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In Vitro Activity of Loracarbef (LY163892)

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University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 1991-07-01 In vitro activity of loracarbef (LY163892), a new oral carbacephem antimicrobial agent, against respiratory isolates of Haemophilus influenzae and Moraxella catarrhalis Gary V. Doern University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Medical Microbiology Commons Repository Citation Doern GV, Vautour R, Parker D, Tubert TA, Torres BB. (1991). In vitro activity of loracarbef (LY163892), a new oral carbacephem antimicrobial agent, against respiratory isolates of Haemophilus influenzae and Moraxella catarrhalis. Open Access Articles. Retrieved from https://escholarship.umassmed.edu/oapubs/ 191 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, JUlY 1991, P. 1504-1507 Vol. 35, No. 7 0066-4804/91/071504-04$02.00/0 Copyright C 1991, American Society for Microbiology In Vitro Activity of Loracarbef (LY163892), a New Oral Carbacephem Antimicrobial Agent, against Respiratory Isolates of Haemophilus influenzae and Moraxella catarrhalis GARY V. DOERN,* RAYMOND VAUTOUR, DOUGLAS PARKER, TRACEY TUBERT, AND BRENDA TORRES Department of Clinical Microbiology and Division ofInfectious Diseases, University of Massachusetts Medical Center, Worcester, Massachusetts 01655 Received 4 January 1991/Accepted 17 April 1991 The in vitro activity of a new orally administered carbacephem analog of cefaclor, loracarbef (LY163892), was compared with those of cefaclor and several other oral antimicrobial agents against recent clinical isolates of Haemophilus influenzae and Moraxella catarrhalis. Loracarbef was found to be slightly more active than cefaclor against H. influenzae and had activity essentially equivalent to that of cefaclor for M. catarrhalis. Resistance to loracarbef was uncommon and was noted only with rare ,l-lactamase-producing strains of H. influenzae. On the basis of these observations, loracarbef may be of utility in the management of localized, non-life-threatening infections caused by H. influenzae and M. catarrhalis. Loracarbef (LY163892) is a new orally administered car- ceptibility testing was performed in one laboratory (Univer- bacephem class antimicrobial agent in which the sulfur atom sity of Massachusetts Medical Center). of the dihydrothiazine ring of cefaclor has been replaced A broth microdilution MIC procedure was used to deter- with a carbon atom. The result of this substitution is that mine the MICs of 12 antimicrobial agents (3, 10). A final loracarbef is more stable in serum than is cefaclor. Loracar- volume of 100 ,u per well was used with a final inoculum size bef is the first carbacephem class beta-lactam antimicrobial of ca. 5 x 105 CFU/ml. Microdilution trays were incubated agent to undergo clinical development. Its chemical name is for 22 to 24 h at 35°C in ambient air prior to determination of (6R,7S)-7-[(R)-2-amino-2-phenylacetamido]-3-chloro-8-oxo- MICs. Haemophilus Test Medium broth prepared in-house 1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid monohy- was used for MIC determinations with both H. influenzae drate (C1604N3H16Cl H20). The molecular weight of lora- and M. catarrhalis (7). Extensive preliminary studies dem- carbef is 367.8. onstrated concordance between microdilution MIC results Since loracarbef will be marketed as an oral agent for obtained with M. catarrhalis when it was tested in Hae- use in the management of respiratory tract infections such mophilus Test Medium broth versus those when it was as acute otitis media, sinusitis, and bacterial bronchopul- tested in cation-adjusted Mueller-Hinton broth (unpublished monary infections (10a), and since, as a beta-lactam anti- data). microbial agent, its activity against 3-lactamase-producing The antimicrobial agents tested in this study were ob- organisms is of concern, the in vitro activity of loracarbef tained from their respective manufacturers as reagent-grade was assessed against Haemophilus influenzae and Moraxella powders. These included ampicillin (Bristol-Myers); amoxi- catarrhalis, two frequent causes of these infections which cillin-clavulanate (Smith-Kline Beecham); cephalothin, ce- often produce ,-lactamase. The in vitro activity of lora- faclor, and loracarbef (Lilly); cefuroxime (Glaxo); cefixime carbef was compared with those of several other com- (Lederle); chloramphenicol (Parke-Davis); trimethoprim and monly used oral antimicrobial agents: ampicillin, amoxicil- sulfamethoxazole (Hoffmann-LaRoche); and erythromycin lin-clavulanate, cefaclor, cefuroxime, cefixime, trimetho- (Abbott). The