Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 2002 Mar;46(3):871–874. doi: 10.1128/AAC.46.3.871-874.2002

In Vitro Activities of BAL9141, a Novel Broad-Spectrum Pyrrolidinone Cephalosporin, against Gram-Negative Nonfermenters

R Zbinden 1,*, V Pünter 1, A von Graevenitz 1
PMCID: PMC127485  PMID: 11850276

Abstract

The activities of BAL9141 (formerly Ro 63-9141), a novel pyrrolidinone-3-ylidenemethyl cephalosporin, against 244 strains of gram-negative nonfermenters were evaluated. The overall MIC at which 50% of isolates are inhibited (MIC50) and the overall MIC90 were 2 and 64 μg/ml, respectively, which are similar to those of imipenem, lower than those of the other cephalosporins tested, amoxicillin, and the ticarcillin-clavulanic acid combination, and much higher than those of ciprofloxacin. BAL9141 shows species-dependent activity in vitro against a variety of gram-negative nonfermentative pathogens.

BAL9141 (formerly Ro 63-9141) is a novel pyrrolidinone-3-ylidenemethyl cephalosporin that consistently has activity against methicillin-resistant strains of Staphylococcus spp. but that exhibits promising in vitro and in vivo activities against a variety of gram-negative pathogens (1). The purpose of this study was to evaluate the activity of BAL9141 against a broad range of aerobic gram-negative glucose-nonfermentative rods.

(Part of this work was presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif., 1998 [R. Zbinden, V. Puenter, and A. von Graevenitz, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-19, 1998].).

The MICs of BAL9141 and nine other antimicrobials were determined by the NCCLS agar dilution method on non-cation-adjusted Mueller-Hinton agar (Becton Dickinson Microbiology Systems, Cockeysville, Md.) for 244 gram-negative nonfermenters that were collected through 1995 in the Department of Medical Microbiology, University of Zurich, Zurich, Switzerland, and a reference strain, Pseudomonas aeruginosa ATCC 27853 (5). A 0.5 McFarland suspension in phosphate-buffered saline was diluted 1/10 to obtain the desired inoculum of 107 CFU/ml. A multipoint inoculator was used to deliver 104 CFU per spot to each test plate and to control plates without antibiotics. Cultures were incubated at 35°C for 20 h in an aerobic atmosphere in accordance with the NCCLS methodology (5). BAL9141 of known potency was supplied by F. Hoffmann-La Roche, Basel, Switzerland (courtesy of P. Hebeisen). The other compounds were obtained from commercial sources. Identification of the isolates studied was in accordance with recommended methods (4).

The MICs of BAL9141 and the other antimicrobial agents are shown in Table 1.

TABLE 1.

Comparative in vitro activities of BAL9141 against 244 gram-negative nonfermenters

