ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1979, p. 209-212 0066-4804/79/02-0209/04$02.00/0
Vol. 15, No. 2
Cefatrizine Activity Compared with That of Other Cephalosporins HAROLD C. NEU* AND KWUNG P. FU Departments of Medicine and Pharmacology, College ofPhysicians and Surgeons, Columbia University, New York, New York 10032 Received for publication 6 November 1978
Cefatrizine, a new orally administered cephalosporin, was tested against 400 clinical isolates. Cefatrizine had excellent activity against gram-positive cocci, inhibiting all except enterococci at miniimal inhibitory concentrations below 1 jig/ml. Cefatrizine inhibited the majority of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Salmonella at concentrations below 12.5 ,ug/ml. Although cefatrizine was not hydrolyzed by many ,8-lactamases, it did not inhibit a number of strains of Enterobacter, Serratia, or indole-positive Proteus. Cefatrizine was more active than cephalothin or cephalexin against E. coli, Klebsiella, Enterobacter, Citrobacter, Salmonella, and Shigella. Its overall activity was less than that of cefoxitin against strains resistant to cephalothin, but its activity against cephalothin-susceptible strains was equivalent to that of cefamandole. Although there has been a proliferation .of new cephalosporins with increased resistance to hydrolysis by gram-negative ,6-lactamases and with a concomitant increase in antibacterial spectrum, the oral agents available have been limited to cephalexin and cephradine. Cephaloglycine is no longer used because of its poor oral absorption. Cefatrizine has been reported to have an increased spectrum of activity against some gram-negative bacteria compared with that of the currently available oral drugs. We wished to evaluate the activity of this compound in comparison with cephalothin and cephalexin, as well as cefamandole and cefoxitin, whose spectrum is increased (3-5). If cefatrizine inhibits bacterial isolates resistant to the older agents, it might provide an oral -agent to complete therapy initiated with cefoxitin or cefamandole. (These results were presented in part at the 16th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill., 27-29 October 1976.) MATERIALS AND METHODS
there was no visible growth or less than five colonies. The MIC values of streptococci were determined in Mueller-Hinton agar supplemented with 5% sheep blood. ,B-Lactamase assays were performed by using a spectrophotometric assay at 30°C in pH 7 0.05 M phosphate buffer as previously described (3, 4). f8Lactamases were prepared by sonic treatment of latelogarithmic-phase bacteria. The resulting material was centrifuged at 30,000 x g for 2 h to remove cell debris. Enzymes were classified by the system of Richmond and Sykes (7) based on substrate activity and inhibition by other ,B-lactams.
RESULTS The data in Table 1 compare the activities of cefatrizine against various strains of both grampositive and gram-negative bacteria with the activities of cephalothin, cephalexin, cefamandole, and cefoxitin. Cefatrizine was less active against Staphylococcus aureus than cephalothin or cefamandole, with a concentration of 0.4 ,ug of cefatrizine per ml required to inhibit 50% of isolates, compared with 0.1 jig/ml for the latter two agents. But cefatrizine was two- to. fourfold more active against S. aureus than were cephalexin or cefoxitin. The activity of* cefatrizine against Staphylococcus epidermidis was similar to its activity against S. aureus, but cefatrizine was distinctly more active than cephalexin or cefoxitin. A total of90% of isolates were inhibited by 1.6 ,ug of cefatrizine per ml, compared with 50% inhibited by cefoxitin and 40% inhibited by cephalexin at this same concentration. Although cefatrizine was two- to fourfold more active than the other agents against Streptococcus faecalis,
Cefatrizine was a gift of Bristol Laboratories. All of the other cephalosporins were obtained from their respective manufacturers. Bacterial isolates were from urine, sputum, throat, stool, and wound cultures of patients seen at the Columbia-Presbyterian Medical Center. Susceptibility tests were performed in agar by utilizing an inoculum of 105 colony-forming units applied to Mueller-Hinton agar (Baltimore Biological Laboratory). Serial twofold dilutions were prepared, and the minimum inhibitory concentration (MIC) was considered to be the lowest concentration at which 209
