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Background: 'Last-line' antimicrobial usage has promoted the emergence of MDR bacteria. Production of Klebsiella pneumoniae carbapenemases (KPCs) is increasingly common and leads to resistance to most antimicrobials. However, ceftazidime/avibactam demonstrates activity against KPC-producing strains. Ceftazidime/avibactam in the empirical setting remains unknown., Methods: Strains underwent genetic analysis evaluating blaKPC presence/production and MICs were determined. Four strains were assessed in an in vitro, one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for 96 h. The following bolus dosing exposures were tested: 2.5 g of ceftazidime/avibactam every 8 h, 2 g of meropenem every 8 h, 1.25 mg/kg polymyxin B every 12 h, amikacin 'once-daily dosing' (peak of 70-80 mg/L), tigecycline at 200 mg ×1 dose followed by 100 mg every 12 h, and a drug-free growth control., Results: Thirty blaKPC-producing strains were evaluated; 97% of strains were ceftazidime/avibactam susceptible with MIC50/MIC90 values of 0.38/1.5 mg/L (range 0.032-16 mg/L). Two K. pneumoniae strains, one Klebsiella oxytoca strain and one Citrobacter freundii strain underwent further analysis in PK/PD models. Ceftazidime/avibactam displayed potent activity with a reduction of 4.23 ± 0.42 cfu/mL from the initial inoculum at 96 h. Against susceptible isolates, amikacin displayed similar activity compared with ceftazidime/avibactam at 96 h, although this was not demonstrated against all strains. Polymyxin B produced comparable activity to ceftazidime/avibactam against two strains. Neither meropenem nor tigecycline produced effective killing and were comparable to the drug-free growth control at 96 h., Conclusions: blaKPC-producing organisms demonstrated susceptibility to ceftazidime/avibactam and bactericidal activity was observed in the PK/PD model. Based on these data, ceftazidime/avibactam is a valuable agent for treating KPC-producing organisms and should be considered for treatment of infections caused by these pathogens.

Objectives: Tedizolid displays potent activity against Gram-positive pathogens. In vitro studies against clinical isolates of Staphylococcus aureus and enterococci demonstrated improved tedizolid activity over linezolid. However, this is not well-characterized against a large collection of resistant isolates, including vancomycin-intermediate S. aureus (VISA), heterogeneous VISA (hVISA), daptomycin-non-susceptible (DNS) S. aureus, linezolid-resistant (LR) S. aureus and VRE. Therefore, our objective was to determine tedizolid activity versus other agents, against MRSA and VRE with various resistance phenotypes., Methods: In total, 302 MRSA (75 DNS, 100 VISA, 120 hVISA and 7 LR) and 220 VRE [100 Enterococcus faecalis (all susceptible to daptomycin and linezolid) and 120 E. faecium (25 DNS and 10 LR)] were evaluated. LR isolates were analysed for the cfr gene. MICs of tedizolid, linezolid, ampicillin, clindamycin, daptomycin, gentamicin, levofloxacin, oxacillin, tigecycline, trimethoprim/sulfamethoxazole and vancomycin were determined in accordance with CLSI guidelines., Results: Tedizolid MIC90 values for hVISA, VISA and DNS were 0.5 mg/L (versus 4, 4 and 2 mg/L, respectively, for linezolid). The tedizolid MIC range for LR MRSA was 0.063-1 mg/L. Two LR MRSA possessed the cfr gene with tedizolid MICs of 0.125 and 0.25 mg/L (linezolid MICs of 16 and 8 mg/L). The tedizolid MIC90 for vancomycin-resistant E. faecalis and E. faecium was 0.25 and 1 mg/L, respectively; three dilutions lower for E. faecalis and two dilutions lower for E. faecium compared with linezolid., Conclusions: Tedizolid MICs demonstrate activity against isolates with decreased susceptibility to alternative agents, including linezolid. Tedizolid may be a viable treatment option in clinical situations with MDR Gram-positive pathogens., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We previously demonstrated that ceftaroline enhances daptomycin against MRSA in vitro. However, prolonged combination therapy is clinically undesirable and possibly unnecessary. The purpose of this study was to determine if this combination could be de-escalated to a single agent without compromising efficacy., Methods: We investigated the following simulated regimens against two clinical, daptomycin-non-susceptible MRSA isolates in an in vitro pharmacokinetic/pharmacodynamic hollow-fibre model over 192 h: 600 mg of