Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus

Sakoulas, George; Okumura, Cheryl; Thienphrapa, Wdee; Olson, Joshua; Nonejuie, Poochit; Dam, Quang; Dhand, Abhay; Pogliano, Joseph; Yeaman, Michael R.; Hensler, Mary E.; Bayer, Arnold S.; Nizet, Victor

doi:10.1007/s00109-013-1100-7

Cited by 128 publications

(129 citation statements)

References 58 publications

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“…Specifically, beta-lactam antibiotics appear to have profound effects on betalactam-resistant Gram-positive organisms. Similar to the effects on VRE by ampicillin that we previously discussed (5), we have shown that antistaphylococcal beta-lactams increase susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) to daptomycin and innate immunity (14,18). Not all beta-lactams are equal in this effect, as PBP-1 binding beta-lactams are better at potentiating daptomycin activity than non-PBP-1-specific betalactams (19).…”

Section: Discussionsupporting

confidence: 71%

“…Daptomycin-nonsusceptible enterococci are different from their susceptible counterparts in sensing cell wall stress (via liaFSR) (15,16,18), phospholipid composition (via cls) (20)(21)(22), and increased proclivity to septation (via ezrA) (6). While we did not perform analysis of phospholipid content with ceftaroline therapy, we noticed changes in septation and cell wall thickness induced by ceftaroline.…”

Section: Discussionmentioning

confidence: 99%

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Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Sakoulas

Rose

Nonejuie

et al. 2014

Antimicrob Agents Chemother

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c Daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium (VRE) strains are a formidable emerging threat to patients with comorbidities, leaving few therapeutic options in cases of severe invasive infections. Using a previously characterized isogenic pair of VRE strains from the same patient differing in their daptomycin susceptibilities (Etest MICs of 0.38 mg/liter and 10 mg/liter), we examined the effect of ceftaroline, ceftriaxone, and ampicillin on membrane fluidity and susceptibility of VRE to surface binding and killing by daptomycin and human cathelicidin antimicrobial peptide LL37. Synergy was noted in vitro between daptomycin, ampicillin, and ceftaroline for the daptomycin-susceptible VRE strain, but only ceftaroline showed synergy against the daptomycin-nonsusceptible VRE strain (ϳ2 log 10 CFU reduction at 24 h). Ceftaroline cotreatment increased daptomycin surface binding with an associated increase in membrane fluidity and an increase in the net negative surface charge of the bacteria as evidenced by increased poly-L-lysine binding. Consistent with the observed biophysical changes, ceftaroline resulted in increased binding and killing of daptomycin-nonsusceptible VRE by human cathelicidin LL37. Using a pair of daptomycinsusceptible/nonsusceptible VRE strains, we noted that VRE is ceftaroline resistant, yet ceftaroline confers significant effects on growth rate as well as biophysical changes on the cell surface of VRE that can potentiate the activity of daptomycin and innate cationic host defense peptides, such as cathelicidin. Although limited to just 2 strains, these finding suggest that additional in vivo and in vitro studies need to be done to explore the possibility of using ceftaroline as adjunctive anti-VRE therapy. Loss of susceptibility to daptomycin is an increasing concern among vancomycin-resistant Enterococcus faecium (VRE) (1). When faced with invasive infections by daptomycin-nonsusceptible VRE, clinicians have limited therapeutic options. Of great concern are the lack of a bactericidal agent, antibiotic-associated side effects such as linezolid-induced thrombocytopenia and quinupristin-dalfopristin (QD)-associated myalgias, and drug-drug interactions such as microsomal P450 effects of QD and serotonin syndrome concerns with linezolid and concomitant serotonin reuptake inhibitors. Therefore, a great need exists for infectiousdisease physicians practicing in tertiary medical centers with patients at high risk for VRE infections, e.g., bone marrow and liver transplant recipients, to develop innovative pharmacotherapies to treat such patients (2, 3). The clinical dilemma faced by physicians treating these patients is further compounded by the facts that novel therapeutics targeting VRE are lacking and that single or combination antibiotics with in vitro activity against VRE have not been clinically validated by appropriate trials (4).Our group has previously shown a perhaps counterintuitive effect of ampicillin in converting daptomycin from a bacteriostatic to a bactericidal an...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Sakoulas