Organism (no. of strains) and drug MIC (μg/ml)
Organism (no. of strains) and drug MIC (μg/ml)
Range 50% 90% Range 50% 90%
Achromobacter xylosoxidans subsp. denitrificans and A. xylosoxidans subsp. xylosoxidans (17)
    BAL9141 1-32 4 16
    Cefepime 2->64 32 >64
    Cefotetan 32->64 >64 >64
    Cefozopran 8->64 >64 >64
    Ceftazidime 1-32 8 16
    Ceftriaxone 1->64 64 >64
    Amoxicillin-clavulanic acid 8->64 32 >64
    Ticarcillin-clavulanic acid 2-64 8 64
    Imipenem 0.25-4 2 4
    Ciprofloxacin 1-32 4 8
Acinetobacter baumannii (10)
    BAL9141 0.5->64 2 16
    Cefepime 1->64 8 32
    Cefotetan 32->64 64 >64
    Cefozopran 1-64 8 32
    Ceftazidime 2->64 8 64
    Ceftriaxone 4->64 16 64
    Amoxicillin-clavulanic acid 32->64 64 >64
    Ticarcillin-clavulanic acid 1->64 64 >64
    Imipenem 0.25-4 0.5 0.5
    Ciprofloxacin ≤0.06->64 0.25 0.25
Acinetobacter iwoffii (10)
    BAL9141 ≤0.06 ≤0.06 ≤0.06
    Cefepime ≤0.06-1 ≤0.06 0.5
    Cefotetan 0.5-64 4 32
    Cefozopran ≤0.06-0.5 ≤0.06 ≤0.06
    Ceftazidime ≤0.06-8 0.5 4
    Ceftriaxone ≤0.06-4 1 2
    Amoxicillin-clavulanic acid ≤0.06-8 2 8
    Ticarcillin-clavulanic acid 0.25-8 2 4
    Imipenem ≤0.06-0.13 ≤0.06 0.13
    Ciprofloxacin ≤0.06 ≤0.06 ≤0.06
Agrobacterium radiobacter (10)
    BAL9141 ≤0.06-0.5 0.13 0.25
    Cefepime 1-8 2 8
    Cefotetan 0.25-8 4 8
    Cefozopran 1-16 4 8
    Ceftazidime 4-64 64 64
    Ceftriaxone 1-32 4 16
    Amoxicillin-clavulanic acid 0.25-16 16 16
    Ticarcillin-clavulanic acid 4-16 8 16
    Imipenem ≤0.06-1 0.25 0.25
    Ciprofloxacin ≤0.06-1 ≤0.06 0.5
Alcaligenes faecalis (10)
    BAL9141 0.25-8 0.5 2
    Cefepime 0.25->64 8 8
    Cefotetan 0.5->64 2 >64
    Cefozopran 0.5->64 8 16
    Ceftazidime 2-16 4 8
    Ceftriaxone 0.13->64 0.25 >64
    Amoxicillin-clavulanic acid 8-64 16 64
    Ticarcillin-clavulanic acid 4-16 8 8
    Imipenem ≤0.06-4 0.5 4
    Ciprofloxacin ≤0.06-4 1 4
Bordetella bronchiseptica (10)
    BAL9141 0.06-8 2 4
    Cefepime 0.25-64 16 32
    Cefotetan 8->64 >64 >64
    Cefozopran 0.25->64 32 32
    Ceftazidime 1-32 16 32
    Ceftriaxone 0.5->64 >64 >64
    Amoxicillin-clavulanic acid 8-64 16 64
    Ticarcillin-clavulanic acid 4->64 16 32
    Imipenem 0.13-2 1 2
    Ciprofloxacin ≤0.06-2 1 2
Brevundimonas vesicularis (14)
    BAL9141 1->64 4 >64
    Cefepime 0.25-32 8 32
    Cefotetan 8->64 32 >64
    Cefozopran 1->64 8 >64
    Ceftazidime 0.5->64 32 >64
    Ceftriaxone 0.5->64 4 >64
    Amoxicillin-clavulanic acid 4->64 8 >64
    Ticarcillin-clavulanic acid 4->64 16 >64
    Imipenem 0.25->64 0.5 >64
    Ciprofloxacin 0.25-16 4 16
Burkholderia cepacia (14)
    BAL9141 0.5-64 8 64
    Cefepime ≤0.06-32 8 32
    Cefotetan 8->64 64 >64
    Cefozopran 16->64 64 >64
    Ceftazidime 2-32 16 16
    Ceftriaxone 4->64 16 64
    Amoxicillin-clavulanic acid >64 >64 >64
    Ticarcillin-clavulanic acid >64 >64 >64
    Imipenem ≤0.06-16 8 8
    Ciprofloxacin 1-4 1 4
Chryseobacterium indologenes (14)
    BAL9141 0.25->64 16 64
    Cefepime ≤0.06-16 1 4
    Cefotetan 4->64 >64 >64
    Cefozopran 0.5->64 4 >64
    Ceftazidime 4-32 8 32
    Ceftriaxone 8-64 64 64
    Amoxicillin-clavulanic acid 0.5->64 32 >64
    Ticarcillin-clavulanic acid 2->64 >64 >64
    Imipenem ≤0.06->64 16 >64
    Ciprofloxacin ≤0.06-2 0.5 0.5
Chryseobacterium meningo- septicum (10)
    BAL9141 8-64 32 64
    Cefepime 8-64 32 64
    Cefotetan 64->64 >64 >64
    Cefozopran 16->64 32 64
    Ceftazidime 64->64 >64 >64
    Ceftriaxone 32->64 64 >64
    Amoxicillin-clavulanic acid 32->64 >64 >64
    Ticarcillin-clavulanic acid >64 >64 >64
    Imipenem 32-64 32 64
    Ciprofloxacin 0.5-8 1 2
Comamonas acidovorans (10)
    BAL9141 1-32 4 16
    Cefepime 8->64 8 64
    Cefotetan 4 4 4
    Cefozopran 4->64 16 64