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the MICs were 25 ,ug/ml. There was a marked, eightfold difference between the MICs and the minimal bactericidal concentrations for five isolates tested in broth. Cefatrizine had activity similar to that of cefamandole against most of the Escherichia coli isolates tested. It inhibited the majority of cephalothin-susceptible E. coli at concentrations two to fourfold below the concentrations required with cephalothin or cephalexin. A total of 80% of E. coli isolates were inhibited by 25 ,tg of cefatrizine per ml, but cefoxitin inhibited 97% and cefamandole inhibited 87% at this concentration. Against Klebsiella, cefatrizine had activity similar to that of the other agents, with minor differences among the individual isolates. Cefatrizine inhibited most Enterobacter aerogenes at concentrations of 12.5 ,ig/ml or less, but some Enterobacter cloacae and Enterobacter hafnia were fully resistant (MICs, >200 ,ug/ml). Cefatrizine was more active than cephalothin, cephalexin, or cefoxitin against Enterobacter spp., but less active than cefamandole. Cefatrizine was more active than cephalothin, cephalexin, or cefoxitin, against Citrobacter freundii, but less active than cefamandole. It inhibited the majority of Citrobacter isolates at concentrations of 12.5,ug/ml. It also inhibited all Citrobacter diversus (12 isolates at concentrations of 6.3 ytg/ml or less. All of the agents inhibited the majority of the Proteus mirabilis strains tested. The minor differences shown in Table 1 are due to only a few strains and do not indicate a clear superiority of any compound. The indole-positive Proteus included P. morganii, P. rettgeri, and P. vulgaris. Although some isolates resistant to cephalothin and cephalexin were inhibited by cefatrizine, the MICs of cefatrizine for the majority of the isolates were greater than 25 ,ug/ml whereas at this concentration cefoxitin inhibited more than 90% of the isolates and cefamandole inhibited 65%. Similarly, cefatrizine was no more active than either cephalothin or cephalexin against strains of Providencia stuartii, many of which were inhibited by cefoxitin and cefamandole. Cefatrizine inhibited 60% of Serratia marcescens isolates at 50 ,ug/ml, whereas none of the isolates was inhibited by 400 ,tg of cephalothin or cephalexin per ml. Cefatrizine was more active than cefamandole, but less active than cefoxitin, against Serratia. Cefatrizine had excellent activity against Salmonella species, including S. typhi, S. typhimurium, S. heidelberg, and S. enteritidis. It inhibited 81% of the isolates at concentrations of 6.3 ,ug/ml or less. All S. typhi (4 isolates) and S. typhimurium (8 isolates) resistant to ampicillin were inhibited by cefatrizine. Cefatrizine in-
CEFATRIZINE ACTIVITY
VOL. 15, 1979
211
hibited 81% of Shigella sonnei (16 isolates to be related to its stability against the ,B-lactatested) at 6.3 ,ug/ml and 100% of Shigella flex- mases present in these species (Table 3). It was neri (8 isolates) at this concentration. Cefatrizine not hydrolyzed by the most common plasmidinhibited only 30% of Bacteroides fragilis mediated fi-lactamase (Richmond class III) strains at 50 ,Lg/ml, an activity similar to that of present in E. coli and Salmonella. It was also cephalexin, whereas 100% were inhibited by ce- resistant to hydrolysis by the less common plasfoxitin at this concentration. Cefatrizine did not mid-mediated /3-lactamase in S. sonnei, which inhibit Pseudomonas aeruginosa (10 isolates) hydrolyzes the isoxazolyl penicillins as readily as Pseudomonas cepacia (10 isolates), or Pseudo- it does ampicillin (Table 3). Cefatrizine was not monas maltophilia (5 isolates). Cefatrizine did hydrolyzed by S. aureus f8-lactamases. not inhibit the 10 isolates of Acinetobacter In contrast, although cefatrizine was not hytested. drolyzed by the inducible 3-lactamases (cephalThe activity of cefatrizine against streptococci osporinases) of most Serratia, Providencia, was not compared with that of the other agents. Acinetobacter, and Citrobacter, it did not inhibit It