Activity of a peptide deformylase inhibitor LBM415 (NVP PDF-713) tested against recent clinical isolates from Japan

Jan M. Bell1, John D. Turnidge1, Matsuhisa Inoue2, Shigeru Kohno3, Yoichi Hirakata3, Yasuo Ono4 and Ronald N. Jones5

1 Women's and Children's Hospital, Adelaide, Australia; 2 Kitasato University School of Medicine, Kanagawa; 3 Nagasaki University School of Medicine, Nagasaki; 4 Teikyo University School of Medicine, Tokyo, Japan; 5 The JONES Group/JMI Laboratories, North Liberty, IA, USA


* Correspondence address. Microbiology and Infectious Diseases, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006, Australia. Tel: +61-8-8161 6359; Fax: +61-8-161-6051; Email: bellj{at}mail.wch.sa.gov.au

Keywords: in vitro activity , MDR , novel antimicrobial

Sir,

Peptide deformylase (PDF) has been recognized as a new target for antibacterial agents and several PDF inhibitors have been developed.1 LBM415 (NVP PDF-713) is a new PDF inhibitor with documented activities against Gram-positive organisms.25 The aim of this study was to evaluate the potency of LBM415 against key Gram-positive pathogens, as well as Haemophilus influenzae, from Japan where antimicrobial resistance levels are very high among clinically significant Gram-positive organisms and community-acquired respiratory pathogens.6,7

A total of 695 clinical isolates originally collected in Japan included Staphylococcus aureus (n=222), Haemophilus influenzae (n=119), Streptococcus pneumoniae (n=122), coagulase-negative staphylococci (CoNS; n=119), Enterococcus spp. (n=65) and Streptococcus spp. (n=48). No vancomycin-resistant enterococci were detected during this period. LBM415 (Novartis Pharmaceuticals, Basel, Switzerland) was diluted in broth microdilution trays or agar using NCCLS methods and media supplements as required.8 NCCLS quality control strains with established MIC ranges were included throughout the study.

The MIC distribution, MIC50 and MIC90 values are shown in Table 1. Oxacillin-resistant S. aureus had slightly lower LBM415 MIC values than oxacillin-susceptible strains. MIC50 and MIC90 values for LBM415 against oxacillin-resistant S. aureus were 2 log10 dilutions lower than those observed by Credito et al.,2 although they tested a smaller number of strains. CoNS had similar MIC results to S. aureus, although oxacillin-resistant strains appeared to be less susceptible than oxacillin-susceptible strains. All enterococci were inhibited at ≤8 mg/L of LBM415. All S. pneumoniae were inhibited at ≤2 mg/L of the PDF inhibitor, regardless of penicillin or multi-drug resistance (MDR). Similar results have been shown by Ednie et al.3 The LBM415 MIC90 for the ß-haemolytic streptococci was 0.5 mg/L; all streptococci were inhibited at ≤4 mg/L.


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Table 1. MIC distribution, MIC50 and MIC90 of LBM415 against bacterial isolates from Japan collected during 2002

 
Japan has the highest incidences of ß-lactamase-negative ampicillin-resistant H. influenzae (BLNAR) in the world.9 It is of interest that, although the MIC90 for ß-lactamase-negative ampicillin-susceptible (BLNAS) strains was 8 mg/L, 28% of the BLNAR isolates tested had LBM415 MIC results at >8 mg/L, and the MIC90 was four-fold higher. This finding may limit the PDF inhibitor effectiveness against H. influenzae in Japan.

The in vitro spectrum of LBM415 was similar to that of other recently published PDF inhibitor agents, such as BB-83698, BB-81384 and others with predominant Gram-positive activity.10,11 LBM415 has greater in vitro activity against H. influenzae.

This study indicates that LBM415 appears to be an active agent that may be suitable for the treatment of infections caused by Gram-positive organisms, including oxacillin-resistant staphylococci and MDR S. pneumoniae, but with lower activity against H. influenzae.

Acknowledgements

This study was supported by an educational/research grant from Novartis Pharmaceuticals, Inc.

References

1 . Apfel, C. M., Locher, H., Evers, S. et al. (2001). Peptide deformylase as an antibacterial drug target: target validation and resistance development. Antimicrobial Agents and Chemotherapy 45, 1058–64.[Abstract/Free Full Text]

2 . Credito, K., Lin, G., Ednie, L. M. et al. (2004). Antistaphylococcal activity of LBM415, a new peptide deformylase inhibitor, compared with those of other agents. Antimicrobial Agents and Chemotherapy 48, 4033–6.[Abstract/Free Full Text]

3 . Ednie, L. M., Pankuch, G. & Appelbaum, P. C. (2004). Antipneumococcal activity of LBM415, a new peptide diformylase inhibitor, compared with those of other agents. Antimicrobial Agents and Chemotherapy 48, 4027–32.[Abstract/Free Full Text]

4 . Jones, R. N., Fritsche, T. R. & Sader, H. S. (2004). Antimicrobial spectrum and activity of NVP PDF-713, a novel peptide deformylase inhibitor, tested against 1,837 recent Gram-positive clinical isolates. Diagnostic Microbiology and Infectious Disease 49, 63–5.[CrossRef][ISI][Medline]

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 . Bell, J. M. & Turnidge, J. D. (2002). High prevalence of oxacillin-resistant Staphylococcus aureus isolates from hospitalized patients in Asia-Pacific and South Africa: results from SENTRY antimicrobial surveillance program, 1998–1999. Antimicrobial Agents and Chemotherapy 46, 879–81.[Abstract/Free Full Text]

7 . Bell, J. M., Turnidge, J. D. & Jones, R. N. (2002). Antimicrobial resistance trends in community-acquired respiratory tract pathogens in the Western Pacific Region and South Africa: report from the SENTRY antimicrobial surveillance program, (1998–1999) including an in vitro evaluation of BMS284756. International Journal of Antimicrobial Agents 19, 125–32.[CrossRef][ISI][Medline]

8 . National Committee for Clinical Laboratory Standards. (2003). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically-Sixth Edition: Approved Standard M7-A6. NCCLS, Wayne, PA, USA.

9 . Hasegawa, K., Chiba, N., Kobayashi, R. et al. (2004). Rapidly increasing prevalence of ß-lactamase-nonproducing, ampicillin-resistant Haemophilus influenzae type b in patients with meningitis. Antimicrobial Agents and Chemotherapy 48, 1509–14.[Abstract/Free Full Text]

10 . Gross, M., Clements, J., Beckett, R. P. et al. (2004). Oral anti-pneumococcal activity and pharmacokinetic profiling of a novel peptide deformylase inhibitor. Journal of Antimicrobial Chemotherapy 53, 487–93.[Abstract/Free Full Text]

11 . Lofland, D., Difuntorum, S., Waller, A. et al. (2004). In vitro antibacterial activity of the peptide deformylase inhibitor BB-83698. Journal of Antimicrobial Chemotherapy 53, 664–8.[Abstract/Free Full Text]





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