ceftaroline every 12 h (fCmax 17.0 mg/L, t½ 2.66 h); 10 mg/kg/day daptomycin (fCmax 11.3 mg/L, t½ 8 h); 6 mg/kg/day daptomycin (fCmax 7.5 mg/L, t½ 8 h); ceftaroline+daptomycin; and ceftaroline+daptomycin de-escalated to ceftaroline, daptomycin or drug-free simulations., Results: Daptomycin and ceftaroline MICs were 2 and 2 and 0.5 and 1 mg/L for strains R6063 and R5563, respectively. Ceftaroline+daptomycin (6 or 10 mg/kg/day) achieved a >5 log10 cfu/mL reduction within 96 h against both strains. Bacterial counts remained <1.5 log10 cfu/mL from 96 to 192 h regardless of de-escalation to either agent. There were no significant differences between combination or de-escalation regimens for either organism at either daptomycin dose. All combination/de-escalation to monotherapy regimens resulted in significantly improved activity compared with drug-free control, ceftaroline or daptomycin monotherapy (P<0.01)., Conclusions: These findings confirm that ceftaroline+daptomycin is a potent combination against MRSA. The high degree of bactericidal activity observed with this combination appears sufficiently robust to allow for de-escalation to a single agent without bacterial regrowth. The equivalent activity observed with ceftaroline+daptomycin (6 and 10 mg/kg/day) suggests this combination could also be daptomycin sparing. Further research is warranted to optimize dose and de-escalation timing., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The synergistic combination of daptomycin plus ampicillin has proven to be effective against VRE including daptomycin-non-susceptible strains. Ceftobiprole is a cephalosporin with broad binding affinity for enterococcal PBP subtypes including PBP5. Given the synergy between β-lactams and daptomycin against VRE, it was of interest to determine whether ceftobiprole offered any synergistic advantage with daptomycin compared with ampicillin., Methods: MICs were determined by broth microdilution in the presence and absence of ampicillin or ceftobiprole for 20 ampicillin-resistant VRE. Six strains, including two isogenic pairs of vancomycin-resistant Enterococcus faecium and two vancomycin-resistant Enterococcus faecalis, were evaluated for synergy using time-kill methods. Synergy was defined as a ≥2 log10 cfu/mL reduction of the combination over the most active single agent. Binding of daptomycin-bodipy in the presence and absence of ceftobiprole was quantified., Results: Daptomycin MICs ranged from 2 to 256 mg/L. The addition of ceftobiprole and ampicillin reduced daptomycin MICs by a median of 3 and 4 log2 dilutions, respectively. In time-kill studies, daptomycin plus either ceftobiprole or ampicillin was synergistic against four of six strains, but not the same strains. Both combinations were synergistic against the vancomycin-resistant E. faecalis strains. Ceftobiprole exposure increased daptomycin-bodipy binding by 2.8 times (P<0.0001)., Conclusions: Ceftobiprole appears to offer a similar degree of synergistic activity to ampicillin when combined with daptomycin against VRE. Further research should explore the genetic and phenotypic qualities of strains that respond preferentially to ceftobiprole as opposed to ampicillin., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and β-lactams (BLs). In vitro data suggest synergy between several BLs and glycopeptides or lipopeptides against resistant pathogens. Our objective was to conduct combination MIC and time-kill experiments to evaluate BL synergy with daptomycin against enterococci., Methods: Fifteen Efc and 20 Efm strains were evaluated for daptomycin enhancement via combination MICs. Daptomycin MICs were obtained by microdilution in the absence and presence of ceftaroline, ertapenem, cefepime, ceftriaxone, cefotaxime, cefazolin and ampicillin. Two Efc strains (R6981 and R7808) and one isogenic daptomycin-susceptible/daptomycin-non-susceptible Efm pair (8019/5938) were evaluated in time-kill experiments. Daptomycin at 0.5 × MIC was used in combination with BL at biological free concentration. Strain 5938 was evaluated for enhancement of daptomycin binding in fluorescently labelled daptomycin (BoDipy) experiments., Results: Ceftaroline reduced daptomycin MIC values the most against all strains. In time-kill experiments, ceftaroline, ertapenem, cefepime, ceftriaxone and ampicillin demonstrated synergy with daptomycin against all strains, cefazolin demonstrated none and cefotaxime demonstrated synergy against only