inhibited 8 of 10 Streptococcus pyogenes iso- these strains. Cefatrizine had an MIC of 100 lates at 0.1 jig/ml and all at 0.2 ,ug/ml. It also jig/ml against a Providencia strain which did inhibited all 10 isolates of Streptococcus agalac- not hydrolyze cefatrizine. Cefamandole, which tiae and Streptococcus bovis at 0.2 ,ug/ml. The was hydrolyzed by the strain, inhibited this MICs for 12 isolates of Streptoccus pneumoniae Providencia at 3.1 tLg/ml. A similar situation ranged from 0.05 to 0.5 ILg/ml, whereas 4 ,g of was found with an Acinetobacter isolate. cephalexin per ml was required to inhibit all of DISCUSSION the same isolates. Earlier publications (1, 2, 6, 8, 9) have sugA direct comparison of the activities of cefatrizine and three /8-lactamase-stable cephalospo- gested that cefatrizine is an agent that would rins is given in Table 2. All of the isolates were extend the spectrum of oral and parenteral cephresistant to cephalothin (MICs, >400 ,ug/ml) and alosporins, but these studies compared its activity with that of older agents and not with that of were 83-lactamase-producing strains as determined by the Glaxo chromogenic cephalosporin cefamandole, cefuroxime, and cefoxitin, which have an expanded spectrum of activity (3-5). assay. Except for a C. freundii strain and an S. typhi isolate, the MICs were 50 tig/ml or greater. Although cefatrizine has excellent stability comIn contrast, the MICs for the other three agents TABLE 3. /3-Lactamase hydrolysis of cefatrizine in a number of instances were 3.1 to 25 ,ug/ml, compared with that of the other cephalosporins concentrations which could be achieved in clinRelative rate of hydrolysis (%) a ical practice. Type Type of The activity of cefatrizine against E. coli, isolate lactamase Cefatrizine Cefaman Cefoxitin Klebsiella, Salmonella, and Shigella appeared TABLE 2. Activity of cefatrizine against cephalothin-resistant isolates compared with that of other cephalosporinsa MIC
(fig/ml) of:
Type of isolates Cefatrizine mandole Cefoxitin
Cefuro-
une
400 12.5 3.2 25 S. marcescens >400 200 25 200 S. marcescens 50 50 200 12.5 E. cloacae E. cloacae 200 200 100 25 P. stuartii 200 3.1 3.1 12.5 200 3.1 3.1 3.1 Acinetobacter 400 12.5 12.5 50 P. morganii 200 12.5 6.2 400 Klebsiella pneumoniae 6.2 25 25 50 E. coli 25 25 200 25 E. coli 100 3.1 25 25 S. sonnei 1.6 12.5 3.1 100 C. freundii 3.1 1.6 6.3 12.5 S. typhi All of the isolates and cephalothin MIC values of >400 ,tg/ml. a
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I
Serratia
I
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I
0 (400) 0 (100)
I
76
0
0
(400)
(100)
0 0
(50) 0 (3.1)
31
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(3.1)
(1.6)
44
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(0.8) 77 (6.3)
(1.6) 0 (3.1)
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0
75
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(25) 0 (1.6)
(200) 0 (1.6)
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(400) (100) Acinetobacter
0 (100) 0 (12.5)
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(1.6) 0 (6.3) 0
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(3.1) 0 (0.2)
212
NEU AND FU
pared to many of the ,B-lactamases found in the Enterobacteriaceae, this stability failed in many situations to correlate with in vitro activity. Cefatrizine was more stable to ,B-lactamase hydrolysis than was cefamandole. It was less active than that compound against certain organisms. This has also been noted for cefoxitin, which is stable to all f8-lactamases but does not inhibit many Enterobacter and Citrobacter species. Cefatrizine has added to the overall activity of the cephalosporins against a number of the Enterobacteriaceae, albeit to a lesser degree than have other /)-lactamase-stable cephalosporins (3, 5, 7). Its gram-positive activity, on the other hand, is two- to eightfold greater than that of cephalexin. The clinical relevance of this will be difficult to demonstrate even with comparative trials since the MIC values of both compounds against gram-positive bacteria are well below readily achievable levels. LITERATURE CITED 1. Blackwell, C. C., E. H. Freimer, and G. C. Tuke. 1976. In vitro evaluation of the new oral cephalosporin cefatrizine: comparison with other cephalosporins. Antimi-
