Aminothiazolyl oc-methoxyimino Cephalosporin

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1984, p /84/ $00/0 Copyright 1984, American Society for Microbiology Vol. 25, No. 6 In Vitro Evaluation of, a New Wide-Spectrum Aminothiazolyl oc-methoxyimino Cephalosporin RONALD N. JONES,l* CLYDE THORNSBERRY,2 AND ARTHUR L. BARRY3 Department of Pathology, Kaiser-Permanente Medical Care Program (Oregon Region), Clackamas, Oregon ; Centers for Disease Control, Atlanta, Georgia 3033; and The Clinical Microbiology Institute, Tualatin, Oregon Received 1 December 1983/Accepted March 1984 (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.) is a new, cyclical-pyridinium cephalosporin that appeared superior to numerous comparison drugs against 658 strains of aerobic and facultative anaerobic bacteria. Seventeen Enterobacteriaceae spp. were tested by broth microdilution methods, and the 50% MICs (MIC50s) and 90%o MICs (MIC90s) were to and to jxg/ml, respectively. Only one strain had an MIC >,ug/ml (99.6% is considered susceptible). inhibited 98% of Pseudomonas aeruginosa isolates at <,ug/ml, and the MIC90 for Acinetobacter spp. was,ug/ml. It was also very active against Pseudomonas spp. and Staphylococcus aureus (MIC90, jlg/ml) but marginally active against methicillin-resistant staphylococcal strains (MICgo, 1Lg/ml) and enterococcus (MIC90, jig/ml). Non-enterococcal streptococci had MIC50s ranging from 0.008,ug/ml for Streptococcus pyogenes to tg/ml for pneumococci. All MICs of against I-Jaemophilus and Neisseria spp. were s jig/ml (MIC50, to 0.008,ug/ml). poorly inhibited,b-lactamases and was very stable against 11 tested P-lactamases of plasmid (TEM, OXA, SHV-i, and PSE) and chromosomal (Kl, K14, P99) types. HR81O (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.) is a new 3'-pyridinium-substituted cephalosporin (Fig. 1). It has a 2,3-cyclopentenopyridine instead of the 3'- acetoxy group found on cefotaxime sodium, and the compound is produced as a sulfate salt. Preliminary reports by the manufacturers, Hoechst AG (Frankfurt, Federal Republic of Germany) and Roussel-tJCLAF (Paris, France), indicate that the compound has marked antimicrobial activity against Pseudornonas aeruginosa, Staphylococcus aureus, enterococci, and members of the family Enterobacteriaceae; it is stable to P-lactamases and penetrates to penicillinbinding protein target sites, with binding comparable to that of ceftazidime; and it is bactericidal, is primarily excreted in the urine, and has a prolonged serum half-life in the early animal studies (2, 4, 14, 22; K. Seeger, J. F. Chantot, W. Durckheimer, R. Kirrstetter, N. Klesel, R. Lattrell, M. Limbert, E. Schrinner, G. Seibert, and I. Winkler, Program Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 23rd, Las Vegas, Nev., absir. no. 336, '1983; R. Lattrell, J. Blumbach, W. Durckheimer, R. Kirrstetter, N. Klesel, W. Schwab, K. Seeger, G. Seibert, and M. Wieduwilt, 23rd ICAAC, abstr. no. 571, 1983; and N. Klesel, W. Durckheimer, R. Lattrell, M. Limbert, E. Schrinner, W. Schwab, K. Seeger, G. Seibert, and I. Winkler, 23rd ICAAC, abstr. no. 574, 1983). In this in vitro evaluation, we compare the antimicrobial activity of with that of new,b-lactams and also compare these results with those previously published for chemically similar drugs (1, 5-7, 10, 12, 20, 21). We also report the results of studies of P-lactamase stability, 1Blactamase inhibition by, and the effect of salt content in the medium on the MICs against methicillinresistant S. aureus strains. (This work was presented in part at the 23rd Interscience Conference on Antimicrobial Agents and Chemotherapy [R. N. Jones, A. L. Barry, and C. Thornsberry, Program * Corresponding author. 