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JAC Advance Access originally published online on April 11, 2005
Journal of Antimicrobial Chemotherapy 2005 55(6):1024-1028; doi:10.1093/jac/dki107
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions{at}oupjournals.org

Evaluation of the in vitro activity of NVP-LMB415 against clinical anaerobic isolates with emphasis on the Bacteroides fragilis group

David R. Snydman1,2,*, Nilda V. Jacobus1 and Laura A. McDermott1

1 Tufts-New England Medical Center, Boston, MA 02111; 2 Tufts University School of Medicine, Boston, MA 02111, USA

* Corresponding author. Tel: +1-617-636-5785; Fax: +1-617-636-8525; Email: dsnydman{at}tufts-nemc.org

Received 22 June 2004; returned 15 November 2004; revised 15 December 2005; accepted 25 February 2005


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results and discussion
 Conclusions
 References
 
Objectives: To compare the in vitro activity of NVP-LMB415 (formerly referred to as NVP-PDF 713) with that of other agents with anti-anaerobe activity against clinical anaerobic isolates, with emphasis on the Bacteroides fragilis group.

Methods: The MICs for 405 B. fragilis group and 102 Gram-positive anaerobic isolates were determined using NCCLS-recommended procedures. The activity of NVP-LMB415 was compared with that of cefoxitin, clindamycin, imipenem, garenoxacin, linezolid, moxifloxacin and tigecycline. Vancomycin was included in the evaluation of the Gram-positive organisms.

Results: NVP-LMB415 showed excellent in vitro activity against all the species of the B. fragilis group isolates (MIC range ≤ 0.03–0.5 mg/L and MIC90 0.5 mg/L). NVP-LMB415 was active against B. fragilis group strains resistant to ß-lactams, quinolones or clindamycin, and the MICs were much lower than those of newer agents such as linezolid, tigecycline and garenoxacin. The MICs of NVP-LMB415 ( ≥ 4 mg/L) for Clostridium species were higher than the MICs for other anaerobes.

Conclusions: Given the frequency of isolation of anaerobic bacteria and their increasing resistance to all classes of antibiotics, NVP-LMB415 is an ideal agent for potential use against mixed infections caused by resistant anaerobic pathogens such as of B. fragilis and Gram-positive aerobic strains such as methicillin-resistant staphylococci, streptococci and enterococci.

Keywords: novel peptide deformylase inhibitor , peptide deformylase inhibitor (PDF) , bacterial metalloproteases , anaerobic pathogens


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results and discussion
 Conclusions
 References
 
The increased resistance of anaerobic bacteria, particularly the Bacteroides fragilis group, against current antibiotics has highlighted the need to search for new antibiotics as therapy for mixed infections.1,2 NVP-LMB415 is a novel peptide deformylase inhibitor (PDF) that targets bacterial metalloproteases.3 Reports on these classes of compounds have demonstrated their potent in vitro activity against respiratory and skin pathogens such as methicillin-resistant Staphylococcus aureus, coagulase-negative Staphylococcus spp., Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae and enterococci.3,4 NVP-LMB415 was recently evaluated and proven to be very active in vitro against staphylococcal and enterococcal strains resistant to newer antibiotics such as linezolid and streptogramin.5 The novel compound, however, has not been evaluated against important anaerobic pathogens. We undertook this study to evaluate the in vitro activity of NVP-LMB415 against recent clinical isolates of the B. fragilis group and selected Gram-positive anaerobic pathogens and to compare its in vitro activity with that of other agents with anti-anaerobe activity using NCCLS-recommended procedures.6


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results and discussion
 Conclusions
 References
 
Bacterial isolates

A total of 405 B. fragilis group isolates were included in the evaluation. The isolates had been referred to Tufts-New England Medical Center by 10 medical centres in the USA as part of a multicentre survey of resistance of the B. fragilis group. The number of isolates within each species was selected according to the general frequency of isolation. Selected strains resistant to some of the comparative agents were purposely included. Identification of the isolates was confirmed using API AnidentTM and/or standard methodology7 when applicable. The strains included were 28 Bacteroides distasonis, 209 B. fragilis, 32 Bacteroides ovatus, 76 Bacteroides thetaiotaomicron, 22 Bacteroides vulgatus, 22 Bacteroides uniformis and 16 other Bacteroides (13 Bacteroides caccae, two Bacteroides eggerthii, one Bacteroides stercoris).