ANTIMICROB. AGENTS CHEMOTHER. crob. Agents Chemot.her. 10:288-292. 2. Leitner, F., R. E. Buck, M. Misiek, T. A. Pursiano, and K. E. Price. 1975. BLS 640, a cephalosporin with a broad spectrum of antibacterial activity: properties in vitro. Antimicrob. Agents Chemother. 7:298-305. 3. Neu, H. C. 1974. Cefamandole, a cephalosporin antibiotic with an unusually wide spectrum of activity. Antimicrob. Agents Chemother. 6:177-182. 4. Neu, H. C. 1974. Cefoxitin, a semisynthetic cephamycin antibiotic: antibacterial spectrum and resistance to hydrolysis by gram-negative beta-lactamases. Antimicrob. Agents Chemother. 6:170-176. 5. O'Callaghan, C. H., R. B. Sykes, A. Griffiths, and J. E. Thornton. 1976. Cefuroxime, a new cephalosporin antibiotic: activity in vitro. Antimicrob. Agents Chemother. 9:511-514. 6. Overturf, G. D., R. L Ressler, P. B. Marengo, and J. Wilkins. 1975. In vitro evaluation of BL-S640, a new oral cephalosporin antibiotic. Antimicrob. Agents Chemother. 8:305-310. 7. Richmond, M. H., and R. B. Sykes. 1973. The 8-lactamases of gram-negative bacteria and their possible physiological role. Adv. Microb. Physiol. 9:314-8. 8. Stilwell, G. A., H. G. Adams, and M. Turck. 1975. In vitro evaluation of a new oral cephalosporin, cefatrizine (BL-S640). Antimicrob. Agents Chemother. 8:751-753. 9. Watanakunakorn, C., T. Bannister, and C. Glotzbecker. 1975. Susceptibility of clinical isolates of Enterobacteriaceae to BL-S640, a new oral cephalosporin. Antimicrob. Agents Chemother. 7:381-385.
Vol. 15, No. 2
Cefatrizine Activity Compared with That of Other Cephalosporins HAROLD C. NEU* AND KWUNG P. FU Departments of Medicine and Pharmacology, College ofPhysicians and Surgeons, Columbia University, New York, New York 10032 Received for publication 6 November 1978
Cefatrizine, a new orally administered cephalosporin, was tested against 400 clinical isolates. Cefatrizine had excellent activity against gram-positive cocci, inhibiting all except enterococci at miniimal inhibitory concentrations below 1 jig/ml. Cefatrizine inhibited the majority of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Salmonella at concentrations below 12.5 ,ug/ml. Although cefatrizine was not hydrolyzed by many ,8-lactamases, it did not inhibit a number of strains of Enterobacter, Serratia, or indole-positive Proteus. Cefatrizine was more active than cephalothin or cephalexin against E. coli, Klebsiella, Enterobacter, Citrobacter, Salmonella, and Shigella. Its overall activity was less than that of cefoxitin against strains resistant to cephalothin, but its activity against cephalothin-susceptible strains was equivalent to that of cefamandole. Although there has been a proliferation .of new cephalosporins with increased resistance to hydrolysis by gram-negative ,6-lactamases and with a concomitant increase in antibacterial spectrum, the oral agents available have been limited to cephalexin and cephradine. Cephaloglycine is no longer used because of its poor oral absorption. Cefatrizine has been reported to have an increased spectrum of activity against some gram-negative bacteria compared with that of the currently available oral drugs. We wished to evaluate the activity of this compound in comparison with cephalothin and cephalexin, as well as cefamandole and cefoxitin, whose spectrum is increased (3-5). If cefatrizine inhibits bacterial isolates resistant to the older agents, it might provide an oral -agent to complete therapy initiated with cefoxitin or cefamandole. (These results were presented in part at the 16th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill., 27-29 October 1976.) MATERIALS AND METHODS
there was no visible growth or less than five colonies. The MIC values of streptococci were determined in Mueller-Hinton agar supplemented with 5% sheep blood. ,B-Lactamase assays were performed by using a spectrophotometric assay at 30°C in pH 7 0.05 M phosphate buffer as previously described (3, 4). f8Lactamases were prepared by sonic treatment of latelogarithmic-phase bacteria. The resulting material was centrifuged at 30,000 x g for 2 h to remove cell debris. Enzymes were classified by the system of Richmond and Sykes (7) based on substrate activity and inhibition by other ,B-lactams.
