Multicenter Comparison of In Vitro Activities of FK-037, Cefepime, Ceftriaxone, Ceftazidime, and Cefuroxime

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ANTIMICROBiAL AGENTS AND CHEMOTHERAPY, Aug. 3, p. 6-66-/93/6-5$./ Copyright 3, American Society for Microbiology Vol. 3, No. Multicenter Comparison of In Vitro Activities of,,,, and J. A. WASHINGTON,"* R.

1 ANTIMICROBiAL AGENTS AND CHEMOTHERAPY, Aug. 3, p /93/6-5$./ Copyright 3, American Society for Microbiology Vol. 3, No. Multicenter Comparison of In Vitro Activities of,,,, and J. A. WASHINGTON,"* R. N. JONES, E. H. GERLACH,3 P. R. MURRAY, S. D. ALLEN,s AND C. C. KNAPP Foundation, Clinics, 95; Iowa City, Iowa 5; St. Francis Regional Medical Center, Wichita, Kansas 63; Washington University Medical Center, St. Louis, Missouri 63; and Indiana University Medical Center, Indianapolis, Indiana 635 Received 3 February 3/Accepted June 3 In a multicenter study, the MICs of for 9%o of the strains tested (MIC9s) were <,ug/ml for members of the family Enterobacteriaceae other than Citrobacter freundii, Enterobacter spp., and Serratia marcescens. Activity against Pseudomonas aeruginosa was variable, with a MIC5 and a MIC, of and 3,ug/ml, respectively. Relative to cefepime, however, was less active against ceftazidime-resistant isolates of Enterobacter cloacae. The MIC, of for methicillin-resistant staphylococci was,ug/ml. is a novel injectable oxime-type cephalosporin antibiotic with a -hydroxyethyl-5-aminopyrazole moiety at the three position (5). Data presented in abstracts in and suggested that was more active than currently available extended-spectrum cephalosporins against staphylococci, including methicillin-resistant strains (5,, 5); however, at four times its MIC, reduced the number of CFU of methicillin-resistant Staphylococcus aureus by only order of magnitude while vancomycin reduced the number of CFU by over 3 orders of magnitude in killing curve studies (). In studies by Neu et al. (), 6,ug of per ml inhibited 5% of the S. aureus isolates tested with oxacillin MICs of,ug/ml. has also been reported to have a broad spectrum of activity against gram-negative bacilli, including members of the family Enterobacteriaceae and Pseudomonas aeruginosa, and to be active against many ceftazidime-resistant isolates of Citrobacter spp., Enterobacter spp., and P. aeruginosa (, -,, 3, 6). Fu et al. (), Neu et al. (), and Nishino et al. (5) have also demonstrated the activity of this compound against isolates of streptococci, including beta-hemolytic groups and Streptococcus pneumoniae, and Haemophilus influenzae. has also been shown to be active against a variety of anaerobic bacteria other than the Bacteroides fragilis group (9). Neu et al. () found that the MICs of for 9% of the strains tested (MIC%s) in the family Enterobacteriaceae were similar to those of cefepime and lower than those of ceftazidime and imipenem but that resistant mutants of Enterobacter cloacae, Citrobacter freundii, and S. aureus could be selected by daily transfer in the presence of. The current study was undertaken to examine the activity of in comparison with those of cefepime, ceftriaxone, ceftazidime, and cefuroxime against clinical isolates of gram-negative and gram-positive bacteria from five different medical centers. The five laboratories participating in the study were Barnes Hospital and Washington University Medical Center, St. Louis, Mo.; The Cleveland Clinic Foundation, Cleveland, Ohio; Indiana University Medical Center, Indianapolis, Ind.; St. Francis Regional Medical Center, * Corresponding author. Wichita, Kans.; and the University of Iowa Hospitals and Clinics, Iowa City, Iowa. Each laboratory tested approximately, recent clinical isolates against (R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J.), cefepime (Bristol-Myers Squibb Company, Princeton, N.J.), ceftriaxone (Hoffmann-La Roche, Inc., Nutley, N.J.), and cefuroxime sodium (Eli Lilly & Company, Indianapolis, Ind.). Microdilution trays containing each of these antibiotics were prepared by Prepared Media Laboratories, Tualatin, Oreg., and distributed to each participating laboratory for testing. Susceptibility tests were performed in accordance with guidelines published by the National Committee for Clinical Laboratory Standards (3). The test results of 3, gram-negative bacteria are presented in Table. The MIC9s of and cefepime were ',ug/ml for Citrobacter diversus, Escherichia coli, Klebsiella oxytoca, K pneumoniae, Morganella morganii, Proteus mirabilis, P. vulgaris, Providencia rettgeri, Serratia spp., and miscellaneous members of the family Enterobacteriaceae other than C. freundii, Enterobacter spp., and Serratia marcescens. was times more active than ceftazidime and times more active than cefuroxime, on the basis of their MIC%s, against E. coli. Of interest was the finding of ceftazidime-resistant isolates of K oxytoca and K pneumoniae, suggesting the presence of extended-spectrum cephalosporinases among these populations. Eleven of these isolates were inhibited by < p,g of per ml ( isolates were inhibited by,g/ml, 6 were inhibited by,ug/ml, and 3 were inhibited by,ug/ml). Of the isolates, were inhibited by c,ug of cefepime per ml ( isolates were inhibited by,ug/ml, were inhibited by ug/iml, and were inhibited by,ug/ml). Among isolates of C. freundii, Enterobacter aerogenes, E. cloacae, Morganella morganii, and Serratia marcescens, which are frequently associated with the chromosomally mediated Bush group I,-lactamase and for which the MIC9s of ceftriaxone, ceftazidime, and cefuroxime were generally in excess of 6,ug/ml, the MIC9s of were,, 6,, and p,g/ml, respectively. In contrast, the corresponding MIC9s of cefepime were,,,.5, and p.g/ml, respectively. Closer examination of the MICs of and cefepime for ceftazidime-resistant isolates of E. cloacae demonstrated that cefepime was more active than. For example, 55% of these isolates were Downloaded from on June 9, by guest 6

