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

doi:10.1186/s13063-019-3452-y

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

Trials. 2019 Jun 13;20(1):353. doi: 10.1186/s13063-019-3452-y.

Authors

Ravindra Dotel^{1

2}, Steven Y C Tong^{3

4}, Asha Bowen^{5

6}, Jane N Nelson⁴, Matthew V N O'Sullivan^{7

8}, Anita J Campbell^{5

6}, Brendan J McMullan^{9

10

11}, Philip N Britton^{12

13}, Joshua R Francis^{4

14}, Damon P Eisen^{15

16}, Owen Robinson^{17

18

19

20}, Laurens Manning^{18

21}, Joshua S Davis^{4

22

23}

Affiliations

¹ Centre for Infectious Diseases and Microbiology, Westmead Hospital, University of Sydney, Sydney, Australia. ravindra.dotel@health.nsw.gov.au.
² Department of Infectious Diseases, Blacktown Hospital, 18 Blacktown Road, Blacktown, NSW, 2148, Australia. ravindra.dotel@health.nsw.gov.au.
³ Victorian Infectious Disease Service, The Royal Melbourne Hospital-Doherty Department, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
⁴ Menzies School of Health Research, Darwin, Australia.
⁵ Department of Infectious Diseases, Perth Children's Hospital, Perth, Australia.
⁶ Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Perth, Australia.
⁷ Centre for Infectious Diseases and Microbiology, Westmead Hospital, University of Sydney, Sydney, Australia.
⁸ New South Wales Health Pathology, Newcastle, Australia.
⁹ Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, Australia.
¹⁰ School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
¹¹ National Centre for Infections in Cancer, University of Melbourne, Melbourne, Australia.
¹² Department of Infectious Diseases and Microbiology, Children's Hospital Westmead, Sydney, Australia.
¹³ Discipline of Child and Adolescent Health, Sydney Medical School and Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, Australia.
¹⁴ Department of Paediatrics, Royal Darwin Hospital, Darwin, Australia.
¹⁵ Townsville Hospital and Health Service, Townsville, Australia.
¹⁶ College of Medicine and Dentistry, James Cook University, Townsville, Australia.
¹⁷ Department of Infectious Diseases, Royal Perth Hospital, Perth, Australia.
¹⁸ Department of Infectious Diseases, Fiona Stanley Hospital, Perth, Australia.
¹⁹ Department of Microbiology, Pathwest Laboratory Medicine, Perth, WA, Australia.
²⁰ Antimicrobial Resistance and Infectious Diseases Research Laboratory, School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia.
²¹ Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia.
²² John Hunter Hospital, University of Newcastle, Newcastle, Australia.
²³ School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.

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.

Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12617001416381p . Registered on 6 October 2017.

Keywords: Clindamycin; Exotoxins; Leukocidins; Prospective studies; Staphylococcus aureus.

Publication types

Clinical Trial Protocol

MeSH terms

Adolescent
Adult
Anti-Bacterial Agents* / therapeutic use
C-Reactive Protein / analysis
Child
Child, Preschool
Clindamycin* / adverse effects
Clindamycin* / therapeutic use
Humans
Infant
Multicenter Studies as Topic
Outcome Assessment, Health Care
Pilot Projects
Randomized Controlled Trials as Topic
Research Design
Staphylococcal Infections* / drug therapy

Substances

Anti-Bacterial Agents
C-Reactive Protein
Clindamycin

Grants and funding

GNT1131932/National Health and Medical Research Council