Activity of meropenem and other antimicrobial agents against uncommon Gram-negative organisms

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1 Journal of Antimicrobial Chemotherapy (993) 3, Activity of and other antimicrobial agents against uncommon Gram-negative organisms Richard B. Clark and Suzanne E. Joyce Department of Pathology, Crozer-Chester Medical Center, One Medical Center Blvd. Upland, PA 903, USA The in-vitro activity of and other antimicrobial agents was tested by agar dilution against 3 uncommon Gram-negative pathogens. Both and showed the most activity against the test isolates. The potency of was greater than against Pasteurella multocida, Eikenella corrodens, Haemophilus parainfluenzae, Moraxella spp., Kingella spp., and Actinobacillus actinomycetemcomitans. Further work is necessary to assess the invivo activity of against these Gram-negative isolates. Introduction Meropenem is an investigational carbapenem antibiotic with potent activity against a number of Gram-negative and Gram-positive species. This drug usually shows greater activity than against various Gram-negative organisms (Moellering, Eliopoulos & Sentochnik, 99). It is important to evaluate thoroughly the in-vitro activity of investigational compounds. In this study we assessed the activity of against a number of uncommon Gram-negative pathogens. Many of the isolates tested, including Cardiobacterium hominis, Eikenella corrodens, Pasteurella multocida, Kingella spp., and Actinobacillus actinomycetemcomitans, have caused serious human infections such as endocarditis, bacteraemia, empyema, and even brain abscesses (Wormser & Bottone, 93; Kaplan et at., 99; Morrison & Wagner, 99; Pickett, Hollis & Bottone, 99). In addition, organisms such as P. multocida and E. corrodens are commonly associated with wound infections produced by animal or human bites respectively (Goldstein & Citron, 9). Downloaded from at Pennsylvania State University on March 6, 06 Organisms Methods The following 3 Gram-negative bacteria were tested in this study: P. multocida (0 isolates), Moraxella spp. other than Moraxella calarrhalis (0) Kingella spp. 0), E. corrodens (7), Haemophilus parainfluenzae (), C. hominis (0), A. actinomycetemcomitans (9), Haemophilus aphrophilus (), and Haemophilus paraphrophilus (). Isolates were stored at 70 C in heat-inactivated horse serum and were identified by routine methods (Kilian, 99; Pickett et al., 99). 03O5-753/93/OO33 + $ The British Society for Antimicrobial Chemotherapy

2 3 R. B. Clark and S. E. Joyce Antibiotic susceptibility testing Antibiotic susceptibility studies were performed by the agar dilution method as outlined by the National Committee for Clinical Laboratory Standards (NCCLS, 990). The antibiotics were obtained from their manufacturers and used according to their instructions. Approximately 0 5 cfu of the test strains were spot inoculated with a multipoint inoculator on to Mueller-Hinton agar supplemented with 5% lysed horse blood and incubated at 35 C in 7% CO for h. The MIC was defined as the lowest concentration of drug that inhibited growth of the test organism. Single colonies or faint growth were disregarded. Antibiotic susceptibility breakpoint concentrations were as follows: mg/l, mg/l, mg/l, mg/l, mg/l, and mg/l. For the Haemophilus spp. only, a lower breakpoint ( mg/l) was also used. Control organisms used for this study included Pseudomonas aeruginosa ATCC 753, Escherichia coli ATCC 59, and Enterococcus faecalis ATCC 9. All isolates were tested for /Mactamase production by a commercial nitrocephin disc method (Cefinase, BBL Microbiology Systems, Cockeysville, MD). Discs which did not reveal a colour change from yellow to red within h at room temperature were considered negative. Results The Table shows MIC results of test drugs against the 3 Gram-negative isolates. Meropenem and showed the most potent activity against these strains. No resistance to either drug was observed. Less activity was observed with against these test isolates. Meropenem was up to 6-fold more potent than against P. multocida, E. corrodens, and H. parainfluenzae and was two to four-fold as active against the Moraxella spp., Kingella spp., and A. aclinomycetemcomilans. The activity of both carbapenems against C. hominis was similar. Resistance was observed to several test drugs including and. Most strains of P. multocida and E. corrodens were resistant to. Resistance to was common among the H. parainfluenzae and A. actinomycetemcomitans isolates. Ciprofloxacin showed potent activity against most of the test isolates; however, single isolates of moraxella and kingella were resistant to this drug. Only four strains of Moraxella spp. (two strains each of Moraxella non-liquefaciens and Moraxella phenylpyruvica) and two strains of H. parainfluenzae were /Mactamase positive as determined by the nitrocephin method. The and MICs of all six isolates were not significantly different from their /Mactamase negative counterparts. The /Mactamase producing M. phenylpyruvica and H. parainfluenzae strains were highly resistant to (MICs ^ 6 mg/l), whereas both /Mactamase producing M. non-liquefaciens remained susceptible to (MICs ^ mg/l). All other test species were negative for /Mactamase production by the nitrocephin method. Downloaded from at Pennsylvania State University on March 6, 06 Discussion The new investigational carbapenem,, showed excellent activity against the uncommon Gram-negative pathogens isolates tested in this study. Meropenem MICs were in most cases well below the susceptible concentration of mg/l. Imipenem also showed good activity against many of the test species, but was less active when

