Antimicrobial activity of a novel peptide deformylase inhibitor, LBM415, tested against respiratory tract and cutaneous infection pathogens: A global surveillance report (2003-2004)

Amy A. Watters, Ronald N. Jones, Jennifer A. Leeds, Gerald Denys, Helio S. Sader, Thomas R. Fritsche

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Objectives: To evaluate the spectrum of activity and potency of LBM415, the first of the peptide deformylase inhibitor (PDFI) class to be developed for treatment of community-acquired respiratory tract infections and uncomplicated skin and soft tissue infections (uSSTI), against a large, contemporary international collection of targeted pathogens collected during 2003-2004. Methods: A total of 21636 isolates were tested by reference broth microdilution methods as part of a longitudinal international antimicrobial resistance surveillance study. Characteristics of the organism collection included resistance to oxacillin among 35.0% of Staphylococcus aureus and 76.0% of coagulase-negative staphylococci (CoNS); resistance to penicillin (MIC ≥ 2 mg/L) among 18.0% of Streptococcus pneumoniae vancomycin resistance among 20.0% of Enterococcus spp. and ampicillin resistance among 22.0% of Haemophilus influenzae. Results: LBM415 displayed potent activity against staphylococci, streptococci, Enterococcus faecium and Moraxella catarrhalis, with ≥99.0% of strains being inhibited at ≤4 mg/L 97.0% of Enterococcus faecalis isolates and 92.0% of H. influenzae isolates were also inhibited at this concentration. Seventy-seven percent of Burkholderia cepacia and 82.0% of Stenotrophomonas maltophilia were inhibited at ≤8 mg/L. No differences in LBM415 activity against S. aureus, CoNS, S. pneumoniae, Enterococcus spp. and H. influenzae were detected for subsets susceptible or resistant to antimicrobials such as oxacillin, penicillin, ampicillin, macrolides, vancomycin and fluoroquinolones. While regional differences were apparent with some comparator agents, sensitivity to LBM415 did not vary significantly among strains from the various geographic areas sampled. One isolate of S. aureus displayed high-level resistance to LBM415 owing to multiple sequence changes in resistance phenotype genes defB and fmt), despite the absence of the compound in clinical practice. This isolate remained susceptible to all other antimicrobials tested except for penicillin. Conclusions: With few differences detected among strains from various geographic regions, the first PDFI class agent to enter clinical development has consistently demonstrated a broad spectrum of activity against commonly isolated pathogens associated with uncomplicated respiratory and cutaneous infections. These compounds represent a significant therapeutic advance owing to their novel mechanism of action and antibacterial spectrum, including activity against resistant organisms, should pharmacokinetic and pharmacodynamic parameters support their continued development. Given the detection of a pre-existing PDFI-resistant isolate of S. aureus as demonstrated here, surveillance for resistance among the PDFI-targeted pathogens following introduction of this class of agent into clinical usage will be an important component of future studies.

Original languageEnglish (US)
Pages (from-to)914-923
Number of pages10
JournalJournal of Antimicrobial Chemotherapy
Volume57
Issue number5
DOIs
StatePublished - May 1 2006

Fingerprint

peptide deformylase
Respiratory Tract Infections
Staphylococcus aureus
Haemophilus influenzae
Skin
Staphylococcus
Oxacillin
Enterococcus faecium
Coagulase
Enterococcus
Streptococcus pneumoniae
Penicillins
Vancomycin Resistance
Stenotrophomonas maltophilia
Ampicillin Resistance
Penicillin Resistance
Community-Acquired Infections
Burkholderia cepacia
Moraxella (Branhamella) catarrhalis
Soft Tissue Infections

Keywords

  • PDFI
  • Resistance
  • Respiratory tract infections
  • uSSTI

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Antimicrobial activity of a novel peptide deformylase inhibitor, LBM415, tested against respiratory tract and cutaneous infection pathogens : A global surveillance report (2003-2004). / Watters, Amy A.; Jones, Ronald N.; Leeds, Jennifer A.; Denys, Gerald; Sader, Helio S.; Fritsche, Thomas R.

In: Journal of Antimicrobial Chemotherapy, Vol. 57, No. 5, 01.05.2006, p. 914-923.