    Ceftazidime 0.5-4 1 2
    Ceftriaxone 1-64 8 32
    Amoxicillin-clavulanic acid 32->64 >64 >64
    Ticarcillin-clavulanic acid 8->64 64 >64
    Imipenem 0.25-4 1 2
    Ciprofloxacin ≤0.06-0.5 0.13 0.25
Moraxella spp. (10) (except M. catarrhalis)
    BAL9141 ≤0.06-0.25 ≤0.06 0.13
    Cefepime ≤0.06-2 0.5 1
    Cefotetan 0.13-8 1 8
    Cefozopran ≤0.06-1 0.5 1
    Ceftazidime ≤0.06-8 2 4
    Ceftriaxone ≤0.06-0.5 ≤0.06 0.5
    Amoxicillin-clavulanic acid 0.13-1 0.25 0.5
    Ticarcillin-clavulanic acid ≤0.06-4 0.5 1
    Imipenem ≤0.06-0.25 ≤0.06 0.13
    Ciprofloxacin ≤0.06-0.13 ≤0.06 0.13
Ochrobactrum anthropi (10)
    BAL9141 0.5-2 1 2
    Cefepime 8-64 16 64
    Cefotetan 16->64 64 >64
    Cefozopran 4->64 16 >64
    Ceftazidime 64->64 >64 >64
    Ceftriaxone 2->64 8 >64
    Amoxicillin-clavulanic acid 32->64 >64 >64
    Ticarcillin-clavulanic acid 64->64 >64 >64
    Imipenem 1-2 1 2
    Ciprofloxacin ≤0.06-0.5 0.5 0.5
Oligella ureolytica (10)
    BAL9141 0.25->64 0.5 >64
    Cefepime 0.25->64 4 16
    Cefotetan 0.13->64 64 >64
    Cefozopran 1->64 2 >64
    Ceftazidime 0.5->64 16 >64
    Ceftriaxone ≤0.06-64 4 64
    Amoxicillin-clavulanic acid 0.25->64 8 >64
    Ticarcillin-clavulanic acid 0.25->64 8 >64
    Imipenem ≤0.06->64 0.5 64
    Ciprofloxacin ≤0.06-1 0.5 0.5
Pseudomonas aeruginosa (15)
    BAL9141 0.25-64 8 32
    Cefepime 1-16 4 16
    Cefotetan >64 >64 >64
    Cefozopran 0.5-16 2 16
    Ceftazidime 2-32 4 8
    Ceftriaxone 2->64 >64 >64
    Amoxicillin-clavulanic acid >64 >64 >64
    Ticarcillin-clavulanic acid 8->64 >64 >64
    Imipenem 0.13-32 2 4
    Ciprofloxacin ≤0.06-2 0.13 2
Pseudomonas oryzihabitans (10)
    BAL9141 ≤0.06-2 0.13 0.25
    Cefepime ≤0.06->64 0.13 8
    Cefotetan 0.5->64 2 32
    Cefozopran ≤0.06->64 0.13 0.5
    Ceftazidime 0.13->64 0.5 2
    Ceftriaxone 0.13->64 0.5 32
    Amoxicillin-clavulanic acid 2 2 2
    Ticarcillin-clavulanic acid 0.13->64 2 64
    Imipenem 0.13-2 0.13 0.25
    Ciprofloxacin ≤0.06-0.5 ≤0.06 0.5
Pseudomonas stutzeri (12)
    BAL9141 ≤0.06-16 1 16
    Cefepime ≤0.06->64 0.25 >64
    Cefotetan ≤0.06->64 2 16
    Cefozopran ≤0.06->64 0.25 >64
    Ceftazidime ≤0.06->64 1 >64
    Ceftriaxone 0.13->64 2 >64
    Amoxicillin-clavulanic acid 0.25-16 8 16
    Ticarcillin-clavulanic acid 0.25->64 8 64
    Imipenem 0.06-1 0.5 0.5
    Ciprofloxacin ≤0.06 ≤0.06 ≤0.06
Ralstonia pickettii (10)
    BAL9141 1-4 2 4
    Cefepime 1-4 2 4
    Cefotetan 8->64 >64 >64
    Cefozopran 0.25-4 2 4
    Ceftazidime 2-16 8 16
    Ceftriaxone ≤0.06-0.25 0.25 0.25
    Amoxicillin-clavulanic acid 1->64 >64 >64
    Ticarcillin-clavulanic acid 2->64 >64 >64
    Imipenem ≤0.06-2 1 2
    Ciprofloxacin ≤0.06-0.25 0.13 0.25
Sphingomonas spp. (10)
    BAL9141 4-16 8 16
    Cefepime 2-16 2 8
    Cefotetan 64->64 64 >64
    Cefozopran 0.5-16 4 16
    Ceftazidime 2->64 16 >64
    Ceftriaxone 1-32 8 16
    Amoxicillin-clavulanic acid 8-32 16 32
    Ticarcillin-clavulanic acid 8->64 >64 >64
    Imipenem 0.5->64 32 64
    Ciprofloxacin ≤0.06-4 0.25 2
Stenotrophomonas maltophilia (15)
    BAL9141 0.5->64 >64 >64
    Cefepime 4->64 >64 >64
    Cefotetan 8->64 64 >64
    Cefozopran 32->64 >64 >64
    Ceftazidime 4->64 64 >64
    Ceftriaxone >64 >64 >64
    Amoxicillin-clavulanic acid 8->64 >64 >64
    Ticarcillin-clavulanic acid 16->64 >64 >64
    Imipenem 8->64 >64 >64
    Ciprofloxacin 0.5-8 4 8
Weeksella virosa (15)
    BAL9141 ≤0.06-2 ≤0.06 2
    Cefepime 0.5-16 4 16
    Cefotetan 0.5-8 2 4
    Cefozopran 0.25-32 0.25 8
    Ceftazidime 0.25-8 1 4
    Ceftriaxone 0.5-4 2 4
    Amoxicillin-clavulanic acid ≤0.06-0.5 0.13 0.5
    Ticarcillin-clavulanic acid 0.13-16 0.25 1
    Imipenem ≤0.06-0.13 ≤0.06 ≤0.06
    Ciprofloxacin <0.06-0.13 <0.06 0.13
Open in a new tab