3 Activity of 35 Table. Antibiotic susceptibilities of various uncommon Gram-negative bacilli Organism (no.) Antibiotic Range MIC MIQo MIC*, % inhibited by breakpoint concentration" P. multocida (0) Moraxella spp (0) Kingella spp. (0) E. corrodens (7) H. parainfluenzae () C. hominis (0) Actinobacillus- Haemophilia spp. (^ O =3 0-0 sj * «S 000-3= 6 < < J < O-OO-O-O3 JS «c O-O5-O-O =$ O » 6 ^ - ^ 0-00 (all) s J O-OO-O-03 s s < ^ sj 0-00 O =S 0-00 O < 0-00 <O ^0-00 < <O00 0 O 0 0-3=3 0 OI 3= 6 O < = 6 <O00 *S 0-00 O0I (50)* 0 (33)* 9 Downloaded from at Pennsylvania State University on March 6, 06 "See text for breakpoint concentrations. *High breakpoint is in parenthesis. Includes nine isolates of A. actinomycetemcomitans, two isolates of H. aphrophilus, and one isolate of H. paraphrophilus.

4 36 R. B. Clark and S. E. Joyce compared to against a number of organisms. Imipenem activity against H. parainfluenzae in this report was similar to an earlier study (Rosenau et al., 99). Both and showed good activity against the isolates tested. Ciprofloxacin resistance was limited to one strain of the Kingella and Moraxella spp. Others have previously noted the excellent activity of these drugs against a number of uncommon Gram-negative organisms (Goldstein & Citron, 9, 9; Goldstein et al., 96; Hirai et al., 96; Noel & Teele, 96; Goldstein, Citron & Richwald, 9; Quentin et al., 9; Smith et al., 9). Interestingly, in combination with streptomycin has been reported to cure endocarditis due to A. actinomycetemcomitans (Kaplan et al., 99). Penicillin retains good in-vitro activity against most of the isolates tested in this study except for H. parainfluenzae, A. actinomycetemcomitans, and a few moraxella isolates. Others have noted decreased susceptibility of H. parainfluenzae to the s (Golberg & Washington, 97). No /?-lactamase activity was detected among our isolates except among several H. parainfluenzae and moraxella strains. Some isolates of P. multocida and E. corrodens have been reported to produce /?-lactamases even though such strains were not detected in our study (Philippon et al., 96; Lacroix and Walker, 99; Rosenau et al., 99). In conclusion, showed excellent activity against a variety of uncommon Gram-negative pathogens. Further work is necessary to determine whether this drug will eradicate these organisms in vivo. Acknowledgements This study was funded in part by ICI Pharmaceuticals Group, Wilmington, DE. The authors thank H. Dalton and T. Robin for supplying some of the strains used in this study. References Golberg, R. & Washington, J. A. (97). The taxonomy and antimicrobial susceptibility of Haemophilus species in clinical specimens. American Journal of Clinical Pathology 70, Goldstein, E. J. C. & Citron, D. M. (9). Susceptibility of Eikenella corrodens to, apalcillin, and twelve new cephalosporins. Antimicrobial Agents and Chemotherapy 6, 97-. Goldstein, E. J. C. & Citron, D. M. (9). Comparative activities of cefuroxime, amoxicillinclavulanic acid,, enoxacin, and ofloxacin against aerobic and anaerobic bacteria isolated from bite wounds. Antimicrobial Agents and Chemotherapy 3, 3-. Goldstein, E. J. C, Citron, D. M. & Richwald, G. A. (9). Lack of in vitro efficacy of oral forms of certain cephalosporins, erythromycin, and oxacillin against Pasteurella multocida. Antimicrobial Agents and Chemotherapy 3, 3-5. Goldstein, E. J. C, Citron, D. M., Vagvolgyi, A. E. & Gombert, M. E. (96). Susceptibility of Eikenella corrodens to newer and older quinolones. Antimicrobial Agents and Chemotherapy 30, 7-3. Hirai, K., Aoyama, H., Hosaka, M., Oomori, Y., Niwata, Y., Suzue, S. et al. (96). In vitro and in vivo antibacterial activity of AM-33, a new quinolone derivative. Antimicrobial Agents and Chemotherapy 9, Kaplan, A. H., Weber, D. J., Oddone, E. Z. & Perfect, J. R. (99). Infection due to Actinobacillus actinomycetemcomitans: 5 cases and review. Reviews of Infectious Diseases,6-63. Kilian, M. (99). Haemophilus. In Manual of Clinical Microbiology, 5th edn. (Barlows, A., Hausler, W. J., Herrmann, K. L., Isenberg, H. D. & Shadomy, H. J., Eds), pp American Society for Microbiology, Washington, DC. Downloaded from at Pennsylvania State University on March 6, 06