Research output: Contribution to journalArticle

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abstract = "Objectives: To evaluate the spectrum of activity and potency of LBM415, the first of the peptide deformylase inhibitor (PDFI) class to be developed for treatment of community-acquired respiratory tract infections and uncomplicated skin and soft tissue infections (uSSTI), against a large, contemporary international collection of targeted pathogens collected during 2003-2004. Methods: A total of 21636 isolates were tested by reference broth microdilution methods as part of a longitudinal international antimicrobial resistance surveillance study. Characteristics of the organism collection included resistance to oxacillin among 35.0{\%} of Staphylococcus aureus and 76.0{\%} of coagulase-negative staphylococci (CoNS); resistance to penicillin (MIC ≥ 2 mg/L) among 18.0{\%} of Streptococcus pneumoniae vancomycin resistance among 20.0{\%} of Enterococcus spp. and ampicillin resistance among 22.0{\%} of Haemophilus influenzae. Results: LBM415 displayed potent activity against staphylococci, streptococci, Enterococcus faecium and Moraxella catarrhalis, with ≥99.0{\%} of strains being inhibited at ≤4 mg/L 97.0{\%} of Enterococcus faecalis isolates and 92.0{\%} of H. influenzae isolates were also inhibited at this concentration. Seventy-seven percent of Burkholderia cepacia and 82.0{\%} of Stenotrophomonas maltophilia were inhibited at ≤8 mg/L. No differences in LBM415 activity against S. aureus, CoNS, S. pneumoniae, Enterococcus spp. and H. influenzae were detected for subsets susceptible or resistant to antimicrobials such as oxacillin, penicillin, ampicillin, macrolides, vancomycin and fluoroquinolones. While regional differences were apparent with some comparator agents, sensitivity to LBM415 did not vary significantly among strains from the various geographic areas sampled. One isolate of S. aureus displayed high-level resistance to LBM415 owing to multiple sequence changes in resistance phenotype genes defB and fmt), despite the absence of the compound in clinical practice. This isolate remained susceptible to all other antimicrobials tested except for penicillin. Conclusions: With few differences detected among strains from various geographic regions, the first PDFI class agent to enter clinical development has consistently demonstrated a broad spectrum of activity against commonly isolated pathogens associated with uncomplicated respiratory and cutaneous infections. These compounds represent a significant therapeutic advance owing to their novel mechanism of action and antibacterial spectrum, including activity against resistant organisms, should pharmacokinetic and pharmacodynamic parameters support their continued development. Given the detection of a pre-existing PDFI-resistant isolate of S. aureus as demonstrated here, surveillance for resistance among the PDFI-targeted pathogens following introduction of this class of agent into clinical usage will be an important component of future studies.",
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AU - Jones, Ronald N.

AU - Leeds, Jennifer A.

AU - Denys, Gerald

AU - Sader, Helio S.

AU - Fritsche, Thomas R.

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N2 - Objectives: To evaluate the spectrum of activity and potency of LBM415, the first of the peptide deformylase inhibitor (PDFI) class to be developed for treatment of community-acquired respiratory tract infections and uncomplicated skin and soft tissue infections (uSSTI), against a large, contemporary international collection of targeted pathogens collected during 2003-2004. Methods: A total of 21636 isolates were tested by reference broth microdilution methods as part of a longitudinal international antimicrobial resistance surveillance study. Characteristics of the organism collection included resistance to oxacillin among 35.0% of Staphylococcus aureus and 76.0% of coagulase-negative staphylococci (CoNS); resistance to penicillin (MIC ≥ 2 mg/L) among 18.0% of Streptococcus pneumoniae vancomycin resistance among 20.0% of Enterococcus spp. and ampicillin resistance among 22.0% of Haemophilus influenzae. Results: LBM415 displayed potent activity against staphylococci, streptococci, Enterococcus faecium and Moraxella catarrhalis, with ≥99.0% of strains being inhibited at ≤4 mg/L 97.0% of Enterococcus faecalis isolates and 92.0% of H. influenzae isolates were also inhibited at this concentration. Seventy-seven percent of Burkholderia cepacia and 82.0% of Stenotrophomonas maltophilia were inhibited at ≤8 mg/L. No differences in LBM415 activity against S. aureus, CoNS, S. pneumoniae, Enterococcus spp. and H. influenzae were detected for subsets susceptible or resistant to antimicrobials such as oxacillin, penicillin, ampicillin, macrolides, vancomycin and fluoroquinolones. While regional differences were apparent with some comparator agents, sensitivity to LBM415 did not vary significantly among strains from the various geographic areas sampled. One isolate of S. aureus displayed high-level resistance to LBM415 owing to multiple sequence changes in resistance phenotype genes defB and fmt), despite the absence of the compound in clinical practice. This isolate remained susceptible to all other antimicrobials tested except for penicillin. Conclusions: With few differences detected among strains from various geographic regions, the first PDFI class agent to enter clinical development has consistently demonstrated a broad spectrum of activity against commonly isolated pathogens associated with uncomplicated respiratory and cutaneous infections. These compounds represent a significant therapeutic advance owing to their novel mechanism of action and antibacterial spectrum, including activity against resistant organisms, should pharmacokinetic and pharmacodynamic parameters support their continued development. Given the detection of a pre-existing PDFI-resistant isolate of S. aureus as demonstrated here, surveillance for resistance among the PDFI-targeted pathogens following introduction of this class of agent into clinical usage will be an important component of future studies.

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