Assessment of the In Vivo Activity of SPR741 in Combination with Azithromycin against Multidrug-Resistant Enterobacteriaceae Isolates in the Neutropenic Murine Thigh Infection Model

Abstract

SPR741 is a novel agent with structural similarity to polymyxins that is capable of potentiating the activities of various classes of antibiotics. Previously published studies indicated that although isolates had minimal susceptibilities to azithromycin (AZM), the antimicrobial activity of AZM against was enhanced when it was combined with SPR741. The current study evaluated the activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg given intravenously (i.v.) every 24 h (q24h) and SPR741 equivalent to clinical doses of 400 mg q8h i.v. (1-h infusion), alone and in combination, against multidrug-resistant (MDR) We studied 30 MDR isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM, and KPC), including a subset of isolates positive for genes conferring macrolide resistance (, ,, and ). activity was assessed as the change in log CFU per thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log CFU/thigh. Among isolates with AZM MICs of ≤16 mg/liter, treatment with AZM-SPR741was associated with an average reduction in bacterial burden of -0.53 ± 0.82 log CFU/thigh, and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy with an AZM-SPR741 HSR showed promising activity against MDR isolates with AZM MICs of ≤16 mg/liter, including those producing a variety of β-lactamases. These data support a potential role for AZM-SPR741 in the treatment of infections due to MDR .

Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance

“…The rise of antibiotic resistance in Gram-negative pathogens has brought renewed attention to this area. Indeed, a wealth of recent work shows that OM perturbants in combination with traditionally Gram-positive active antibiotics can successfully treat murine infection models of Acinetobacter baumannii ( 10 , 21 ), Klebsiella pneumoniae ( 22 ), and Escherichia coli ( 23 ). In 2017, the first OM perturbant SPR741, a derivative of PMBN ( 24 ), completed phase Ia and Ib clinical trials with a promising pharmacokinetic and tolerability profile ( 25 ).…”

Outer Membrane Interaction Kinetics of New Polymyxin B Analogs in Gram-Negative Bacilli

“…Analogs of polymyxin tested in this study have been synthesized with shorter peptide chains (as observed for the deacylated polymyxin B nonapeptide [PMBN]), modified acyl chains, and substituted amino acid residues ( Fig. 1) (10)(11)(12)(13). These modifications were made to reduce nephrotoxicity and allow for treatment at more effective concentrations.…”

A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models

“…Therefore, researchers have attempted to develop derivatives of polymyxin to improve its properties. Analogs of polymyxin, SPR741, SPR1205, SPR206, and SPR946 have been designed by shortening the peptide chains, by modifying the acyl chains, and by substituting the amino acid residues to reduce nephrotoxicity and to improve potency [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. SPR206 is a novel polymyxin B analog for the treatment of gram-negative infection that is undergoing a phase I clinical trial [ 56 ].…”