Publications by authors named "Michael J Rybak"

277 Publications

Validity of 2020 vancomycin consensus guidelines and further guidance for practical application.

Am J Health Syst Pharm 2021 Mar 25. Epub 2021 Mar 25.

University of Arkansas for Medical Sciences College of Pharmacy & Arkansas Children's Hospital Little Rock, AR.

In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
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http://dx.doi.org/10.1093/ajhp/zxab123DOI Listing
March 2021

Impact of COVID-19 pandemic on training of pharmacy residents and fellows: Results from a national survey of postgraduate pharmacy trainees.

Am J Health Syst Pharm 2021 Mar 19. Epub 2021 Mar 19.

Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, Downers Grove, IL, and Department of Pharmacy, Northwestern Medicine, Downers Grove, IL, USA.

Purpose: The coronavirus disease 2019 (COVID-19) pandemic has impacted the activities of healthcare workers, including postgraduate pharmacy trainees. Quality training experiences must be maintained to produce competent pharmacy practitioners and maintain program standards.

Methods: A cross-sectional survey of postgraduate pharmacy trainees in the United States was conducted to evaluate training experience changes and assess perceived impacts on residents and fellows following the COVID-19 pandemic's onset.

Results: From June 4 through June 22, 2020, 511 pharmacy trainees in 46 states completed the survey. Participants' median age was 26 (interquartile range [IQR], 25-28) years, with included responses from postgraduate year 1 residents (54% of sample), postgraduate year 2 residents (40%), and postgraduate fellows (6%). Compared to experiences prior to the onset of the COVID-19 pandemic, fewer trainees conducted direct patient care (38.5% vs 91.4%, P < 0.001), more worked from home (31.7% vs 1.6%, P < 0.001), and less time was spent with preceptors per day (2 [IQR, 2-6] hours vs 4 [IQR, 1-4] hours, P < 0.001). Sixty-five percent of respondents reported experiencing changes in their training program, 39% reported being asked to work in areas outside of their routine training experience, and 89% stated their training shifted to focus on COVID-19 to some degree. Most respondents perceived either major (9.6%) or minor (52.0%) worsening in quality of experience, with major and minor improvement in quality of experience reported by 5.5% and 8.4% of respondents, respectively.

Conclusion: Pharmacy resident/fellow experiences were perceived to have been extensively impacted by the COVID-19 pandemic in varying ways. Our findings describe shifts in postgraduate training and may aid in the development of best practices for optimizing trainee experiences in future crises.
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http://dx.doi.org/10.1093/ajhp/zxab114DOI Listing
March 2021

Preliminary, Real-world, Multicenter Experience With Omadacycline for Infections.

Open Forum Infect Dis 2021 Feb 7;8(2):ofab002. Epub 2021 Jan 7.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.

Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for . The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.
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http://dx.doi.org/10.1093/ofid/ofab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890947PMC
February 2021

Questions on Vancomycin dosing.

Clin Infect Dis 2020 Nov 26. Epub 2020 Nov 26.

University of Arkansas for Medical Sciences College of Pharmacy & Arkansas Children's Hospital, Little Rock, AR.

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http://dx.doi.org/10.1093/cid/ciaa1775DOI Listing
November 2020

The Evolving Reduction of Vancomycin and Daptomycin Susceptibility in MRSA-Salvaging the Gold Standards with Combination Therapy.

Antibiotics (Basel) 2020 Oct 30;9(11). Epub 2020 Oct 30.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.

Methicillin-resistant (MRSA) is associated with substantial morbidity and mortality. Vancomycin (VAN) has been used as the gold standard treatment for invasive MRSA infections for decades but, unfortunately, the reliance of VAN as the primary treatment option against these infections has led to a reduction in VAN susceptibility in MRSA isolates. Although daptomycin (DAP) is another common treatment option against invasive MRSA infections, it has been shown that the development of VAN resistance can lead to DAP nonsusceptibility. VAN or DAP backbone regimens in combination with other antibiotics has been advocated as an alternative approach to improve patient outcomes in VAN/DAP-susceptible infections, enhance outcomes in infections caused by isolates with reduced VAN/DAP susceptibility, and/or prevent the emergence of VAN/DAP resistance or further resistance. A peer-reviewed literature search was conducted using Medline, Google Scholar and PubMed databases. The primary purpose of this review is to describe the mechanisms and epidemiology of MRSA isolates with a reduction in VAN and/or DAP susceptibility, evaluate in vitro and in vivo literature describing combination therapy (CT) against MRSA isolates with reduced VAN and/or DAP susceptibility and describe studies involving the clinical outcomes of patients treated with CT against invasive MRSA infections.
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http://dx.doi.org/10.3390/antibiotics9110762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692208PMC
October 2020

Novel approaches for the treatment of methicillin-resistant Staphylococcus aureus: Using nanoparticles to overcome multidrug resistance.