Rose

Nonejuie

et al. 2014

Antimicrob Agents Chemother

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“…In addition, these data demonstrate that PBP1-specific ␤-lactams appear to discriminate between enhancement of DAP and of cationic antimicrobial peptides such as cathelicidin (LL37). We have previously shown that penicillins and cephalosporins sensitize MRSA to killing by LL37 and other host defense peptides, but we did not include carbapenems in that analysis (25). Interestingly, in this study we found that growth of MRSA in the PBP1-specific carbapenems did not enhance LL37 killing, despite potentiation of DAP activity.…”

Section: Discussionmentioning

confidence: 54%

“…Therefore, the primary antimicrobial peptide LL37 was evaluated in combination with ␤-lactams. S. aureus D712 was grown in antibiotic-free LB broth or broth containing 5 mg/liter of the test ␤-lactam antibiotic overnight (15 to 18 h), resuspended in phosphate-buffered saline (PBS), and subjected to killing assays in 128 M LL37, as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

“…This study provides a more comprehensive evaluation of ␤-lactams with distinct PBP inhibition profiles. S. aureus D712 was grown in antibiotic-free LB broth or broth containing 5 mg/liter of the test ␤-lactam antibiotic to an optical density at 600 nm (OD 600 ) of 0.4 to 0.6, stained for 30 min with dipyrromethene boron difluoride (BODIPY)-DAP (16 mg/liter) and Ca 2ϩ (50 mg/liter), and visualized microscopically as previously described (25). DAP binding was evaluated visually and measured by binding intensity and spots per cell to determine the quality and focus of binding.…”

Section: Methodsmentioning

confidence: 99%

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Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for β-Lactam–Daptomycin Synergy

Berti

Theisen

Sauer

et al. 2016

Antimicrob Agents Chemother

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fThe activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of ␤-lactam antibiotics. This effect is more pronounced with ␤-lactam antibiotics that exhibit avid binding to penicillin binding protein 1 (PBP1). Here, we present evidence that PBP1 has a significant role in responding to DAP-induced stress on the cell. Expression of the pbpA transcript, encoding PBP1, was specifically induced by DAP exposure whereas expression of pbpB, pbpC, and pbpD, encoding PBP2, PBP3, and PBP4, respectively, remained unchanged. Using a MRSA COL strain with pbpA under an inducible promoter, increased pbpA transcription was accompanied by reduced susceptibility to, and killing by, DAP in vitro. Exposure to ␤-lactams that preferentially inactivate PBP1 was not associated with increased DAP binding, suggesting that synergy in the setting of anti-PBP1 pharmacotherapy results from increased DAP potency on a per-molecule basis. Combination exposure in an in vitro pharmacokinetic/pharmacodynamic model system with ␤-lactams that preferentially inactivate PBP1 (DAP-meropenem [MEM] or DAP-imipenem [IPM]) resulted in more-rapid killing than did combination exposure with DAPnafcillin (NAF) (nonselective), DAP-ceftriaxone (CRO) or DAP-cefotaxime (CTX) (PBP2 selective), DAP-cefaclor (CEC) (PBP3 selective), or DAP-cefoxitin (FOX) (PBP4 selective).Compared to ␤-lactams with poor PBP1 binding specificity, exposure of S. aureus to DAP plus PBP1-selective ␤-lactams resulted in an increased frequency of septation and cell wall abnormalities. These data suggest that PBP1 activity may contribute to survival during DAP-induced metabolic stress. Therefore, targeted inactivation of PBP1 may enhance the antimicrobial efficiency of DAP, supporting the use of DAP-␤-lactam combination therapy for serious MRSA infections, particularly when the ␤-lactam undermines the PBP1-mediated compensatory response.

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Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia

Tong

Lye

Yahav

et al. 2020

JAMA

192

152

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IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. OBJECTIVE To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. DESIGN, SETTING, AND PARTICIPANTS Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018.INTERVENTIONS Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal β-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the β-lactam was administered for 7 days. MAIN OUTCOMES AND MEASURESThe primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. RESULTSThe data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, −4.2%; 95% CI, −14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, −3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, −8.9%; 95% CI, −16.6% to −1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%).CONCLUSIONS AND RELEVANCE Among patients with MRSA bacteremia, addition of an antistaphylococcal β-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings.

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Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus

Cited by 128 publications

References 58 publications

Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for β-Lactam–Daptomycin Synergy

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia

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