710 Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 23rd, Las Vegas, Nev., abstr. no ]). MATERIALS AND METHODS Antimicrobial agents. and cefotaxime were obtained from Hoechst-Roussel Pharmaceuticals, Inc. (Somerville, N.J.). The other reference antimicrobial agents were provided by the following firms: amikacin and dicloxacillin, Bristol Laboratories (Syracuse, N.Y.); azlocillin and mezlocillin, Miles Pharmaceuticals (West Haven, Conn.); aztreonam, E. R. Squibb & Sons (Princeton, N.J.); cefoperazone, Pfizer Inc. (New York, N.Y.); cefsulodin, Abbott Laboratories (North Chicago, Ill.); ceftazidime and nitrocefin, Glaxo Inc.. (Research Triangle Park, N.C.); and moxalactam and tobramycin, Eli Lilly Research Laboratories (Indianapolis, Ind.). Bacterial strains. Recent isolates, typical of current clinical strains, were collected from the microbiology laboratories at The Cleveland Clinic Foundation (Cleveland, Ohio), St. Francis Hospital (Wichita, Kans.), St. Vincent Hospital and Medical Center (Portland, Oreg.), Northwestern Memorial H4ospital (Chicago, Ill.), and the Kaiser-Permanente Health Care Program Regional Laboratory (Clackamas, Oreg.). These 658 isolates were distributed as follows: 255 Enterobacteriaceae (17 species), 96 gram-negative bacilli other than Enterobacteriaceae (8 species), 40 Haemophilus influenzae (20 1-lactamase-positive strains), 50 Neisseria gonorrhoeae (25 penicillin-resistant strains), 26 N. meningitidis, 80 S. aureus (30 methicillin-resistant strains), 25 coagulase-negative Staphylococcus spp., and 86 Streptococcus spp., including enterococci, pneumococci, and beta-hemolytic strains. Other stock strains tested included 10 organisms known to produce,b-lactamases (7-12, 18). Antimicrobial susceptibility and j-lactamase testing procedures. The MICs were determined by the broth microdilution methods described in more detail in previous publications (1, 7-12) and by the National Committee for Clinical Laboratory Standards (15). The inoculum contained ca. 5 x 105 CFU/ml, and the MIC was read as the lowest antimicrobial concentration completely inhibiting bacterial growth in a Downloaded from on May 2, 2018 by guest

2 VOL. 25, 1984 IN VITRO ACTIVITY 711 N C-CO-~NH H2N soch3 0 COOf8 H2S04 FIG. 1. Chemical structure of HR81O. well after to 20 h of incubation at 350C. 3-Lactamase screening tests were performed with nitrocefin reagent in microdilution trays (17). The short-term P-lactamase hydrolysis analysis (15 to 20 min) were performed on a scanning UV spectrophotometer (model 552; Perkin-Elmer, Norwalk, Conn.) at the appropriate wavelength (AEmax) for each,-lactam. These cephalosporin and related substrates were diluted in M phosphate buffer (ph 7.0) to a final concentration of 10-4 M (100,iM) in a -ml total volume at 37 C. Reaction mixtures were monitored for a maximum of 15 to 20 min in a continuous wavelength mode (7-10, 12). Inhibition studies were performed in a centrifugal fast analyzer (CentrifiChem 400; Union Carbide Corp., Tarrytown, N.Y.) at a final volume of ml, under the conditions described above. The reaction mixtures consisted of a labile 1-lactam substrate (nitrocefin) combined with four or five log10 dilutions (0.1 to 1,000,uM) of each P-lactam or control drug used as an inhibitor. These and other inhibition test methods have been described previously (7-10, 12). The 10 3-lactamase enzyme preparations were made by methods described before (7-10) from organisms known to produce various Richmond-Sykes types of P-lactamase (19). A single commercially prepared penicillinase (BBL Microbiology Systems, Cockeysville, Md.) derived from Bacillus cereus was also studied. Cell membrane permeability by and some reference,b-lactams were determined with the strains and procedures of Richmond et al. (18). Escherichia coli DCO and DC2 were obtained from E. Schrinner, Hoechst AG. The MICs of each strain were determined by the broth microdilution method on at least five occasions, and geometric means were calculated. The permeability index was the ratio of the genometric mean MIC of strain DCO to that of mutant DC2. An index of