Drug Discov Today 2021 Jan 20;26(1):31-43. Epub 2020 Oct 20.

Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA; Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address:

Methicillin-resistant Staphylococcus aureus (MRSA) causes serious infections in both community and hospital settings, with high mortality rates. Treatment of MRSA infections is challenging because of the rapidly evolving resistance mechanisms combined with the protective biofilms of S. aureus. Together, these characteristic resistance mechanisms continue to render conventional treatment modalities ineffective. The use of nanoformulations with unique modes of transport across bacterial membranes could be a useful strategy for disease-specific delivery. In this review, we summarize treatment approaches for MRSA, including novel techniques in nanoparticulate designing for better therapeutic outcomes; and facilitate an understanding that nanoparticulate delivery systems could be a robust approach in the successful treatment of MRSA.
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http://dx.doi.org/10.1016/j.drudis.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855522PMC
January 2021

Bacteriophage AB-SA01 Cocktail in Combination with Antibiotics against MRSA-VISA Strain in an Pharmacokinetic/Pharmacodynamic Model.

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

Anti-Infective Research Laboratory, College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA

This study aimed to test the efficacy of bacteriophage-antibiotic combinations (BACs) in 24-h time-kill settings and in simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic models for 96 h. BACs prevented the development of bacteriophage resistance, while some bacteriophage resistance emerged in bacteriophage-alone treatments. In addition, BACs resulted in an enhancement of bacterial eradication in SEV models. Our findings support the potential activity of BAC therapy for combating serious methicillin-resistant (MRSA) infections.
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http://dx.doi.org/10.1128/AAC.01863-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927802PMC
December 2020

Cefiderocol: A Novel Siderophore Cephalosporin against Multidrug-Resistant Gram-Negative Pathogens.

Pharmacotherapy 2020 12 19;40(12):1228-1247. Epub 2020 Nov 19.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.

Cefiderocol (CFDC), (formerly S-649266), is a novel injectable siderophore cephalosporin developed by Shionogi & Co., Ltd., with potent in vitro activity against Gram-negative pathogens including multidrug-resistant (MDR) Enterobacteriaceae and non-fermenting organisms, such as Pseudomonas aeruginosa, Acinetobacter baumannii, Burkholderia cepacia, and Stenotrophomonas maltophilia. Characterized by its siderophore catechol-moiety, CFDC uses a "trojan-horse approach" to navigate through the bacterial periplasmic space, thus evading various beta-lactam degrading enzymes and other mechanisms of resistance present in Gram-negative bacteria. More specifically in carbapenem-resistant Enterobacteriaceae, CFDC has been shown to have activity against extended spectrum beta-lactamases (ESBLs), such as CTX-type, SHV-type, and TEM-type, as well as the Ambler classes of beta-lactamases, including class A (KPC), class B (NDM, IMP, and VIM), class C (AmpC), and class D (OXA, OXA-24, OXA-48, and OXA-48-like). In addition to the strong activity that CFDC has been shown to have against MDR P. aeruginosa, it has also displayed activity against the OXA-23, OXA-24, and OXA-51, beta-lactamases commonly found in MDR A. baumannii. Cefiderocol was recently approved by the US Food and Drug Administration (FDA) for use in complicated urinary tract infections (cUTI), including pyelonephritis, for use in patients 18 years or older with limited or no alternative options for treatment, and is currently being evaluated in a phase III trial for use in nosocomial pneumonia caused by Gram-negative pathogens. The unique features and enhanced activity of CFDC suggest that it is likely to serve as a viable therapeutic option in the treatment of MDR Gram-negative infections. The purpose of this review is to provide an overview of previously published literature explaining CFDC's pharmacology, pharmacokinetic / pharmacodynamic (PK / PD) properties, microbiologic activity, resistance mechanisms, safety parameters, dosing and administration, clinical data, and potential place in therapy.
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http://dx.doi.org/10.1002/phar.2476DOI Listing
December 2020

Dalbavancin, Vancomycin and Daptomycin Alone and in Combination with Cefazolin against Resistant Phenotypes of in a Pharmacokinetic/Pharmacodynamic Model.

