A world-first, three-year multi-centre study involved 352 patients at 27 hospitals in Australia, Singapore, Israel and New Zealand has called into question the effectiveness of using more than one antibiotic to treat the deadly ‘super-bug’, Methicillin-resistant staphylococcus aureus (MRSA) Bacteremia, commonly known as Golden Staph. Researchers from The University of Queensland, in collaboration with global counterparts, have found using two antibiotics to treat MRSA infection provides no advantage over using a single antibiotic.
UQ Professor David Paterson said researchers tested whether adding a second antibiotic for seven days to a standard antibiotic treatment would lead to improved health outcomes after 90 days. “We found no significant difference in mortality, bacteria in the blood, infection relapse or treatment failure,” Paterson said.
“Furthermore, patients who received two antibiotics had a higher rate of side effects related to kidney function than those who received just one antibiotic. For many years doctors have debated whether MRSA should be treated with two antibiotics or just one antibiotic. This trial now puts that debate to rest and will have a huge impact on how antibiotics are used for MRSA infections worldwide. These findings are hugely important on a number of levels – one of the most important implications of the research is how it can impact antibiotic use and the global issue of antibiotic resistance.”
MRSA is a common and very serious cause of infection that affects more than 10,000 people in Australia every year, especially women aged 60 and over. Treating the infection can take up to several months and requires lab testing for diagnosis.
Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-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 β-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 β-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 β-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 β-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.
Steven YC Tong, David C Lye, Dafna Yahav, Archana Sud, J Owen Robinson, Jane Nelson, Sophia Archuleta, Matthew A Roberts, Alan Cass, David L Paterson, Hong Foo, Mical Paul, Stephen D Guy, Adrian R Tramontana, Genevieve B Walls, Stephen McBride, Narin Bak, Niladri Ghosh, Benjamin A Rogers, Anna P Ralph, Jane Davies, Patricia E Ferguson, Ravindra Dotel, Genevieve L McKew, Timothy J Gray, Natasha E Holmes, Simon Smith, Morgyn S Warner, Shirin Kalimuddin, Barnaby E Young, Naomi Runnegar, David N Andresen, Nicholas A Anagnostou, Sandra A Johnson, Mark D Chatfield, Allen C Cheng, Vance G Fowler, Benjamin P Howden, Niamh Meagher, David J Price, Sebastiaan J van Hal, Matthew VN O’Sullivan, Joshua S Davis