of its prodrug--looks promising as to its therapeutic perspective.     

RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. II. Stability to beta-lactamases and affinity for penicillin-binding proteins.

The aminothiazolyl-cephalosporin RU 29 246, the active metabolite of the prodrug-ester HR 916, is active against strains producing the widespread plasmid-encoded TEM-1, TEM-2 and SHV-1 beta-lactamases. Except for TEM-7 the activity of RU 29 246 against strains producing extended broad spectrum beta-lactamases (TEM-3, TEM-5, TEM-6, SHV-2, SHV-4, SHV-5, CMY-1, CTX-M), however, is low. Relative hydrolysis rates of RU 29 246 are comparable with those of cefpodoxime, the active metabolite of CS-807, and are extremely low for the TEM-1 and SHV-1 beta-lactamases. The compound demonstrates remarkable inhibitory activity against the chromosomal beta-lactamase of Enterobacter cloacae P99. In the presence of 1.7 microM this enzyme loses 50% of its activity. At concentrations of 0.43, 0.003 and 0.01 micrograms/ml the compound binds preferentially to the penicillin-binding protein (PBP) 3 of Escherichia coli K12, to the PBPs 2x and 3 of Streptococcus pneumoniae R6 and to PBP 1 of Staphylococcus aureus SG 511, respectively.     

In vivo antibacterial activity of FK041, a new orally active cephalosporin.

The therapeutic activities of orally administered FK041 were evaluated in mouse models of systemic and local infections with a variety of bacteria and were compared with those of cefdinir (CFDN) and cefditoren pivoxil (CDTR-PI). FK041 exhibited potent therapeutic activity against lethal systemic infections induced by intraperitoneally inoculated Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae with 50% effective doses (ED50) in the range of 0.20 to 0.36 mg/kg and was more active than CFDN and CDTR-PI. This result correlated well with its in vitro activity. The therapeutic effects of FK041 and reference drugs on murine local infections were evaluated in an in vivo pharmacokinetic model simulating human plasma concentrations for oral administration of 50 mg, 100 mg, and 200 mg. Against murine subcutaneous abscess induced by S. aureus, FK041 was as effective as CFDN and significantly more effective than CDTR-PI in reducing the number of recoverable viable bacteria in the skin at the infection sites. The efficacy of FK041 against murine pneumonia with H. influenzae was comparable to that of CDTR-PI and was superior to that of CFDN in reducing viable bacteria activity in the lungs. These results strongly suggest that FK041 has potential for clinical use against various bacterial infections.     

In vitro activity of HR 756, a new cephalosporin compound.

The in vitro activity of HR 756, a new cephalosporin, has been determined against recent clinical isolates and compared with that of other beta-lactam antibiotics. The geometric means of the minimum inhibitory concentrations (MIC) for different isolates of Escherichia coli (100 isolates), Klebsiella pneumoniae (84), Pseudomonas aeruginosa (121), Proteus mirabilis (52), indole-positive Proteus species (9), Salmonella species (19), Staphylococcus aureus penicillin-sensitive (29) and penicillin-resistant (39) were: 0.095, 0.124, 11.1, 0.095, 0.0107, 0.078, 1 and 0.95 mcg/ml, respectively. Its activity was affected by rise in inoculum against S. aureus and P. aeruginosa but not against K. pneumoniae and E. coli. Bactericidal activity was determined by membrane filtration method. HR 756 was found to be bactericidal to E. coli, K. pneumoniae, P. aeruginosa and Proteus species. Although the MICs of the tested S. aureus strains were 1 mcg/ml, 5 mcg/ml of HR 756 failed to kill 99% of the inoculum within 24 hours.     