Antibiotics (Basel) 2020 Oct 14;9(10). Epub 2020 Oct 14.

Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.

The most efficacious antimicrobial therapy to aid in the successful elimination of resistant infections is unknown. In this study, we evaluated varying phenotypes of 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 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 ( < 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 phenotypes.
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http://dx.doi.org/10.3390/antibiotics9100696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602181PMC
October 2020

The Pharmacokinetic and Pharmacodynamic Properties of Hydroxychloroquine and Dose Selection for COVID-19: Putting the Cart Before the Horse.

Infect Dis Ther 2020 Sep 1;9(3):561-572. Epub 2020 Aug 1.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.

Coronavirus disease 2019 (COVID-19), caused by the 2019 novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a global pandemic. To date, only remdesivir and dexamethasone have demonstrated a positive response in a prospective, randomized trial for the treatment of patients with COVID-19. Hydroxychloroquine (HCQ) is an agent available in an oral formulation with in vitro activity against SARS-CoV-2 that has been suggested as a potential agent. Unfortunately, results of randomized trials evaluating HCQ as treatment against a control group are lacking, and little is known about its pharmacokinetic/pharmacodynamic (PK/PD) profile against SARS-CoV-2. The objective of this review was to describe the current understanding of the PK/PD and dose selection of HCQ against SARS-CoV-2, discuss knowledge gaps, and identify future studies that are needed to optimize the efficacy and safety of treatments against COVID-19.
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http://dx.doi.org/10.1007/s40121-020-00325-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395206PMC
September 2020

Vancomycin Area Under the Curve to Predict Timely Clinical Response in the Treatment of Methicillin-resistant Staphylococcus aureus Complicated Skin and Soft Tissue Infections.

Clin Infect Dis 2020 Jul 27. Epub 2020 Jul 27.

Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.

Introduction: Although recent guidelines have recommended monitoring vancomycin (VAN) area under the curve (AUC)/minimum inhibitory concentration (MIC) to ensure clinical efficacy and minimize toxicity in methicillin-resistant Staphylococcus aureus (MRSA) for various infections, there are no recommendations regarding complicated skin and soft tissue infections (cSSTIs). We aimed to evaluate the association between VAN AUC and clinical outcomes in MRSA cSSTIs.

Methods: This was a retrospective cohort study of adult patients treated with ≥ 72 hours of VAN for MRSA cSSTI from 2008-2013 at Detroit Medical Center. The primary outcome was timely clinical success (TCS) defined as 1) resolution of signs and symptoms of infection within 72 hours, 2) stabilization and/or reduction in lesion size, 3) alternative agents not required due to VAN failure or toxicity as elected by the prescribing clinician. Classification and regression tree (CART) analysis was performed to determine the AUC associated with TCS in the cohort. Multivariable logistic regression was used to evaluate the association between VAN-AUC and the primary outcome.

Results: A total of 154 patients were included in this analysis. CART identifed an AUC ≥435 mg*hr/L for TCS. Overall, 60.9% of patients experienced TCS; 69.7% in the target-AUC group vs. 52.5% in the below-target AUC group, (P=0.013). Target-AUC attainment was independently associated with increased odds of TCS ([aOR], 2.208; 95% [CI], 1.047 -4.659).

Discussion: In adults treated with VAN for MRSA cSSTI, target-AUC attainment was independently associated with improved clinical outcomes and maybe most warrated for patients at high risk of VAN-failure or VAN-associated toxicity.
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http://dx.doi.org/10.1093/cid/ciaa1039DOI Listing
July 2020

Therapeutic Monitoring of Vancomycin for Serious Methicillin-resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review by the American Society of Health-system Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

Clin Infect Dis 2020 Sep;71(6):1361-1364

Albany Medical Center Hospital, Albany, New York, USA.

