Antibacterial Activity of Cefuroxime, a New Cephalosporin Antibiotic, Compared with That of Cephaloridine, Cephalothin, and Cefamandole

The in vitro activity of cefuroxime, a new cephalosporin derivative, was compared with that of cephaloridine, cephalothin, and cefamandole against strains of gram-positive and gram-negative bacteria recently isolated from clinical sources. Cefuroxime showed very similar activity to cefamandole against Staphylococcus aureus, Haemophilus influenzae, and most members of the Enterobacteriaceae. It was more active than cefamandole against gonococci, pneumococci, and most streptococci. Increasing the inoculum size appeared to have less effect on the minimum inhibitory concentrations of cefuroxime for gram-negative bacilli than has been found with the other cephalosporin derivatives, and minimum bactericidal concentrations of cefuroxime were only marginally greater than minimum inhibitory concentrations.     

Comparison of Cefazolin, a New Cephalosporin Antibiotic, with Cephalothin

Resistance to cephalothin was associated in general with a lack of susceptibility to cefazolin, a new 7-amino cephalosporanic acid derivative.     

In Vitro Activity and Pharmacokinetics in Patients of Cefamandole, a New Cephalosporin Antibiotic

Cefamandole nafate, a new cephalosporin for parenteral use, was evaluated in vitro against 231 recent clinical isolates and in 12 patients. Cefamandole had activity equivalent to cefazolin against Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae. Cefamandole was more active than cephalothin or cefazolin against Proteus mirabilis. Both cefamandole and cefazolin were as active as cephalothin against S. aureus, were slightly more active against K. pneumoniae, and were considerably more active against E. coli. All strains of indole-positive Proteus sp. were inhibited by 6.3 mug of cefamandole per ml but only 20% were inhibited by 25 mug of cefazolin or cephalothin per ml. Eighty-eight percent of Enterobacter sp. was inhibited by 25 mug of cefamandole per ml, but only 20 and 5% were inhibited by the same concentration of cefazolin and cephalothin, respectively. Peak levels of cefamandole ranged from 6.0 to 110 mug/ml in serum and levels ranged from 440 to 16,800 mug/ml in a 4- to 6-h collection of urine after a 500-mg or 1-g intramuscular dose (6.1 to 17.3 mg/kg) in patients with endogenous creatinine clearances of >/=31 ml/min. These levels were done after the first dose, at mid-therapy, and at the end of therapy. There was no evidence of accumulation with the 500-mg or 1-g dose given every 4 to 6 h. The percentage of the dose excreted in the urine within the first 4 to 6 h after administration of cefamandole was >/=43%. The half-life of cefamandole in serum was 49 to 126 min.     

In Vitro Comparison of Cefoxitin, Cefamandole, Cephalexin, and Cephalothin

The in vitro effect of cefoxitin, cefamandole, cephalexin, and cephalothin was tested against 645 strains of bacteria recently isolated from clinical sources. Against gram-positive organisms cephalothin and cefamandole were the most effective, generally being three- to fourfold more active than cephalexin or cefoxitin. Enterococci were not inhibited by less than 25 μg of any of the antibiotics per ml. Against Enterobacteriaceae, cefoxitin and cefamandole were the most active. An exception was the Enterobacter strains, against which cefoxitin was the least effective. None of the Pseudomonas aeruginosa strains were susceptible to 100 μg of any of the cephalosporins per ml. Cefamandole was the most active agent against Neisseria meningitidis and Neisseria gonorrhoeae. It was also the most effective agent against Haemophilus influenzae, even when taking into account a threefold inoculum effect.     