range of concentrations tested for each anti- prim-sulfamethoxazole, erythromycin, and the combination test strains yielded In cephalothin, chlor- microbial agent was such that most erythromycin-sulfisoxazole. addition, on-range MIC values, i.e., defined MICs rather than values amphenicol, and sulfisoxazole (alone) were also tested. tested. A total of 307 clinical isolates of H. influenzae and 146 less than or greater than the specific concentrations were examined. Isolates Five strains of H. influenzae, including ATCC 49247 and clinical isolates of M. catarrhalis ATCC 10211, were used as daily controls. Three strains of were obtained from patients in the United States who were in enrolled in multicenter clinical trials of loracarbef during M. catarrhalis, all previously extensively characterized 1989. The disease associations ofthe isolates and the number our laboratory, were also used as daily controls. P-Lacta- of study centers contributing strains are listed in Table 1. In mase production was assessed with all study isolates by use patients with otitis media, isolates were recovered from of a chromogenic cephalosporin assay (9) which used nitro- tympanocentesis fluid. Sinus aspirates were the source of cefin-impregnated filter paper disks (cefinase disks; Becton- isolates from patients with acute maxillary sinusitis. In Dickinson Microbiology Systems, Cockeysville, Md.). patients with acute bronchitis, acute purulent exacerbation All MIC determinations were performed twice on different of chronic bronchitis, or pneumonia, isolates were usually days, and the results were averaged to achieve an assigned obtained from expectorated sputa that had been judged to be MIC for a given organism-antimicrobial agent combination. on the basis of Gram-stained smears. All sus- When duplicate MICs varied by one twofold concentration satisfactory increment, the higher MIC was taken as the assigned MIC. Among a total of 3,684 duplicate MIC determinations with H. influenzae, the two results were the same or varied by * Corresponding author. one or two twofold concentration increments in 3,448 (94%), 1504 VOL. 35, 1991 NOTES 1505 TABLE 1. Description of sources of clinical isolates of used to define strains of H. influenzae as being susceptible, H. influenzae and M. catarrhalis 87 and 95% of ,B-lactamase-positive and -negative strains, were found to be loracarbef Use of No. of Disease No. of strains of: respectively, susceptible. an MIC of .8.0 ,ug/ml to define the susceptible category with study ting association H. influenzae M. catarrhalis loracarbef seems appropriate, insofar as this same criterion 15 Acute otitis media 105 (36, 34) 59 (54, 91) has been applied to cefaclor when tested against H. influ- 4 Acute maxillary sinusitis 17 (3, 18) 3 (3, 100) enzae (10). Furthermore, peak achievable levels of loracar- 74 Bronchitis 147 (28, 19) 84 (57, 68) bef in plasma are typically ca. twofold higher than this 6 Pneumonia 38 (5, 13) 0 breakpoint when the drug is administered orally in standard Total 307 (72, 23) 146 (114, 78) doses (i.e., 200 mg) (8). Of 73 ,B-lactamase-positive strains, a Numbers in parentheses refer to the number, percentage of strains that for 4 strains (6%) loracarbef MICs were -32 ,ug/ml, and were P-lactamase positive. thus, the strains would have been categorized as resistant. Loracarbef resistance was not noted with strains of H. influenzae that lacked P-lactamase. Among the cephalospo- 202 (5%), and 34 (0.9%) cases, respectively. With M. ca- rins tested, cephalothin and cefaclor had essentially compa- tarrhalis (1,752 duplicate MIC determinations), the following rable activities against H. influenzae. Both were slightly less was observed: no difference, 1,677 cases (96%); a difference active than loracarbef, which was, in turn, less active than of one dilution, 62 cases (3%); and a difference of two cefuroxime. Cefixime was clearly the most active of the dilutions, 13 cases (0.7%). cephalosporins tested against H. influenzae. As seen in As seen in Table 2, loracarbef was active against both Table 3, when compared on a strain-by-strain basis, lora- ,-lactamase-positive and -negative strains of H. influenzae. carbef MICs were typically about one twofold concentration The geometric mean loracarbef MICs for P-lactamase-posi- increment lower than the corresponding cefaclor MICs for tive and -negative strains of H. influenzae were 1.4 and 2.0 both ,-lactamase-positive and -negative strains of H. influ- ,ug/ml, respectively. If a loracarbef MIC of .8.0 ,ug/ml was enzae. TABLE 2. In vitro activities of loracarbef and other selected antimicrobial agents against
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