Ceftobiprole and ampicillin increase daptomycin susceptibility of daptomycin-susceptible and -resistant VRE

Werth, Brian J.; Barber, Katie E.; Tran, Kieu-Nhi; Nonejuie, Poochit; Sakoulas, George; Pogliano, Joe; Rybak, Michael J.

doi:10.1093/jac/dku386

Cited by 36 publications

(18 citation statements)

References 15 publications

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“…The beta-lactam concentrations used in the combinations were 0.5 ϫ the MICs listed below or the biological free peak concentrations presented in the text, whichever one was lower. (A) Strain 8019; ORI MIC, 0.125 g/ml; AMP MIC, Ͼ128 g/ml; ERT MIC, Ͼ32 g/ml; CPT MIC, 32 g/ml; (B) strain R6815; ORI MIC, 0.125 g/ml; AMP MIC, Ͼ64 g/ml; ERT MIC, Ͼ32 g/ml; CPT MIC, Ͼ64 g/ml; (C) strain R7164; ORI MIC, 0.125 g/ml; AMP MIC, 8 g/ml; ERT MIC, Ͼ32 g/ml; CPT MIC, been demonstrated when beta-lactams were combined with VAN or DAP, and the findings of our study suggest that beta-lactams confer similar benefits upon ORI in vitro (22,23,(25)(26)(27)(32)(33)(34)(35).…”

Section: Discussionsupporting

confidence: 64%

“…In vitro time-kill experiments have demonstrated the concentration-dependent bactericidal activity of ORI against daptomycin-nonsusceptible (DNS) MRSA, VAN-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), and VRE in 24-h time-kill experiments (17)(18)(19)(20). Recent data suggest that lipopeptides and glycopeptides demonstrate enhanced activity against these resistant, Gram-positive organisms when beta-lactams are added (9,13,15,16,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). However, the activity of ORI in combination with beta-lactams against multidrug-resistant MRSA or VRE strains has yet to be evaluated.…”

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confidence: 99%

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Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

Smith

Yim

Raut

et al. 2016

Antimicrob Agents Chemother

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Oritavancin possesses activity against vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). In vitro data suggest synergy between beta-lactams (BLs) and vancomycin or daptomycin, agents similar to oritavancin. We evaluated the activities of BLs combined with oritavancin against MRSA and VRE. Oritavancin MICs were determined for 30 strains, 5 each of MRSA, daptomycin-nonsusceptible (DNS) MRSA, vancomycin-intermediate MRSA (VISA), heteroresistant VISA (hVISA), vancomycin-resistant Enterococcus faecalis, and vancomycin-resistant Enterococcus faecium. Oritavancin MICs were determined in the presence of subinhibitory concentrations of BLs. Oritavancin combined with ceftaroline, cefazolin, or nafcillin was evaluated for lethal synergy against MRSA, and oritavancin combined with ceftaroline, ampicillin, or ertapenem was evaluated for lethal synergy against VRE in 24-h time-kill assays. Oritavancin at 0.5؋ the MIC was combined with BLs at 0.5؋ the MIC or the biological free peak concentration, whichever one was lower. Synergy was defined as a >2-log 10 -CFU/ml difference between the killing achieved with the combination and that achieved with the most active single agent at 24 h. Oritavancin MICs were <0.125 g/ml for all MRSA isolates except three VISA isolates with MICs of 0.25 g/ml. Oritavancin MICs for VRE ranged from 0.03 to 0.125 g/ml. Oritavancin in combination with ceftaroline was synergistic against all MRSA phenotypes and statistically superior to all other combinations against DNS MRSA, hVISA, and MRSA isolates (P < 0.02). Oritavancin in combination with cefazolin and oritavancin in combination with nafcillin were also synergistic against all MRSA strains. Synergy between oritavancin and all BLs was revealed against VRE strain 8019, while synergy between oritavancin and ampicillin or ertapenem but not ceftaroline was demonstrated against VRE strain R7164. The data support the potential use of oritavancin in combination with BLs, especially oritavancin in combination with ceftaroline, for the treatment of infections caused by MRSA. The data from the present study are not as strong for oritavancin in combination with BLs for VRE. Further study of both MRSA and VRE in more complex models is warranted. O ritavancin (ORI) is a novel lipoglycopeptide antibiotic recently approved by the Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) (1-3). Unique to ORI among the agents approved for use for the treatment of ABSSSIs, the antibiotic is administered as a single dose of 1,200 mg as the entire treatment course. ORI is active against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) (4). It possesses three mechanisms of action, acting via inhibition of both transglycosylation and transpeptidation at the cell wall, along with disruption of the cell membrane (5). ORI is a potent agent against Gram-positive organisms. Against ov...