Recent clinical data on vancomycin pharmacokinetics and pharmacodynamics suggest a reevaluation of current dosing and monitoring recommendations. The previous 2009 vancomycin consensus guidelines recommend trough monitoring as a surrogate marker for the target area under the curve over 24 hours to minimum inhibitory concentration (AUC/MIC). However, recent data suggest that trough monitoring is associated with higher nephrotoxicity. This document is an executive summary of the new vancomycin consensus guidelines for vancomycin dosing and monitoring. It was developed by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee. These consensus guidelines recommend an AUC/MIC ratio of 400-600 mg*hour/L (assuming a broth microdilution MIC of 1 mg/L) to achieve clinical efficacy and ensure safety for patients being treated for serious methicillin-resistant Staphylococcus aureus infections.
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http://dx.doi.org/10.1093/cid/ciaa303DOI Listing
September 2020

Combinations of (lipo)glycopeptides with β-lactams against MRSA: susceptibility insights.

J Antimicrob Chemother 2020 10;75(10):2894-2901

Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI, USA.

Background: Increasing application of vancomycin due to the high prevalence of MRSA infections has led to the emergence of vancomycin intermediate-resistant Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA). Consequently, the need for alternative therapies that target MRSA has become evident.

Objectives: To evaluate the synergy between (lipo)glycopeptides (LGP/GPs) (vancomycin, teicoplanin, telavancin, dalbavancin and oritavancin) and β-lactams (ceftaroline, cefepime, cefazolin and oxacillin) against MRSA, hVISA, VISA and daptomycin non-susceptible (DNS) phenotypes.

Methods: Twenty randomly selected clinical MRSA strains (i.e. 5 MRSA, 5 hVISA, 5 VISA and 5 DNS) were assessed versus LGP/GPs alone and LGP/GPs in combination with β-lactams for MICs. Although verification of antibiotic potency against bacterial strains is assessed by the microbroth dilution (MBD) MIC method recommended by the CLSI, some antibiotics need modified assay conditions in order to demonstrate their optimal activity.

Results: Addition of β-lactams reduced MIC values of LGP/GPs against all strains (up to 160-fold reduction). In general, LGPs (dalbavancin, oritavancin and telavancin) were more active (significant differences in MIC values, up to 8-fold) compared with vancomycin and teicoplanin. The majority of these combinations were bactericidal and superior to any single agent.

Conclusions: This report has examined the susceptibility patterns of LGP/GPs and their combination with β-lactams. Of interest, the impact of susceptibility tests (in terms of MIC plates and their surface area) on the synergistic activity in 24 h time-kill experiments was apparent for LGPs. Further clinical research is required to investigate synergy with LGP/GPs and β-lactams against these Staphylococcus strains.
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http://dx.doi.org/10.1093/jac/dkaa237DOI Listing
October 2020

Corrigendum to: The Impact of Concomitant Empiric Cefepime on Patient Outcomes of Methicillin-Resistant Bloodstream Infections Treated With Vancomycin.

Open Forum Infect Dis 2020 Jun 15;7(6):ofaa059. Epub 2020 Jun 15.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan.

[This corrects the article DOI: 10.1093/ofid/ofz079.].
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http://dx.doi.org/10.1093/ofid/ofaa059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295326PMC
June 2020

Bacteriophage-Antibiotic Combinations for Enterococcus faecium with Varying Bacteriophage and Daptomycin Susceptibilities.

Antimicrob Agents Chemother 2020 08 20;64(9). Epub 2020 Aug 20.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA

Concerns regarding increased prevalence of daptomycin (DAP)-resistant strains necessitate novel therapies for infections. Obligately lytic bacteriophages are viruses that target, infect, and kill bacterial cells. Limited studies have evaluated phage-antibiotic combinations against After an initial screen of eight strains, three strains with varying DAP/phage susceptibilities were selected for further experiments. Phage-to-strain specificity contributed to synergy with antibiotics by time-kill analyses and was associated with lower development of phage resistance.
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http://dx.doi.org/10.1128/AAC.00993-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449186PMC
August 2020

A comparison of daptomycin alone and in combination with ceftaroline fosamil for methicillin-resistant Staphylococcus aureus bacteremia complicated by septic pulmonary emboli.

