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

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

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

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

Global differences in the management of Staphylococcus aureus bacteremia: no international standard of care

BackgroundDespite being the leading cause of mortality from bloodstream infections worldwide, little is known about regional variation in treatment practices for Staphylococcus aureus bacteremia (SAB). The aim of this study was to identify global variation in management, diagnostics, and definitions of SAB.MethodsDuring a 20-day period in 2022, physicians throughout the world were surveyed on SAB treatment practices. The survey was distributed through listservs, e-mails, and social media.ResultsIn total, 2031 physicians from 71 different countries on 6 continents (North America [701, 35%], Europe [573, 28%], Asia [409, 20%], Oceania [182, 9%], South America [124, 6%], and Africa [42, 2%]) completed the survey. Management-based responses differed significantly by continent for preferred treatment of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) bacteremia, use of adjunctive rifampin for prosthetic material infection, and use of oral antibiotics (P P –4 days of positive blood cultures, responses ranged from 2 days in 31% of European respondents to 7 days in 38% of Asian respondents (P ConclusionsLarge practice variations for SAB exist throughout the world, reflecting the paucity of high-quality data and the absence of an international standard of care for the management of SAB.Immunogenetics and cellular immunology of bacterial infectious disease

Vancomycin exposure and acute kidney injury outcome: A Snapshot From the CAMERA2 Study

Among patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia from a prospective randomized clinical trial, acute kidney injury (AKI) rates increased with increasing vancomycin exposure, even within the therapeutic range. AKI was independently more common for the (flu)cloxacillin group. Day 2 vancomycin AUC ≥470 mg·h/L was significantly associated with AKI, independent of (flu)cloxacillin receipt

The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial

Objectives: To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. Trial design: ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. Participants: Participants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently

High-resolution melting analysis of the spa locus reveals significant diversity within sequence type 93 methicillin-resistant Staphylococcus aureus from northern Australia

High-resolution melting analysis is an inherently robust, easy and inexpensive approach to the examination of genomic regions containing single-nucleotide polymorphisms and hypervariable loci. Staphylococcus aureus sequence type (ST) 93 is a singleton, Panton–Valentine leukocidin-positive clone unique to Australia. A high-resolution melting-based method for the identification of ST93 was developed, and a similar approach was used to reveal diversity within the spa locus of this lineage. Statistical and graphical methods that account for instrumental and operator-dependent variation in high-resolution melting curves were developed, to allow greater confidence and reproducibility in deciding whether another curve is truly different from the baseline curve of an amplicon with known sequence. The data support a very early acquisition, or multiple independent acquisitions, of SCCmec by ST93 methicillin-susceptible S. aureus (MSSA), and the coexistence of MSSA and methicillin-resistant S. aureus versions of the same lineage within northern Australia

Benzylpenicillin versus flucloxacillin for penicillin-susceptible Staphylococcus aureus bloodstream infections from a large retrospective cohort study

In clinical practice, differing opinions exists regarding the optimal management of patients with penicillin-susceptible Staphylococcus aureus (PSSA) bloodstream infection (BSI). The aim of this study was to compare the 30-day mortality of patients treated with benzylpenicillin or flucloxacillin for PSSA BSI from a large prospectively collected data set from Australia and New Zealand. A logistic regression model and propensity score treatment analysis using inverse probability of treatment weighting were used. A total of 915 patients were included in the study, with an overall mortality rate of 12.9% (118/915) [benzylpenicillin 10.5% (33/315) and flucloxacillin 14.2% (85/600)]. Endocarditis was associated with benzylpenicillin treatment choice, whereas skin and soft-tissue infection was associated with flucloxacillin treatment choice. In the multivariate analysis, increased 30-day mortality was associated with flucloxacillin compared with benzylpenicillin [odds ratio (OR) = 1.6, 95% confidence interval (CI) 1.0-2.5; P = 0.05). When adjusted for treatment choice in the propensity score analysis, flucloxacillin was again associated with increased 30-day mortality (OR = 1.06, 95% CI 1.01-1.1; P = 0.03). An increase in 30-day mortality associated with flucloxacillin use suggests a potential benefit for benzylpenicillin therapy in patients with PSSA BSI.A. Henderson, P. Harris, G. Hartel, D. Paterson, J. Turnidge, J. S. Davis, S. Y. C. Ton

Evolution and global transmission of a multidrug-resistant, community-associated methicillin-resistant Staphylococcus aureus lineage from the Indian subcontinent

The evolution and global transmission of antimicrobial resistance have been well documented for Gram-negative bacteria and health care-associated epidemic pathogens, often emerging from regions with heavy antimicrobial use. However, the degree to which similar processes occur with Gram-positive bacteria in the community setting is less well understood. In this study, we traced the recent origins and global spread of a multidrug-resistant, community-associated Staphylococcus aureus lineage from the Indian subcontinent, the Bengal Bay clone (ST772). We generated whole-genome sequence data of 340 isolates from 14 countries, including the first isolates from Bangladesh and India, to reconstruct the evolutionary history and genomic epidemiology of the lineage. Our data show that the clone emerged on the Indian subcontinent in the early 1960s and disseminated rapidly in the 1990s. Short-term outbreaks in community and health care settings occurred following intercontinental transmission, typically associated with travel and family contacts on the subcontinent, but ongoing endemic transmission was uncommon. Acquisition of a multidrug resistance integrated plasmid was instrumental in the emergence of a single dominant and globally disseminated clade in the early 1990s. Phenotypic data on biofilm, growth, and toxicity point to antimicrobial resistance as the driving force in the evolution of ST772. The Bengal Bay clone therefore combines the multidrug resistance of traditional health care-associated clones with the epidemiological transmission of community-associated methicillin-resistant S. aureus (MRSA). Our study demonstrates the importance of whole-genome sequencing for tracking the evolution of emerging and resistant pathogens. It provides a critical framework for ongoing surveillance of the clone on the Indian subcontinent and elsewhere