Classical β-Lactamase Inhibitors Potentiate the Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus and Colistin against Acinetobacter baumannii

Abstract

We asked whether beta-lactamase inhibitors (BLIs) increased the activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA), the peptide antibiotic colistin (COL) against the emerging Gram-negative nosocomial pathogen Acinetobacter baumannii, and the human host defense peptide cathelicidin LL37 against either pathogen. DAP and LL37 kill curves were performed with or without BLIs against MRSA, vancomycin-intermediate S. aureus (VISA), and heterogeneous VISA (hVISA). COL and LL37 kill curves were performed against A. baumannii. Boron-dipyrromethene (BODIPY)-labeled DAP binding to MRSA grown with the BLI tazobactam (TAZ) was assessed microscopically. The combination of COL plus TAZ was studied in a murine model of A. baumannii pneumonia. TAZ alone lacked in vitro activity against MRSA or A. baumannii. The addition of TAZ to DAP resulted in a 2- to 5-log10 reduction in recoverable MRSA CFU at 24 h compared to the recoverable CFU with DAP alone. TAZ plus COL showed synergy by kill curves for 4 of 5 strains of A. baumannii tested. Growth with 20 mg/liter TAZ resulted in 2- to 2.5-fold increases in the intensity of BODIPY-DAP binding to MRSA and hVISA strains. TAZ significantly increased the killing of MRSA and A. baumannii by LL37 in vitro. TAZ increased the activity of COL in a murine model of A. baumannii pneumonia. Classical BLIs demonstrate synergy with peptide antibiotics. Since BLIs have scant antimicrobial activity on their own and are thus not expected to increase selective pressure toward antibiotic resistance, their use in combination with peptide antibiotics warrants further study.

Humanized Exposures of a β-Lactam-β-Lactamase Inhibitor, Tazobactam, versus Non-β-Lactam-β-Lactamase Inhibitor, Avibactam, with or without Colistin, against <b><i>Acinetobacter baumannii</i></b> in Murine Thigh and Lung Infection Models

“…When compared with the lack of in vivo activity demonstrated by avibactam, a non-β-lactam-BLI, our findings further suggest that binding to the organism's PBPs is required for tazobactam activity against A. baumannii. This influence on PBP activity likely alters the bacterial surface, rendering it more susceptible to endogenous antimicrobial peptides like cathelicidins that are present at very high concentrations in sites of infection [14].…”

“…We had previously shown that β-lactam-BLIs provide additional collateral antibacterial activity by enhancing the activities of administered peptide antibiotics such as daptomycin against MRSA and colistin against A. baumannii, and even endogenous peptide antibiotics such as cathelicidin LL37 that are produced by the innate immune system against these pathogens [14]. While the activity of sulbactam, another β-lactam-BLI, alone has been characterized against some strains of A. baumannii, tazobactam has been less extensively studied against A. baumannii.…”

“…In previous in vivo murine thigh and lung models, colistin alone and in combination with other antimicrobials against MDR A. baumannii demonstrated efficacy, although inconsistent, requiring further investigation [9,[11][12][13]. Most recently, we have found that β-lactam-BLIs can potentiate not only the activity of colistin against some strains of A. baumannii but also the activity of daptomycin against MRSA, further expanding upon the β-lactam-peptide antibiotic see-saw effect [14].…”

β-Lactamase Inhibitors Enhance the Synergy between β-Lactam Antibiotics and Daptomycin against Methicillin-Resistant Staphylococcus aureus

“…Traditional ␤-lactamase inhibitors (BLIs) are themselves BL compounds that act as suicide substrates for the ␤-lactamases, rendering them inactive, thus protecting penicillins (e.g., penicillin, ampicillin [ (17). In addition, in a pharmacokinetic/pharmacodynamic in vitro hollow fiber model, we demonstrated that the addition of TAZ enhanced the synergy between ceftolozane (TOL) and DAP against MRSA (9).…”

Monitoring of multiresistant community-associated MRSA strains from patients with pathological processes of different localization

“…However, the resistance mechanisms of Staphylococcus spp. to these antibiotics have been also described today (Rybak et al, 2014;Miller et al, 2016;Sakoulas et al, 2017). Monitoring of the level of resistance both to traditional preparations and to the new ones is an important element in formation of a strategy of rational antibacterial therapy of infections caused by MRSA.…”