Clinical Pharmacology of Cefamandole as Compared with Cephalothin

We compared the pharmacology of cefamandole and cephalothin in six healthy adult male volunteers. After a 1-g, 20-min intravenous (i.v.) infusion, the average peak blood level of cefamandole was 87.6 versus 64.1 mug/ml for cephalothin. An i.v. infusion of 500 mg/h for 2 h (after a loading dose of 750 mg) gave an average steady-state blood level of 28.5 mug/ml for cefamandole and 18.2 mug/ml for cephalothin. Mean peak serum levels after 1 g intramuscularly were similar for the two antibiotics (about 21 mug/ml), but with cefamandole they persisted longer, and the area under the blood level curve was about 25% greater. The average t((1/2)) as determined from both i.v. studies was 34 min for cefamandole versus 30 min for cephalothin. The mean serum clearance for cephalothin, due to its partial conversion to a metabolite, was much greater than for cefamandole (425 versus 272 ml/min per 1.73 m(2)), but the renal clearances were similar for the two antibiotics (268 versus 257 ml/min per 1.73 m(2)). Other values for cefamandole and cephalothin were: 24-h urinary excretion, 80 and 66%; serum protein binding, 74 and 70%; and apparent volume of distribution, 12.8 and 18.5 liters/1.73 m(2), respectively. Thus, the pharmacology of the two antibiotics was similar. Blood levels were somewhat higher with cefamandole i.v., but the results suggest that dosage regimens should be the same for the two antibiotics.     

Antibacterial Activity of a New Parenteral Cephalosporin—HR 756: Comparison with Cefamandole and Ceforanide

HR 756, a new parenteral cephalosporin that is beta-lactamase resistant, was tested against 271 bacterial isolates. Both agar and broth dilution testing were employed, using two media and two inoculum sizes of bacteria. Antibacterial activity of the drug was compared to that of cefamandole (CFM) and ceforanide (CFN). In agar, HR 756 was more active than CFM and CFN against all bacteria tested except isolates of Staphylococcus aureus, which were better inhibited by CFM. HR 756 exhibited some antipseudomonas activity in agar, although a marked inoculum effect was apparent. A comparison of median minimum inhibitory and bactericidal concentrations in broth showed again that HR 756 was the most active of these three drugs. HR 756 demonstrated enhanced antibacterial activity compared to CFM and CFN against bacteria sensitive to all three drugs as well as against more resistant isolates of Serratia marcescens, Enterobacter species, and indole-positive Proteus. As with other cephalosporins, results for most bacteria were affected by inoculum size, medium, and type of dilution test employed in in vitro studies.     

Cefamandole: Antimicrobial Activity In Vitro of a New Cephalosporin

Cefamandole, a new cephalosporin derivative, was found to have a broad spectrum of activity against a cross-section of both gram-positive and gram-negative bacteria isolated from clinical material. Gram-positive cocci, except for Streptococcus faecalis, were very susceptible. Penicillin G-resistant Staphylococcus aureus also was susceptible to cefamandole. Minimal bactericidal concentrations for gram-positive cocci approximated the minimal inhibitory concentrations. Strains of Haemophilus influenzae were very susceptible to the drug. Most strains of Escherichia coli, Klebsiella sp., and Proteus sp. were inhibited by low concentrations. Increasing resistance occurred with larger inocula. Strains of Pseudomonas sp. were resistant to cefamandole.     

Antibacterial Activity of Netilmicin, a New Aminoglycoside Antibiotic, Compared with That of Gentamicin

The antibacterial activity of netilmicin (Sch 20569), a new semisynthetic aminoglycoside, was compared with that of gentamicin against a variety of gram-negative bacteria, staphylococci, and streptococci. Both antibiotics had similar activity against most organisms, but netilmicin had appreciably greater activity against gram-negative organisms that were resistant to gentamicin because these species synthesized aminoglycoside 3-N-acetyltransferase I or aminoglycoside 2'-O-nucleotidyltransferase. Netilmicin was also more active than gentamicin against gentamicin-resistant strains of Staphylococcus aureus that produced two enzymes-aminoglycoside-2'-O-phosphotransferase and aminoglycoside-6'-N-acetyltransferase.     

Antibacterial Activity of a New 1-Oxa Cephalosporin Compared with That of Other β-Lactam Compounds

The in vitro activity of (6R,7R)-7-{[carboxy(4-hydroxyphenyl)acetyl]amino}-7-methoxy-3-[[(1-methyl -1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-oxa-1-azabicyclo-[4.2.0]oct-2-ene -2-carboxylic acid was tested against isolates of gram-positive and negative bacteria and compared with those of cephalothin, cefuroxime, cefamandole, cefoxitin, cefotaxime, and carbenicillin. The compound was less active than the other compounds when tested against Staphylococcus aureus and Staphylococcus epidermidis. It had equal or slightly less activity than did cefotaxime when tested against members of the Enterobacteriaceae, but was 8- to 32-fold more active than the other cephalosporins against the Enterobacteriaceae, inhibiting most isolates at concentrations less than 0.5 mug/ml. The compound was twofold more active than cefotaxime and cefoxitin against Bacteroides, and it was twofold more active than cefotaxime and fourfold more active than carbenicillin against Pseudomonas aeruginosa. In vitro activity did not correlate with either the presence or type of beta-lactamase in either Enterobacteriaceae or Pseudomonas. The compound showed minimal synergy when combined with aminoglycosides or carbenicillin.     