RESULTS The data in Table 1 compare the activities of cefatrizine against various strains of both grampositive and gram-negative bacteria with the activities of cephalothin, cephalexin, cefamandole, and cefoxitin. Cefatrizine was less active against Staphylococcus aureus than cephalothin or cefamandole, with a concentration of 0.4 ,ug of cefatrizine per ml required to inhibit 50% of isolates, compared with 0.1 jig/ml for the latter two agents. But cefatrizine was two- to. fourfold more active against S. aureus than were cephalexin or cefoxitin. The activity of* cefatrizine against Staphylococcus epidermidis was similar to its activity against S. aureus, but cefatrizine was distinctly more active than cephalexin or cefoxitin. A total of90% of isolates were inhibited by 1.6 ,ug of cefatrizine per ml, compared with 50% inhibited by cefoxitin and 40% inhibited by cephalexin at this same concentration. Although cefatrizine was two- to fourfold more active than the other agents against Streptococcus faecalis,
Cefatrizine was a gift of Bristol Laboratories. All of the other cephalosporins were obtained from their respective manufacturers. Bacterial isolates were from urine, sputum, throat, stool, and wound cultures of patients seen at the Columbia-Presbyterian Medical Center. Susceptibility tests were performed in agar by utilizing an inoculum of 105 colony-forming units applied to Mueller-Hinton agar (Baltimore Biological Laboratory). Serial twofold dilutions were prepared, and the minimum inhibitory concentration (MIC) was considered to be the lowest concentration at which 209
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the MICs were 25 ,ug/ml. There was a marked, eightfold difference between the MICs and the minimal bactericidal concentrations for five isolates tested in broth. Cefatrizine had activity similar to that of cefamandole against most of the Escherichia coli isolates tested. It inhibited the majority of cephalothin-susceptible E. coli at concentrations two to fourfold below the concentrations required with cephalothin or cephalexin. A total of 80% of E. coli isolates were inhibited by 25 ,tg of cefatrizine per ml, but cefoxitin inhibited 97% and cefamandole inhibited 87% at this concentration. Against Klebsiella, cefatrizine had activity similar to that of the other agents, with minor differences among the individual isolates. Cefatrizine inhibited most Enterobacter aerogenes at concentrations of 12.5 ,ig/ml or less, but some Enterobacter cloacae and Enterobacter hafnia were fully resistant (MICs, >200 ,ug/ml). Cefatrizine was more active than cephalothin, cephalexin, or cefoxitin against Enterobacter spp., but less active than cefamandole. Cefatrizine was more active than cephalothin, cephalexin, or cefoxitin, against Citrobacter freundii, but less active than cefamandole. It inhibited the majority of Citrobacter isolates at concentrations of 12.5,ug/ml. It also inhibited all Citrobacter diversus (12 isolates at concentrations of 6.3 ytg/ml or less. All of the agents inhibited the majority of the Proteus mirabilis strains tested. The minor differences shown in Table 1 are due to only a few strains and do not indicate a clear superiority of any compound. The indole-positive Proteus included P. morganii, P. rettgeri, and P. vulgaris. Although some isolates resistant to cephalothin and cephalexin were inhibited by cefatrizine, the MICs of cefatrizine for the majority of the isolates were greater than 25 ,ug/ml whereas at this concentration cefoxitin inhibited more than 90% of the isolates and cefamandole inhibited 65%. Similarly, cefatrizine was no more active than either cephalothin or cephalexin against strains of Providencia stuartii, many of which were inhibited by cefoxitin and cefamandole. Cefatrizine inhibited 60% of Serratia marcescens isolates at 50 ,ug/ml, whereas none of the isolates was inhibited by 400 ,tg of cephalothin or cephalexin per ml. Cefatrizine was more active than cefamandole, but less active than cefoxitin, against Serratia. Cefatrizine had excellent activity against Salmonella species, including S. typhi, S. typhimurium, S. heidelberg, and S. enteritidis. It inhibited 81% of the isolates at concentrations of 6.3 ,ug/ml or less. All S. typhi (4 isolates) and S. typhimurium (8 isolates) resistant to ampicillin were inhibited by cefatrizine. Cefatrizine in-