2 VOL. 3, 3 NOTES TABLE. Activities of (ARC-), cefepime, ceftriaxone, ceftazidime, and cefuroxime against gram-negative clinical isolates from five medical centers MIC (p.g/ml) Organism(s) A * * * % with MIC of (no. of isolates) ntibiotic Range For 5% For 9% <,ug/ml of isolates of isolates Citrobacter diversus (5) Citrobacterfreundii (5) Enterobacter aerogenes (6) Enterobacter agglomerans (5) Enterobacter cloacae (3) Escherichia coli (,) Klebsiella oxytoca () Kebsiella pneumoniae (3) Morganella morganii (6) Proteus mirabilis (36) Proteus vulgaris () C.5-> <->6 <.5- - < >6 - - <.5->3 <.5- <->6 -.- <.5- - <-6 <.5- _- _.5->3 <.5- <->6 C.5- C- <.5- C C.5- C C.5-> 6 <-6 <.5- C- _.5->3 C.5-6 C->6 C.5- C- <.5-3 <.5- <-6 C.5- <- <.5- - <- <.5- C- <.5->3 <.5- <->6 <.5-6 < C.5..5 <.5. C.5 > >6...5 s <.5 <.5 < < <.5 >6 6 <.5 95 Continued on following page Downloaded from on June 9, by guest

3 NOTES ANTIMICROB. AGENTS CHEMOTHER. TABLE -Continued MIC (,ug/ml) Organism(s).. % with MIC of (no. of isolates) Antibiotic Range For 5% For 9% s pg/ml Providenci rettgeriof isolates Serratia marcescens () Serratia spp. () Other enteric bacillia (5) Acinetobacter baumanii (5) Acinetobacter iwoffii () Pseudomonas aeruginosa (65) Pseudomonas spp. (3) Xanthomonas maltophilia () Other nonenteric gramnegative organisms' () Moraxella catarrhalis () of isolates Pr-ovidencia rettgeni (5)..5- ' ' > 6 '-6 ' >3 - '->6 -> 6 '-> 6 '.5-6 -> > >3 '.5-.->6 -> 6 - ->3 -> 6 ->6 ' >3 -> 6 ->6 - '.5->3 -> 6 '->6 - ' '-.. 6 >3 6 >6 3 6 <.5 3 a Numbers of isolates: Citrobacter amalonaticus, ; Escherichia hennanii, ; Hafnia alvei, ; Enterobacter spp., ; Kluyvera spp., ; Proteus penneri, ; Providencia alcalifaciens, 3; Providencia stuartii, ; Salmonella Spp., ; Shigella spp., 5. b Numbers of isolates: Agrobacterium spp., 5; Aeromonas spp., ; Alcaligenes spp., 9; Achromobacter (Alcaligenes) xylosoxidans, 6; Bordetella bronchiseptica, ; Chrysomonas luteola, ; Flavobacterium meningosepticum, ; Oligella urethralis, ; Pasteurella multocida, ; Flavimonas oryizihabitans, >6 >3 >6 6 >3 >6 >3 > S Downloaded from on June 9, by guest

