Abstract
BackgroundExotoxins 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.MethodsAn 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.DiscussionThis 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 registrationAustralian New Zealand Clinical Trials Registry, ACTRN12617001416381p. Registered on 6 October 2017.
Highlights
Exotoxins are important virulence factors in Staphylococcus aureus
Discussion animal studies and observational reports support the concept of effective S. aureus exotoxin suppression with clindamycin [17], adequate supporting clinical evidence is lacking
The proposed study is an open-label, pilot, randomised controlled trial to determine whether 7 days of clindamycin in combination with standard therapy will lead to a faster resolution of systemic inflammation than standard therapy alone in adults and children with severe S. aureus infection
Summary
Study setting The CASSETTE study is an investigator-initiated, openlabel, parallel-group, superiority, multicentre RCT (Fig. 1). Participant timeline (Table 2) Eligibility screening We will identify potential patients as those who meet the two main inclusion criteria of: S. aureus (MSSA and MRSA) identified in a clinically relevant specimen; and clinically defined severe disease (septic shock, necrotising lung/pleural space infection, complicated multifocal skin or soft tissue, or osteoarticular infection). All such identified patients will be screened and assessed for potential enrolment and randomisation.
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