Article Figures & Data
Figures
- FIG 1
Time-kill curves of CF strains AMT 0307-5 (MSSA), AMT 0012-33, WIS 664 (MRSA), and TMH 5007 (MRSA CPTr), determined using the following human peak free serum drug concentrations: 8 mg/liter for TLV, 16 mg/liter for VAN, 10.4 mg/liter for LZD, and 16 mg/liter for CPT. The limit of detection of that assay was 10.
- FIG 2
Comparison of virulence of S. aureus strains and their isogenic TLV-resistant mutants in G. mellonella model of infection. The worms were infected at a dose of 106 bacteria per worm. Survival was monitored for 10 days.
Tables
- TABLE 1
Telavancin MIC90 of CPT for 333 S. aureus strains from CF patientsa
Strain MIC (μg/ml)b CPT TLV DAP VAN LZD MSSA (n = 180) 0.5 (100) 0.06 (100) 0.25 (100) 1.0 (100) 1–2 (99.4) MRSA (n = 153) CPTs (n = 130) <1.5 (85) CPTir (n = 20) 1.5–2 (13) 0.06 (100) 0.5–1 (100) 1–1.5 (100) 1–2 (98.1) CPThr (n = 3) >32 (2) ↵a The MIC90 of CPT was determined by the microdilution method in Mueller-Hinton broth supplemented with polysorbate 80 (0.002%) and was compared to the MIC90s of the DAP, VAN, LZD, and CPT agents following CLSI guidelines.
↵b Values in parentheses represent the percentage of isolates with the indicated MIC.
- TABLE 2
MICs of TLV, VAN, and DAP for the parent strains and in vitro-derived TLVr mutants obtained by serial passage with subinhibitory concentrations of TLV for 40 daysa
Strain MIC (μg/ml) Day 0 Day 40 TLV VAN DAP TLV VAN DAP ATCC 25913 0.064 1.5 0.25 3 4 8 TMH 5007 0.047 2 0.75 1.5 6 8 AMT 0114-48 0.047 2 0.75 2 6 6 WIS 664 0.032 2 1 1.5 3 6 ↵a As shown, a 3- to 4-fold increase in the VAN MIC (from 1.5 to 6 μg/ml) and an 8- to 10-fold increase in DAP MICs (0.25 to 8 μg/ml) were determined, suggesting potential cross-resistance between TLV, VAN, and DAP antibiotics.
- TABLE 3
Most relevant mutations identified in telavancin-resistant mutants
Gene Locus Functiona SNP Amino acid change TMH 5007 AMT 0114-48 ATCC 25913 WIS 664 Seattle_90 acuC SA1556 NAD-independent protein deacetylase AcuC A>T A>T A>T A>T A>T I159L adh1 SA0562 Alcohol dehydrogenase G>T G>T G>T G>T G>T K325N ald SA1531 Alanine dehydrogenase G>A G>A G>A G>A G>A S126L capB SA0145 Capsular polysaccharide synthesis enzyme Cap5A T>C T>C T>C T>C T>C C81R ebhA SA1267 Putative staphylococcal surface-anchored protein A>G A>G A>G A>G A>G V4497A fni SA2136 Isopentenyl diphosphate delta-isomerase, FMN dependent G>C G>C G>C G>C G>C R88G gltB SA0430 Glutamate synthase (NADPH) large chain T>C T>C T>C T>C T>C V1177A holA SA1415 DNA polymerase III delta subunit (EC 2.7.7.7) T>G T>G T>G T>G T>G K45T hsdM SA0391 Type I restriction-modification system, DNA methyltransferase subunit M T>C T>C T>C T>C T>C V387A lacE SA1992 PTS system, lactose-specific IIB component T>C T>C T>C T>C T>C I365 M lytH, SA1459 SA1458 LytH protein involved in methicillin resistance/N-acet T>C T>C T>C T>C T>C I1F mutS2 SA0991 Recombination inhibitory protein MutS2 G>A G>A G>A G>A G>A V252I pbp2 SA1283 Multimodular transpeptidase-transglycosylase G>A G>A G>A G>A G>A C197Y pbuX SA0374 Xanthine permease T>G T>G T>G T>G T>G L231V pgm SA0730 2,3-Bisphosphoglycerate-independent phosphoglycerate mutase A>G A>G A>G A>G A>G T250A rho SA1923 Transcription termination factor Rho T>G T>G T>G T>G T>G I48L rplA SA0496 LSU ribosomal protein L1p (L10Ae) A>G A>G A>G A>G A>G T92A rpsQ SA2038 SSU ribosomal protein S17p T>A T>A T>A T>A T>A I77L sigA SA1390 RNA polymerase sigma factor RpoD C>T C>T C>T C>T C>T V253I sdrC SA0519 Adhesin of unknown specificity SdrC G>A G>A G>A G>A G>A E75K sdrD SA0520 Adhesin of unknown specificity SdrD G>T G>T G>T G>T G>T D1141Y sucA SA1245 2-Oxoglutarate dehydrogenase E1 component T>G T>G T>G T>G T>G K842N tagG SA0594 Teichoic acid translocation permease protein TagG T>C T>C T>C T>C T>C V227A tcaA SA2146 Membrane protein TcaA, associated with teicoplanin resistance A>G A>G A>G A>G A>G L218P thrS SA1506 Threonyl-tRNA synthetase C>T C>T C>T C>T C>T G60E treP SA0432 PTS system, trehalose-specific IIB component C>G C>G C>G C>G C>G A381G uvrA SA0714 Excinuclease ABC subunit A T>C T>C TA>CG T>C TA>CG L857P murQ SA0185 N-Acetylmuramic acid 6-phosphate etherase C>T G257D clfA SA0742 Clumping factor ClfA, fibrinogen-binding protein C>A P208T dltA SA0793 d-Alanine–poly(phosphoribitol) ligase subunit 1 A>G K177E dltA SA0793 d-Alanine–poly(phosphoribitol) ligase subunit 1 G>A S275N dltA SA0793 d-Alanine–poly(phosphoribitol) ligase subunit 1 T>C L318P dltA SA0793 d-Alanine–poly(phosphoribitol) ligase subunit 1 C>A D327E dltD SA0796 Poly(glycerophosphate chain) d-alanine transfer protein DltD T>A I264K dltD SA0796 Poly(glycerophosphate chain) d-alanine transfer protein DltD T>A D350E spa SA0107 Protein A, von Willebrand factor binding protein Spa CC>TT G321N spa SA0107 Protein A, von Willebrand factor binding protein Spa T>G K274N spa SA0107 Protein A, von Willebrand factor binding protein Spa GT>AG N234T ↵a FMN, flavin mononucleotide; PTS, phosphotransferase; N-acet, N-acetyl; LSU, long subunit; SSU, short subunit.