In vivo antibacterial activity of FK482, a new orally active cephalosporin

The therapeutic activities of orally administered FK482 were compared with those of reference antibiotics against systemic and local infections with a variety of bacteria in mice and rabbits. In systemic infections in mice, oral FK482 was almost as effective as oral cefaclor (CCL) and more effective than oral cephalexin (CEX) against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis infections. However, FK482 afforded superior protective activity when given subcutaneously against E. coli infection in mice, and this activity was more potent than that of subcutaneously given CCL. In comparison with CCL, the reason that the in vivo activity of orally given FK482 against mouse systemic infections was weaker than had been anticipated from its potent in vitro activity was due to its poor oral absorption in mice. In local infections in rabbits, a species in which FK482 was better absorbed than in mice, FK482 was more effective than CCL, CEX or amoxicillin (AMPC). Against pneumonia induced by S. aureus or Streptococcus pyogenes, FK482 was as effective as AMPC and more effective than CCL in reducing the number of viable bacteria in the lungs of infected rabbits. In the oral treatment of experimental ascending pyelonephritis in rabbits, FK482 was superior to CCL and AMPC against methicillin-resistant S. aureus infection, as effective as AMPC and more effective than CCL against Enterococcus faecalis infection, and as effective as cefixime (CFIX) and more effective than CCL and AMPC against E. coli infection in reducing the number of viable bacteria in the kidneys and urine.     

In vitro and in vivo antibacterial activity of KY-109, a new orally active cephalosporin

The in vitro and in vivo antimicrobial potencies of KY-109, a pro-drug of KY-087, were compared with those of amoxicillin, cephalexin (CEX), and cefaclor (CCL). The following results were obtained. KY-087, which is the active form of KY-109, had broad antimicrobial spectrum against Gram-positive and Gram-negative organisms, but showed low antimicrobial activity against Enterobacter sp., Serratia, and Pseudomonas sp. The antimicrobial activities of KY-087 against clinically isolated Gram-positive organisms were superior to those of CEX and CCL. The antimicrobial activities of KY-087 against Gram-negative organisms, such as Enterobacter sp., Serratia, and Pseudomonas sp., were less active. KY-087 showed dose-related bactericidal activity against Staphylococcus aureus and Escherichia coli. The therapeutic efficacy of KY-109 against experimental intraperitoneal infections caused by Gram-positive and Gram-negative organisms in mice was comparable to that of CEX but inferior to that of CCL. In experimental granuloma pouch models in rats and kidney infection in rabbits, therapeutic efficacy of KY-109 was either comparable or superior to that of CEX and CCL.     

In vivo antibacterial activity of cefodizime, a new cephalosporin antibiotic

The in vivo activity of cefodizime (HR 221) was compared with that of cefotaxime (CTX), cefmenoxime, latamoxef, cefazolin and cefmetazole (CMZ). The protective effects of HR 221 on experimental infections in mice caused by Staphylococcus aureus Smith, Escherichia coli C-11, Proteus vulgaris GN-76 and Serratia marcescens No. 2 were directly related to its in vitro activity against these strains. In contrast, the compound showed the smallest ED50 values, among the 5 antibiotics tested (not including CMZ), for Klebsiella pneumoniae 3K-25 and Pseudomonas aeruginosa PI 67 against which it had relatively low in vitro activity, and its ED50 for Citrobacter freundii GN-346 was as small as 1.821 mg/mouse in spite of its MIC of greater than 100 micrograms/ml. HR 221 exerted potent bactericidal activity against Streptococcus pneumoniae Sp-1 inoculated into the mouse lung; the duration of action was prolonged. When tested against the E. coli Ec-89 infection induced in the rat uterus, the activity of HR 221 given to rats once daily was equal to that of CTX or CMZ given at the same dose twice daily.     

In vitro antibacterial activity of FK041, a new orally active cephalosporin.

The in vitro activity of FK041, a new orally active cephem antibiotic, against a wide variety of clinical isolates of bacteria was investigated and compared with those of cefdinir (CFDN) and cefditoren (CDTR). FK041 exhibited broad spectrum activity against reference strains of Gram-positive and Gram-negative aerobes and anaerobes. FK041 was active against clinical isolates of Gram-positive organisms except Enterococcus faecalis with MIC90s less than 1.56 microg/ml. FK041 was more active than CFDN and CDTR against Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus agalactiae and was comparable to CFDN and CDTR against Streptococcus pyogenes and Streptococcus pneumoniae. FK041 had no activity against methicillin-resistant staphylococci, like CFDN and CDTR. FK041 showed moderate activity against penicillin-resistant S. pneumoniae with an MIC range of 0.05 approximately 3.13 microg/ml, and was superior to CFDN but inferior to CDTR. Against clinical isolates of many Gram-negative organisms such as Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, FK041 had good activity comparable or superior to those of CFDN and CDTR. However, it was inferior to CDTR in activity against Moraxella catarrhalis, Haemophilus influenzae, Morganella morganii, and Serratia marcescens, and was inactive against Pseudomonas aeruginosa. With FK041 a small difference between MIC and MBC against S. aureus, E. coli, K. pneumoniae, and H. influenzae was found, indicating that its action is bactericidal against these species. FK041 was stable to group 2beta-lactamase hydrolysis but was unstable to group 1beta-lactamase hydrolysis. The stability of FK041 to these enzymes was similar to those of CFDN and CDTR. FK041 showed high affinity for the main penicillin-binding proteins (PBPs) of S. aureus (PBP 3, 2, and 1) and E. coli (PBP 3, 4, lbs, 2, and 1a).     