4 TABLE. Activities of (ARC-), cefepime, ceftriaxone, ceftazidime, and cefuroxime against gram-positive clinical isolates from five medical centers MIC (p.g/ml) % with Organism(s) (no. of isolates) Antibiotic For For MIC Range 5% of 9% of of s Staphylococcus aureus, oxacillin susceptible (56) Staphylococcus aureus, oxacillin resistant (9) Staphylococcus epidennidis, oxacillin susceptible (36) Staphylococcus epidennidis, oxacillin resistant () Staphylococcus haemolyticus () Undetermined Staphylococcus spp., coagulase negative () Staphylococcus spp. (6)a Streptococcus pyogenes ()b Streptococcus agalactiae (9) Enterococcus faecalis () Enterococcus spp. (5) _-.->3.5-> 6.5->6 - - ' > >3 - -> >3 -> 6.-> >3 - ->6 - r _ _- ->3 - ->6 - ->3.5-> 6.->6 - - isolates isolates ilg/m 6 >6.5 < 6 6 >6 6 < >6 3 >6 3 >6 _ >6 >6 > _. _ a Number of isolates: S. auricularis, ; S. capitis, 5; S. cohnii, 3; S. hominis, ; S. saprophyticus, 5; S. sciun, ; S. simulans, 5; S. warneri,. b The total number of isolates tested with ceftriaxone and cefuroxime was 5. 6 >3 >6 >3 > Downloaded from on June 9, by guest