Cefuroxime, a New Cephalosporin Antibiotic: Activity In Vivo

The pharmacokinetic properties of cefuroxime have been evaluated in laboratory animals. On injection into mice, rats, and rabbits by the subcutaneous or intramuscular routes, high serum level peaks were recorded. There was no significant absorption after oral administration. After injection, the antibiotic was excreted in large amounts in the urine. It was well distributed in the body and penetrated into the tissues at a satisfactory rate. This, coupled with a low degree of serum protein binding, was correlated with a very good protective effect in animals (mice, rats, and rabbits) experimentally infected with a wide range of bacteria, including beta-lactamase-producing strains. It is concluded that cefuroxime should have a good potential for treating a wide range of bacterial infections in humans.     

Cefuroxime, a New Cephalosporin Antibiotic: Activity In Vitro

Cefuroxime is a new broad-spectrum cephalosporin antibiotic with increased stability to beta-lactamases. This stability, although no absolute in all cases, has the effect of widening the antibacterial spectrum of the compound so that many organisms resistant to the established cephalosporins are susceptible to cefuroxime. It is active against gram-positive organisms, including penicillinase-producing staphylococci, but it is less active against methicillin-resistant strains. In addition to its high activity against non-beta-lactamase-producing gram-negative bacteria, cefuroxime effectively inhibits the growth of many beta-lactamase-producing strains, including Enterobacter, Klebsiella, and indole-positive Proteus spp. It is highly active against Neisseria gonorrhoeae, Neisseria meningitidis, and also Haemophilus influenzae, including ampicillin-resistant strains. Cefuroxime is rapidly bactericidal and induces the formation and subsequent lysis of filamentous forms over a small concentration range.     

In Vitro Activity of Piperacillin Compared with That of Carbenicillin, Ticarcillin, Ampicillin, Cephalothin, and Cefamandole Against Pseudomonas aeruginosa and Enterobacteriaceae

Piperacillin (T-1220), a semisynthetic derivative of aminobenzylpenicillin, was more active than either carbenicillin or ticarcillin against Pseudomonas aeruginosa; over 60% of isolates were inhibited at a concentration of 6.3 mug/ml. Piperacillin was bactericidal for 84% of Pseudomonas strains at 100 mug/ml, carbenicillin killed 60%, and ticarcillin killed 68% at that concentration. Piperacillin was also more active than the other penicillins against isolates of Escherichia coli, Enterobacter, and Proteus mirabilis. The combination of piperacillin and tobramycin, demonstrating synergistic inhibition of 87% of strains of P. aeruginosa, was the most active of the penicillin-aminoglycoside combinations tested for synergism.     

In Vitro Activity of Cefaclor, a New Orally Administered Cephalosporin Antibiotic

The in vitro antibacterial activity of cefaclor, cephalothin, and cephalexin against 261 clinical isolates of Staphylococcus aureus and Enterobacteriaceae was compared. Cefaclor and cephalexin were about equally active against S. aureus. Cefaclor was the most active cephalosporin against Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. The effect on the antimicrobial activity using a relatively high and low inoculum was pronounced for cefaclor when compared with that of cephalothin.     

Delineation of the Relative Antibacterial Activity of Cefamandole and Cefamandole Nafate

By conventional laboratory evaluation procedures, the in vitro antibacterial activities of cefamandole and its O-formyl ester, cefamandole nafate, appear virtually identical. When the activities of these two compounds were examined for their ability to lyse log-phase cultures of susceptible bacteria, however, cefamandole was found to be about 10 times more active than cefamandole nafate. Cefamandole nafate was shown to be rapidly converted to cefamandole in bacteriological media, with a half-life of less than 1 h at a pH of 7.0 or above. At pH 6.0, in log-phase inhibition experiments, however, cefamandole nafate is more stable, allowing delineation of the activity between cefamandole and cefamandole nafate. The efficacy of cefamandole was identical to that of cefamandole nafate in treating experimental animal infections, indicating that rapid conversion of cefamandole nafate to cefamandole occurs in vivo.     