In vitro and in vivo antibacterial activity of the new semisynthetic cephalosporin cefpirome

Cefpirome (HR 810), a new semisynthetic cephalosporin derivative, was found to have a broad antibacterial spectrum against gram-positive and gram-negative bacteria. Against Staphylococcus aureus, cefpirome was more active than not only cefotaxime and ceftazidime but also cefotiam. Against gram-negative bacteria, especially, Enterobacter cloacae and Citrobacter freundii, it was also more active than the other antibiotics tested, but against Pseudomonas aeruginosa, it was less active than ceftazidime. Cefpirome was stable to hydrolysis by the common plasmid mediated beta-lactamases and was stable to the action of chromosomal cephalosporinases. But it was slightly hydrolyzed by both Rms 213 mediated penicillinase and oxyiminocephalosporinases produced by Proteus vulgaris and Pseudomonas cepacia. When cefpirome was administered subcutaneously to mice experimentally infected with Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa, its efficacy well reflected its in vitro potency.     

In vitro antibacterial activity of FK482, a new orally active cephalosporin

FK482 is a new orally active cephem antibiotic which offers some advantages over the commercially available oral beta-lactam antibiotics. It displayed a broad spectrum of activity in vitro against stock strains of Gram-positive and Gram-negative aerobes and anaerobes. FK482 was more active in vitro than cefixime (CFIX), cefaclor (CCL) or cephalexin (CEX) against clinical isolates of Gram-positive organisms such as methicillin-sensitive Staphylococcus aureus, coagulase-negative Staphylococci including Staphylococcus epidermidis and strains of the Streptococcus group. Moderate activity was found against methicillin-resistant S. aureus and Enterococcus faecalis. Against clinical isolates of many Gram-negative species, including opportunistic pathogens, FK482 had good in vitro activity similar or slightly inferior to that of CFIX but superior to that of CCL or CEX. However, it was clearly inferior to CFIX in activity against Serratia marcescens, and was inactive against Pseudomonas aeruginosa. Strains of S. aureus resistant to methicillin were moderately susceptible to FK482. All tested strains of Klebsiella pneumoniae resistant to CCL and CEX were susceptible to FK482, as were all the strains of Escherichia coli, Proteus mirabilis, Haemophilus influenzae and Branhamella catarrhalis resistant to amoxicillin (AMPC). FK482, like CFIX, was relatively stable to all type of beta-lactamases except Bacteroides fragilis and its stability was superior to that of CCL or CEX. The antibacterial activity of FK482 against CSH2 strains containing ampicillin-resistance plasmids was not affected by the presence of the ampicillin resistance determinants. FK482 showed higher affinity for the penicillin-binding proteins (PBPs) (3, 2 and 1) of S. aureus than did CFIX, CCL and CEX. FK482 also showed very high affinity for the PBPs (2 and 3) of E. faecalis and PBPs (3, 1a, 4, 2 and 1 bs) of E. coli. The bactericidal activity of FK482 against S. aureus was almost as strong as that of AMPC and superior to that of CCL or CEX. Against Gram-negative bacteria such as E. coli, K. pneumoniae and P. mirabilis, FK482 was similar to CFIX and superior to CCL and CEX in bactericidal activity.     

