Treatment of Staphylococcus aureus infections continues to be a challenge due to antimicrobial resistance. Endogenous antimicrobial peptides may offer a new option for treating S. aureus infections but several factors limit their clinical utility. Herein, we studied the activity of the antimicrobial peptide LL-37 and two truncated derivatives, LL-13 and LL-17 alone and in combination with vancomycin against a range of drug-resistant S. aureus strains including methicillin resistant S. aureus (MRSA) and vancomycin resistant S. aureus (VRSA) strains in vitro. When used with vancomycin, LL-13 and LL-17 displayed synergy against VRSA and showed the ability to restore sensitivity to vancomycin after pretreatment. In addition, LL-13 and LL-17 showed a strong ability to inhibit S. aureus biofilm production. LL-37 derivatives may be useful in treating infections that are resistant to vancomycin or in scenarios where biofilm formation is a concern.
BackgroundCeftolozane/tazobactam (CT) is a cephalosporin/β-lactamase inhibitor with excellent activity against multi-drug-resistant (MDR) P. aeruginosa (PSA). Several cases of CT-resistance (CT-R) development after exposure have been reported. We recovered a PSA isolate with high-level CT-R from a bacteremic patient with severe, prolonged neutropenia and 5 weeks of CT exposure. Then, multiple mutational pathways and the role of combination therapy were evaluated.MethodsMinimum inhibitory concentrations (MIC) to CT were determined by Etest. Synergy tests between CT and tobramycin (TOB) were conducted and interpreted based on the fractional inhibitory concentration index (FICI). Furthermore, whole genome sequencing was performed. Paired-end reads were mapped and compared with reference strain PAO1. Variant analyses were conducted using CLC Genomics Workbench.ResultsThe MICs for CT and TOB were >256 and 4 mg/L, respectively. The combination revealed synergistic effects (FICI < 0.5) with reduced CT and TOB MICs to 16 and 1 mg/L, respectively. Clinically, combination therapy of CT 3g q8h given over 4 hours and TOB 7 mg/kg q24h successfully cleared the bacteremia within 2 days. Genomic analysis revealed the CT-R isolate contained multiple variants in the ampC gene, including G183D associated with low level CT-R. Two additional variants in aminoacid position 79 (R79Q) and position 105 (T105A) were located inside or near helix-H2 which interacts with the Ω-loop through hydrogen-binding rendering the serine active site more pliable to accommodate larger molecules. Moreover, the CT-R isolate showed a truncated ampD and multiple mutations in mexD, mexT, mexI, and mexR, a primary regulator of mexAB-oprM. The isolate also contained the oprD mutation (Q142X) and an oprD-inactivating mutation (W417X). In addition to these chromosomal mutations, the isolate harbored OXA-50, blaPAO1, and aph(3′)-IIb.ConclusionHigh-level CT-R was likely driven by multiple mutations in the ampC region causing structural changes. While resistance to CT is worrisome, our case of a severe neutropenic patient who rapidly cleared bacteremia on CT 3g qh8 given over 4 hours plus TOB emphasizes the importance of strategic combination and dosing in combating MDR PSA.Disclosures
All authors: No reported disclosures.
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