Comparison of the in vitro and in vivo antibacterial activities of cefepime (BMY-28142) with ceftazidime, cefuzonam, cefotaxime and cefmenoxime

Cefepime (BMY-28142), a new semisynthetic cephalosporin, was evaluated for in vitro and in vivo antibacterial activities in comparison with ceftazidime, cefuzonam, cefotaxime and cefmenoxime. Cefepime showed a well-balanced, broad spectrum of activity against a number of clinical isolates collected in Japan. The activity of cefepime against Gram-positive bacteria was several times greater than that of ceftazidime, nearly comparable to cefotaxime and cefmenoxime, and slightly weaker than cefuzonam. Against Enterobacteriaceae, cefepime showed superior activity to the reference cephalosporins against Proteus inconstans, Providencia rettgeri, Morganella morganii, Citrobacter freundii and Enterobacter cloacae. The activity of cefepime against Pseudomonas aeruginosa was nearly comparable to that of ceftazidime. Cefotaxime, cefuzonam and cefmenoxime were substantially less active against P. aeruginosa. Cefepime was more stable than cefuzonam, cefotaxime and cefmenoxime to various types of beta-lactamases from Gram-negative bacteria. The high in vitro activity of cefepime was reflected in its in vivo efficacy against experimental infections in normal and immuno-suppressed mice. Cefepime was the most effective among the cephalosporins tested against four Gram-negative bacterial infections.     

Antibacterial activity of BMY-28142, a novel broad-spectrum cephalosporin

BMY-28142, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- (1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate, exhibited a well-balanced, extended-spectrum of antibacterial activity both in vitro and in vivo. Against Staphylococci and Streptococci, BMY-28142 was about four to ten times more active than ceftazidime and comparable to cefotaxime. Most Enterobacteriaceae were more susceptible to BMY-28142 than to ceftazidime, though strains of Pseudomonas aeruginosa were slightly more sensitive to ceftazidime. BMY-28142 showed potent activity against Gram-negative bacteria resistant to ceftazidime and/or cefotaxime. Bactericidal activity of BMY-28142 against 10 strains of P. aeruginosa was superior to that of ceftazidime. In bacterial infection models in mice, BMY-28142 was more effective than ceftazidime against three Gram-positive and three Gram-negative pathogens. The anti-pseudomonal in vivo activity of BMY-28142 was nearly comparable to that of ceftazidime. The blood levels and urinary excretion rates of BMY-28142 in mice were similar to those of ceftazidime.     

Synthesis and structure-activity relationships of a new series of cephalosporins, BMY-28142 and related compounds

The synthesis of a series of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-oxyiminoacetamido] -3-ammoniomethyl-3-cephems is described. Variations of an oxyimino moiety in the 7-side chain and a quaternary ammonium moiety in the 3-side chain were examined and structure-activity relationships studied. BMY-28142, the 3-(N-methylpyrrolidinio)methyl derivative of the 7-alpha-methoxyimino series of cephalosporins, exhibited broad antimicrobial activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.     

头孢噻肟、头孢曲松、头孢他啶中高分子杂质的含量测定

以建立头孢噻肟、头孢曲松、头孢他啶中高分子杂质含量的快速测定方法为目的,对不同离子对试剂、洗脱剂ｐＨ、洗脱剂类型、离子对浓度、洗脱速度等因素进行了研究。所建立的测定头孢噻肟、头孢曲松中高分子杂质含量的测定方法为Ｓｅｐｈａｄｅｘ Ｇ－１０（粒度４０～１２０μｍ）凝胶柱,内径１．５ｃｍ,柱长４５０ｃｍ,Ｖ,５０ｍｌ;洗脱剂采用ｐＨ７．０的０．１ｍｏｌ／Ｌ磷酸盐缓冲液;洗脱速度为１．８ｍｌ／ｍｉｎ。上样     

Mechanism of action, antimicrobial activity, pharmacology, adverse effects, and clinical efficacy of cefotaxime

