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Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration
Gabriel Trova Cuba
Universidade Federal de Sao Paulo
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8732-8946
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Infectious Diseases.
Background: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. I n silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC .
Methods: Steady-state drug area under the curve ratio to MIC (AUC⁄MIC) or the percent time above MIC ( f T>MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI.
Results: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg every 12h followed by 400 mg every 24h and for teicoplanin 400 mg every 12h, respectively; 61% and 76% for vancomycin 1000 mg every 12h and every 8h, respectively.
Conclusions: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥ 2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥ 2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.
Keywords
Bloodstream infections, Staphylococcus aureus, pharmacodynamic targets, ceftaroline, daptomycin, vancomycin
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CURRENT STATUS: Published
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Posted 20 Dec, 2019
Published
On 23 Jan, 2020
No community comments so far
Submission checks complete
On 17 Dec, 2019
Editor assigned
On 16 Dec, 2019
Editorial decision: Accept
On 16 Dec, 2019
Editor invited
On 15 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 13 Dec, 2019
Editor assigned
On 17 Oct, 2019
Reviewers invited
Invitations sent on 17 Oct, 2019
Submission checks complete
On 16 Oct, 2019
Editor invited
On 16 Oct, 2019
No comments provided
Editorial decision: Major revision
On 17 Sep, 2019
Review #2 received
Received 15 Sep, 2019
Reviewer #2 agreed
On 08 Aug, 2019
Review #1 received
Received 11 Jul, 2019
Reviewer #1 agreed
On 25 Jun, 2019
Submission checks complete
On 03 May, 2019
Reviewers invited
Invitations sent on 03 May, 2019
Editor invited
On 01 May, 2019
Editor assigned
On 01 May, 2019
First submitted
On 30 Apr, 2019
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Subject Areas
Infectious Diseases
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This preprint is under consideration at BMC Infectious Diseases. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration
Gabriel Trova Cuba
Universidade Federal de Sao Paulo
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8732-8946
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 3
Posted 20 Dec, 2019
Published
On 23 Jan, 2020
No community comments so far
Submission checks complete
On 17 Dec, 2019
Editor assigned
On 16 Dec, 2019
Editorial decision: Accept
On 16 Dec, 2019
Editor invited
On 15 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 13 Dec, 2019
Editor assigned
On 17 Oct, 2019
Reviewers invited
Invitations sent on 17 Oct, 2019
Submission checks complete
On 16 Oct, 2019
Editor invited
On 16 Oct, 2019
No comments provided
Editorial decision: Major revision
On 17 Sep, 2019
Review #2 received
Received 15 Sep, 2019
Reviewer #2 agreed
On 08 Aug, 2019
Review #1 received
Received 11 Jul, 2019
Reviewer #1 agreed
On 25 Jun, 2019
Submission checks complete
On 03 May, 2019
Reviewers invited
Invitations sent on 03 May, 2019
Editor invited
On 01 May, 2019
Editor assigned
On 01 May, 2019
First submitted
On 30 Apr, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Infectious Diseases
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Infectious Diseases.
Background: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. I n silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC .
Methods: Steady-state drug area under the curve ratio to MIC (AUC⁄MIC) or the percent time above MIC ( f T>MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI.
Results: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg every 12h followed by 400 mg every 24h and for teicoplanin 400 mg every 12h, respectively; 61% and 76% for vancomycin 1000 mg every 12h and every 8h, respectively.
Conclusions: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥ 2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥ 2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.
Figure 1
Figure 2