CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation: Study protocol for a randomised controlled trial

Ravindra Dotel, Steven Y.C. Tong, Asha Bowen, Jane N. Nelson, Matthew V.N. O'sullivan, Anita J. Campbell, Brendan J. McMullan, Philip N. Britton, Joshua R. Francis, Damon P. Eisen, Owen Robinson, Laurens Manning, Joshua S. Davis

Research output: Contribution to journalArticle

Abstract

Background: Exotoxins are important virulence factors in Staphylococcus aureus. Clindamycin, a protein synthesis inhibitor antibiotic, is thought to limit exotoxin production and improve outcomes in severe S. aureus infections. However, randomised prospective data to support this are lacking. Methods: An open-label, multicentre, randomised controlled trial (RCT) will compare outcome differences in severe S. aureus infection between standard treatment (flucloxacillin/cefazolin in methicillin-susceptible S. aureus; and vancomycin/daptomycin in methicillin-resistant S. aureus) and standard treatment plus an additional clindamycin given for 7 days. We will include a minimum of 60 participants (both adult and children) in the pilot study. Participants will be enrolled within 72 h of an index culture. Severe infections will include septic shock, necrotising pneumonia, or multifocal and non-contiguous skin and soft tissue/osteoarticular infections. Individuals who are immunosuppressed, moribund, with current severe diarrhoea or Clostridiodes difficile infection, pregnant, and those with anaphylaxis to β-lactams or lincosamides will be excluded. The primary outcomes measure is the number of days alive and free (1 or 0) of systemic inflammatory response syndrome (SIRS) within the first 14 days post randomisation. The secondary outcomes measure will include all-cause mortality at 14, 42, and 90 days, time to resolution of SIRS, proportion with microbiological treatment failure, and rate of change of C-reactive protein over time. Impacts of inducible clindamycin resistance, strain types, methicillin susceptibility, and presence of various exotoxins will also be analysed. Discussion: This study will assess the effect of adjunctive clindamycin on patient-centred outcomes in severe, toxin-mediated S. aureus infections. The pilot study will provide feasibility for a much larger RCT.

Original languageEnglish
Article number353
JournalTrials
Volume20
Issue number1
DOIs
Publication statusPublished - 13 Jun 2019

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Clindamycin
Staphylococcus aureus
Randomized Controlled Trials
Exotoxins
Infection
Systemic Inflammatory Response Syndrome
Floxacillin
Lincosamides
Outcome Assessment (Health Care)
Daptomycin
Therapeutics
Cefazolin
Lactams
Soft Tissue Infections
Methicillin Resistance
Protein Synthesis Inhibitors
Methicillin
Anaphylaxis
Virulence Factors
Vancomycin

Cite this

Dotel, Ravindra ; Tong, Steven Y.C. ; Bowen, Asha ; Nelson, Jane N. ; O'sullivan, Matthew V.N. ; Campbell, Anita J. ; McMullan, Brendan J. ; Britton, Philip N. ; Francis, Joshua R. ; Eisen, Damon P. ; Robinson, Owen ; Manning, Laurens ; Davis, Joshua S. / CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation : Study protocol for a randomised controlled trial. In: Trials. 2019 ; Vol. 20, No. 1.
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abstract = "Background: Exotoxins are important virulence factors in Staphylococcus aureus. Clindamycin, a protein synthesis inhibitor antibiotic, is thought to limit exotoxin production and improve outcomes in severe S. aureus infections. However, randomised prospective data to support this are lacking. Methods: An open-label, multicentre, randomised controlled trial (RCT) will compare outcome differences in severe S. aureus infection between standard treatment (flucloxacillin/cefazolin in methicillin-susceptible S. aureus; and vancomycin/daptomycin in methicillin-resistant S. aureus) and standard treatment plus an additional clindamycin given for 7 days. We will include a minimum of 60 participants (both adult and children) in the pilot study. Participants will be enrolled within 72 h of an index culture. Severe infections will include septic shock, necrotising pneumonia, or multifocal and non-contiguous skin and soft tissue/osteoarticular infections. Individuals who are immunosuppressed, moribund, with current severe diarrhoea or Clostridiodes difficile infection, pregnant, and those with anaphylaxis to β-lactams or lincosamides will be excluded. The primary outcomes measure is the number of days alive and free (1 or 0) of systemic inflammatory response syndrome (SIRS) within the first 14 days post randomisation. The secondary outcomes measure will include all-cause mortality at 14, 42, and 90 days, time to resolution of SIRS, proportion with microbiological treatment failure, and rate of change of C-reactive protein over time. Impacts of inducible clindamycin resistance, strain types, methicillin susceptibility, and presence of various exotoxins will also be analysed. Discussion: This study will assess the effect of adjunctive clindamycin on patient-centred outcomes in severe, toxin-mediated S. aureus infections. The pilot study will provide feasibility for a much larger RCT.",
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author = "Ravindra Dotel and Tong, {Steven Y.C.} and Asha Bowen and Nelson, {Jane N.} and O'sullivan, {Matthew V.N.} and Campbell, {Anita J.} and McMullan, {Brendan J.} and Britton, {Philip N.} and Francis, {Joshua R.} and Eisen, {Damon P.} and Owen Robinson and Laurens Manning and Davis, {Joshua S.}",
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Dotel, R, Tong, SYC, Bowen, A, Nelson, JN, O'sullivan, MVN, Campbell, AJ, McMullan, BJ, Britton, PN, Francis, JR, Eisen, DP, Robinson, O, Manning, L & Davis, JS 2019, 'CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation: Study protocol for a randomised controlled trial' Trials, vol. 20, no. 1, 353. https://doi.org/10.1186/s13063-019-3452-y

CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation : Study protocol for a randomised controlled trial. / Dotel, Ravindra; Tong, Steven Y.C.; Bowen, Asha; Nelson, Jane N.; O'sullivan, Matthew V.N.; Campbell, Anita J.; McMullan, Brendan J.; Britton, Philip N.; Francis, Joshua R.; Eisen, Damon P.; Robinson, Owen; Manning, Laurens; Davis, Joshua S.

In: Trials, Vol. 20, No. 1, 353, 13.06.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation

T2 - Study protocol for a randomised controlled trial

AU - Dotel, Ravindra

AU - Tong, Steven Y.C.

AU - Bowen, Asha

AU - Nelson, Jane N.

AU - O'sullivan, Matthew V.N.

AU - Campbell, Anita J.

AU - McMullan, Brendan J.

AU - Britton, Philip N.

AU - Francis, Joshua R.

AU - Eisen, Damon P.

AU - Robinson, Owen

AU - Manning, Laurens

AU - Davis, Joshua S.

PY - 2019/6/13

Y1 - 2019/6/13

N2 - Background: Exotoxins are important virulence factors in Staphylococcus aureus. Clindamycin, a protein synthesis inhibitor antibiotic, is thought to limit exotoxin production and improve outcomes in severe S. aureus infections. However, randomised prospective data to support this are lacking. Methods: An open-label, multicentre, randomised controlled trial (RCT) will compare outcome differences in severe S. aureus infection between standard treatment (flucloxacillin/cefazolin in methicillin-susceptible S. aureus; and vancomycin/daptomycin in methicillin-resistant S. aureus) and standard treatment plus an additional clindamycin given for 7 days. We will include a minimum of 60 participants (both adult and children) in the pilot study. Participants will be enrolled within 72 h of an index culture. Severe infections will include septic shock, necrotising pneumonia, or multifocal and non-contiguous skin and soft tissue/osteoarticular infections. Individuals who are immunosuppressed, moribund, with current severe diarrhoea or Clostridiodes difficile infection, pregnant, and those with anaphylaxis to β-lactams or lincosamides will be excluded. The primary outcomes measure is the number of days alive and free (1 or 0) of systemic inflammatory response syndrome (SIRS) within the first 14 days post randomisation. The secondary outcomes measure will include all-cause mortality at 14, 42, and 90 days, time to resolution of SIRS, proportion with microbiological treatment failure, and rate of change of C-reactive protein over time. Impacts of inducible clindamycin resistance, strain types, methicillin susceptibility, and presence of various exotoxins will also be analysed. Discussion: This study will assess the effect of adjunctive clindamycin on patient-centred outcomes in severe, toxin-mediated S. aureus infections. The pilot study will provide feasibility for a much larger RCT.

AB - Background: Exotoxins are important virulence factors in Staphylococcus aureus. Clindamycin, a protein synthesis inhibitor antibiotic, is thought to limit exotoxin production and improve outcomes in severe S. aureus infections. However, randomised prospective data to support this are lacking. Methods: An open-label, multicentre, randomised controlled trial (RCT) will compare outcome differences in severe S. aureus infection between standard treatment (flucloxacillin/cefazolin in methicillin-susceptible S. aureus; and vancomycin/daptomycin in methicillin-resistant S. aureus) and standard treatment plus an additional clindamycin given for 7 days. We will include a minimum of 60 participants (both adult and children) in the pilot study. Participants will be enrolled within 72 h of an index culture. Severe infections will include septic shock, necrotising pneumonia, or multifocal and non-contiguous skin and soft tissue/osteoarticular infections. Individuals who are immunosuppressed, moribund, with current severe diarrhoea or Clostridiodes difficile infection, pregnant, and those with anaphylaxis to β-lactams or lincosamides will be excluded. The primary outcomes measure is the number of days alive and free (1 or 0) of systemic inflammatory response syndrome (SIRS) within the first 14 days post randomisation. The secondary outcomes measure will include all-cause mortality at 14, 42, and 90 days, time to resolution of SIRS, proportion with microbiological treatment failure, and rate of change of C-reactive protein over time. Impacts of inducible clindamycin resistance, strain types, methicillin susceptibility, and presence of various exotoxins will also be analysed. Discussion: This study will assess the effect of adjunctive clindamycin on patient-centred outcomes in severe, toxin-mediated S. aureus infections. The pilot study will provide feasibility for a much larger RCT.

KW - Clindamycin

KW - Exotoxins

KW - Leukocidins

KW - Prospective studies

KW - Staphylococcus aureus

UR - http://www.scopus.com/inward/record.url?scp=85067308662&partnerID=8YFLogxK

U2 - 10.1186/s13063-019-3452-y

DO - 10.1186/s13063-019-3452-y

M3 - Article

VL - 20

JO - Trials

JF - Trials

SN - 1745-6215

IS - 1

M1 - 353

ER -