1 Tufts-New England Medical Center, Boston, MA 02111; 2 Tufts University School of Medicine, Boston, MA 02111, USA
Received 22 June 2004; returned 15 November 2004; revised 15 December 2005; accepted 25 February 2005
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 0.030.5 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 (PharmaciaUpJohn, 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
![]() |
Conclusions |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Acknowledgements |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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, 32769.
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, 8047.
6 . National Committee for Clinical Laboratory Standards. (2001). Methods for Antimicrobial Susceptibility Testing of Anaerobic BacteriaFifth 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.
|