would represent maximal permeability, with higher indexes indicating lesser degrees of cell membrane permeability. RESULTS The antimicrobial activity of against 255 Enterobacteriaceae isolates is compared with that of eight other broad-spectrum parenteral antimicrobial agents in Table 1. The 50% MICs (MIC50s) for all 17 tested species ranged from 0.015,ug/ml for Proteus mirabilis to,ug/ml for Proteus vulgaris; 10 of the 15 listed species had an MIC50 of <,u/ml. All 90% MICs (MIC90s) were below,ug/ml, except for Proteus vulgaris (MIC90,,ug/ml). Since only one strain had an MIC of > jig/ml, 99.6% of the strains were considered susceptible. was the most potent of the new,3-lactams tested against Citrobacter, Enterobacter, Morganella, and Serratia spp. and occasionally cefotaxime or ceftazidime were the most active new agents against the other enteric bacilli, especially Proteus mirabilis, Proteus vulgaris, and some Providencia spp. Several species had a >10% incidence of resistance to the acylamino penicillins (azlocillin and mezlocillin) and one of the tested aminoglycosides, tobramycin. Table 1 also shows the results for 96 Acinetobacter and Pseudomonas strains. was compared with the same eight drugs indicated above and was found to be most similar to ceftazidime. and ceftazidime were the most active,b-lactams against Acinetobacter calcoaceticus subsp. anitratus and had the same activity as the two aminoglycosides in total coverage of the strains at drug concentrations achievable in vivo. All of the comparison drugs were active against this generally carbenicillin- and aminoglycosidesusceptible population of Pseudomonas aeruginosa. The rank order of 1-lactam activity against these strains based on MIC50 values was ceftazidime > aztreonam > (MIC50, pug/ml) = azlocillin > cefoperazone = cefotaxime = mezlocillin. Based on MIC90s, the rank order of activity is only slightly different with ceftazidime > aztreonam > = cefoperazone = azlocillin > cefotaxime = mezlocillin. Eighty-six percent of Pseudomonas aeruginosa strains had MICs.,ug/ml and 98% had MICs < pug/ml. was most comparable to aztreonam against the more rarely isolated Pseudomonas spp. Only three Pseudomonas species had MICs -,ug/ml: P. acidovorans (one strain), P. cepacia (three strains), and P. maltophilia (two strains). Only 14 strains had an MIC. pg/ml against the 351 gram-negative bacilli (Table 1). Of the 14 strains, the MICs of 9 were at jiglml, 2 each were at and,g/ml, and a Pseudomonas cepacia strain was at 256,ug/ml. The comparative activity of against H. influenzae and Neisseria spp. is summarized in Table 2. Like other new cephalosporins and monocylic,-lactams, had very low MICs against H. influenzae. No significant difference in the MIC50 or MIC90 was observed between the 1- lactamase-producing and nonproducing isolates, in contrast to azlocillin and mezlocillin which demonstrated a 128- to -fold shift in the MIC%0 results because of enzyme instability. was similarly very active against Neisseria spp., with all MIC50s.0.004,ug/ml. The aminoglycosides were not effective against the meningococci, and ampicillin was not active on penicillinase-producing N. gonorrhoeae strains. MICs for the tested Staphylococcus spp. and Streptococcus spp. are presented in Tables 3 and 4. S. aureus and coagulase-negative Staphylococcus spp. were more susceptible to than to any other cephalosporin tested. The MIC50s and MIC90s were most comparable to those reported for old cephalosporins, such as

3 712 JONES, THORNSBERRY, AND BARRY ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. In vitro activity of and eight other antimicrobial agents against members of the family Enterobacteriaceae, and Pseudomonas and Acinetobacter spp. Antimicrobial MIC range MIC50 MIC90 Organism (no. tested) agent (Lg/ml) (4g/ml) (p.g/ml) Acinetobacter calcoaceticus subsp. anitratus (15) '- Citrobacter diversus (10) Citrobacterfreundii (10) Enterobacter aerogenes (20) Enterobacter agglomerans (10) ' so <O s- - - <O.12 so.06 Enterobacter cloacae (20) - _ Escherichia coli (25) Continued on following page