HR 756, the syn Isomer of a New Methoxyimino Cephalosporin with Unusual Antibacterial Activity

HR 756, the syn derivative of 7-[(2-(2-amino-4-thiazolyl)-2-methoxyimino)acetamido]cephalosporanic acid, is a new semisynthetic cephalosporin. It was 80 times more active than the anti derivative against beta-lactamase-producing strains of gram-negative bacteria. The range of inhibitory concentrations of HR 756 against gram-negative bacteria, including Haemophilus influenzae, susceptible or resistant to penicillins and cephalosporins was from 0.01 to 0.1 mug/ml. This activity was consistently higher than those observed with cephalothin, cephaloridine, cephalexin, and cefazolin. Nevertheless, some strains of Enterobacter cloacae were resistant. HR 756 showed very similar activity to that of ampicillin against group A streptococci and Streptococcus pneumoniae.     

Evaluation of Cefazolin, a New Cephalosporin Antibiotic

Cefazolin sodium was tested in vitro against 308 isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus aureus, and enterococcus. Broth and agar dilution and disk diffusion techniques were used with at least two sizes of inocula of organisms. Cefazolin was also studied in the treatment of 85 hospitalized patients with a variety of serious infections. In concentations of 5 μg or less/ml, cefazolin inhibited and killed more than 90% of isolates of Enterobacteriaceae with the exception of indole-positive Proteus and Enterobacter species. No isolate of P. aeruginosa and only a few of Enterobacter and enterococci were killed by 25 μg of cefazolin/ml, a concentration readily attainable in serum with a 500-mg dose given intramuscularly. Penicillin-susceptible as well as penicillin-resistant isolates of S. aureus were killed by 1 μg or less of cefazolin per ml; however, 25 μg/ml was required to kill 100% of the strains when the inoculum size was increased 100-fold. Cefazolin treatment appeared effective in 82 of 85 patients, including four with endocarditis. Pain was minimal after intramuscular injection, and thrombophlebitis was not observed in those treated intravenously. No patient developed a positive Coombs test, and no evidence of renal toxicity was apparent in clinical studies.     

Evaluation of a New Cephalosporin Antibiotic, Cephapirin

Cephapirin sodium, a parenterally administered derivative of cephalosporanic acid, was tested in vitro against 150 stock cultures of Enterobacteriaceae and 30 stock cultures each of Pseudomonas aeruginosa and Staphylococcus aureus. Both broth- and agar-dilution techniques were employed with two sizes of inocula of organisms. At a concentration of 7.5 mug or less/ml, cephapirin inhibited and killed 100% of strains of Escherichia coli and Proteus mirabilis and more than 80% of Klebsiella species when tested against an inoculum of 10(5) bacterial cells/ml. However, even at 100 mug/ml, only a few isolates of other Enterobacteriaceae and Pseudomonas were inhibited. A 100-fold increase in the inoculum resulted in decreased susceptibility of organisms. All penicillin-susceptible as well as penicillin-resistant S. aureus isolates were inhibited and killed by 5 mug or less of cephapirin/ml when tested with an inoculum of either 10(4) or 10(6) organisms/ml. The drug also was studied in various doses in the treatment of 77 patients with diverse infections. Cephapirin was effective in the treatment of 27 of 32 patients with pulmonary infection, as well as in 6 of 7 patients with staphylococcal or streptococcal soft tissue infection. Of 25 patients with urinary-tract infections, 19 developed a negative culture during therapy. A single 4-g intramuscular dose of cephapirin was effective in only 2 of 11 patients with gonococcal urethritis or endocervicitis. Two patients with gonococcal urethritis treated with multiple injections were cured. The drug was well tolerated except for pain at the site of injection in 14 patients and phlebitis in 4 patients. No abnormalities in renal or hepatic function could be attributed to cephapirin. In addition, no abnormalities were found in the renal tubules of rabbits challenged with 500 mg of cephapirin/kg. If further studies document that cephapirin is well tolerated by the parenteral route, it may have advantages over cephalothin or cephaloridine.     