Eur J Clin Microbiol Infect Dis 2020 Nov 13;39(11):2199-2203. Epub 2020 Jun 13.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI, 48201, USA.

The use of daptomycin (DAP) in septic pulmonary emboli (SPE) remains controversial. We analyzed 29 cases of MRSA bacteremia complicated by SPE treated with DAP (n = 14) or DAP-ceftaroline fosamil (CPT; n = 15). Initial treatment with DAP monotherapy was found to have a success rate comparable with DAP-CPT (71% vs. 80%; p = 0.68).
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http://dx.doi.org/10.1007/s10096-020-03941-5DOI Listing
November 2020

Combination of Vancomycin or Daptomycin and Beta-lactam Antibiotics: A Meta-analysis.

Pharmacotherapy 2020 07 6;40(7):648-658. Epub 2020 Jul 6.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, Michigan, USA.

Introduction: Observational and randomized controlled trials of the combination of vancomycin or daptomycin with a beta-lactam (BL) in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia have shown conflicting results on patient outcomes.

Objectives: The primary purpose of this meta-analysis was to compare clinical failure with the combination of vancomycin or daptomycin with a BL versus vancomycin or daptomycin monotherapy in MRSA bacteremia or endocarditis.

Methods: A systematic literature search of PubMed, Embase, CINAHL, and meeting proceedings was conducted from inception through February 11, 2020, to identify relevant studies. The primary outcome was clinical failure and secondary outcomes were mortality, nephrotoxicity, and bacteremia. The meta-analysis was performed using Comprehensive Meta Analysis (version 3.0) with a random effects model. Outcomes were reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs).

Results: Nine studies of 1636 patients receiving vancomycin or daptomycin monotherapy versus the combination of vancomycin or daptomycin plus BL for MRSA bacteremia were included. Results showed combination therapy was associated with significantly lower clinical failure rates (OR 0.56, 95% CI 0.39-0.79, I  = 26.22%, p=0.001). Improvement in clinical failure was driven by lower rates of bacteremia relapse and persistence. However, no difference was seen with mortality.

Conclusions: Combination therapy with vancomycin or daptomycin plus BL for MRSA bacteremia showed lower clinical failure rates, however, no significant difference was seen in mortality.
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http://dx.doi.org/10.1002/phar.2437DOI Listing
July 2020

Mechanistic Insights Into the Differential Efficacy of Daptomycin Plus β-Lactam Combinations Against Daptomycin-Resistant Enterococcus faecium.

J Infect Dis 2020 10;222(9):1531-1539

Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy & Health Sciences, Detroit, Michigan, USA.

Background: The combination of daptomycin (DAP) plus ampicillin (AMP), ertapenem (ERT), or ceftaroline has been demonstrated to be efficacious against a DAP-tolerant Enterococcus faecium strain (HOU503). However, the mechanism for the efficacy of these combinations against DAP-resistant (DAP-R) E. faecium strains is unknown.

Methods: We investigated the efficacy of DAP in combination with AMP, ERT, ceftaroline, ceftriaxone, or amoxicillin against DAP-R E. faecium R497 using established in vitro and in vivo models. We evaluated pbp expression, levels of penicillin-binding protein (PBP) 5 (PBP5) and β-lactam binding affinity in HOU503 versus R497.

Results: DAP plus AMP was the only efficacious regimen against DAP-R R497 and prevented emergence of resistance. DAP at 8, 6, and 4 mg/kg in combination with AMP was efficacious but showed delayed killing compared with 10 mg/kg. PBP5 of HOU503 exhibited amino acid substitutions in the penicillin-binding domain relative to R497. No difference in pbp mRNA or PBP5 levels was detected between HOU503 and R497. labeling of PBPs with Bocillin FL, a fluorescent penicillin derivative, showed increased β-lactam binding affinity of PBP5 of HOU503 compared with that of R497.

Conclusions: Only DAP (10 mg/kg) plus AMP or amoxicillin was efficacious against a DAP-R E. faecium strain, and pbp5 alleles may be important contributors to efficacy of DAP plus β-lactam therapy.
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http://dx.doi.org/10.1093/infdis/jiaa319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529040PMC
October 2020

Early Experience With Eravacycline for Complicated Infections.