4 VOL. 25, 1984 Klebsiella spp. (24) Morganella morganii (10) Proteus mirabilis (25) Proteus vulgaris (10) Providencia rettgeri (10) Providencia stuartii (20) Pseudomonas aeruginosa (50) IN VITRO ACTIVITY 713 TABLE 1-Continued Antimicrobial MIC range MIC50 MICgo agent (~Lg/ml) (,ug/ml) (,ug/ml) - Aziocillin <- - ' < ' '- - < t '- so.12- : < ' ' _ < Continued on following page

5 714 JONES, THORNSBERRY, AND BARRY ANTIMICROB. AGENTS CHEMOTHER. TABLE 1-Continued Organism (no. tested) Antimicrobial agent MIC range (>g/ml) MIC50 (>Lg/ml) MICgo (p.g/ml) - - Pseudomonas spp. (31)' > > Mezlocilin > > - Salmonella enteriditis () - -> Serratia marcescens (25) ' Shigella spp. (20) <- < a Includes P. acidovorans (2 strains), P. cepacia (6 strains), P. fluorescens (5 strains), P. maltophilia (3 strains), P. putida (5 strains), and P. stutzeri (10 strains). TABLE 2. In vitro activity of and nine other antimicrobial agents against H. influenzae and Neisseria spp. Antimicrobial MIC range MIC50 MIC90 Organism (no. tested) agent (pg/ml) (p.g/ml) (pg/ml) H. influenzae Ampicillin susceptible (20) '. ' '- ' ' c.... c - - Ampicillin resistant (20) '- ' ' ' '. ' ' 4.5 <- 128 s- - - N. gonorrhoeae Penicillin susceptible (25) < < < Ampicillin '- < Penicillin resistant (25) s < < Ampicillin <- N. meningitidis (26) Continued on following page

6 VOL. 25, 1984 IN VITRO ACTIVITY 715 Organiism(no. tested) TABLE 2-Continued Antimicrobial MIC range MIC50 agent (qg/ml) (>g/ml) MlCgo (jig/ml) s s <: s s --O.5 so s< so so -< -> - TABLE 3. In vitro activity of and eight other antimicrobial agents against Staphylococcus and Streptococcus spp. Organism (no. tested) Antimicrobial agent MIC range (,Ig/ml) MIC50 (pkg/ml) MIC90 (p.g/ml) Staphylococcus aureus Methicillin and penicillin susceptible (24) Methicillin susceptible and penicillin resistant (26) Methicillin resistant (30) Staphyloccoccus spp. Coagulase negative (25)a Streptococcus faecalis (26) Streptococcus pneumoniae (20) Meziocillin <- < A > - - so.5- s- - _b > - - s-128 <- - _ > - - '- - -> '- r - <: <: > -< > > <O.5 > < Continued on following page

7 7 JONES, THORNSBERRY, AND BARRY ANTIMICROB. AGENTS CHEMOTHER. TABLE 3-Continued Organism (no. tested) Antimicrobial MIC range MICs MICgo agent (,ug/ml) (.g/ml) (,ug/ml) - so-.5- so s- s -O.5 -> > - Streptococcus pyogenes (20) so.12 < so.12 - <- O s so.5- O c -> > > - Streptococcus agalactiae (20) so.5 O s < < so.5 > > > - a The 25 strains include 19 that produce detectable penicillinase. cephalothin, cefazolin, and cefamandole. All other thirdgeneration cephalosporins had MIC50s ranging from to jlg/ml against S. aureus. had no grampositive antimicrobial activity. was the most active cephalosporin tested against the enterococci, including S. faecalis. The highest MIC was p.g/ml, with an MIC50 and mode MIC of jig of per ml. was also very active against the beta-hemolytic streptococci (MIC50, to 0.008,ug/ml) and pneumococci (MIC50, jig/ml). Strains of streptococci relatively-resistant to penicillin (MICs > to,ug/ml) also had higher and thirdgeneration cephalosporin MICs. The methicillin-resistant S. aureus strains (Tables 3 and 4) generally had MICs - to -fold higher than their methicillin-susceptible counterparts. The addition of 2% NaCl to the Mueller-Hinton broth medium elevated the MICs by two- to fourfold and narrowed the range of MICs to only three log2 dilution steps. was found to be very stable to 11 commonly encountered bacterial 3-lactamases (Table 5). The hydrolysis rates compared with those of cephaloridine and nitrocefin and were most similar to ceftazidime and moxalactam. Only cefoperazone showed a slightly higher rate against TEM-1 and TEM-2 plasmid-mediated type III enzymes. The TABLE 4. Effects of salt (2% NaCl) in Mueller-Hinton broth on the antimicrobial activity against methicillin-resistant S. aureus isolatesa NaCl (2%) Cumulative % strains inhibited at MIC (Lg/ml) of: added < aincubated at 350C for 24 h. differences among these drug hydrolysis rates seem insignificant, and all five of these newer cephalosporins must be considered enzyme-stable 1-lactams. The P-lactamase hydrolysis inhibition data in Table 6 show that, cefsulodin, and ceftazidime are generally poor inhibitors (i.e., have low affinity) of both chromosomal and plasmid-mediated enzymes. Repeated studies with the type I cephalosporinase (P99) failed to show significant inhibition by, a common characteristic of other enzyme-stable cephalosporins. was again demonstrated to be the most inhibitory cephalosporin with high affinity for P99, Kl, K14, PSE-1, and B. cereus 1-lactamases. Dicloxacillin was also a good inhibitor. The ability of to penetrate into the E. coli periplasmic space was determined by the method of Richmond et al. (18). The permeability index of was, which was identical to the best control indices calculated for cephaloridine and cefoxitin. DISCUSSION The newer P-lactamase-stable cephalosporins and other,blactams appear to have found a significant place in modem chemotherapy of serious infections. Several reviews cite major therapeutic advantages over the earlier 3-lactam compounds and some combination regimens in which potentially toxic, expensive drugs from other antimicrobial classes were used (3, ). We found to be similar in vitro to previously studied potent antimicrobial agents, such as the aminothiazolyl cephalosporins (1, 5-12, 20), cefoperazone (1, 8), moxalactam (1, 5, 21), and aztreonam (20). However, we additionally cite several spectrum features that would favor over these previously studied drugs, i.e., better antistaphylococcal activity, better activity against all Streptococcus spp., including the enterococci, greater coverage of the Enterobacteriaceae resistant to other P-lactamase-stable,B-lactams (4, 22), and a spectrum of antimicrobial activity

8 VOL. 25, 1984 IN VITRO ACTIVITY 717 TABLE 5. P-lactamase hydrolysis rates of compared with those of six other cephalosporins Organismn (,-lactamase) Hydrolysis rate of RHR compared with nitrocefina cephaloridine iamlminb RHRa Cefsulodin Moxalactam E. cloacae (P99) <0.1 < K. oxytoca (K1) <0.1 K. oxytoca (K14) E. coli (TEM-1) <0.1 E. coli (TEM-2) E. coli (OXA-1) 2.7 < < E. coli (OXA-2) E. coli (SHV-1) P. aeruginosa (PSE-1) < < < P. aeruginosa (PSE-2) < < < B. cereusc a RHR, Relative hydrolysis rate compared with that of nitrocefin, expressed as a value of 100%. The P-lactamase hydrolysis was determined by the UV spectrophotometric method at 258 to 482 nm at 37 C. Reaction mixtures were at a volume with ml of 10-4 cephalosporin substrate in 0.05 M phosphate buffer at ph 7. b,um/min per ml of partially purified P-lactamase preparation. c NT, Not typed (commercial penicillinase from B. cereus). against the nonfermentative gram-negative bacilli, combining the best features of the aminoglycoside and.,l-lactams, such as aztreonam, cefoperazone, and ceftazidime. Specifically, the MICs for the staphylococci most resemble cephalothin, cefazolin, and cefamandole, with an MIC50 of,ug/ml, which is identical to that of previous reports (2, 14). The methicillin-resistant S. aureus strains had MICs that were lowest among the cephalosporins (MIC90,,ug/ml). Although Klesel et al. (23rd ICAAC, abstr. no. 574) reported responses in animals infected with methicillin-resistant S. aureus cells treated with modestly elevated doses, the use of therapeutically for methicillin-resistant staphylococci must await its application to more animal models and human clinical trials. Similarly, coagulase-negative staphylococci have emerged as a therapeutic problem in some medical centers (13). Currently, the drug of choice remains vancomycin, with or