R7808. Bacterial reduction at 24 h was greater for daptomycin + ceftaroline, ertapenem, cefepime, ceftriaxone or ampicillin for all strains compared with any single agent or daptomycin + cefazolin or cefotaxime (P < 0.001). In BoDipy daptomycin experiments, ceftaroline enhanced daptomycin binding most compared with all other agents (P < 0.001)., Conclusions: The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clinical research involving daptomycin combinations is warranted., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Ceftobiprole is a broad-spectrum cephalosporin that demonstrates activity against Staphylococcus aureus resistant to methicillin, including strains with reduced susceptibility to glycopeptides and lipopeptides. The addition of this agent provides a potential therapeutic option for difficult-to-treat infections. Synergy has been demonstrated between β-lactams combined with glycopeptides and lipopeptides against S. aureus. This study sought to determine whether ceftobiprole was synergistic with daptomycin, vancomycin or standard-of-care combination agents (gentamicin or rifampicin) against methicillin-resistant S. aureus (MRSA) strains with varying degrees of vancomycin susceptibility., Methods: Broth microdilution MICs of ceftobiprole, daptomycin, vancomycin, rifampicin and gentamicin were evaluated for 20 MRSA isolates. Combination MICs were additionally evaluated in the presence of subinhibitory concentrations of ceftobiprole to assess synergism. Time-kill curves for five representative isolates were performed utilizing combinations of ceftobiprole plus daptomycin, vancomycin, rifampicin and gentamicin to further quantify the degree of synergy for each regimen., Results: Ceftobiprole plus daptomycin represented the most potent combination with a 4-fold decrease in MIC and synergy against all strains evaluated in time-kill evaluations. Additionally, binding studies demonstrated enhanced daptomycin binding in the presence of subinhibitory concentrations of ceftobiprole., Conclusions: The use of combination therapy with ceftobiprole may provide a needed addition for the treatment of Gram-positive infections resistant to daptomycin or vancomycin. Consistent with what has been observed with other β-lactams, ceftobiprole increased bodipy-tagged daptomycin binding on the surface of S. aureus, potentially explaining this potent synergy observed in time-kill evaluations. More detailed evaluation of ceftobiprole is warranted to better characterize observed synergy., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Daptomycin has demonstrated synergy with β-lactams against Enterococcus faecium and this combination has been used successfully to treat infections refractory to daptomycin. We investigated daptomycin alone and combined with ceftriaxone against vancomycin-resistant enterococci (VRE) in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation (SEV) model., Methods: Daptomycin (6 and 12 mg/kg/day) with and without 2 g of ceftriaxone every 24 h were evaluated against two clinical E. faecium strains (8019 and 5938) and one Enterococcus faecalis (6981) in a 96 h in vitro pharmacokinetic/pharmacodynamic SEV model. FITC-labelled poly-l-lysine was used to assess β-lactam-induced changes in cell surface charge., Results: For 8019 and 6981, daptomycin 6 mg/kg with ceftriaxone and daptomycin 12 mg/kg alone and in combination with ceftriaxone displayed significantly more activity than daptomycin 6 mg/kg alone from 48 to 96 h (P ≤ 0.005). The addition of ceftriaxone significantly enhanced activity of daptomycin 6 mg/kg against both strains at 96 h (8019, reductions -0.55 versus 3.64 log10 cfu/g; 6981, reductions 1.11 versus 5.67 log10 cfu/g; P < 0.001) and improved daptomycin 12 mg/kg against 8019 at 96 h. Daptomycin 12 mg/kg plus ceftriaxone displayed no appreciable activity against 5938 (daptomycin MIC 32 mg/L). Daptomycin non-susceptibility developed in 8019 and 6981 versus daptomycin 6 mg/kg by 96 h. Ampicillin or ceftriaxone exposure reduced daptomycin surface charge in 8019, resulting in significantly increased FITC-poly-l-lysine binding., Conclusions: The combination of daptomycin and ceftriaxone may be promising for eradicating high-inoculum, deep-seated enterococcal infections. Further research is warranted to examine the enhancement of daptomycin and innate immunity killing of VRE by ceftriaxone and other β-lactams., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)