BAL9141 was particularly active against Agrobacterium radiobacter, Alcaligenes faecalis, Bordetella bronchiseptica, Moraxella spp., Ochrobactrum anthropi, Pseudomonas oryzihabitans, Ralstonia pickettii, and Weeksella virosa. The results of our study of the activities of BAL9141 against P. aeruginosa and Acinetobacter spp. were by and large in agreement with those of Hebeisen et al. (1), except that, across the board, our pathogens were more susceptible than the selected isolates used by those investigators. Our results for the other antimicrobials are in line with those obtained by Jones et al. (2), Klein et al. (3), Spangler et al. (7), and von Graevenitz and Bucher (8).

The overall activities of BAL9141 against the glucose-nonfermentative gram-negative rods tested were most similar to those of imipenem in terms of MIC50s and MIC90s. Imipenem, however, had clearly superior activity against Achromobacter xylosoxidans, Acinetobacter baumannii, Brevundimonas vesicularis, Burkholderia cepacia, Comamonas acidovorans, P. aeruginosa, Pseudomonas stutzeri, and W. virosa. For the other species tested, their activities were similar. Cefepime was more active against Chryseobacterium indologenes and Sphingomonas spp. and, to some extent, was also more active against P. aeruginosa. Cefozopran was, overall, as active as cefepime. With the exception of ceftazidime against B. cepacia, C. acidovorans, and P. aeruginosa, the expanded-spectrum and broad-spectrum cephalosporins were less active than BAL9141 or the penicillin-clavulanic acid combinations.

