Adjunctive β-Lactam for MRSA Bacteremia: No 90-Day Outcome Gain, Higher AKI Risk

Authors:Steven Y. C. 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 V. N. O’Sullivan, Joshua S. Davis

Journal:JAMA

DOI:10.1001/jama.2020.0103

In CAMERA2, adding 7 days of flucloxacillin, cloxacillin, or cefazolin to IV vancomycin or daptomycin for MRSA bacteremia did not improve the 90-day composite endpoint vs standard therapy alone: 35% (59/170) vs 39% (68/175); absolute difference -4.2% (95% CI, -14.3% to 6.0%; P...

February 11, 2020

Quick Take

In CAMERA2, adding 7 days of flucloxacillin, cloxacillin, or cefazolin to IV vancomycin or daptomycin for MRSA bacteremia did not improve the 90-day composite endpoint vs standard therapy alone: 35% (59/170) vs 39% (68/175); absolute difference -4.2% (95% CI, -14.3% to 6.0%; P = .42).

The combination arm cleared bacteremia faster by day 5 (11% vs 20% persistent bacteremia) but at a renal cost: acute kidney injury (AKI) 23% vs 6% in patients not on baseline dialysis. For stewardship teams, the key signal is no overall outcome gain despite faster microbiologic clearance.

What They Did

Multicenter, open-label randomized clinical trial across 27 hospitals in Australia, Singapore, Israel, and New Zealand.

Enrolled hospitalized adults with MRSA bacteremia; patients were randomized to IV vancomycin or daptomycin alone vs the same standard therapy plus 7 days of flucloxacillin, cloxacillin, or cefazolin.

The prespecified primary endpoint was a 90-day composite of all-cause mortality, persistent bacteremia at day 5, microbiologic relapse, or microbiologic treatment failure.

Endpoint adjudication was blinded, but the trial was stopped early by the DSMB for safety after excess AKI emerged and no mortality benefit signal was seen.

What They Found

Primary endpoint: 35% with combination therapy vs 39% with standard therapy; not statistically significant.

Persistent bacteremia at day 5 was lower with combination therapy: 19/166 (11%) vs 35/172 (20%).

90-day mortality was not improved: 21% (35/170) with combination therapy vs 16% (28/174) with standard therapy.

AKI was substantially higher with combination therapy: 34/145 (23%) vs 9/145 (6%); post hoc analyses also suggested more severe AKI.

The renal signal mainly reflects vancomycin plus antistaphylococcal penicillin add-on therapy; the trial provides less certainty for daptomycin-based or cefazolin-based combinations because exposure to those regimens was limited.

Bottom Line

CAMERA2 argues against routine adjunctive β-lactam add-on therapy—especially vancomycin plus antistaphylococcal penicillins—for MRSA bacteremia, while leaving more uncertainty for daptomycin- or cefazolin-based combinations.

Why It Matters

Persistent MRSA bacteremia is a common stewardship escalation point, especially when teams are balancing source control, repeat cultures, and optimization of core anti-MRSA therapy.

Adjunctive therapy adds IV complexity, renal monitoring burden, and toxicity risk in already high-acuity inpatients.

For formulary and medication-safety leaders, synergy strategies can spread ahead of definitive evidence and create avoidable practice variation.

What This Means for Us

This is a negative randomized trial for routine adjunctive β-lactam addition in the studied setting: faster day-5 clearance did not translate into better 90-day outcomes.

These findings do not support routine adjunctive β-lactam addition here; if considered, use should be individualized rather than treated as a default synergy strategy.

For Pharmacists: the key question is not whether “combination therapy” works in general, but which specific backbone and β-lactam are being paired, why escalation is being considered, and what renal-risk tradeoff is acceptable.

Least transferable area: pathways centered on daptomycin or cefazolin combinations, since CAMERA2 was dominated by vancomycin plus flucloxacillin/cloxacillin exposure.

Strengths & Limitations

Strengths

Randomized, multicenter design addressing a real stewardship decision in bloodstream infection care.

Blinded endpoint adjudication and clinically meaningful follow-up to 90 days.

Limitations

Stopped early for safety, so modest efficacy differences could have been missed.

Open-label design and limited use of daptomycin and cefazolin reduce confidence in generalizing the findings across all MRSA combination strategies.

Citation

Steven Y. C. 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 V. N. O’Sullivan, Joshua S. Davis. Adjunctive β-Lactam for MRSA Bacteremia: No 90-Day Outcome Gain, Higher AKI Risk. JAMA. 2020-02-11T00:00:00+00:00. DOI: 10.1001/jama.2020.0103