Steven Y. Tong

Staphylococcus aureus, a gram-positive bacterium, is the leading cause of death from bacteremia worldwide, with a case fatality rate of 15% to 30% and an estimated 300 000 deaths per year. Staphylococcus aureus bacteremia causes metastatic infection in more than one-third of cases, including endocarditis (≈12%), septic arthritis (7%), vertebral osteomyelitis (≈4%), spinal epidural abscess, psoas abscess, splenic abscess, septic pulmonary emboli, and seeding of implantable medical devices. Patients with S aureus bacteremia commonly present with fever or symptoms from metastatic infection, such as pain in the back, joints, abdomen or extremities, and/or change in mental status. Risk factors include intravascular devices such as implantable cardiac devices and dialysis vascular catheters, recent surgical procedures, injection drug use, diabetes, and previous S aureus infection. Staphylococcus aureus bacteremia is detected with blood cultures. Prolonged S aureus bacteremia (≥48 hours) is associated with a 90-day mortality risk of 39%. All patients with S aureus bacteremia should undergo transthoracic echocardiography; transesophageal echocardiography should be performed in patients at high risk for endocarditis, such as those with persistent bacteremia, persistent fever, metastatic infection foci, or implantable cardiac devices. Other imaging modalities, such as computed tomography or magnetic resonance imaging, should be performed based on symptoms and localizing signs of metastatic infection. Staphylococcus aureus is categorized as methicillin-susceptible (MSSA) or methicillin-resistant (MRSA) based on susceptibility to β-lactam antibiotics. Initial treatment for S aureus bacteremia typically includes antibiotics active against MRSA such as vancomycin or daptomycin. Once antibiotic susceptibility results are available, antibiotics should be adjusted. Cefazolin or antistaphylococcal penicillins should be used for MSSA and vancomycin, daptomycin, or ceftobiprole for MRSA. Phase 3 trials for S aureus bacteremia demonstrated noninferiority of daptomycin to standard of care (treatment success, 53/120 [44%] vs 48/115 [42%]) and noninferiority of ceftobiprole to daptomycin (treatment success, 132/189 [70%] vs 136/198 [69%]). Source control is a critical component of treating S aureus bacteremia and may include removal of infected intravascular or implanted devices, drainage of abscesses, and surgical debridement. Staphylococcus aureus bacteremia has a case fatality rate of 15% to 30% and causes 300 000 deaths per year worldwide. Empirical antibiotic treatment should include vancomycin or daptomycin, which are active against MRSA. Once S aureus susceptibilities are known, MSSA should be treated with cefazolin or an antistaphylococcal penicillin. Additional clinical management consists of identifying sites of metastatic infection and pursuing source control for identified foci of infection.

Adherence to quality-of-care indictors (QCIs) is associated with better Staphylococcus aureus bacteremia (SAB) outcomes. It is unknown whether clinical trial participation adventitiously improves QCI adherence and clinical outcomes compared with nontrial routine care for SAB. To evaluate whether health care practitioners of trial participants with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia have better QCI adherence compared with practitioners of contemporaneous nontrial patients with MRSA bacteremia and whether QCI adherence or trial participation is associated with lower mortality. This ad hoc, post hoc analysis of the Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Trial included 17 CAMERA2 hospital sites from 4 countries. The present study involved data collection mirroring the CAMERA2 case report forms from nontrial patients selected from sites' CAMERA2 screening logs. The newly collected data were analyzed with existing data from trial participants. Both groups of patients were diagnosed with MRSA bacteremia between August 2015 and July 2018. Statistical analyses were performed from September 2024 to February 2025. Nontrial vs trial participation, including health care practitioner adherence to 7 evidence-based QCIs (individually and collectively) for SAB management. All-cause 90-day mortality; the association of the exposures with this outcome was assessed using Cox proportional hazards regressions. Multiple sensitivity analyses were performed, including propensity score matching and exclusion of early deaths. This study included 722 participants (467 nontrial [64.7%] and 255 trial [35.3%]; mean [SD] age, 63.2 [18.4] years; 482 [66.8%] male). Demographics were comparable in the 2 study groups. Nontrial patients had a higher range of Charlson Comorbidity Index (median, 2.0 [range, 0-16.0] vs 2.0 [range, 0-13.0]; P < .001) and Pitt bacteremia score (median, 1.0 [range, 1.0-12.0] vs 1.0 [range, 1.0-7.0]; P < .001) compared with trial participants. Ninety-day mortality was not significantly different in the nontrial and trial groups (106 of 457 [23.2%] vs 48 of 251 [19.1%]; P = .25). Health care practitioners of nontrial patients had a lower mean (SD) number of adherent QCIs compared with practitioners of trial participants (3.90 [1.38] vs 4.28 [1.17]; P = .003). While increasing number of adherent QCIs was associated with lower 90-day mortality (adjusted hazard ratio [AHR], 0.73; 95% CI, 0.59-0.91; P = .005), adherence to QCIs individually was not associated with lower mortality. Study group (nontrial vs trial) was not associated with mortality (AHR, 1.08; 95% CI, 0.73-1.61; P = .68). In this post hoc analysis of a randomized clinical trial, health care practitioners of trial participants had greater adherence to QCIs for MRSA bacteremia management compared with practitioners of nontrial patients. Trial participation was not associated with lower mortality.