without additional non-,-lactam antimicrobial agents such as rifampin (23). TABLE 6. Inhibition of P-lactamase hydrolysis of nitrocefin by equimolar concentrations of and comparison I3-lactamsa Nitrocefin RHR combined with': Organism (3-lactamase) R81 Cefo- Cef- Ceftaz- Diclox- Moxa- HR81 perazone sulodin idime acillin lactam E. cloacae (P99) <1 <1 E. coli (OXA-2) E. coli (TEM-1) E. coli (TEM-2) E. coli (SHV-1) K. oxytoca (K1) K. oxytoca (K14) P. aeruginosa (PSE-1) P. aeruginosa (PSE-2) B. cereus a The reference P-lactamase-labile substrate (nitrocefin) concentration was 10-4 M in 0.05 M phosphate buffer (ph 7) combined with inhibiting,3-lactam. b RHR, Relative hydrolysis rate compared with that of nitrocefin and added P-lactamase, expressed as a value of 100%.,B-lactamase hydrolysis was determined by a centrifugal fast analyzer at 482 nm at 37 C. Reaction mixtures contained five different concentrations of inhibitor drug, ranging from 0.1 to 1,000% that of the nitrocefin substrate concentration. The enterococcal MICs (MIC90,,ug/ml) suggest that might prevent or suppress the development of superinfections and might possibly be therapeutic in some cases, such as urinary tract infections. Certainly was the most potent cephalosporin against all Streptococcus spp. (2, 14), and clinical use awaits in vivo results. The gram-negative spectrum of was significantly superior to all other reference drugs tested. The Enterobacteriaceae strains resistant to third-generation cephalosporins were not always resistant to (usual MICs were ' pug/ml for Citrobacter and Enterobacter spp.). This may be explained by better penetration into the periplasmic space (22) or by the lower affinity of for the type I cephalosporinases compared with similar cephalosporins (Table 6) (4, 14, 22). We must agree with Tolxdorff-Neutzling and Wiedemann that the rate of enzyme hydrolysis of a I8- lactam may have been "over-valued" and that the binding competition (affinity) for the penicillin-binding proteins and the affinity of drugs for the,b-lactamase enzymes may be more important determinations of resistance (22). By whatever mechanism, inhibited 463 of 468 (98.9%) gramnegative bacteria at ',ug/ml. The activity of against anaerobes appears to be comparable to cefotaxime (H. C. Neu, T. Kumada, N. Chin, and P. Labthavikul, Program Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 23rd, Las Vegas, Nev., abstr. no. 572, 1983). We consider a very promising parenteral cephalosporin, expanding the gram-negative spectrum of thirdgeneration cephalosporins and providing more potent activity against the commonly isolated gram-positive species. Further studies are necessary in the areas of toxicology and human pharmacokinetics. ACKNOWLEDGMENTS We thank Barbara Beardsley and Jane Benson for word processing and R. R. Packer and Harold Wilson for their technical support. LITERATURE CITED 1. Baker, C. N., C. Thornsberry, and R. N. Jones In vitro antimicrobial activity of cefoperazone, cefotaxime, moxalactam (LY127935), azlocillin, mezlocillin, and other P-lactam antibiotics against Neisseria gonorrhoeae and Haemophilus influenzae, including P-lactamase-producing strains. Antimicrob. Agents Chemother. 17:

9 718 JONES, THORNSBERRY, AND BARRY 2. Bauernfeind, A Susceptibility of gram-positive aerobic cocci to the new cephalosporin. Eur. J. Clin. Microbiol. 2: Brooks, G. F., and S. L. Barriere Clinical use of the new beta-lactam antimicrobial drugs. Ann. Intern. Med. 98: Cullpian, W., W. Opferkuch, and M. Stieglitz Relation between beta-lactamase production and antimicrobial activity: comparison of the new compound with cefotaxime. Eur. J. Clin. Microbiol. 2: Fu, K. P., and H. C. Neu The comparative beta-lactamase resistance and inhibitory activity of 1-oxa cephalosporin, cefoxitin and cefotaxime. J. Antibiot. : Fu, K. P., and H. C. Neu Antibacterial activity of ceftizoxime, a P-lactamase-stable cephalosporin. Antimicrob. Agents Chemother. 