Reduced glycopeptide and lipopeptide susceptibility in Staphylococcus aureus and the “seesaw effect”: Taking advantage of the back door left open?

Ortwine, Jessica; Werth, Brian J.; Sakoulas, George; Rybak, Michael J.

doi:10.1016/j.drup.2013.10.002

Cited by 57 publications

(44 citation statements)

References 57 publications

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“…As in these previous studies, it appears that as the MICs of VAN and DAP increase, the synergistic activity between ORI and betalactams is greater, possibly owing to the seesaw effect, the phenomenon in which glycopeptide and lipopeptide MICs are inversely proportional to beta-lactam MICs (41). Because the mechanism of action of ORI bears similarities to the mechanisms of action of both VAN and DAP, the seesaw effect hypothesis likely does help explain the synergistic activity.…”

Section: Discussionmentioning

confidence: 50%

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: Discussionmentioning

confidence: 50%

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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“…Not only did cefazolin decrease the daptomycin MIC appreciably against both MRSA strains, it also demonstrated sustained bactericidal activity at 96 h in the PK/PD models when combined with daptomycin. Of interest, the cefazolin MIC decreased as the daptomycin MIC increased between the strains, demonstrating the presence of the "seesaw effect" phenomenon, where glycopeptide and lipopeptide MIC values are inversely proportional to those of beta-lactams (32,33). Here, the seesaw effect was not present with ceftolozanetazobactam, perhaps suggesting that antistaphylococcal beta-lactam activity may play an important role in daptomycin synergy or, perhaps, the demonstrated PBP1 binding of cefazolin.…”

Section: Discussionmentioning

confidence: 85%

Daptomycin in Combination with Ceftolozane-Tazobactam or Cefazolin against Daptomycin-Susceptible and -Nonsusceptible Staphylococcus aureus in an In Vitro , Hollow-Fiber Model

Smith

Arya

Yim

et al. 2016

Antimicrob Agents Chemother

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c Ceftolozane-tazobactam (TOL-TAZ) is a novel cephalosporin/beta-lactamase inhibitor with activity against several Gram-negative pathogens. Daptomycin (DAP) has demonstrated synergistic activity with beta-lactams against methicillin-resistant Staphylococcus aureus (MRSA) isolates with reduced lipopeptide and glycopeptide susceptibilities. Our objective was to determine if DAP and TOL-TAZ possess synergy in hollow-fiber pharmacokinetic/pharmacodynamic (PK/PD) models. One isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible MRSA strains was evaluated. DAP, TOL-TAZ, and cefazolin (CFZ) MIC determinations were performed. DAP MIC determinations were also performed in the presence of subinhibitory concentrations of TOL-TAZ and CFZ. Ninety-six-hour in vitro models were run, simulating DAP at 10 mg/kg of body weight/day; TOL-TAZ at 1,500 mg every 8 h; TOL at 1,000 mg every 8 h; and DAP combined with TOL-TAZ (DAP؉TOL-TAZ), DAP؉TOL, DAP؉TAZ, and DAP؉CFZ at 2,000 mg every 8 h. DAP MICs were 0.5 and 4 g/ml for strains R8845 and R8846, respectively. In the presence of CFZ, R8845 and R8846 DAP MICs were reduced 8-fold and 16-fold, respectively. TOL and TAZ had no effect on DAP MICs. PK/PD models demonstrated bactericidal activity with DAP؉CFZ against both strains. The combination of DAP؉TOL-TAZ was bactericidal against R8845 but was not bactericidal against daptomycin-nonsusceptible strain R8846. DAP؉TOL and DAP؉TAZ were not bactericidal. No other regimens were bactericidal. DAP؉TOL-TAZ did not demonstrate synergistic activity against daptomycin-nonsusceptible S. aureus but prevented daptomycin-nonsusceptible MRSA emergence. Because DAP؉TOL or TAZ alone did not prevent daptomycin-nonsusceptible MRSA emergence, the combination TOL-TAZ may be necessary for synergy with DAP. DAP؉CFZ demonstrated enhancement against both strains. The combination of DAP؉CFZ warrants further clinical study. Staphylococcus aureus is the leading cause of hospital-associated infections in the United States, and methicillin-resistant S. aureus (MRSA) strains comprise up to 50% of isolates (1). More problematic is the emergence of MRSA isolates with reduced susceptibility to vancomycin, a drug which has been a mainstay of MRSA therapy for more than 40 years (2). Treatment options against such isolates are limited. Among them is daptomycin (DAP), a lipopeptide antibiotic with bactericidal activity against Gram-positive pathogens (3). Daptomycin maintains activity against MRSA isolates with reduced vancomycin susceptibility, and nonsusceptibility to daptomycin is rare, occurring in Ͻ0.05% of a sampling of Ͼ9,000 S. aureus isolates (4). Daptomycin nonsusceptibility has been reported, however, and creative therapies are needed to combat this problem (5-10). Recent data have demonstrated that beta-lactam antibiotics in combination with daptomycin are efficacious in both preventing daptomycin nonsusceptibility and providing bactericidal activity (6,8,(10)(11)(12)(13).Because antibiotic resistance among Gram-negative bacteria is as much, if no...

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“…In vitro studies have demonstrated synergistic interactions between vancomycin and a wide variety of β‐lactams against S. aureus . The proposed mechanism for vancomycin and β‐lactam synergy is related to cell wall thinning via the addition of a β‐lactam, which increases vancomycin binding to target sites during cell wall synthesis . The degree of synergy demonstrated between vancomycin and β‐lactams appears to correlate with increasing vancomycin MIC .…”

Section: Resultsmentioning

confidence: 99%

Treatment strategies for persistent methicillin‐resistantStaphylococcus aureusbacteraemia

et al. 2018

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Reduced glycopeptide and lipopeptide susceptibility in Staphylococcus aureus and the “seesaw effect”: Taking advantage of the back door left open?

Cited by 57 publications

References 57 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

Daptomycin in Combination with Ceftolozane-Tazobactam or Cefazolin against Daptomycin-Susceptible and -Nonsusceptible Staphylococcus aureus in an In Vitro , Hollow-Fiber Model

Treatment strategies for persistent methicillin‐resistantStaphylococcus aureusbacteraemia

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