Does adjunctive clindamycin have a role in Staphylococcus aureus bacteremia? A protocol for the adjunctive treatment domain of the S. aureus Network Adaptive Platform (SNAP) randomized controlled trial.

INTRODUCTION: The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and is recommended in many guidelines, but there is limited evidence underpinning this. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leucocidins (e.g., Panton-Valentine Leucocidin (PVL), toxic shock syndrome toxin 1 (TSST-1), exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question. METHODS AND ANALYSIS: The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multi-center adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either five days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard of care antibiotics. Most participants with SAB (within 72hr of index blood culture and not contraindicated) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and PVL-positive isolate.

Daptomycin plus ceftaroline salvage therapy for persistent Staphylococcus epidermidis bacteremia.

Initial antibiotics for true Staphylococcus epidermidis bacteremia include vancomycin or linezolid, but if bacteremia persists, consideration should be made for salvage combination therapy regimes such as daptomycin with ceftaroline.

Longer-term Mortality and Kidney Outcomes of Participants in the Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Trial: A Post Hoc Analysis.

Background: The Combination Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus (CAMERA2) trial ceased recruitment in July 2018, noting that a higher proportion of patients in the intervention arm (combination therapy) developed acute kidney injury (AKI) compared to the standard therapy (monotherapy) arm. We analyzed the long-term outcomes of participants in CAMERA2 to understand the impact of combination antibiotic therapy and AKI. Methods: Trial sites obtained additional follow-up data. The primary outcome was all-cause mortality, censored at death or the date of last known follow-up. Secondary outcomes included kidney failure or a reduction in kidney function (a 40% reduction in estimated glomerular filtration rate to <60 mL/minute/1.73 m2). To determine independent predictors of mortality in this cohort, adjusted hazard ratios were calculated using a Cox proportional hazards regression model. Results: This post hoc analysis included extended follow-up data for 260 patients. Overall, 123 of 260 (47%) of participants died, with a median population survival estimate of 3.4 years (235 deaths per 1000 person-years). Fifty-five patients died within 90 days after CAMERA2 trial randomization; another 68 deaths occurred after day 90. Using univariable Cox proportional hazards regression, mortality was not associated with either the assigned treatment arm in CAMERA2 (hazard ratio [HR], 0.84 [95% confidence interval [CI], .59-1.19]; P = .33) or experiencing an AKI (HR at 1 year, 1.04 [95% CI, .64-1.68]; P = .88). Conclusions: In this cohort of patients hospitalized with methicillin-resistant S aureus bacteremia, we found no association between either treatment arm of the CAMERA2 trial or AKI (using CAMERA2 trial definition) and longer-term mortality.

Pneumococcal bacteraemia in adults over a 10-year period (2011-2020): a clinical and serotype analysis.

BACKGROUND: Streptococcus pneumoniae (pneumococcus) is a human nasopharyngeal tract coloniser responsible for invasive pneumococcal disease, which is largely vaccine preventable. Vaccination is recommended from birth for all, and through adulthood for those with risk conditions. AIMS: To describe the clinical and serotype analysis of pneumococcus bacteraemia over a 10-year period. METHODS: A 10-year (February 2011-December 2020) retrospective review was performed on all adult (age ≥18 years) pneumococcus bacteraemia presenting to the four public hospitals in Western Sydney, Australia. Comorbidities and risk factors were recorded. RESULTS: Three hundred unique episodes of S. pneumoniae bloodstream infection (SPBI) were identified during the study period. The median age for SPBI was 63 years with 31.7% aged 70 years or older. A 94.7% had one or more risks factors for SPBI. Pneumonia was reported in 80% of all SPBI, whereas meningitis was reported in 6% and infective endocarditis in <1%. Asplenia was noted in 2.4%. Seven- and 30-day mortality was 6.6% and 11.9%, with a higher 30-day mortality in those aged ≥70 years (24.4%). The serotype distribution showed 7-valent conjugate vaccine covered 11.0% of all isolates, whereas 13-valent conjugate vaccine (13vPCV) and a 23-valent polysaccharide vaccine (23vPPV) covered 41.7% and 69.0% respectively. Immunisation details were available for 110 individuals, of whom, only 7.3% had received pneumococcal vaccination. CONCLUSIONS: Most patients with pneumococcal bacteraemia had age- or comorbidity-related risk factors but were not vaccinated. Two-thirds of cases occurred in people aged <70 years. 13vPCV and 23vPPV covered 41.7% and 69.0% of bacteraemic isolates.

Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19.

BACKGROUND: Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain. METHODS: In an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints. RESULTS: Between February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation. CONCLUSIONS: In hospitalized non­critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

A Randomized Trial of Nafamostat for Covid-19.

