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Exebacase is a lysin (cell wall hydrolase) with direct lytic activity against Staphylococcus aureus including methicillin-resistant S. aureus (MRSA). Time-kill analysis experiments illustrated bactericidal activity of exebacase-daptomycin against MRSA strains MW2 and 494. Furthermore, exebacase in addition to daptomycin (10, 6, and 4 mg/kg/day) in a two-compartment ex vivo pharmacokinetic/pharmacodynamic simulated endocardial vegetation model with humanized doses resulted in reductions of 6.01, 4.99, and 2.81 log(10) CFU/g (from initial inoculum) against MRSA strain MW2.

Cefiderocol (CFDC), a novel siderophore cephalosporin, demonstrates strong activity against multidrug-resistant (MDR) Acinetobacter baumannii. Limited studies have evaluated CFDC alone and in combination with other Gram-negative antibiotics against MDR A. baumannii isolates. Susceptibility testing revealed lower CFDC minimum inhibitory concentration (MIC) values than the comparator Gram-negative agents (87% of MICs ≤ 4mg/L). Six isolates, with elevated CFDC MICs (16-32 mg/L), were selected for further experiments. Time-kill analyses presented with synergistic activity and beta-lactamase inhibitors increased CFDC susceptibility in each of the isolates.

Acinetobacter baumannii is currently classified as one of six pathogens that contribute to increased patient mortality. Thus, exploratory studies navigating alternative treatment strategies are of supreme interest. Herein, we completed minimum inhibitory concentration (MIC) testing, and time-kill analyses (TKA) on 50 carbapenem-resistant Acinetobacterbaumannii isolates including 28 colistin-resistant isolates. Upon testing of MEM or TGC in the presence of sub-inhibitory COL against the 50 isolates, there was a median 2-fold reduction in MEM and TGC MICs. In the TKAs, the COL+MEM combination was synergistic in 45 (90%) isolates and bactericidal in 43 (86%) isolates at 24 hours, whereas the COL+TGC combination TKAs demonstrated synergy in 32 (64%) isolates and bactericidal activity was shown in 28 (56%) isolates. Additionally, sulbactam (SUL) and TGC were added to the COL+MEM dual therapy regimen to assess the possible utility of a triple therapy regimen against five non-responsive isolates. The COL+MEM+SUL and COL+MEM+TGC regimens effectively restored synergy in (5/5) 100% of the isolates. The results of this study demonstrate the potential utility of COL combinations in the treatment of carbapenem-resistant isolates.

The most efficacious antimicrobial therapy to aid in the successful elimination of resistant S. aureus infections is unknown. In this study, we evaluated varying phenotypes of S. aureus against dalbavancin (DAL), vancomycin (VAN), and daptomycin (DAP) alone and in combination with cefazolin (CFZ). The objective of this study was to observe whether there was a therapeutic improvement in adding a beta-lactam to a glycopeptide, lipopeptide, or a lipoglycopeptide. We completed a series of in vitro tests including minimum inhibitory concentration testing (MIC) of the antimicrobials in combination, time-kill analysis (TKA), and a 168 h (7-day) one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model on two daptomycin non-susceptible (DNS), vancomycin intermediate S. aureus strains (VISA), D712 and 6913. Results from our MIC testing demonstrated a minimum 2-fold and a maximum 32-fold reduction in MIC values for DAL, VAN, and DAP in combination with CFZ, in contrast to either agent used alone. The TKAs completed on four strains paralleled the enhanced activity demonstrated via the combination MICs. In the one-compartment PK/PD models, the combination of DAP plus CFZ or VAN plus CFZ resulted in a significant (p &lt, 0.001) improvement in bactericidal activity and overall reduction in CFU/ml over the 7-day period. While the addition of CFZ to DAL improved time to bactericidal activity, DAL alone demonstrated equal and more sustained overall activity compared to all other treatments. The use of DAL alone, with or without CFZ and the combinations of VAN or DAP with CFZ appear to result in increased bactericidal activity against various recalcitrant S. aureus phenotypes.

Background Enterococcus faecium infections are difficult to treat and there is a growing concern regarding the rising occurrence of daptomycin resistance. We have previously demonstrated that only daptomycin plus ampicillin combination was effective against DAP-R E. faecium R497. The efficacy and systematic screening DAP plus β-lactams and DAP plus other combinations against daptomycin-resistant strains of E. faecium has not been investigated. Here, we evaluated 40 selected single, dual and triple combinations of antibacterial regimens against two clinical isolates of DAP-R E. faecium (R497 and R496 (with daptomycin MIC of 16 and 32 µg/ml, respectively). Methods E.faecium R497 and R496 were tested against an array of antibacterial agents including daptomycin, tigecycline, linezolid, ertapenem, ceftaroline and ceftriaxone using MIC susceptibility tests and 24h time-kill curves (TKC). All susceptibility tests and TKCs were performed in MHB broth containing 50 mg/L calcium. TKCs were performed at half MIC or free peak concentration of each antibacterial (whichever was lower). Synergy was defined as >2 log10 CFU/ml decrease compared to the most potent antibacterial agent. Results Susceptibility tests demonstrated resistance to all listed β-lactams for both organisms. TKCs demonstrated that combination of daptomycin-ertapenem, daptomycin-ceftriaxone and daptomycin-ceftaroline was not effective against R497. However, addition of ceftriaxone or linezolid to either daptomycin-ertapenem or daptomycin-ceftaroline combinations resulted in synergy against this organism. Combinations of daptomycin-ertapenem and daptomycin-ceftaroline were synergistic against R496. Addition of linezolid, ceftriaxone or tigecycline to either daptomycin-ceftaroline or daptomycin-ertapenem combination did not increase killing activity against R496. Conclusion Differential affinity of β-lactams to specific PBP isotypes seems to be a key parameter for the success of daptomycin- β-lactam combinations against multi-drug resistant E. faecium . The optimized use of double β-lactam therapy in addition to daptomycin can potentially lead to improved patient outcomes and preserving antibiotic therapy for serious enterococcus infections. Disclosures Cesar A. Arias, MD, MSc, PhD, FIDSA, Entasis Therapeutics (Scientific Research Study Investigator)MeMed (Scientific Research Study Investigator)Merck (Grant/Research Support) Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support)