Open Forum Infect Dis 2020 May 2;7(5):ofaa071. Epub 2020 Mar 2.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit ,Michigan, USA.

Eravacycline (ERV) was used in 35 patients for various infections. The most common pathogen was and 30-day survival was 74%. Absence of 30-day recurrence and resolution of signs and symptoms of infection were 91% and 57%, respectively. ERV was well-tolerated, with adverse events leading to drug discontinuation in one patient.
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http://dx.doi.org/10.1093/ofid/ofaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210802PMC
May 2020

Bacteriophage-Antibiotic Combination Strategy: an Alternative against Methicillin-Resistant Phenotypes of Staphylococcus aureus.

Antimicrob Agents Chemother 2020 06 23;64(7). Epub 2020 Jun 23.

Anti-Infective Research Laboratory, College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA

Comparative time-kill experiments with bacteriophage (phage) Sb-1 alone and phage-antibiotic combinations (PACs) against two methicillin-resistant (MRSA) strains have shown synergy with both daptomycin-phage and vancomycin-phage combinations. PACs prevented development of phage resistance and demonstrated bactericidal activity for all triple combinations. In addition, the extracellular membrane vesicle (MV) formation and the potential impact of phage on MV suppression were examined. Our results demonstrate the potential of PAC for combating MRSA infections.
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http://dx.doi.org/10.1128/AAC.00461-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318012PMC
June 2020

Opportunities for antimicrobial stewardship among carbapenem-treated patients in 18 North American hospitals.

Int J Antimicrob Agents 2020 Jun 10;55(6):105970. Epub 2020 Apr 10.

Making a Difference in Infectious Diseases, P.O. Box 1604, Fairfield, CT 06825, USA.

Here we describe the characteristics of carbapenem use at 18 hospitals across North America. Adult inpatients treated with a carbapenem for ≥24 h were included in this multicentre, retrospective, cross-sectional study. Outcomes evaluated included classification of therapy as empirical or definitive, discharge disposition and 30-day re-admission. A total of 621 patients were included in this study. Of these, 467 patients (75.2%) received a carbapenem empirically, among whom negative cultures occurred in 313 (67.0%) and 93% were eligible for de-escalation of therapy. In-hospital mortality occurred in 72 patients (11.6%) and 549 patients (88.4%) were discharged. Of the 549 patients who were discharged, 349 patients (63.6%) went home and 30-day infection-related re-admission occurred in 95 patients (17.3%). This population represents a significant need for carbapenem stewardship. Institutional guidelines should focus on four common disease states (respiratory, genitourinary, intra-abdominal and bloodstream), and diagnostic stewardship should be employed to aid in rapid de-escalation of carbapenem therapy. Additional studies aiming to identify antimicrobial stewardship techniques that may help to optimise carbapenem therapy and increase education about the importance of utilising carbapenem-sparing regimens are required.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.105970DOI Listing
June 2020

COVID-19: Important Therapy Considerations and Approaches in this Hour of Need.

Pharmacotherapy 2020 05 5;40(5):379-381. Epub 2020 May 5.

Wayne State University, Detroit, Michigan.

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http://dx.doi.org/10.1002/phar.2396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262098PMC
May 2020

Monotherapy with Vancomycin or Daptomycin versus Combination Therapy with β-Lactams in the Treatment of Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections: A Retrospective Cohort Analysis.

Infect Dis Ther 2020 Jun 4;9(2):325-339. Epub 2020 Apr 4.

Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with high morbidity and mortality. More in vitro, in vivo, and clinical data suggest that vancomycin (VAN) or daptomycin (DAP) combination therapy with β-lactams (BL) improves outcomes of MRSA infections. We hypothesize that BL combination with VAN or DAP would reduce the odds of clinical failure compared to VAN or DAP monotherapy.

Methods: A retrospective cohort study of adult patients ≥ 18 years treated with VAN or DAP for MRSA BSI from 2006 to 2019 at Detroit Medical Center. Combination therapy (CT) was defined as VAN or DAP plus any BL for ≥ 24 h within 72 h of index culture. Monotherapy (MT) was defined as ≥ 72 h VAN or DAP within 72 h of index culture and no BL for ≥ 24 h up to 7 days following VAN/DAP initiation. Primary outcome was composite endpoint of clinical failure defined as: (1) 30-day mortality, (2) 60-day recurrence, or (3) persistent bacteremia (PB). PB was defined as bacteremia > 5 days. Multivariable logistic regression was used to evaluate the association between CT and the primary outcome.