5 Activity of 37 Lacroix, J.-M. & Walker, C. (99). Characterization of a 0-lactamase found in Eikenella corrodens. Antimicrobial Agents and Chemotherapy 35, 6-9. Moellering, R. C, Eliopoulos, G. M. & Sentochnik, D. E. (99). The carbapenems: new broad spectrum /J-lactam antibiotics. Journal of Antimicrobial Chemotherapy, Suppl. A, -7. Morrison, V. A. & Wagner, K. F. (99). Clinical manifestations of Kingella kingae infections: case report and review. Reviews of Infectious Diseases, Noel, G. J. & Teele, D. W. (96). In vitro activities of selected new and long-acting cephalosporins against Pasteurella multocida. Antimicrobial Agents and Chemotherapy 9, 3-5. National Committee for Clinical Laboratory Standards (990). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically Second Edition; Approved Standard M7-A. NCCLS, Villanova, PA. Philippon, A., Joly, B., Reynaud, D., Paul, G., Maarte, J. L., Sirto, D. et al. (96). Characterization of a beta-lactamase from Pasteurella multocida. Annales de Microbiologie 37A, 53-. Pickett, M. J., Hollis, D. G. & Bottone, E. J. (99). Miscellaneous Gram-negative bacteria. In Manual of Clinical Microbiology, 5th edn (Balows, A., Hausler, W. J., Herrmann, K. L., Isenberg, H. D. & Shadomy, H. J., Eds), pp. 0-. American Society for Microbiology, Washington, DC. Quentin, R., Koubaa, N., Cattier, B., Gavignet, M. & Goudeau, A. (9). In vitro activities of five new quinolones against genital and neonatal Haemophilus isolates. Antimicrobial Agents and Chemotherapy 3, 7-9. Rosenau, A., Labigne, A., Escande, F., Courcoux, P. & Philippon, A. (99). Plasmid-mediated ROB- /J-lactamase in Pasteurella multocida from a human specimen. Antimicrobial Agents and Chemotherapy 35, 9-. Smith, R.. P., Baltch, A. L., Hammer, M C. & Conroy, J. V. (9). In vitro activities of PD 7,596 and reference antibiotics against clinical bacterial strains. Antimicrobial Agents and Chemotherapy 3, Wormser, G.P. & Bottone, E. J. (93). Cardiobaclerium hominis: review of microbiologie and clinical features. Reviews of Infectious Diseases 5, (Received December 99; revised version accepted 7 April 993) Downloaded from at Pennsylvania State University on March 6, 06