Cefotaxime sodium, a parenteral cephalosporin antibiotic, exerts its bactericidal action through inhibition of bacterial cell wall synthesis. Chemical structure modifications have enabled this compound to be resistant to the action of Richmond I, III, IV, and V beta-lactamase enzymes. Excellent activity against many gram-negative bacilli, especially Enterobacteriaceae, has been demonstrated. Antipseudomonal activity is generally poor, however. Activity against gram-positive cocci, with the notable exception of Streptococcus fecalis, is adequate. Anaerobic activity is variable, particularly against Clostridia and Bacteroides species. Acute, subacute, and chronic toxicity studies in animals were generally unremarkable. No mutagenic effects or reproductive toxicity have been noted in animals. In man, cefotaxime is desacetylated to a microbiologically active metabolite. Urinary excretion is approximately 50-60% and 15-20% of a dose for the parent compound and desacetyl metabolite, respectively. The elimination half-life of cefotaxime is about one hour, with the total body clearance being approximately twice that of the renal clearance. Severe renal dysfunction causes a prolongation of the elimination half-life of cefotaxime and particularly desacetyl cefotaxime. A relatively low degree of protein binding in part attributes to a wide bodily distribution of cefotaxime. Cefotaxime is effective in a variety of infectious processes caused by susceptible organisms. Local reactions at the injection site and hypersensitivity phenomena are the most common adverse effects. Comparative trials attesting to cefotaxime's clinical utility over other parenteral cephalosporins or amino-glycosides are very limited. Based on the available evidence, cefotaxime should be most useful in combating serious gram-negative infections, because of its excellent activity against most of these organisms and its low toxicity profile.     

Comparative in vitro evaluation of BMY-28142, a new broad-spectrum cephalosporin, versus other beta-lactams against multiresistant gram-negative isolates

The in vitro activity of the new parenteral cephalosporin BMY-28142 was compared with that of cephalothin, cefoxitin, cefotaxime, ceftriaxone, moxalactam, aztreonam and ceftazidime, against a total of 374 recent multiresistant Gram-negative microorganisms of nosocomial origin. Against all species of Enterobacteriaceae resistant to the first- and second-generation cephalosporins, BMY-28142 had superior inhibitory activity than the newer beta-lactams tested, with intrinsic activity against E. coli and Pr. mirabilis slightly less than that of cefotaxime and ceftriaxone. BMY-28142 differed from the other beta-lactams mainly in being at least 16-fold more active against E. cloacae, while BMY-28142 and ceftazidime showed comparable activity against Ps. aeruginosa strains. Against strains of Ps. aeruginosa resistant to both BMY-28142 and amikacin, the combination of the two antibiotics proved to be synergistic in vitro.     

头孢他啶与头孢噻肟治疗新生儿败血症临床疗效比较

目的:评价头孢他啶和头孢噻肟治疗新生儿败血症的临床效果。方法:以头孢呋辛作对照,回顾性观察头孢他啶和头孢噻肟在新生儿败血症治疗中的疗效及安全性。结果:头孢他啶组、头孢噻肟组的有效率分别为91.30％、94.12％,与对照组头孢呋辛组(89.12％)比较均无显著差异(P>0.05);不良反应发生率也无显著差异(P>0.05);但头孢噻肟钠组与头孢他啶组住院天数均比对照组短(P<0.05)。结论:头孢他啶与头孢噻肟可作为新生儿败血症治疗的首选药物。     

In vitro antimicrobial activity of a novel aminothiazolylglycylcephalosporin, MT0703S, compared with that of ceftazidime, cefoperazone and aztreonam

The antibacterial activity of a novel aminothiazolylglycylcephalosporin, MT0703S, possessing a dihydroxypyridone moiety was compared in vitro with the activity of ceftazidime, cefoperazone, aztreonam and other beta-lactam antibiotics using seven bacterial species of a clinical origin. MT0703S showed the most potent activity against P. aeruginosa, including the ceftazidime-resistant strains, E. coli, K. pneumoniae and C. freundii. MT0703S was comparable to aztreonam but more active than ceftazidime and cefoperazone in its activity against K. oxytoca and E. cloacae, and comparable to ceftazidime against S. aureus and S. marcescens. MT0703S was more active than cefoperazone against S. marcescens but less active against S. aureus. The stability of MT0703S against various beta-lactamases appeared to be intermediate between the stability of ceftazidime and that of cefoperazone. The antimicrobial activity of MT0703S increased in a low-iron environment and decreased in a high ferric ion concentration.     