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Section: Discussionsupporting

confidence: 64%

mentioning

confidence: 99%

Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

Smith

Yim

Raut

et al. 2016

Antimicrob Agents Chemother

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“…CRO and AMP together are active against PBPs 1 to 5, and recent clinical data describing the effective use of this combination further establish this possibility (43). Recent data have also demonstrated that ceftobiprole is synergistic with DAP against VRE that are both DAP susceptible and DAP nonsusceptible (44). Previous work has demonstrated that ceftobiprole possesses activity against enterococcal PBP5 and PBPs 1 to 4 similar to, although not quite as potent as, that of CPT (40).…”

Section: Discussionmentioning

confidence: 89%

β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models

Smith

Barber

Raut

et al. 2015

Antimicrob Agents Chemother

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Enterococcus faecalis and Enterococcus faecium are frequently resistant to vancomycin and ␤-lactams. In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate ␤-lactam synergy with daptomycin (DAP) against resistant enterococci. One E. faecalis strain (R6981) and two E. faecium strains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37, an antimicrobial peptide, in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). After 96 h, in vitro models were run simulating 10 mg DAP/kg body weight/day, 600 mg CPT every 8 h (q8h), 2 g AMP q4h, and 1 g ERT q24h, both alone and in combination against all strains. DAP MICs were 2, 4, and 4 g/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP-CPT, DAP-AMP, and DAP-ERT combinations against strain 8019 (P < 0.001 and log 10 CFU/ml reduction of >2 compared to any single agent). Against strains R6981 and R6370, the DAP-AMP combination demonstrated enhancement against R6370 but not R6981, while the combinations of DAP-CPT and DAP-ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 h (P < 0.001) against both strains. CPT, ERT, and AMP similarly augmented LL37 killing against strain 8019. In strains R6981 and R6370, CPT and ERT aided LL37 more than AMP (P < 0.001). Compared to DAP alone, combination regimens provide better killing and prevent resistance. Clinical research involving DAP combinations is warranted. Enterococcus faecalis and Enterococcus faecium together account for 12% of hospital-acquired infections in the United States (1). Often, enterococcal infections are caused by multidrug-resistant strains. For example, 0.4 to 5.2% and 70 to 92.6% of E. faecalis and E. faecium strains are resistant to ampicillin, respectively, and vancomycin resistance is present in up to 12.5% of E. faecalis and 79.7% of E. faecium (2-4). Vancomycin-resistant enterococci (VRE) are associated with increased mortality and complicated infections, such as infective endocarditis (5). Treatment of VRE infections can prove problematic, as available treatment options are potentially limited by static activity and/or platelet suppression with long-term use (6-8). Daptomycin (DAP) is a bactericidal lipopeptide often used against resistant enterococci (9). Mechanistically, it binds with calcium to form a cationic moiety that disrupts membrane potential to confer its antimicrobial effects, similar to endogenous, cationic antimicrobial peptides (10, 11). DAP is frequently dosed at 6 mg/kg body weight daily, although recent clinical and in vitro data suggest improved efficacy at higher doses (7,(12)(13)(14). DAP retains excellent in vitro activity against E. faecalis and E. faecium, with MIC 50/90 values of 1/2 and 2/4 g/ml, respectively (15). Reports of DAP-nonsuscept...

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“…This is an intriguing possibility to be further investigated in clinical studies, since it could represent an important option for salvage therapy of MRSA bacteremia and/or endocarditis. Of note, synergy between ceftobiprole and daptomycin has also been demonstrated against enterococci, including vancomycin-resistant isolates [20,53]. However, the related evidence is currently limited to in vitro studies, and further evidence from either animal models or clinical studies is needed regarding the possible use of ceftobiprole/daptomycin combinations for severe enterococcal infections in humans.…”

Section: Bacteremia Endocarditis and Mediastinitismentioning

confidence: 99%

Ceftobiprole: drug evaluation and place in therapy

Giacobbe

Rosa

Bono

et al. 2019

Expert Review of Anti-infective Therapy

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Introduction: Ceftobiprole is a fifth-generation cephalosporin with a broad spectrum of antimicrobial activity, including also methicillin-resistant Staphylococcus aureus (MRSA). Ceftobiprole is approved for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia, in several European and non-European countries. Areas covered: In this narrative review, we discuss the current place in therapy of ceftobiprole, both within and outside approved indications. An inductive MEDLINE/PubMed search of the available literature was conducted. Expert opinion: There are three main reasons which render ceftobiprole an attractive option for the empirical and targeted treatment of CAP and HAP: (i) its broad spectrum of activity; (ii) its activity against MRSA; (iii) its good safety profile. For these indications, ceftobiprole should be employed thoughtfully, in those scenarios in which its intrinsic advantages could be maximized. The use of ceftobiprole outside approved indications could be justified in specific scenarios, such as when other approved alternatives are ineffective, when the risk of toxicity due to other agents is unacceptable, and for salvage therapy. In the near future, ongoing phase 3 studies and further observational experiences could both enlarge the current panel of approved indications and enrich our knowledge on the use of ceftobiprole for off-label indications. ARTICLE HISTORY

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Ceftobiprole and ampicillin increase daptomycin susceptibility of daptomycin-susceptible and -resistant VRE

Abstract: 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.

Cited by 36 publications

References 15 publications

Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

Oritavancin Combinations with β-Lactams against Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci

β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models

Ceftobiprole: drug evaluation and place in therapy

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