5 NOTES inhibited by,g of cefepime per ml, in contrast to only % for. All but 5 (6%) of these isolates were inhibited by,g of cefepime per ml, whereas only 6% of these isolates were inhibited by p,g of per ml. Moreover, 9% of the ceftazidime-resistant isolates of E. cloacae had MICs of >3 ug/nml, whereas no ceftazidime-resistant E. cloacae isolate had a cefepime MIC of.3,ug/ml. With c,g/ml as a potential breakpoint for defining susceptibility to, the percentage of isolates of C. freundii, E. aerogenes, M. morganii, and S. marcescens susceptible to and cefepime was in excess of %; however, only 5% of E. cloacae isolates were inhibited by this concentration of, in contrast to the 9% of isolates of this species that were inhibited by jig of cefepime per ml. The MIC9s of, cefepime, and ceftazidime against Acinetobacter baumanii were identical at,ug/ml, and the percentage of isolates inhibited by these antibiotics was in excess of 9%, compared with only 5% inhibited by ceftriaxone. The activity of against Pseudomonas aeruginosa was more variable, with MIC5s and MIC9s of and 3,g/ml, respectively, compared with corresponding values of and 6,g of cefepime per ml and and,ug of ceftazidime per ml. The percentages of 65 P. aeruginosa isolates inhibited by,g of, cefepime, or ceftazidime per ml were 9,, and %, respectively. None of the cephalosporins tested was particularly active against isolates of Xanthomonas maltophilia. The activities of, cefepime, ceftriaxone, ceftazidime, and cefuroxime against, gram-positive bacteria are shown in Table. All of the cephalosporins tested were active against oxacillin-susceptible staphylococci; however, activity against oxacillin-resistant isolates was more variable, with MIC ranges extending from the lowest to above the highest concentrations tested. The MIC9,s of all of the cephalosporins tested against oxacillin-resistant S. aureus were greater than 6,ug/ml. The MIC9 of against oxacillin-resistant S. epidermidis was,ug/ml, in contrast to 6 p,g of cefepime per ml and jig/ml for the remaining cephalosporins. All of the cephalosporins tested were highly active against isolates of Streptococcus pyogenes and S. agalactiae. In conclusion, our data confirm and extend findings previously reported by others regarding the high level of activity of against Enterobacteriaceae species other than those characterized by Bush group I chromosomally mediated,-lactamase, such as C. freundii, Enterobacter spp., and P. aeruginosa. In the latter regard, has an activity in common with that of cefepime (3, 9), which has been shown to be usually active against isolates of species that are resistant to cefoperazone, cefotaxime, and ceftazidime (,, ). While was highly active against gram-positive bacteria, its activity against oxacillin-resistant staphylococci was variable, undoubtedly reflecting variabilities in the degree of heterogeneous expression of resistance to oxacillin among the isolates tested. This study was supported by a grant from the R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J. ANTIMICROB. AGENTS CHEMOTHER. REFERENCES. Eng, R. H. K., S. M. Smith, and C. E. Cherubin.. activity for methicillin-resistant Staphylococcus aureus as compared to cefazolin, methicillin, and vancomycin. Program Abstr. 3nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. 39, p... Fu, K. P., B. D. Folleno, S. C. Lafredo, J. M. LoCoco, and D. M. Isaacson. 3. In vitro and in vivo antibacterial activities of FK3, a novel parenteral broad-spectrum cephalosporin. Antimicrob. Agents Chemother. 3: Fung-Tomc, J., T. J. Dougherty, F. J. DeOrio, V. Simich- Jacobson, and R. E. Kessler.. Activity of cefepime against ceftazidime- and cefotaxime-resistant gram-negative bacteria and its relationship to P-lactamase levels. Antimicrob. Agents Chemother. 33:9-5.. Goto, S., S. Higashi, S. Miyazaki, Y. Kaneko, and K. Yamaguchi.. FK3, a new parenteral cephalosporin: in vitro and in vivo antibacterial activity. Program Abstr. 3st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 56, p.. 5. Inoue, K., Y. Hamana, and S. Mitsuhashi.. In-vitro antibacterial activity of FK3, a new cephalosporin. Program Abstr. 3st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 5, p.. 6. Jones, R. N.. In vitro antimicrobial activity evaluations of FK3 (FK), a new broad-spectrum parenteral cephalosporin. Program Abstr. 3nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. 39, p... Jones, R. N., M. S. Barrett, and M. E. Erwin. Spectrum and antibacterial activity of, a new parenteral cephalosporin. Submitted for publication.. Jones, R. N., and P. C. Fuchs.. Activity of cefepime (BMY-) and cefpirome (HR ) against gram-negative bacilli resistant to cefotaxime or ceftazidime. J. Antimicrob. Chemother. 3: Kato, N., H. Kato, Y. Tanaka, K. Bando, K. Watanabe, and K. Ueno. 3. Activity of FK3, a new parenteral cephalosporin, against anaerobic bacteria. Antimicrob. Agents Chemother. 3:95-.. Knapp, C. C., and J. A. Washington.. Activity of cefepime, ceftazidime, and ceftizoxime against mutants of Enterobacteriaceae and Pseudomonas aeruginosa derepressed for class I P-lactamase. J. Antimicrob. Chemother. :-.. Mine, Y., Y. Watanabe, H. Sakamoto, K. Hatano, T. Kamimura, F. Matsumoto, and S. Kuwahara.. FK3, a novel parenteral broad-spectrum cephalosporin: I. In vitro antibacterial activity. Program Abstr. 3st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 9, p... Mine, Y., Y. Watanabe, H. Sakamoto, T. Kamimura, F. Matsumoto, and F. Kuwahara.. FK3, a novel parenteral broad-spectrum cephalosprin. III. Excellent activity against methicillin-resistant staphylococci. Program Abstr. 3st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 5, p.. 3. National Committee for Clinical Laboratory Standards.. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, nd ed. Approved standard. NCCLS document M-A, National Committee for Clinical Laboratory Standards, Villanova, Pa.. Neu, H. C., N.-X. Chin, and H.-B. Huang. 3. In vitro activity and P-lactamase stability of, a parenteral cephalosporin. Antimicrob. Agents Chemother. 3: Nishino, T., M. Otsuki, and Y. Nishihara.. In vitro and in vivo antibacterial activities of FK3, a new broad-spectrum cephalosporin. Program Abstr. 3st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 5, p.. 6. Yokota, T., and E. Suzuki.. A new, improved, parenteral cephem antibiotic-fk3, its in vitro antibacterial activity. Program Abstr. 3st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 53, p.. 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Most common dose (mg) 1g x 1 1g x 1 1g x 1 1g x 1 1g x 1 1g x 1. Maximum dose schedule (mg) 1g x 1 1g x 1 1g x 1 1g x 1 1g x 1 1g x 1

Most common dose (mg) 1g x 1 1g x 1 1g x 1 1g x 1 1g x 1 1g x 1. Maximum dose schedule (mg) 1g x 1 1g x 1 1g x 1 1g x 1 1g x 1 1g x 1 Ertapenem Rationale for the EUCAST clinical breakpoints, version 1.3 1 st June 2009 Introduction Ertapenem is a carbapenem, available only for parenteral use. Ertapenem is relevant for therapy of septicaemia,