Background: The role of adjunctive fosfomycin in Staphylococcus aureus bacteremia (SAB) remains uncertain. Methods: We performed a post-hoc pooled analysis of individual participant data from the multicenter BACSARM and SAFO randomized controlled trials, which assessed fosfomycin combined with daptomycin or cloxacillin versus monotherapy for methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) SAB. The primary outcome was treatment success at 8 weeks, defined as the patient being alive, without signs of relapse, and showing resolution of fever and improvement in clinical signs and symptoms of infection. Secondary outcomes included persistent bacteremia at days 3 and 7, all-cause mortality at days 14, 30, and 60, and adverse events leading to treatment discontinuation. Bayesian and frequentist methods were used to estimate treatment effects, with the primary Bayesian analysis using a minimally informative prior centred on no treatment effect. This study is registered with ClinicalTrials.gov, NCT06695832. Results: The intention-to-treat population comprised 369 participants, of whom 178 received fosfomycin combination therapy and 191 received monotherapy. The primary Bayesian analysis showed a 91.8% posterior probability that fosfomycin improves treatment success at 8 weeks (median relative risk [RR] 1.10, 95% credibility interval [Crl] 0.97-1.26) with sensitivity analyses (using pessimistic, sceptical, and optimistic priors) yielding probabilities between 75.8% and 97.2%. Fosfomycin was associated with a significant reduction in persistent bacteremia at day 3 (median RR 0.19, 95% CrI 0.07-0.41) and day 7 (median RR 0.22, 95% CrI 0.03-0.84). The adjusted frequentist analysis demonstrated an association between fosfomycin combination therapy and treatment success at 8 weeks (RR 1.04, 95% CI 1.02-1.06; p<0.001). Combination therapy was associated with a higher risk of adverse events (RR 2.03, 95% CI 1.13-3.63; p=0.017). Conclusions: Adjunctive fosfomycin may improve early bacterial clearance and treatment success in SAB but at the cost of increased toxicity.

Background: In the Northern Territory (NT) of Australia, First Nations people with chronic hepatitis B (CHB) are infected with a unique sub-genotype, C4, which contains mutations linked to progressive fibrosis and hepatocellular carcinoma. This cohort study aimed to investigate disease progression in C4 sub-genotype infection and estimate how many untreated individuals may benefit from antiviral therapy with broadening treatment indications. Methods: Included individuals were part of Hep B PAST, a co-designed program to improve the cascade of care for people living with CHB in the NT. Disease phase and cirrhotic status were determined algorithmically using clinical and laboratory data at two time points. Loss of HBV antigens was assessed longitudinally. Treatment need was assessed cross-sectionally in the cohort at study completion. Key outcomes were estimated rates of HBsAg/HBeAg loss in sub-genotype C4 infection and quantification of how many untreated individuals qualify for therapy under current Australian and expanded global treatment guidelines. Results: HBsAg and HBeAg loss occurred at a rate of 1·04 and 8·06 events/100 person-years respectively (7342·6 and 545·6 years follow up). 783 people living with CHB were included (40% female, median age 48 years). Of these, 16% had cirrhosis (an additional 6% having FibroScan > 7 kPa, meaning 22% had cirrhosis or significant fibrosis) and 25% were prescribed antivirals. Only 6·7% of untreated individuals were treatment eligible under current guidelines. Using the 2024 World Health Organisation guidelines, this increased to 50% due mostly to fibrosis and population prevalence of diabetes. Conclusions: Despite advanced liver disease in people living with CHB in the NT, rates of antigen loss in sub-genotype C4 hepatitis B infection are similar to other genotypes. Further work is needed to understand drivers of cirrhosis and significant fibrosis in this population.

Hierarchical composite endpoints (HCEs), combining features of simple composite endpoints and conventional ordinal endpoints, are increasingly being used in infectious diseases research. However, many clinicians may be unfamiliar with these novel endpoints, including the variety of different target parameters that may be of interest and the methods that can be used to estimate them. In this review, we provide a conceptual overview of HCEs by defining them and providing examples from the infectious diseases literature. We explain different methods for analyzing HCEs, including: (a) the Wilcoxon rank sum approach (often used in studies with a Desirability of Outcome Ranking [DOOR] endpoint); (b) generalized pairwise comparisons (used to estimate a win ratio or win odds); (c) proportional odds model (and the relevance of the proportional odds assumption); and, (d) the probabilistic index model. This review will help infectious disease clinicians and healthcare providers interpret current and future research using such endpoints.

CAMERA 2 - Combination Antibiotic Therapy for Methicillin Resistant Staphylococcus Aureus Infection - An Investigator-initiated, Multi-centre, Parallel Group, Open Labelled Randomised Controlled Trial