Results: Overall, 597 patients were included in this analysis, 153 in the MT group and 444 in the CT group. CT was independently associated with reduced odds of clinical failure (adjusted odds ratio, 0.523; 95% confidence interval, 0.348-0.787). The composite endpoint was driven by 60-day recurrence and PB but not 30-day mortality. There were no difference in adverse events including nephrotoxicity between the two study arms.

Conclusions: In hospitalized adults with MRSA BSI, CT with any BL was independently associated with improved clinical outcomes and may ultimately be selected as preferred therapy.
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http://dx.doi.org/10.1007/s40121-020-00292-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237588PMC
June 2020

Executive Summary: Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists.

Pharmacotherapy 2020 04 29;40(4):363-367. Epub 2020 Mar 29.

Albany Medical Center Hospital, Albany, New York.

Background: Recent vancomycin PK/PD and toxicodynamic studies enable a reassessment of the current dosing and monitoring guideline in an attempt to further optimize the efficacy and safety of vancomycin therapy. The area-under-the-curve to minimum inhibitory concentration (AUC/MIC) has been identified as the most appropriate pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin. The 2009 vancomycin consenus guidelines recommended specific trough concentrations as a surrogate marker for AUC/MIC. However, more recent toxicodynamic studies have reported an increase in nephrotoxicity associated with trough monitoring.

Methods And Results: This is the executive summary of the new vancomycin consensus guidelines for dosing and monitoring vancomycin therapy and was developed by the American Society of Health-Systems Pharmacists, Infectious Diseases Society of America, Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee.

Conclusions: The recommendations provided in this document are intended to assist the clinician in optimizing vancomycin for the treatment of invasive MRSA infections in adult and pediatric patients. An AUC/MIC by broth microdilution (BMD) ratio of 400 to 600 (assuming MICBMD of 1 mg/L) should be advocated as the target to achieve clinical efficacy while improving patient safety for patients with serious MRSA infections. In such cases, AUC-guided dosing and monitoring is the most accurate and optimal way to manage vancomycin therapy.
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http://dx.doi.org/10.1002/phar.2376DOI Listing
April 2020

Real-world Multicenter Analysis of Clinical Outcomes and Safety of Meropenem-Vaborbactam in Patients Treated for Serious Gram-Negative Bacterial Infections.

Open Forum Infect Dis 2020 Mar 19;7(3):ofaa051. Epub 2020 Feb 19.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.

Fourty patients were treated with meropenem-vaborbactam (MEV) for serious Gram-negative bacterial (GNB) infections. Carbapenem-resistant (CRE) comprised 80.0% of all GNB infections. Clinical success occurred in 70.0% of patients. Mortality and recurrence at 30 days were 7.5% and 12.5%, respectively. One patient experienced a probable rash due to MEV.
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http://dx.doi.org/10.1093/ofid/ofaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060146PMC
March 2020

Impact of Daptomycin Dose Exposure Alone or in Combination with β-Lactams or Rifampin against Vancomycin-Resistant Enterococci in an Biofilm Model.

Antimicrob Agents Chemother 2020 04 21;64(5). Epub 2020 Apr 21.

Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA

strains are commonly resistant to vancomycin and β-lactams. In addition, often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of dosing regimens using daptomycin (DAP) (8, 10, 12, and 14 mg/kg of body weight/day) alone and in combination with ceftaroline (CPT), ampicillin (AMP), ertapenem (ERT), and rifampin (RIF) against 2 clinical strains of biofilm-producing vancomycin-resistant (VREfm), namely, strains S447 and HOU503, in an biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to CPT, AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human antibiotic exposures) were used with titanium and polyurethane coupons to evaluate the efficacy of antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus CPT improved killing, they did not reach bactericidal reduction against S447. Combination of AMP, CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with AMP, ERT, CPT, and RIF in infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.
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http://dx.doi.org/10.1128/AAC.02074-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179592PMC
April 2020

Evaluation of the INCREMENT-CPE, Pitt Bacteremia and qPitt Scores in Patients with Carbapenem-Resistant Enterobacteriaceae Infections Treated with Ceftazidime-Avibactam.