Experimental antitumor activity of BMY-28090, a new antitumor antibiotic

Summary BMY-28090 is a novel actinomycete fermentation derived antitumor agent. The cytotoxic effect of BMY-28090 was evaluated in two murine and eight human tumor cell lines in vitro. Following 72-hour exposures, BMY-28090 was cytotoxic for all of these cell lines with IC50 values of < 0.02 to 3.25 g/ml. BMY-28090 was evaluated for in vivo antitumor activity in a variety of experimental murine tumor and human tumor xenograft models. Initial testing against the murine tumor models was performed using BMY-28090 as the water insoluble free base whereas subsequent antitumor tests were performed using water soluble lactate or succinate salts. BMY-28090 administered ip demonstrated good, reproducible antitumor activity against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma and M5076 sarcoma. The water soluble preparations of BMY-28090 were active iv against sc implanted B16 melanoma and M5076 sarcoma as well as subrenal capsule (src) M5076 sarcoma; activity against src implanted B16 was marginal. BMY-28090 lactate was also evaluated for activity against src implanted MX-1 human mammary tumor xenografts in nude mice and the HCT116 human colon tumor xenografts in immune-suppressed BDF mice. At maximum tolerated doses administered ip, BMY-28090 was active against the MX-1 xenograft in two of three tests, causing > 90% inhibition of tumor growth. BMY-28090 administered iv at maximally tolerated doses had marginal activity against the HCT116 xenografts, producing 61% and 68% inhibition of tumor growth in two tests. The results of these studies demonstrated that BMY-28090 has a broad spectrum of in vitro cytotoxicity against both murine and human tumor cell lines. Moreover, BMY-28090 had in vivo antitumor activity against murine leukemias, murine solid tumors and human tumor xenografts, including tumors located distal to the site of drug administration.A preliminary report of some of this research was presented at the Annual Meeting of the American Association for Cancer Research, Los Angeles, CA, May 1986 (1090).

---

     

Pharmacokinetic interactions of ceftazidime, imipenem and aztreonam with amikacin in healthy volunteers

The common usage of extended spectrum beta-lactams co-administered with amikacin in everyday clinical practice for infections by multidrug-resistant isolates has created the need to search for pharmacokinetic interaction. Eighteen healthy volunteers were enrolled in the study; six were administered 1g of ceftazidime singly intravenously or combined with 0.5 g of amikacin; six received 0.5 g of imipenem singly or combined with 0.5 g of amikacin and six 1g of aztreonam singly or combined with 0.5 g of amikacin. Blood and urine samples were collected at regular time intervals and apparent serum levels were determined by a microbiological assay. Co-administration of ceftazidime and amikacin resulted in higher C(max) and AUC for amikacin than when administered alone. Co-administration of imipenem and amikacin resulted in higher C(max) for imipenem than when administered alone. The tested interactions did not affect plasma half-life (t(1/2)) and clearance rate of any antimicrobial compared with its single administration. All tested drugs were mainly eliminated by glomerular filtration. It is concluded that co-administration of ceftazidime, imipenem or aztreonam with amikacin in healthy volunteers might affect C(max) and AUC without influencing any other pharmacokinetic parameter. The probable clinical endpoint is that giving ceftazidime, imipenem or aztreonam with amikacin might result in a transient elevation of beta-lactam serum levels without further affecting the complete pharmacokinetic profile of each drug as obtained after administration of the drug alone.     