CEFATRIZINE ACTIVITY
VOL. 15, 1979
211
hibited 81% of Shigella sonnei (16 isolates to be related to its stability against the ,B-lactatested) at 6.3 ,ug/ml and 100% of Shigella flex- mases present in these species (Table 3). It was neri (8 isolates) at this concentration. Cefatrizine not hydrolyzed by the most common plasmidinhibited only 30% of Bacteroides fragilis mediated fi-lactamase (Richmond class III) strains at 50 ,Lg/ml, an activity similar to that of present in E. coli and Salmonella. It was also cephalexin, whereas 100% were inhibited by ce- resistant to hydrolysis by the less common plasfoxitin at this concentration. Cefatrizine did not mid-mediated /3-lactamase in S. sonnei, which inhibit Pseudomonas aeruginosa (10 isolates) hydrolyzes the isoxazolyl penicillins as readily as Pseudomonas cepacia (10 isolates), or Pseudo- it does ampicillin (Table 3). Cefatrizine was not monas maltophilia (5 isolates). Cefatrizine did hydrolyzed by S. aureus f8-lactamases. not inhibit the 10 isolates of Acinetobacter In contrast, although cefatrizine was not hytested. drolyzed by the inducible 3-lactamases (cephalThe activity of cefatrizine against streptococci osporinases) of most Serratia, Providencia, was not compared with that of the other agents. Acinetobacter, and Citrobacter, it did not inhibit It inhibited 8 of 10 Streptococcus pyogenes iso- these strains. Cefatrizine had an MIC of 100 lates at 0.1 jig/ml and all at 0.2 ,ug/ml. It also jig/ml against a Providencia strain which did inhibited all 10 isolates of Streptococcus agalac- not hydrolyze cefatrizine. Cefamandole, which tiae and Streptococcus bovis at 0.2 ,ug/ml. The was hydrolyzed by the strain, inhibited this MICs for 12 isolates of Streptoccus pneumoniae Providencia at 3.1 tLg/ml. A similar situation ranged from 0.05 to 0.5 ILg/ml, whereas 4 ,g of was found with an Acinetobacter isolate. cephalexin per ml was required to inhibit all of DISCUSSION the same isolates. Earlier publications (1, 2, 6, 8, 9) have sugA direct comparison of the activities of cefatrizine and three /8-lactamase-stable cephalospo- gested that cefatrizine is an agent that would rins is given in Table 2. All of the isolates were extend the spectrum of oral and parenteral cephresistant to cephalothin (MICs, >400 ,ug/ml) and alosporins, but these studies compared its activity with that of older agents and not with that of were 83-lactamase-producing strains as determined by the Glaxo chromogenic cephalosporin cefamandole, cefuroxime, and cefoxitin, which have an expanded spectrum of activity (3-5). assay. Except for a C. freundii strain and an S. typhi isolate, the MICs were 50 tig/ml or greater. Although cefatrizine has excellent stability comIn contrast, the MICs for the other three agents TABLE 3. /3-Lactamase hydrolysis of cefatrizine in a number of instances were 3.1 to 25 ,ug/ml, compared with that of the other cephalosporins concentrations which could be achieved in clinRelative rate of hydrolysis (%) a ical practice. Type Type of The activity of cefatrizine against E. coli, isolate lactamase Cefatrizine Cefaman Cefoxitin Klebsiella, Salmonella, and Shigella appeared TABLE 2. Activity of cefatrizine against cephalothin-resistant isolates compared with that of other cephalosporinsa MIC