Metabolic Fate of [14C]Cefamandole, a Parenteral Cephalosporin Antibiotic, in Rats and Dogs

The biotransformation of the parenterally effective cephalosporin antibiotic cefamandole nafate (I) has been studied in rats and dogs. After rapid in vivo hydrolysis of the nafate pharmaceutical form to cefamandole (II), the antibiotic was found to be very resistant to metabolic degradation in both species. In dogs, cefamandole escaped metabolism and was eliminated as unaltered antibiotic almost exclusively by renal excretion. In rats, cefamandole was somewhat labile to metabolism; however, a major portion of the administered antibiotic was eliminated unchanged principally by renal excretion.     

Double-Blind Comparison of Cephacetrile with Cephalothin/Cephaloridine

Under double-blind protocol, a controlled comparison was made between a new cephalosporin, cephacetrile, and cephalothin or cephaloridine. The patient's primary physician determined the indications for treatment, and the dosage was uniform for each route of administration. Infecting strains of staphylococci and Proteus mirabilis had a lower median inhibitory concentration for cephalothin than cephacetrile; the opposite was true for Escherichia coli and Klebsiella species. The average peak serum level 1 h after a dose of 2 g intravenously was 74.9 +/- 21 and 21.5 +/- 8.7 mug/ml for cephacetrile and cephalothin, respectively; 6 h after the dose, the respective levels were 12.4 +/- 4.3 and 3.7 +/- 0.9 mug/ml. Renal clearances were similar and the plasma clearance was proportional to the serum levels. In the urine, the concentration of cephacetrile was three times higher than that of cephalothin. Based on a percentage of therapeutic potential, success in the treatment of infections with susceptible organisms was 42 and 44% for the two different drug regimens. Initial bacterial resistance was found in about one-fifth of infections, and concomitant therapy with other drugs was practiced in one-half of the treatment courses. Intravenous use of cephacetrile was discontinued prematurely more often than was use of cephalothin, suggesting less tolerance. Although there was no overt toxicity, more than 75% of patients on either regimen had some form of unwanted response to treatment, the most common being superinfection. From this limited but controlled experience, cephacetrile can be considered comparable to cephalothin in antimicrobial treatment and overall side reactions.     

In Vivo Antibacterial Activity of Vertilmicin,a New Aminoglycoside Antibiotic

Vertilmicin is a novel aminoglycoside antibiotic with potent activity against gram-negative and -positive bacteria in vitro. In this study, we further evaluated the efficacy of vertilmicin in vivo in systemic and local infection animal models. We demonstrated that vertilmicin had relatively high and broad-spectrum activities against mouse systemic infections caused by Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Enterococcus faecalis. The 50% effective doses of subcutaneously administered vertilmicin were 0.63 to 0.82 mg/kg, 0.18 to 0.29 mg/kg, 0.25 to 0.99 mg/kg, and 4.35 to 7.11 mg/kg against E. coli, K. pneumoniae, S. aureus, and E. faecalis infections, respectively. The therapeutic efficacy of vertilmicin was generally similar to that of netimicin, better than that of gentamicin in all the isolates tested, and better than that of verdamicin against E. coli 9612 and E. faecalis HH22 infections. The therapeutic efficacy of vertilmicin was further confirmed in local infection models of rabbit skin burn infection and mouse ascending urinary tract infection.Aminoglycosides are a group of highly potent, broad-spectrum bactericidal antibiotics (8). Their history began with the discovery of streptomycin (12), followed by kanamycin, gentamicin, tobramycin, and a series of semisynthetic aminoglycosides (dibekacin, amikacin, and netilmicin) for the treatment of resistant organisms (8). The mechanisms of aminoglycoside resistance involved (i) modifying enzymes (the most common mechanism), (ii) mutations of the ribosomal binding site (causes resistance to streptomycin), and (iii) reduced drug uptake (mostly seen in Pseudomonas spp.) (2, 13). The semisynthetic aminoglycosides are mainly designed for the treatment of organisms that have developed resistance by producing aminoglycoside-modifying enzymes, i.e., N-acetyltransferase, O-nucleotidyltransferase, and O-phosphotransferases (8).Vertilmicin is a novel semisynthetic aminoglycoside derived from verdamicin. Our earlier study showed that it had broad in vitro antimicrobial activity which is similar to that of netilmicin and has the advantage of lower susceptibility to N-acetyltransferase 6′-Ie modification (5). In this study, we further investigated the in vivo antibacterial activities of this agent in a systemic infection model, as well as local infection models, to fill the gap between in vitro characterization and clinical evaluation. All of our animals studies were approved by the Animal Research Committee of the Institute of Medicinal Biotechnology.