Antimicrobial activity, pharmacokinetics, therapeutic indications and adverse reactions of ceftazidime

Ceftazidime is an aminothiazolyl cephalosporin with potent activity against gram-negative bacteria including multiresistant strains of Pseudomonas aeruginosa. It has limited activity against gram-negative anaerobes, is less active against some gram-positive cocci than other newer beta-lactam compounds and is inactive against Streptococcus faecalis and methicillin-resistant Staphylococcus aureus. Ceftazidime is stable against common plasmid and chromosomally mediated beta-lactamase produced by Enterobacteriaceae and Pseudomonas sp. Its pharmacokinetic properties are similar to those of moxalactam and ceftizoxime, and it has a half-life of 1.9 hours. Excretion is by glomerular filtration. It is not metabolized. Ceftazidime penetrates into most body tissue and fluids, including cerebrospinal fluid, and produces therapeutic levels against most of the pathogenic gram-negative bacteria, including P. aeruginosa. Ceftazidime accumulates during renal failure, but is removed by hemodialysis and peritoneal dialysis. As a single agent it has been shown effectively to treat meningitis; urinary tract infections; gram-negative pneumonia; bone, joint and skin infections; and obstetric and gynecologic infections due to susceptible organisms. When combined with an agent that is effective against gram-positive organisms, it is also beneficial in the treatment of infections in seriously ill neonates. Different investigators have used ceftazidime alone or in combination with other agents in the successful treatment of infections in immunosuppressed patients. Adverse reactions have been few and are mostly reversible laboratory findings. The effects of ceftazidime on prothrombin synthesis and platelet function have been minimal, and no drug-induced clinical bleeding has been reported.     

阿奇霉素与头孢噻肟对肺炎克雷白杆菌联合药敏研究

目的：研究阿奇霉素与头孢噻肟对30株临床分离肺炎克雷白杆菌的联合抗茵效应。方法：采用棋盘法设计,微量肉汤稀释法测定。测定不同浓度组合的两种抗菌药物对30株肺炎克雷白杆菌的最低抑菌浓度,计算FIC指数,并观察两药不同加药顺序对效应的影响。结果：阿奇霉素与头孢噻肟联合应用后对肺炎克雷白杆菌的浓度一累积抑菌百分率均比单独应用有较大提高。FIC指数结果表明,阿奇霉素与头孢噻肟联合应用后对肺炎克雷白杆菌20％为协同作用,63％为相加作用,10％为无关作用,7％为拮抗作用。先后联用与同时应用抗菌效应无显著性差异（P〉0．05）。结论：一般情况下,对临床分离肺炎克雷白杆菌,阿奇霉素与头孢噻肟联合应用是合理的。     

Comparison of the antimicrobial activity and beta-lactamase resistance of cef otiam (CGP/14221 E) with that of cefotaxime,cefuroxime, cefoxitin and cephalothin

Summary

A study was carried out to compare the minimum inhibitory concentrations of cefotiam, cefotaxime, cefuroxime, cefoxitin and cephalothin against 355 strains of Gram-negative bacteria including Pseudomonas aeruginosa. Cefotiam was shown to be more active than cefuroxime, cefoxitin and cephalothin and equal to or slightly less active than cefotaxime. Study of the minimum bactericidal concentrations of cefotiam showed that the time required for eradication of the micro-organisms was rapid. It was found that cefotiam, cefotaxime, cefuroxime and cefoxitin were resistant to the hydrolysis caused by the constitutive beta-lactamases studied.     