(fig/ml) of:
Type of isolates Cefatrizine mandole Cefoxitin
Cefuro-
une
400 12.5 3.2 25 S. marcescens >400 200 25 200 S. marcescens 50 50 200 12.5 E. cloacae E. cloacae 200 200 100 25 P. stuartii 200 3.1 3.1 12.5 200 3.1 3.1 3.1 Acinetobacter 400 12.5 12.5 50 P. morganii 200 12.5 6.2 400 Klebsiella pneumoniae 6.2 25 25 50 E. coli 25 25 200 25 E. coli 100 3.1 25 25 S. sonnei 1.6 12.5 3.1 100 C. freundii 3.1 1.6 6.3 12.5 S. typhi All of the isolates and cephalothin MIC values of >400 ,tg/ml. a
Citrobacter
I
Serratia
I
Serratia
I
Providencia
I
0 (400) 0 (100)
I
76
0
0
(400)
(100)
0 0
(50) 0 (3.1)
31
0
(3.1)
(1.6)
44
0
(0.8) 77 (6.3)
(1.6) 0 (3.1)
E. coli
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Klebsiella
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0
75
V
(25) 0 (1.6)
(200) 0 (1.6)
0
25
Shigella Salmonella
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0 (400) 0 (6.3)
(400) (100) Acinetobacter
0 (100) 0 (12.5)
0
(1.6) 0 (6.3) 0
(1.6) 0 S. aureus (3.1) a Hydrolysis of cephaloridine was set at 100%. A spectrophotometric assay was used. Values in parentheses are MICs of the individual isolates, in micrograms per milliliter. (25) 0 (0.8)
(3.1) 0 (0.2)
212
NEU AND FU
pared to many of the ,B-lactamases found in the Enterobacteriaceae, this stability failed in many situations to correlate with in vitro activity. Cefatrizine was more stable to ,B-lactamase hydrolysis than was cefamandole. It was less active than that compound against certain organisms. This has also been noted for cefoxitin, which is stable to all f8-lactamases but does not inhibit many Enterobacter and Citrobacter species. Cefatrizine has added to the overall activity of the cephalosporins against a number of the Enterobacteriaceae, albeit to a lesser degree than have other /)-lactamase-stable cephalosporins (3, 5, 7). Its gram-positive activity, on the other hand, is two- to eightfold greater than that of cephalexin. The clinical relevance of this will be difficult to demonstrate even with comparative trials since the MIC values of both compounds against gram-positive bacteria are well below readily achievable levels. LITERATURE CITED 1. Blackwell, C. C., E. H. Freimer, and G. C. Tuke. 1976. In vitro evaluation of the new oral cephalosporin cefatrizine: comparison with other cephalosporins. Antimi-
ANTIMICROB. AGENTS CHEMOTHER. crob. Agents Chemot.her. 10:288-292. 2. Leitner, F., R. E. Buck, M. Misiek, T. A. Pursiano, and K. E. Price. 1975. BLS 640, a cephalosporin with a broad spectrum of antibacterial activity: properties in vitro. Antimicrob. Agents Chemother. 7:298-305. 3. Neu, H. C. 1974. Cefamandole, a cephalosporin antibiotic with an unusually wide spectrum of activity. Antimicrob. Agents Chemother. 6:177-182. 4. Neu, H. C. 1974. Cefoxitin, a semisynthetic cephamycin antibiotic: antibacterial spectrum and resistance to hydrolysis by gram-negative beta-lactamases. Antimicrob. Agents Chemother. 6:170-176. 5. O'Callaghan, C. H., R. B. Sykes, A. Griffiths, and J. E. Thornton. 1976. Cefuroxime, a new cephalosporin antibiotic: activity in vitro. Antimicrob. Agents Chemother. 9:511-514. 6. Overturf, G. D., R. L Ressler, P. B. Marengo, and J. Wilkins. 1975. In vitro evaluation of BL-S640, a new oral cephalosporin antibiotic. Antimicrob. Agents Chemother. 8:305-310. 7. Richmond, M. H., and R. B. Sykes. 1973. The 8-lactamases of gram-negative bacteria and their possible physiological role. Adv. Microb. Physiol. 9:314-8. 8. Stilwell, G. A., H. G. Adams, and M. Turck. 1975. In vitro evaluation of a new oral cephalosporin, cefatrizine (BL-S640). Antimicrob. Agents Chemother. 8:751-753. 9. Watanakunakorn, C., T. Bannister, and C. Glotzbecker. 1975. Susceptibility of clinical isolates of Enterobacteriaceae to BL-S640, a new oral cephalosporin. Antimicrob. Agents Chemother. 7:381-385.