Infect Dis Ther 2020 Jun 22;9(2):291-304. Epub 2020 Feb 22.

Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.

Background: The aim of this study was to evaluate the predictive performance of the INCREMENT-CPE (ICS), Pitt bacteremia score (PBS) and qPitt for mortality among patients treated with ceftazidime-avibactam for carbapenem-resistant Enterobacteriaceae (CRE) infections.

Methods: Retrospective, multicenter, cohort study of patients with CRE infections treated with ceftazidime-avibactam between 2015 and 2019. The primary outcome was 30-day all-cause mortality. Predictive performance was determined by assessing discrimination, calibration and precision.

Results: In total, 109 patients were included. Thirty-day mortality occurred in 18 (16.5%) patients. There were no significant differences in discrimination of the three scores [area under the curve (AUC) ICS 0.7039, 95% CI 0.5848-0.8230, PBS 0.6893, 95% CI 0.5709-0.8076, and qPitt 0.6847, 95% CI 0.5671-0.8023; P > 0.05 all pairwise comparisons]. All scores showed adequate calibration and precision. When dichotomized at the optimal cut-points of 11, 3, and 2 for the ICS, PBS, and qPitt, respectively, all scores had NPV > 90% at the expense of low PPV. Patients in the high-risk groups had a relative risk for mortality of 3.184 (95% CI 1.35-8.930), 3.068 (95% CI 1.094-8.606), and 2.850 (95% CI 1.016-7.994) for the dichotomized ICS, PBS, and qPitt, scores respectively. Treatment-related variables (early active antibiotic therapy, combination antibiotics and renal ceftazidime-avibactam dose adjustment) were not associated with mortality after controlling for the risk scores.

Conclusions: In patients treated with ceftazidime-avibactam for CRE infections, mortality risk scores demonstrated variable performance. Modifications to scoring systems to more accurately predict outcomes in the era of novel antibiotics are warranted.
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http://dx.doi.org/10.1007/s40121-020-00288-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223509PMC
June 2020

A Multicenter Evaluation of Vancomycin-Associated Acute Kidney Injury in Hospitalized Patients with Acute Bacterial Skin and Skin Structure Infections.

Infect Dis Ther 2020 Mar 25;9(1):89-106. Epub 2020 Jan 25.

Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI, USA.

Background: We sought to determine the real-world incidence of and risk factors for vancomycin-associated acute kidney injury (V-AKI) in hospitalized adults with acute bacterial skin and skin structure infections (ABSSSI).

Methods: Retrospective, observational, cohort study at ten U.S. medical centers between 2015 and 2019. Hospitalized patients treated with vancomycin (≥ 72 h) for ABSSSI and ≥ one baseline AKI risk factor were eligible. Patients with end-stage kidney disease, on renal replacement therapy or AKI at baseline, were excluded. The primary outcome was V-AKI by the vancomycin guidelines criteria.

Results: In total, 415 patients were included. V-AKI occurred in 39 (9.4%) patients. Independent risk factors for V-AKI were: chronic alcohol abuse (aOR 4.710, 95% CI 1.929-11.499), no medical insurance (aOR 3.451, 95% CI 1.310-9.090), ICU residence (aOR 4.398, 95% CI 1.676-11.541), Gram-negative coverage (aOR 2.926, 95% CI 1.158-7.392) and vancomycin duration (aOR 1.143, 95% CI 1.037-1.260). Based on infection severity and comorbidities, 34.7% of patients were candidates for oral antibiotics at baseline and 39.3% had non-purulent cellulitis which could have been more appropriately treated with a beta-lactam. Patients with V-AKI had significantly longer hospital lengths of stay (9 vs. 6 days, p = 0.001), higher 30-day readmission rates (30.8 vs. 9.0%, p < 0.001) and increased all-cause 30-day mortality (5.1 vs. 0.3%, p = 0.024) CONCLUSIONS: V-AKI occurred in approximately one in ten ABSSSI patients and may be largely prevented by preferential use of oral antibiotics whenever possible, using beta-lactams for non-purulent cellulitis and limiting durations of vancomycin therapy.
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http://dx.doi.org/10.1007/s40121-019-00278-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054514PMC
March 2020