Serum bactericidal activity of ceftazidime increased by netilmicin

Cephalosporins are often used in combination with aminoglycoside antibiotics in the treatment of gram-negative infections. Although ceftazidime possesses activity against gram-negative bacteria, especially against Pseudomonas, combined use with aminoglycosides is useful. In this study, 12 healthy volunteers (6 men, 6 women; mean age 21.5 yr) received a single dose of ceftazidime 1 g iv and one week later ceftazidime 1 g iv with netilmicin 100 mg iv. Both antibiotics were infused over five minutes. Concentrations of ceftazidime were determined by high performance liquid chromatography. Serum bactericidal activity (SBA) was evaluated against seven microorganisms isolated from clinical specimens. The mean peak serum level of ceftazidime was 113.4 micrograms/ml. At eight hours, we observed a concentration of 2.6 micrograms/ml. The total clearance was 126 ml/min, while the renal clearance was 100 ml/min. Ceftazidime exhibited a half-life of 1.9 hours. Up to ten hours, the SBA of ceftazidime against Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, and Salmonella typhi was greater than 1:8 in more than 90 percent of samples. At one hour, ceftazidime exhibited a SBA of 1:4 for Staphylococcus aureus, and 1:16 for Pseudomonas aeruginosa. With the addition of netilmicin, median SBA against Staph. aureus and P. aeruginosa were 1:32 and 1:64, respectively, at one hour. Netilmicin enhanced the SBA of ceftazidime. The combination was not effective against Streptococcus faecalis.     

Experimental antitumor activity of BMY-28175 a new fermentation derived antitumor agent

Summary BMY-28175 is a novel antitumor antibiotic produced in fermentation by Actinomadura verrucosospora. The cytotoxic effects of BMY-28175 were determined using murine and human tumor cell lines in vitro. Following 72 hour exposure, the drug had IC50 values 1.5 to 13.5 ng/ml in a microtiter assay. BMY-28175 was evaluated for antitumor activity against several experimental murine and human tumor models. The drug administered ip was active against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma, M109 lung carcinoma, C26 colon carcinoma, M5076 sarcoma and Lewis lung carcinoma. In addition, BMY-28175 administered iv was active against iv implanted P388 and L1210 leukemias. BMY-28175 was active against sc implanted B16 melanoma (increased lifespan and/or inhibition of primary tumor growth) in about 60% of the tests. The growth of sc implanted M109 was inhibited by BMY-28175 in a single experiment. BMY-28175 was also active against the MX-1 human mammary xenograft implanted in the subrenal capsule of nude mice. The optimal dose for BMY-28175 in these various studies ranged from 0.16 g/kg per injection with consecutive daily (qd1-9) administration, to 51.2 g/kg with single dose administration. The results of these studies indicate that BMY-28175 is one of the most potent antitumor agents yet observed, with a broad spectrum of activity against tumors of murine and human origin and activity against tumors located distal to the site of drug administration.     

In vitro activity of flomoxef compared to moxalactam, cefoxitin, cefotaxime, and clindamycin against anaerobes

To assess the in vitro activity of flomoxef (6315-S), moxalactam, cefoxitin, cefotaxime, and clindamycin against anaerobes 197 clinical isolates (27 Bacteroides fragilis, 42 B. thetaiotaomicron, 10 B. vulgatus, 7 B. ovatus, 6 B. uniformis, 6 B. distasonis, 7 Bacteroides melaninogenicus group, 11 Bacteroides oralis group, 21 Clostridium difficile, 7 C. perfringens, 3 C. sporogenes, 3 Clostridium spp., 33 Propionibacterium acnes, 14 Peptococcaceae) were studied by means of agar dilution tests. The MIC90 of B. fragilis was less than 2 micrograms/ml for flomoxef, less than 4 micrograms/ml for moxalactam, less than 16 micrograms/ml for cefoxitin, less than 128 micrograms/ml for cefotaxime and less than 2 micrograms/ml for clindamycin. The respective MIC90's of B. thetaiotaomicron were less than 64, less than 128, less than 32, less than 256 and 8 micrograms/ml. Strains of the other Bacteroides species and groups were more susceptible to flomoxef and the other antibiotics than B. thetaiotaomicron. Against Clostridium difficile flomoxef (MIC90 less than 4 micrograms/ml) proved to be superior to the other agents tested. Most of the Clostridium strains other than C. difficile were also susceptible to flomoxef; anaerobic grampositive cocci and Propionibacterium acnes were very sensitive (MIC90's less than 1 and less than or equal to 0.125 micrograms/ml, respectively). Its anti-anaerobic activity, together with its efficacy against aerobes, should make flomoxef a useful adjunct to the arsenal of modern antibiotic therapy.