17: Fuchs, P. C.-, R. N. Jones, C. Thornsberry, A. L. Barry, E. H. Gerlwh, and H. M. Sommers Cefmenoxime (SCE-1365), a new cephalosporin: in vitro activity, comparison with other antimicrobial agents, beta-lactamase stability, and disk diffusion testing with tentative interpretive criteria. Antimicrob. Agents Chemother. 20: Jones, R. N., and A. L. Barry sodium: a review of the in vitro characteristics, antimicrobial spectrum, beta-lactamase stability and enzyme inhibition. Rev. Infect. Dis. 5(Suppl.):S Jones, R. N., A. L. Bariy, C. Thornsoerry, E. H. Gerlach, P. C. Fuchs, T. L. Gavan, and H. MI. Sommers , a pseudomonas-active cephalosporin: in vitro antimicrobial activity evaluation including recommendations for disc diffusion susceptibility tests: J. Antimicrob. Chemother. 8(Suppl. B): Jones, R. N., A. L. Barry, C. Thornsberry, and H. W. Wison In vitro antimicrobial activity evaluation of cefodizime (HR221), a new semisynthetic cephalosporin. Antimicrob. Agents Chemother. 20: Jones, R. N., and C. Thornsberry (HR756): a review of the in vitro antimicrobial properties and spectrum of activity. Rev. Infect. Dis. 4(Suppl.):S Jones, R. N., and H. W. Wilson Antimicrobial activity, beta-lactamase stability and betg-lactamase inhibition comparisons of 7-alpha-methoxy beta-lactam 'antimicrobials: cefotetan AN,TIMIC40B. AGENTS CHEMOTHER. (YM09330), cefoxitin and moxalactam. Diagn. Microbiol. Infect. Dis. 1: Karchmer, A. W., G. L. Archer, and W. E. Dismukes Staphylococcus epidermidis causing prosthetic valve endocarditis: microbiologic and clinical observations as guides to therapy. Ann. Intern. Med. 98: Machka, K., and I. Braveny In vitro activity of HiR810, a new broad-spectrum cephalosporin. Eur. J. Clin. Microbiol. 2: National Committee for Clinical Laboratory Standards Standard methods for dilution antimpicrobial susceptibility tests for bacteria which grow aerobically. Tentative standard, M7-T. National Committee for Clinical Laboratory Standards, Villanova, Pa.. Neu, H. C The new beta-lactamase-stable cephalosporins. Ann. Intern. Med. 97: O'Callagian, C. H., A. Morris, S. M. Kirby, and A. H. Shingler Novel method for detection of 0-lactamases by using a chromogenic cephalosporin substrate. AntimicrQb. Agents Chemother. 1: Richmond, M. H., D. C. Clark, and S. Wotton Indirect method for assessing the penetration of beta-lactamase-nonsusceptible penicillins and cephalosporins in Esclrerichia coli strains. Antimicrob. Agents Chemother. 10: Ichmond, M. H., and R. B. Sykes The beta-lactamases of gram-negative bacteria and their possible physiological role. AdV. Microb. Physiol. 9: Shannon, K., A. King, C. Warren, and 1. Phillips In vitro antibacterial activity and susceptibility of the cephalosporin Ro to beta-lactamases. Antimicrob. Agents Chemother. 1$: Sykes, R. B., D. P. Bonner, K. Bush, N. H. Georgopspadakou, and J. S. Wells Monobactams: monocyclic P-lactam antibiotics produced by bacteria. J. Antimicrob. Chemother. 8(Suppl. E): Tolxdorff-Neutzling, R. M., and B. Wiedemann , a cephalosporin with low affinity for Enterobacter cloacae betalactamase. Eur. J. Clin. Microbiol. 2: Watanakunakern, C Treatment of infections due to methicillin-resistant Staphylococcus aureus. Ann. Intern. Med. 97:

10 AUTHOR'S CORRECTION In Vitro Evaluation of, a New Wide-Spectrum Aminothiazolyl ol-methoxyimino Cephalosporin RONALD N. JONES, CLYDE THORNSBERRY, AND ARTHUR L. BARRY Department of Pathology, Kaiser-Permanente Medical Care Program (Oregon Region), Clackamas, Oregon 97015; Centers for Disease Control, Atlanta, Georgia 30333; and The Clinical Microbiology Institute, Tualatin, Oregon Volume 25, no. 6, p : The activity of has been reported previously (Seibert et al., Arzneim. Forsch. 33: , 1983; Seibert et al., Infection 11: , 1983; Klesel and Seeger, Infection 11:318-1, 1983). The authors and the editor regret the omission of these citations. 949