The Gram-positive strains included 25 Peptostreptococcus spp., 25 Clostridium perfringens, six Clostridium innocuum, three Clostridium septicum, three Clostridium ramosum, nine Clostridium spp. (one of which was a Clostridium difficile), 13 Propionibacterium acnes, 15 Propionibacterium spp. and three other Gram-positive anaerobes (two Lactobacillus spp., one Eubacterium lentum).

Antimicrobial agents

Besides NVP-LMB415, provided by Novartis, Cambridge, MA, USA, the following antibiotics, provided by their respective manufacturers, were included in the evaluation: cefoxitin and imipenem (Merck Sharp and Company, Rahway, NJ, USA); clindamycin and linezolid (Pharmacia–UpJohn, Kalamazoo, MI, USA); garenoxacin (Bristol-Myers Squibb, Princeton, NJ, USA); moxifloxacin (Bayer Corporation, West Haven, CT, USA); tigecycline (Wyeth-Ayerst Research, Pearl River, NY, USA); and vancomycin (included only when testing Gram-positive anaerobes; Sigma). Stock solutions of the agents were prepared, following the manufacturers' instructions, at 10 times the desired testing concentration and kept frozen at –70°C until the day of use. The percentages of resistance were calculated using breakpoints listed in NCCLS document M11-A5.6 For cefoxitin, imipenem and clindamycin the breakpoints were ≥ 64, ≥ 16 and ≥ 8 mg/L, respectively. For NVP-LMB415, garenoxacin, linezolid, tigecycline and moxifloxacin an arbitrary breakpoint of ≥ 4 mg/L was used, as the NCCLS has not issued recommendations for these agents.

Susceptibility testing

The MICs were determined by the agar dilution method following NCCLS recommendations.6 The plates were prepared on the day of the test using enriched brucella agar (brucella agar supplemented with 5% lysed defibrinated sheep red blood cells and 1 µg/mL vitamin K). For preparation of the inocula, the organisms were grown to logarithmic phase, and the turbidity adjusted to that of a 0.5 McFarland standard (~108 cfu/mL). The inocula were delivered to the surface of the agar with a Steers replicator resulting in an organism concentration of ~105 cfu/spot. The inoculated plates were incubated at 37°C in an anaerobic chamber for 48 h. B. fragilis ATCC 25285, B. thetaiotaomicron ATCC 29741 and E. lentum ATCC 43055 were used for quality control.


   Results and discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
Conclusions
 References
 
Table 1 illustrates the MICs of the antimicrobial agents for the B. fragilis group. On a weight by weight basis, NVP-LMB415 was the most active against this group of pathogens, which included strains resistant to imipenem, cefoxitin, clindamycin and strains with MICs > 4 mg/mL for garenoxacin, moxifloxacin, linezolid and tigecycline. All the isolates were inhibited at concentrations of NVP-LMB415 ranging from ≤ 0.03 to 0.5 mg/L. No cross-resistance between NVP-LMB415 and the other agents was observed as strains resistant to one or more of the other agents exhibited MICs ≤ 0.5 mg/L. Because the agent was active at such low concentrations for all the species within the group, we could not determine whether the activity (or lack of) was associated with species.