Vancomycin is the treatment of choice for infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Clinically, combinations of vancomycin (VAN) and beta-lactams have been shown to improve patient outcomes compared to VAN alone for the treatment of MRSA bloodstream infections. However, VAN is known to cause nephrotoxicity, which could be ameliorated using biocompatible lipid drug delivery systems or liposomes. Previous attempts have been made for encapsulation of VAN in liposomes, however, drug loading has been poor, mainly because of the high aqueous solubility of VAN. In this study, we report a robust method to achieve high loading of VAN and cefazolin (CFZ) in unilamellar liposomes. Liposomes of sizes between 170&ndash, 198 nm were prepared by modified reverse phase evaporation method and achieved high loading of 40% and 26% (weight/weight) for VAN and CFZ, respectively. Liposomal VAN reduced minimum inhibitory concentration (MIC) values 2-fold in comparison to commercial VAN. The combination of liposomal VAN (LVAN) and liposomal CFZ (LCFZ) demonstrated a 7.9-fold reduction compared to LVAN alone. Rhodamine dye-loaded liposomes demonstrated superior cellular uptake in macrophage-like RAW 264.7 cells. Fluorescent images of LVAN-encapsulating near-infrared (NIR) dye, S0456 (LVAN-S0456) clearly indicated that LVAN-S0456 had reduced renal excretion with very low fluorescent intensity in the kidneys. It is anticipated that the long circulation and reduced kidney clearance of LVAN-S0456 compared to VAN-S0456 injected in mice can lead to enhanced efficacy against MRSA infections with reduced nephrotoxicity. Overall, our developed formulations of VAN when administered alone or in combination with CFZ, provide a rational approach for combating MRSA infections.

Background The viridans group streptococci (VGS) are a heterogeneous group of microorganisms that form portion of the normal oral flora of humans. Among the VGS, S. mitis-oralis is the most common cause of infective endocarditis in the developing world, as well as the leading cause of the “toxic Strep syndrome” in neutropenic cancer patients. Therapeutic options are often limited by frequent β-lactam resistance, as well as vancomycin tolerance. Daptomycin (DAP) has been suggested as an alternative therapeutic option for invasive S. mitis-oralis infections. However, the ability of these strains to rapidly evolve high-level and durable DAP-resistance (DAP-R) is problematic. Recent data have suggested the potential for combined DAP +β-lactam therapy to circumvent this issue. Methods Using human-simulated dosing, the activities of DAP (6, 8,10 or 12 mg/kg/day × 4 days) alone vs. DAP (6 mg/kg/day) +(CRO) (500 mg daily × 4 days or 500 mg, given once on day one) were assessed against two DAP-susceptible (DAP-S) S. mitis-oralisstrains (SF100; 351) employing a PK-PD model of simulated endocardial vegetations (SEVs). Results DAP alone was not bactericidal at any dose-regimen, and regrowth of high-level DAP-R isolates was observed in both strains (MIC increase from 0.5 to >64 µg/mL). Combinations of DAP +CRO at either dose-regimen yielded significant reductions in log10CFU/g amounts within SEVs for both strains (~6 log10 CFU/g and to detection limits) within 24 hours. In addition, no DAP-R strains were detected in either DAP+ CRO combination regimens over the 96-hour exposure period. Conclusion Combinations of DAP+ low-dose CRO (even single dosing) showed promise to forestall the emergence of DAP-R in S. mitis-oralis strains. Such regimens can potentially lead to optimizing treatment outcomes with DAP therapy, with minimal β-lactam exposures. Further research in relevant in vivo models and clinically is warranted to determine the most optimized DAP+ CRO dose-regimens for the prevention of emergence of DAP-R among S. mitis-oralis strains. Disclosures J. M. Miro, Abbvie: Consultant and Grant Investigator, Consulting honoraria and Research grant; Bristol-Myers Squibb: Consultant and Grant Investigator, Consulting honoraria and Research grant; Genentech: Consultant and Grant Investigator, Consulting honoraria and Research grant; Medtronic: Consultant and Grant Investigator, Consulting honoraria and Research grant; Novartis: Consultant and Grant Investigator, Consulting honoraria and Research grant; Gilead Sciences: Consultant and Grant Investigator, Consulting honoraria and Research grant; Pfizer: Consultant and Grant Investigator, Consulting honoraria and Research grant; ViiV Healthcare: Consultant and Grant Investigator, Consulting honoraria and Research grant. C. Arias, Merck & Co., Inc.: Grant Investigator, Research support; MeMed: Grant Investigator, Research support; Allergan: Grant Investigator, Research support. A. Bayer, Trellis: grant recipient, Grant recipient; Contrafect: grant recipient, Grant recipient; Theravance: grant recipient, Grant recipient. M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support; Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support; NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support.