BACKGROUND: Nafamostat mesylate is a potent in vitro antiviral agent that inhibits the host transmembrane protease serine 2 enzyme used by severe acute respiratory syndrome coronavirus 2 for cell entry. METHODS: This open-label, pragmatic, randomized clinical trial in Australia, New Zealand, and Nepal included noncritically ill hospitalized patients with coronavirus disease 2019 (Covid-19). Participants were randomly assigned to usual care or usual care plus nafamostat. The primary end point was death (any cause) or receipt of new invasive or noninvasive ventilation or vasopressor support within 28 days after randomization. Analysis was with a Bayesian logistic model in which an adjusted odds ratio <1.0 indicates improved outcomes with nafamostat. Enrollment was closed due to falling numbers of eligible patients. RESULTS: We screened 647 patients in 21 hospitals (15 in Australia, 4 in New Zealand, and 2 in Nepal) and enrolled 160 participants from May 2021 to August 2022. In the intention-to-treat population, the primary end point occurred in 8 (11%) of 73 patients with usual care and 4 (5%) of 82 with nafamostat. The median adjusted odds ratio for the primary end point for nafamostat was 0.40 (95% credible interval, 0.12 to 1.34) with a posterior probability of effectiveness (adjusted odds ratio <1.0) of 93%. For usual care compared with nafamostat, hyperkalemia occurred in 1 (1%) of 67 and 7 (9%) of 78 participants, respectively, and clinically relevant bleeding occurred in 1 (1%) of 73 and 7 (8%) of 82 participants. CONCLUSIONS: Among hospitalized patients with Covid-19, there was a 93% posterior probability that nafamostat reduced the odds of death or organ support. Prespecified stopping criteria were not met, precluding definitive conclusions. Hyperkalemia and bleeding were more common with nafamostat. (Funded by ASCOT and others; ClinicalTrials.gov number, NCT04483960.)

Recurrent Cellulitis: Who is at Risk and How Effective is Antibiotic Prophylaxis?

Recurrent cellulitis following successful treatment is common and prevention should be a major component in the management of cellulitis. Conditions that increase the risk of recurrence include chronic edema, venous disease, dermatomycosis and obesity. These risk factors should be actively managed as further episodes of cellulitis increases the risk of recurrence. The role of non-antibiotic measures is important and should be first-line in prevention. Antibiotic prophylaxis is effective, but its role is limited to non-purulent cellulitis where risk factors are appropriately managed.

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ß-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the ß-lactam was administered for 7 days. Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.

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 ß-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.

Molecular epidemiology of methicillin-resistant Staphylococcus aureus isolates in New South Wales, Australia, 2012-2017.

BACKGROUND: To better understand the molecular epidemiology of MRSA and to assess the utility of 19-target binary typing we undertook large-scale epidemiological surveillance of MRSA from invasive and non-invasive clinical specimens, and screening swabs. METHODS: Binary typing was performed on clinical MRSA isolates collected in New South Wales (NSW), Australia between 01/01/2012 - 31/12/2017. Binary type (BT) predicted multilocus sequence type (ST) and spa types based on results from isolates which had been characterised by both methods. RESULTS: 7624 MRSA isolates were analysed of which 3581 (47%) were wounds or skin & softtissue isolates (W/SSTI), 2436 (32%) screening swabs, 469 (6%) blood cultures (BC), 780 (10%) others, and 358 (5%) unknown. We identified 731 BTs, 54 spa types, and 31 STs. ST239 was the commonest MRSA clone in 2012 (30%), but it decreased to 7% in 2017 (p <0.001). In contrast, <0.5% of MRSA were ST45 in 2012 compared to 14% in 2017 (p<0.001). An emergence of PVL-positive ST22 was also noted. Of all isolates, 28% (2122/7624) were lukS/PVL positive; the proportion, among prospectively collected isolates increased from 24% (1406/5858) to 33% (1933/5858) between 2012 and 2017 (p <0.0001). 43% (1534/3581) W/SSTI, 20% (95/469) BC and 10% (239/2436) screening swabs were PVL-positive. CONCLUSIONS: A major change in the epidemiology of MRSA was noted with a decline of ST239, an emergence of ST45 and PVL-positive ST22, and a significant increase in PVL-positive isolates. Binary typing can be a useful routine laboratory test for prospective molecular surveillance of MRSA colonisation and infection.

Disease of the past re-emerging in modern Australian society.

A 28-year-old man with fever, atraumatic lower limb pain and rash was noted to have multiple areas of ecchymosis involving both lower limbs. He was anaemic and also had a grossly swollen left leg. Differential diagnoses of compartment syndrome, vascular tear, platelet and clotting factor disorders, vasculitis and myositis were ruled out. Scurvy was only considered after failing to reach a diagnosis. A dietary history revealed consumption of a restricted diet with no fresh fruits or vegetables. Diagnosis was supported by an undetectable vitamin C level in blood and a rapid improvement of symptoms on oral vitamin C replacement. Prevalence of vitamin C deficiency in developed countries is also discussed.

Coexisting polyarticular septic arthritis, gout and pseudogout.

A case of a 67-year-old man with coexisting polyarticular septic arthritis due to group G Streptococcus, gout and pseudogout is presented. Septic arthritis of the left knee joint was further complicated by the development of an adjacent osteomyelitis. Appropriate management led to a full clinical recovery. Atypical clinical presentations in elderly, need for a sampling of more than one joint in polyarthritis and a summary of similar cases in literature is discussed.