While imipenem and ciprofloxacin have greater potencies against most of the organisms tested, BAL9141, cefepime, and cefozopran, in decreasing order, appear to be potent enough to be of clinical utility against most of the species evaluated apart from Stenotrophomonas maltophilia and Chryseobacterium spp. All compounds tested were inactive against S. maltophilia and Chryseobacterium meningosepticum (the activity of ciprofloxacin was borderline).

TABLE 2.

Cumulative in vitro activities of BAL9141 and comparator drugs against 244 gram-negative nonfermenters

Compound(s) % strains inhibited by:
2 μg/ml 4 μg/ml 8 μg/ml 16 μg/ml
BAL9141 52 65 73 83
Cefepimea 20 26 37 48
Cefotetan 18 27 39 42
Cefozopran 38 47 57 67
Ceftazidimea 30 43 56 73
Ceftriaxonea 32 44 51 58
Amoxicillin-clavulanic acidb 20 26 37 48
Ticarcillin-clavulanic acidc 19 24 35 47
Imipenemd 69 76 80 82
Ciprofloxacine 84 95 97 99
Open in a new tab
a

NCCLS-approved susceptibility breakpoint for P. aeruginosa and other nonmembers of the family Enterobacteriaceae (6), 8 μg/ml.

b

NCCLS-approved susceptibility breakpoint for ampicillin-sulbactam (6), 8/4 μg/ml.

c

NCCLS-approved susceptibility breakpoint for nonmembers of the family Enterobacteriaceae, 16/2 μg/ml; NCCLS-approved susceptibility breakpoint for P. aeruginosa, 64/2 μg/ml.

d

NCCLS-approved susceptibility breakpoint for P. aeruginosa and other nonmembers of the family Enterobacteriaceae (6), 4 μg/ml.

e

NCCLS-approved susceptibility breakpoint (6), 1 μg/ml.

Acknowledgments

We gratefully acknowledge the support of these studies by F. Hoffmann-La Roche.

We thank P. Hohl and S. Shapiro for critical reading of the manuscript.

REFERENCES

  • 1.Hebeisen, P., I. Heinze-Krauss, P. Angehrn, P. Hohl, M. G. P. Page, and R. L. Then. 2001. In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci. Antimicrob. Agents Chemother. 45:825-836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Jones, R. N., M. A. Pfaller, G. V. Doern, M. E. Erwin, R. J. Hollis, and Cefepime Study Group. 1998. Antimicrobial activity and spectrum investigation of eight broad-spectrum β-lactam drugs: a 1997 surveillance trial in 102 medical centers in the United States. Diagn. Microbiol. Infect. Dis. 30:215-228. [DOI] [PubMed] [Google Scholar]
  • 3.Klein, O., N. X. Chin, H. B. Huang, and H. C. Neu. 1994. In vitro activity of SCE-2787, a new cephalosporin with potent activity against Pseudomonas aeruginosa and members of the family Enterobacteriaceae. Antimicrob. Agents Chemother. 38:2896-2901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Murray, P. R., E. J. Baron, M. A. Pfaller, F. C. Tenover, and R. H. Yolken (ed.). 1999. Manual of clinical microbiology, 7th ed. American Society for Microbiology, Washington, D.C.
  • 5.National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. Approved standard M7-A4. National Committee for Clinical Laboratory Standards, Wayne, Pa.
  • 6.National Committee for Clinical Laboratory Standards. 2001. Performance standards for antimicrobial susceptibility testing, 11th informational supplement. M100-S11. National Committee for Clinical Laboratory Standards, Wayne, Pa.
  • 7.Spangler, S. K., M. A. Visalli, M. R. Jacobs, and P. C. Appelbaum. 1996. Susceptibilities of non-Pseudomonas aeruginosa gram-negative nonfermentative rods to ciprofloxacin, ofloxacin, levofloxacin, d-ofloxacin, sparfloxacin, ceftazidime, piperacillin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, and imipenem. Antimicrob. Agents Chemother. 40:772-775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.von Graevenitz, A., and C. Bucher. 1982. The effect of N-formimidoyl thienamycin, ceftazidime, cefotiam, ceftriaxone and cefotaxime on non-fermentative gram-negative rods Aeromonas, Plesiomonas, and Enterobacter agglomerans. Infection 10:293-298. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES