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9. Multidrug-resistant corynebacterium striatum associated with increased use of parenteral antimicrobial drugs

Author

Hahn, William O., Werth, Brian J., Butler-Wu, Susan M., and Rakita, Robert M.

Subjects
Drug resistance in microorganisms -- Analysis -- Health aspects, Medical records -- Analysis -- Health aspects, Drugs -- Usage -- Analysis -- Health aspects, Infection -- Analysis -- Health aspects, Antibacterial agents -- Usage -- Analysis -- Health aspects, Staphylococcal infections -- Analysis -- Health aspects, Health, Infectious Diseases Society of America, American Medical Association
Abstract

Corynebacteria are a normal component of the microbiota of human skin and mucous membranes. At the University of Washington Medical Center (Seattle, WA, USA), Corynebacterium striatum has historically been the [...]

Published
2016
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19. Synergy Between Beta-Lactams and Lipo-, Glyco-, and Lipoglycopeptides, Is Independent of the Seesaw Effect in Methicillin-Resistant Staphylococcus aureus

Author

Zhang, Rutan, primary, Barreras Beltran, Ismael A., additional, Ashford, Nathaniel K., additional, Penewit, Kelsi, additional, Waalkes, Adam, additional, Holmes, Elizabeth A., additional, Hines, Kelly M., additional, Salipante, Stephen J., additional, Xu, Libin, additional, and Werth, Brian J., additional

Published
2021
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20. 621. Reporting Behaviors and Perceptions Towards the National Healthcare Safety Network Antimicrobial Use (AU) and Antimicrobial Resistance (AR) Options

Author

Werth, Brian J, primary, Werth, Brian J, additional, Dilworth, Thomas J, additional, Escobar, Zahra Kassamali, additional, Gross, Alan E, additional, Suda, Katie, additional, McGregor, Jessina C, additional, Morris, Andrew M, additional, LaPlante, Kerry, additional, and Kuper, Kristi, additional

Published
2020
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23. Reporting behaviors and perceptions toward the National Healthcare Safety Network antimicrobial use (AU) and antimicrobial resistance (AR) modules

Author

Werth, Brian J., Dilworth, Thomas J., Escobar, Zahra Kassamali, Gross, Alan E., Suda, Katie J., Morris, Andrew M., McGregor, Jessina C., and Kuper, Kristi

Abstract

AbstractObjectives:To identify characteristics of US health systems and end users that report antimicrobial use and resistance (AUR) data, to determine how NHSN AUR data are used by hospitals and health systems and end users, and to identify barriers to AUR reporting.Design:An anonymous survey was sent to Society of Infectious Diseases Pharmacists (SIDP) and Society for Healthcare Epidemiology of America (SHEA) Research Network members.Methods:Data were collected via Survey Monkey from January 21 to February 21, 2020. Respondent and hospital data were analyzed using descriptive statistics.Results:We received responses from 238 individuals across 43 US states. Respondents were primarily pharmacists (84%), from urban areas, (44%), from nonprofit medical centers (81%), and from hospitals with >250 beds (72%). Also, 62% reported data to the AU module and 19% reported data to the AR module. Use of software for local AU or AR tracking was associated with increased reporting to the AU module (19% vs 64%) and the AR module (2% vs 30%) (P< .001 each). Only 36% of those reporting data to the AU module used NHSN AUR data analysis tools regularly and only 9% reported data to the AR module regularly. Technical challenges and time and/or salary support were the most common barriers to AUR participation cited by all respondents. Among those not reporting AUR data, increased local expectations to report and better software solutions were the most commonly identified solutions to increase AUR reporting.Conclusions:Efforts to increase AUR reporting should focus on software solutions and salary support for data-entry activities. Increasing expectations to report may incentivize local resource allocation to improve AUR reporting rates.

Published
2023
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26. National Consumption of Antimicrobials in Tanzania: 2017–2019

Author

Mbwasi, Romuald, primary, Mapunjo, Siana, additional, Wittenauer, Rachel, additional, Valimba, Richard, additional, Msovela, Kelvin, additional, Werth, Brian J., additional, Khea, Akida Msallah, additional, Nkiligi, Emmanuel Alphonce, additional, Lusaya, Edgar, additional, Stergachis, Andy, additional, and Konduri, Niranjan, additional

Published
2020
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28. Occurrence of cross-resistance and β-lactam seesaw effect in glycopeptide-, lipopeptide- and lipoglycopeptide-resistant MRSA correlates with membrane phosphatidylglycerol levels

Author

Hines, Kelly M, primary, Shen, Tianwei, additional, Ashford, Nathaniel K, additional, Waalkes, Adam, additional, Penewit, Kelsi, additional, Holmes, Elizabeth A, additional, McLean, Kathryn, additional, Salipante, Stephen J, additional, Werth, Brian J, additional, and Xu, Libin, additional

Published
2020
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29. Pharmacokinetic/pharmacodynamic considerations for new and current therapeutic drugs for uncomplicated gonorrhoea—challenges and opportunities

Author

UCL - SSS/LDRI - Louvain Drug Research Institute, Theuretzbacher, Ursula, Barbee, Lindley, Connolly, Kristie, Drusano, George, Fernandes, Prabha, Hook, Edward, Jerse, Ann, O'Donnell, John, Unemo, Magnus, Van Bambeke, Françoise, VanScoy, Brian, Warn, Peter, Werth, Brian J., Franceschi, François, Alirol, Emilie, UCL - SSS/LDRI - Louvain Drug Research Institute, Theuretzbacher, Ursula, Barbee, Lindley, Connolly, Kristie, Drusano, George, Fernandes, Prabha, Hook, Edward, Jerse, Ann, O'Donnell, John, Unemo, Magnus, Van Bambeke, Françoise, VanScoy, Brian, Warn, Peter, Werth, Brian J., Franceschi, François, and Alirol, Emilie

Abstract

BACKGROUND: Increasing multidrug resistance rates in Neisseria gonorrhoeae have raised concerns and an urgent call for new antibiotics for treatment of gonorrhoea. Several decades of subdued drug development in this field and the recent failures of two new antibiotics to show non-inferiority compared with the current first-line antibiotics ceftriaxone plus azithromycin highlight the need for improved preclinical tools to predict clinical outcome of new drugs in the development process. OBJECTIVES: To summarize current pharmacokinetic/pharmacodynamic (PK/PD) knowledge and dose-finding strategies for antibiotics against gonorrhoea. SOURCES: Literature review of published papers and discussions by global experts at a special workshop on this topic. CONTENT: We review current knowledge of gonococcal specific PK/PD principles and provide an update on new in vitro and in vivo models to correlate drug exposure with clinical outcome, and identify challenges and gaps in gonococcal therapeutic research. IMPLICATIONS: Identifying the ideal antimicrobial agent and dose for treating uncomplicated urogenital and pharyngeal gonococcal disease requires appropriate validated non-clinical PK/PD models. Recent advances in adapting in vitro and in vivo models for use in gonorrhoea are an important step for enabling the development of new drugs with reduced risk of failure in Phase 3 clinical development and diminish the risk of emergence of resistance.

Published
2020

33. Occurrence of cross-resistance and beta-lactam seesaw effect in glycopeptide, lipopeptide, and lipoglycopeptide-resistant MRSA correlates with membrane phosphatidylglycerol levels

Author

Hines, Kelly M., primary, Shen, Tianwei, additional, Ashford, Nate K., additional, Waalkes, Adam, additional, Penewit, Kelsi, additional, Holmes, Elizabeth A., additional, McLean, Kathryn, additional, Salipante, Stephen J., additional, Werth, Brian J., additional, and Xu, Libin, additional

Published
2019
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34. Identification of a novel tedizolid resistance mutation in rpoB of MRSA after in vitro serial passage.

Author

Shen, Tianwei, Penewit, Kelsi, Waalkes, Adam, Xu, Libin, Salipante, Stephen J, Nath, Abhinav, and Werth, Brian J

Subjects
RNA polymerases, MUPIROCIN, METHICILLIN, GRAM-positive bacteria, CHLORAMPHENICOL, PHENOTYPES, LINEZOLID
Abstract

Objectives: Tedizolid is an oxazolidinone antimicrobial with activity against Gram-positive bacteria, including MRSA. Tedizolid resistance is uncommon and tedizolid's capacity to select for cross-resistance to other antimicrobials is incompletely understood. The objective of this study was to further explore the phenotypic and genetic basis of tedizolid resistance in MRSA.Methods: We selected for tedizolid resistance in an MRSA laboratory strain, N315, by serial passage until an isolate with an MIC ≥1 log2 dilution above the breakpoint for resistance (≥2 mg/L) was recovered. This isolate was subjected to WGS and susceptibility to a panel of related and unrelated antimicrobials was tested in order to determine cross-resistance. Homology modelling was performed to evaluate the potential impact of the mutation on target protein function.Results: After 10 days of serial passage we recovered a phenotypically stable mutant with a tedizolid MIC of 4 mg/L. WGS revealed only one single nucleotide variant (A1345G) in rpoB, corresponding to amino acid substitution D449N. MICs of linezolid, chloramphenicol, retapamulin and quinupristin/dalfopristin increased by ≥2 log2 dilutions, suggesting the emergence of the so-called 'PhLOPSa' resistance phenotype. Susceptibility to other drugs, including rifampicin, was largely unchanged. Homology models revealed that the mutated residue of RNA polymerase would be unlikely to directly affect oxazolidinone action.Conclusions: To the best of our knowledge, this is the first time that an rpoB mutation has been implicated in resistance to PhLOPSa antimicrobials. The mechanism of resistance remains unclear, but is likely indirect, involving σ-factor binding or other alterations in transcriptional regulation. [ABSTRACT FROM AUTHOR]

Published
2021
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35. Gentamicin Alone Is Inadequate to Eradicate Neisseria Gonorrhoeae From the Pharynx.

Author

Barbee, Lindley A, Soge, Olusegun O, Morgan, Jennifer, Leclair, Angela, Bass, Tamara, Werth, Brian J, Hughes, James P, and Golden, Matthew R

Subjects
CLINICAL trials, CONFIDENCE intervals, CREATININE, DRUG efficacy, GENTAMICIN, GONORRHEA, HEADACHE, MICROBIAL sensitivity tests, NEISSERIA, PHARYNX, PHARYNGEAL diseases, TREATMENT effectiveness, MEN who have sex with men, DESCRIPTIVE statistics, EVALUATION
Abstract

Background Centers for Disease Control and Prevention (CDC) guidelines recommend 240 mg gentamicin plus 2 g azithromycin for the treatment of gonorrhea in cephalosporin-allergic patients. The efficacy of gentamicin alone in the treatment of pharyngeal gonorrhea is uncertain. Methods Between September 2018 and March 2019, we enrolled men who have sex with men with nucleic acid amplification test–diagnosed pharyngeal gonorrhea in a single-arm, unblinded clinical trial. Men received a single 360-mg intramuscular dose of gentamicin and underwent test of cure by culture 4–7 days later. The study measured creatinine at enrollment and test of cure, serum gentamicin concentration postdose to establish peak concentration (Cmax), and standard antimicrobial minimum inhibitory concentrations (MICs) by agar dilution. The trial was designed to establish a point estimate for gentamicin's efficacy for pharyngeal gonorrhea. We planned to enroll 50 evaluable participants; assuming gentamicin was 80% efficacious, the trial would establish a 95% confidence interval (CI) of 66%–90%. We planned interim analyses at n = 10 and n = 25. Results The study was stopped early due to poor efficacy. Of 13 enrolled men, 10 were evaluable, and only 2 (20% [95% CI, 2.5%–55.6%]) were cured. Efficacy was not associated with gentamicin Cmax or MIC. No participants experienced renal insufficiency. The mean creatinine percentage change was +5.2% (range, −6.7% to 21.3%). Six (46%) participants experienced headache, all deemed unrelated to treatment. Conclusions Gentamicin alone failed to eradicate Neisseria gonorrhoeae from the pharynx. Clinicians should use caution when treating gonorrhea with the CDC's current alternative regimen (gentamicin 240 mg plus azithromycin 2 g) given increases in azithromycin resistance and gentamicin's poor efficacy at the pharynx. Clinical Trials Registration NCT03632109. [ABSTRACT FROM AUTHOR]

Published
2020
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39. Evaluation of Ceftaroline, Vancomycin, Daptomycin, or Ceftaroline plus Daptomycin against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Simulated Endocardial Vegetations

Author

Werth, Brian J., Barber, Katie E., Ireland, Cortney E., and Rybak, Michael J.

Subjects
Pharmacology, Methicillin-Resistant Staphylococcus aureus, Colony Count, Microbial, Endocarditis, Bacterial, Microbial Sensitivity Tests, biochemical phenomena, metabolism, and nutrition, Staphylococcal Infections, Anti-Bacterial Agents, Cephalosporins, Drug Combinations, Daptomycin, Vancomycin, Humans, Computer Simulation, Half-Life
Abstract

Infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin and daptomycin has few adequate therapeutic options. Ceftaroline (CPT) is bactericidal against daptomycin (DAP)-nonsusceptible (DNS) and vancomycin-intermediate MRSA, but supporting data are limited for IE. This study evaluated the activities of ceftaroline, vancomycin, daptomycin, and the combination of ceftaroline plus daptomycin against DNS MRSA in a pharmacokinetic/pharmacodynamic (PK/PD) model of simulated endocardial vegetations (SEVs). Simulations of ceftaroline-fosamil (600 mg) every 8 h (q8h) (maximum concentration of drug in serum [Cmax], 21.3 mg/liter; half-life [t1/2], 2.66 h), daptomycin (10 mg/kg of body weight/day) (Cmax, 129.7 mg/liter; t1/2, 8 h), vancomycin (1 g) q8h (minimum concentration of drug in serum [Cmin], 20 mg/liter; t1/2, 5 h), and ceftaroline plus daptomycin were evaluated against 3 clinical DNS, vancomycin-intermediate MRSA in a two-compartment, in vitro, PK/PD SEV model over 96 h with a starting inoculum of ∼8 log10 CFU/g. Bactericidal activity was defined as a ≥ 3-log10 CFU/g reduction from the starting inoculum. Therapeutic enhancement of combinations was defined as ≥ 2-log10 CFU/g reduction over the most active agent alone. MIC values for daptomycin, vancomycin, and ceftaroline were 4 mg/liter, 4 to 8 mg/liter, and 0.5 to 1 mg/liter, respectively, for all strains. At simulated exposures, vancomycin was bacteriostatic, but daptomycin and ceftaroline were bactericidal. By 96 h, ceftaroline monotherapy offered significantly improved killing compared to other agents against one strain. The combination of DAP plus CPT demonstrated therapeutic enhancement, resulting in significantly improved killing versus either agent alone against 2/3 (67%) strains. CPT demonstrated bactericidal activity against DNS, vancomycin-intermediate MRSA at high bacterial densities. Ceftaroline plus daptomycin may offer more rapid and sustained activity against some MRSA in the setting of high-inoculum infections like IE and should also be considered.

Published
2014

45. Evaluation of Ceftaroline Activity against Heteroresistant Vancomycin-Intermediate Staphylococcus aureus and Vancomycin-Intermediate Methicillin-Resistant S. aureus Strains in an In Vitro Pharmacokinetic/Pharmacodynamic Model: Exploring the 'Seesaw Effect'

Author

Werth, Brian J., Steed, Molly E., Kaatz, Glenn W., and Rybak, Michael J.

Subjects
Pharmacology, Methicillin-Resistant Staphylococcus aureus, Staphylococcus aureus, Vancomycin, Humans, Penicillin-Binding Proteins, Vancomycin Resistance, Microbial Sensitivity Tests, biochemical phenomena, metabolism, and nutrition, Anti-Bacterial Agents, Cephalosporins
Abstract

A "seesaw effect" in methicillin-resistant Staphylococcus aureus (MRSA) has been demonstrated, whereby susceptibility to β-lactam antimicrobials increases as glyco- and lipopeptide susceptibility decreases. We investigated this effect by evaluating the activity of the anti-MRSA cephalosporin ceftaroline against isogenic pairs of MRSA strains with various susceptibilities to vancomycin in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model. The activities of ceftaroline at 600 mg every 12 h (q12h) (targeted free maximum concentration of drug in serum [fC(max)], 15.2 μg/ml; half-life [t(1/2)], 2.3 h) and vancomycin at 1 g q12h (targeted fC(max), 18 μg/ml; t(1/2), 6 h) were evaluated against 3 pairs of isogenic clinical strains of MRSA that developed increased MICs to vancomycin in patients while on therapy using a two-compartment hollow-fiber PK/PD model with a starting inoculum of ~10(7) CFU/ml over a 96-h period. Bacterial killing and development of resistance were evaluated. Expression of penicillin-binding proteins (PBPs) 2 and 4 was evaluated by reverse transcription (RT)-PCR. The achieved pharmacokinetic parameters were 98 to 119% of the targeted values. Ceftaroline and vancomycin were bactericidal against 5/6 and 1/6 strains, respectively, at 96 h. Ceftaroline was more active against the mutant strains than the parent strains, with this difference being statistically significant for 2/3 strain pairs at 96 h. The level of PBP2 expression was 4.4× higher in the vancomycin-intermediate S. aureus (VISA) strain in 1/3 pairs. The levels of PBP2 and PBP4 expression were otherwise similar between the parent and mutant strains. These data support the seesaw hypothesis that ceftaroline, like traditional β-lactams, is more active against strains that are less susceptible to vancomycin even when the ceftaroline MICs are identical. Further research to explore these unique findings is warranted.

Published
2013

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