In this episode, I’ll discuss cefazolin and ertapenem combination therapy for refractory MSSA bacteremia.
A recent case series published in Clinical Infectious Diseases describes the successful treatment of 11 patients with persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia.
The authors had an index case where they discovered apparent synergy against MSSA with this combination, and they continued to use it with success. These 11 patients represent a continuous sample from a single center.
All 11 cases experienced successful clearance of the bacteremia with the combination therapy. 6 of the 11 cases were confirmed infective endocarditis. 2 of the endocarditis patients had exceptionally large vegetations exceeding 2 cm. Blood cultures were drawn daily in only 9 of the patients, and in 8 of those, the bacteremia cleared within just 24 hours. All 11 patients survived until hospital discharge.
Cefazolin is being more frequently used for MSSA infections over nafcillin due to perceived improved tolerability. In infections with a high inoculum of MSSA, there appears to be a “Cefazolin Inoculum Effect” where there is a significant rise in the minimum inhibitory concentration in the presence of a high inoculum of bacteria. Endocarditis is a classic example of a clinical infection with a high bacterial load, which is why the success with endocarditis patients in this case series is so promising.
While there is a slight synergy during in vitro testing with cefazolin plus ertapenem, this appears to be much more significant in vivo. A possible explanation for the synergy is that cefazolin and ertapenem have complementary penicillin-binding protein (PBP)–binding sites. Ertapenem has a very high affinity for penicillin-binding protein 1, which cefazolin has a high affinity for penicillin-binding protein 2. This is the same reasoning behind using ampicillin plus ceftriaxone for synergy when treating Enterococcus faecalis endocarditis.
The authors also developed a rat model of endocarditis and tested the cefazolin+ertapenem combination and found a significant in vivo synergy effect.
Another group of authors has shown that ertapenem reduces the cefazolin concentration that is required to eradicate MSSA biofilms down to a level that is achievable in vivo by standard dosing
After the publication of this study, an additional successful case report was published that details a patient who had COVID-19 pneumonia and concomitant MSSA bacteremia. They experienced blood culture sterilization within 24 hours of starting the combination of cefazolin and ertapenem despite previously having 11 days of positive blood cultures.
Further investigation of this combination is warranted, but until then case series and in vitro data are sufficient to consider this combintation as salvage therapy in patients who have persistent bacteremia with MSSA.
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