Clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation (CASSETTE)-an open-labelled pilot randomized controlled trial

A J Campbell; R Dotel; M Braddick; P N Britton; D P Eisen; J R Francis; S Lynar; B McMullan; N Meagher; J Nelson; M V N O'Sullivan; D J Price; J O Robinson; A Whelan; S Y C Tong; A C Bowen; J S Davis

doi:10.1093/jacamr/dlac014

Clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation (CASSETTE)-an open-labelled pilot randomized controlled trial

JAC Antimicrob Resist. 2022 Feb 17;4(1):dlac014. doi: 10.1093/jacamr/dlac014. eCollection 2022 Mar.

Authors

A J Campbell^{1

2

3}, R Dotel^{4

5}, M Braddick⁶, P N Britton^{7

8

9}, D P Eisen¹⁰, J R Francis^{11

12}, S Lynar^{11

13}, B McMullan^{14

15

16}, N Meagher^{17

18}, J Nelson¹¹, M V N O'Sullivan^{5

19}, D J Price^{17

18}, J O Robinson^{20

21

22

23}, A Whelan², S Y C Tong^{17

24}, A C Bowen^{1

2

3

11}, J S Davis^{11

25

26}

Affiliations

¹ Department of Infectious Diseases, Perth Children's Hospital, Perth, Australia.
² Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Australia.
³ School of Medicine, University of Western Australia, Perth, Australia.
⁴ Department of Infectious Diseases, Blacktown Hospital, Sydney, Australia.
⁵ Centre for Infectious Diseases and Microbiology, Westmead Hospital, University of Sydney, Sydney, Australia.
⁶ Department of Infectious Diseases, Townsville University Hospital, Townsville, Queensland, Australia.
⁷ Department of Infectious Diseases and Microbiology, Children's Hospital Westmead, Sydney, Australia.
⁸ University of Sydney, Discipline of Child and Adolescent Health, Sydney Medical School, Sydney, Australia.
⁹ Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, Australia.
¹⁰ College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.
¹¹ Global and Tropical Health Division, Menzies School of Health Research, Darwin, Australia.
¹² Department of Paediatrics, Royal Darwin Hospital, Darwin, Australia.
¹³ Infectious Diseases, Royal Darwin Hospital, Northern Territory, Australia.
¹⁴ Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, Sydney, Australia.
¹⁵ School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
¹⁶ National Centre for Infections in Cancer, University of Melbourne, Melbourne, Australia.
¹⁷ Department of Infectious Diseases, Doherty Institute for Infection & Immunity, The University of Melbourne & Royal Melbourne Hospital, Melbourne, Australia.
¹⁸ Centre for Epidemiology & Biostatistics, Melbourne School of Population & Global Health, University of Melbourne, Melbourne, Australia.
¹⁹ New South Wales Health Pathology, Newcastle, Australia.
²⁰ Department of Infectious Diseases, Royal Perth Hospital, Perth, Australia.
²¹ Department of Infectious Diseases, Fiona Stanley Hospital, Perth, Australia.
²² Department of Microbiology, Pathwest Laboratory Medicine, Perth, Australia.
²³ College of Science, Health, Engineering and Education, Discipline of Health, Murdoch University, Perth, Australia.
²⁴ Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
²⁵ John Hunter Hospital, University of Newcastle, Newcastle, Australia.
²⁶ School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.

Abstract

Background: Combination antibiotic therapy with an antitoxin agent, such as clindamycin, is included in some guidelines for severe, toxin-mediated Staphylococcus aureus infections. The evidence to support this practice is currently limited to in vitro, animal and observational human case-series data, with no previous randomized controlled trials (RCTs).

Objectives: This pilot RCT aimed to determine the feasibility of conducting a clinical trial to examine if adjunctive clindamycin with standard therapy has greater efficacy than standard therapy alone for S. aureus infections.

Methods: We performed an investigator-initiated, open-label, multicentre, pilot RCT (ACTRN12617001416381p) in adults and children with severe S. aureus infections, randomized to standard antibiotic therapy with or without clindamycin for 7 days.

Results: Over 28 months, across nine sites, 127 individuals were screened and 34 randomized, including 11 children (32%). The primary outcome-number of days alive and free of systemic inflammatory response syndrome ≤14 days-was similar between groups: clindamycin (3 days [IQR 1-6]) versus standard therapy (4 days [IQR 0-8]). The 90 day mortality was 0% (0/17) in the clindamycin group versus 24% (4/17) in the standard therapy group. Secondary outcomes-microbiological relapse, treatment failure or diarrhoea-were similar between groups.

Conclusions: As the first clinical trial assessing adjunctive clindamycin for S. aureus infections, this study indicates feasibility and that adults and children can be incorporated into one trial using harmonized endpoints, and there were no safety concerns. The CASSETTE trial will inform the definitive S. aureus Network Adaptive Platform (SNAP) trial, which includes an adjunctive clindamycin domain and participants with non-severe disease.