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  		Table 1.. Activity of NVP-LMB415 against clinical isolates of the B. fragilis group

 
Table 2 shows the MICs of the antimicrobial agents for the Gram-positive anaerobic isolates. In general, the MICs of NVP-LMB415 (range < 0.03–8 mg/L) were higher for Gram-positive anaerobic bacteria than the MICs for the B. fragilis group. NVP-LMB415 showed very good activity against some clostridial species, specifically C. septicum, C. innocuum and C. ramosum (MIC range 0.06–1 mg/L). However, some Clostridium spp. (including C. perfringens and one strain of C. difficile) showed elevated MICs of ≥ 4 mg/L). Good activity was observed against Peptostreptococcus spp. and Propionibacterium spp. (MIC90s 1 and 2 mg/L, respectively). On a weight by weight basis, imipenem, garenoxacin, moxifloxacin and tigecycline were as active or more active than NVP-LMB415 against most of the Gram-positive anaerobes.


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  		Table 2.. Activity of NVP-LMB415 against Gram-positive anaerobes

 

   Conclusions
Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Conclusions
References
 
Given the frequency of isolation and the increasing resistance of the B. fragilis group of pathogens to commonly used antibiotics, a novel agent such as NVP-LMB415, effective against a new bacterial target, is an ideal agent for potential use against mixed infections. To determine the future clinical indications of the agent, additional information such as its antibacterial spectrum of activity (including bacteriostatic versus bactericidal characteristics), mechanisms and emergence of resistance, as well as pharmacokinetic and pharmacodynamic parameters, and the mechanisms for its compromised activity against some Gram-positive anaerobes, particularly some Clostridium spp., should also be investigated.


   Acknowledgements
 
We acknowledge the excellent technical assistance of Carolina Baez-Giangreco and for assistance in manuscript preparation we thank Roselia Martinez. We also thank Ronald N. Jones, MD, for provision of some Gram-positive anaerobes for testing. This study was supported by an unrestricted research grant from Novartis Pharmaceuticals, Inc. This study was presented in part at the European Congress in Microbiology and Infectious Diseases, Prague, Czech Republic, May 2004.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 Conclusions
 References
 
1 . Snydman, D. R., Jacobus, N. V., McDermott, L. A. et al. (2002). National survey on the susceptibility of B. fragilis group: report and analysis of trends for 1997–2000. Clinical Infectious Diseases 35, Suppl. 1, S126–34.[CrossRef][Web of Science][Medline]

2 . Snydman, D. R., Jacobus, N. V., McDermott, L. A. et al. (2002). In vitro activities of newer quinolones against Bacteroides group organisms. Antimicrobial Agents and Chemotherapy 46, 3276–9.[Abstract/Free Full Text]

3 . Ryder, N. S., Kubik, B., Mlineritsch, W. et al. (2002). NVP-PDF386 (VRC4887), a new antibacterial peptide deformylase inhibitor with potent in vitro activity against drug-resistant organisms, In Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002. Abstract F-1671, p. 221. American Society for Microbiology, Washington, DC, USA.

4 . Wu, C., Chen, D., Ni, Z. J., et al. (2002). Identification of alkyl-succinate-proline hydroxamates as peptide deformylase (PDF) inhibitors through integrated combinatorial and medicinal chemistry. In Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002. Abstract F1668, p. 220. American Society for Microbiology, Washington, DC, USA.

5 . Jones, R. N., Moet, G. J., Sader, H. S. et al. (2004). Potential utility of a peptide deformylase inhibitor (NVP PDF-713) against oxazolidinone-resistant or streptogramin-resistant Gram-positive organism isolates. Journal of Antimicrobial Chemotherapy 53, 804–7.[Abstract/Free Full Text]

6 . National Committee for Clinical Laboratory Standards. (2001). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria—Fifth Edition: Approved Standard M11-A5, M11-A5. NCCLS, Villanova, PA, USA.

7 . Jousimies-Somer, H. R., Summanem, P., Citron, D. M., et al. (2002). Wadsworth-KTL Anaerobic Bacteriology Manual, 6th edn. Star Publishing Co, Belmont, CA, USA.


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