复方黄连凝胶剂体内抗菌活性研究

将药理学研究的基础方法与组织学技术相结合,以细菌和真菌感染皮肤的日本大白兔模型为研究对象,研究了复方黄连凝胶剂对细菌和真菌皮肤感染的治疗效果。并通过皮肤组织学实验,以皮肤细胞修复状况和炎性细胞浸润为主要指标,从组织学角度进一步阐述复方黄连凝胶剂促进皮肤愈合的疗效。结果显示,治疗组愈合率均高于对照组。研究表明复方黄连凝胶剂抗菌作用强,是一种较好的外用抗菌药。     

Cefixime. A review of its antibacterial activity. Pharmacokinetic properties and therapeutic potential

Cefixime, previously designated FK027, FR17027 and CL284635, is an orally active cephalosporin with a broad spectrum of antibacterial activity in vitro. It is particularly active against many Enterobacteriaceae, Haemophilus influenzae. Streptococcus pyogenes, Streptococcus pneumoniae and Branhamella catarrhalis, and is resistant to hydrolysis by many beta-lactamases. Cefixime has little activity against Staphylococcus aureus and is inactive against Pseudomonas aeruginosa. Cefixime is distinguished by its 3-hour elimination half-life which permits twice daily, or in many instances once daily, administration. Comparative trials, though few, indicate that the clinical and bacteriological efficacy of cefixime 200 to 400mg daily administered as a single dose or in 2 divided doses, is comparable with that of multiple daily doses of co-trimoxazole (trimethoprim + sulphamethoxazole) or amoxycillin in acute uncomplicated urinary tract infection, with that of amoxycillin, amoxycillin/clavulanic acid and cefaclor in acute lower respiratory tract infections, and with that of amoxycillin and cefroxidine in adult patients with acute tonsillitis or pharyngitis. Several comparative trials in children with acute otitis media demonstrate the similar effectiveness of cefixime 8 mg/kg daily (in 2 divided doses, or as a single daily dose), cefaclor 20 to 40 mg/kg daily and amoxycillin 40 mg/kg daily in 3 divided doses. The most frequently reported adverse effects, diarrhoea and stool changes, are usually mild to moderate in severity, transient, and mostly occur in the first few days of treatment with cefixime. Thus, cefixime is an effective orally active cephalosporin with a relatively long elimination half-life permitting a simplified treatment regimen. It is a suitable alternative to cefaclor or amoxycillin in acute otitis media and acute upper and lower respiratory tract infections, and to amoxycillin or co-trimoxazole in acute uncomplicated urinary tract infections.     

Comparison of antibacterial activity of a new cephalosporin, ceftizoxime (FK 749) with other cephalosporin antibiotics.

FK 749 is a distinctive new parenteral cephalosporin antibiotic with a broad antibacterial spectrum which is more potently active against a wide variety of Gram-negative bacilli, including the opportunistic pathogens such as Citrobacter and Enterobacter species and Serratia marcescens, than SCE 963, T 1551 and cefmetazole. The activity of FK 749 against Escherichia coli, Klebsiella pneumoniae, pyogenes was by far superior to that of the three other antibiotics. These test organisms were not resistant to FK 749. The antibacterial activity of FK 749 against Pseudomonas aeruginosa was almost the same as that of ticarcillin but was inferior to that of gentamicin and T 1551. The bactericidal activity of FK 749 against E. coli, K. pneumoniae and Proteus mirabilis was more potent than that of the three other antibiotics. FK 749, like cefmetazole, was extremely stable to beta-lactamases. In studies in mice, the therapeutic effect of subcutaneous injection of FK 749 against various infections due to Gram-negative bacilli was by far superior to that of SCE 963, T 1551 and cefmetazole, was almost the same as that of SCE 963 and cefmetazole against Staphylococcus aureus infection and that of ticarcillin against P. aeruginosa infection.     

A new parenteral cephalosporin. SK&F 59962: in vitro and in vivo antibacterial activity and serum levels in experimental animals.

SK&F 59962, a new parenteral cephalosporin was found to have a high order of in vitro and in vivo antibacterial activity against a broad-spectrum of clinical isolates. When tested in vitro against gram-negative organisms, SK&F 59962 was consistently more active than cefazolin and far superior to cephalothin. This new antibiotic had activity equal to that of cephalothin against gram-positive bacteria. Enterobacter species were found to be susceptible to SK&F 59962. In mouse infection studies using bacterial pathogens, SK&F 59962 had protective activity of the order of that of cefazolin and superior to that of cephalothin. Following parenteral administration the serum profile of SK&F 59962 in the mouse, dog and squirrel monkey was similar to that of cephalothin. SK&F 59962 and cephalothin had lower peak serum concentrations and shorter biologic half-lives than those of cefazolin.     

In vitro and in vivo antibacterial activity of KT3777, a new orally active carbacephem

KT3777 is a novel carbacephem antibiotic structurally identical to cefaclor (CCL), except that the sulfur atom of position 1 of the cephem nucleus has been replaced by carbon. KT3777 was investigated for in vitro and in vivo antibacterial activities in comparison with CCL, cephalexin (CEX) and amoxicillin. The MIC50 of KT3777 ranged from 0.2 to 3.13 micrograms/ml for clinical isolates of Staphylococcus aureus, Streptococci, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, and Neisseria gonorrhoeae. KT3777 possessed an antibacterial spectrum and potency similar to that of CCL. However, against E. coli and K. pneumoniae, KT3777 was about twice as active as CCL. KT3777 was more active than CEX against all strains tested. Killing-curve studies demonstrated bactericidal activity of KT3777 at concentrations above the MIC. KT3777 showed good affinity for penicillin-binding proteins 1A, 1Bs, 3 and 4 of E. coli NIHJ JC-2. The protective effect of KT3777 against systemic infections in mice was comparable to that of CCL with a few exceptions and about 3 to 7 times greater than that of CEX. KT3777 also proved effective against localized infections such as acute pneumonia and ascending urinary tract infections in mice.     

A32390A, a new biologically active metabolite. III. In vitro and in vivo antifungal activity.

A32390A, an isonitrile-containing derivative of mannitol, represents a new class of antifungal antibiotics. In vitro antifungal activity of A32390A was found against Candida albicans, Cryptococcus neoformans and Histoplasma capsulatum. In vivo antifungal activity of A32390A was demonstrated in mice infected with C. albicans. Accumulative doses of 37.5 approximately 600 mg/kg, administered subcutaneously over a 24-hour period, showed significant activity without demonstrating toxicity. A32390A was effective, but not as effective as amphotericin B, in reducing the number of Candida cells isolated from the kidney of infected mice. Urinary excretion of A32390A accounted for only 10% of the administered dose. Improved bioavailability of A32390A was accomplished when the antibiotic was combined with polyvinyl pyrrolidone (PVP) in a solid dispersion. Administration of A32390A as a 10% dispersion in PVP resulted in increased urinary excretion of the drug and reduced the amount of drug required for in vivo activity.     

Cefodizime, an aminothiazolyl cephalosporin. III. Therapeutic activity against experimentally induced pneumonia in mice

The activity of the aminothiazolyliminomethoxy cephalosporin cefodizime (HR 221) was compared to that of cefotaxime, cefuroxime and cefazolin in experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice. Cefodizime exhibited high and long-acting levels in the blood and lung homogenates of infected mice; the blood and tissue concentrations obtained with the other cephalosporins tested were low by comparison. In the treatment of experimental Klebsiella pneumonia, cefodizime was superior to cefotaxime and cefuroxime. Counts of the number of viable bacteria present in the infected tissue showed that cefodizime exerted a more marked bactericidal effect than cefotaxime or cefuroxime. Hardly any therapeutic activity was seen with cefazolin.     

In vitro antibacterial activity and beta-lactamase stability of cefodizime, a new cephalosporin antibiotic

The in vitro activity and beta-lactamase stability of cefodizime (HR 221), a new cephalosporin, were compared with those of other cephem antibiotics. HR 221 was highly active against Gram-negative bacteria. The compound inhibited growth of all tested Haemophilus influenzae strains at 0.10 microgram/ml and showed strong activity even against penicillin-resistant Neisseria gonorrhoeae strains, but it was less effective against Pseudomonas aeruginosa than the other antibiotics tested. Against Gram-positive bacteria, HR 221 showed 100% inhibition of growth of Streptococcus pneumoniae at 0.39 microgram/ml, and it was slightly less active against Staphylococcus aureus (MIC90:12.5 micrograms/ml) than other antibiotics such as cefotaxime (CTX). The bactericidal activity of HR 221 against E. coli was dose-related and comparable to that of CTX, cefoperazone and latamoxef. The bactericidal activity of the compound at medium concentrations simulating human serum levels was higher than that of CTX and cefmetazole, and no cell regrowth was noted after beta-lactamase-induced inactivation of the compound. HR 221 was stable to most drug-inactivating enzyme preparations from various bacterial species.