Discussion
The successful management of persistent MSSA bacteremia is highly
dependent on source control, which is a significant challenge in the
LVAD patient population. Source control may only be achieved via a
device exchange, device removal during orthotopic heart transplant or
explantation. It is important to stress here that unlike other medical
device-related infections, exchange of VADs for source control is
generally avoided due to the complexity of the surgical procedure and
concerns regarding risk of reinfection of newly implanted device.
Patients who are a candidate for neither transplant, removal nor
replacement must rely on medical management. Aminoglycosides are
generally discouraged given lack of clear-cut efficacy and documented
toxicity issues. Rifampin may be considered, but frequently not started
until cultures clear to avoid development of resistance. In recent
years, much attention has been given to the synergistic combination of
beta-lactam antibiotics for the management for MRSA bacteremia2. However, few data exist for therapeutic options for
persistent MSSA bacteremia.
Ulloa et al recently published the largest case series of 11 patients
with persistent MSSA bacteremia who were successfully treated with
salvage ertapenem and cefazolin 4. The mean duration
of bacteremia was 6 days (range, 4-9 days) on appropriate antibiotics.
Interestingly, among the 9 cases where blood cultures were collected
daily, bacteremia cleared within 24 hours of ertapenem in 8 cases
(88%). Even more so remarkable considering two of these cases were
tricuspid valve endocarditis with > 2 cm vegetations.
This robust response even without obtaining surgical source control
appears to be mirrored in our patient case. Within in the LVAD
population, there exists one published case series. Carenas-Alvarez et
al. reported 2 cases of refractory MSSA bacteremia in LVAD recipients
successfully treated with cefazolin plus ertapenem 3.
The first patient had ertapenem added to his therapy after 10 days of
cefazolin and cleared cultures one day after starting salvage treatment.
The second patient developed MSSA bacteremia through suppressive
intravenous cefazolin and was therefore treated with intravenous
oxacillin. However, after eight days of persistently positive cultures,
switched to cefazolin with ertapenem with resolution of bacteremia
within 24 hours.
While several studies have noted increased tolerability and even
improved outcomes in patients receiving cefazolin as compared to anti
staphylococcal penicillins (ASP), providers may have concerns regarding
potential inferior cefazolin activity under high inoculum
conditions4. The combination of ASP and ertapenem has
even less data – the largest published in late 2021. El-Dalati describe
eight patients treated with ASP (oxacillin or nafcillin) and ertapenem.
Combination treatment was initiated following 5 days of persistent
bacteremia. Blood sterility was achieved in all patients; six patients
had documented clearance within one day 8. Here,
oxacillin plus ertapenem was the most common regimen, suggesting that
salvage combination therapy may be used with either ASP or cefazolin.
This conclusion is strengthened in our patient case. To the best of our
knowledge, this is the first report describing use of an ASP based
salvage regimen in LVAD-associated bacteremia.
In nearly all cases, a rapid clearance of blood cultures was observed.
The basis for this combination leverages differences in affinity for
various protein binding proteins (PBPs). Beta-lactam antibiotics exert
their bactericidal effects by irreversibly interfering with the enzymes
involved in cell wall synthesis, PBPs. Inhibiting enzymatic activity
results in impaired cell wall synthesis, cell wall destabilization, and
subsequently cell death. Carbapenem antibiotics have a higher affinity
for PBP1 as compared to antistaphylococcal beta-lactams. Therefore,
their addition would complement the relative proclivity of cefazolin and
ASP for PBP2. While oxacillin is thought to have higher affinity for
PBP1, the data presented in this case report and by El-Dalati et al.
suggest oxacillin as a suitable agent for this salvage
therapy8. Oxacillin may exhibit a similar mechanism
for synergy with complimentary PBP-2 binding or may possibly offer more
complete PBP1 saturation.
This combination has repeatedly demonstrated a clear and rapid
resolution of persistent bacteremia. This has serious consequences for
the MCS patient population, as time to blood sterilization with S.
aureus may be associated with improved clinical outcomes and lower rates
of death 9 . However, there are certainly risks
associated with this salvage therapy that warrant consideration.
Virtually every antibiotic has been associated with Clostridioides
difficile infection (CDI). Therefore, it is important to consider the
risk-benefit of adding a secondary antimicrobial agent that may result
in long-lasting changes to the human gut microbiota. Similarly, the
introduction of antibiotics to our patient population invariably leads
to resistance. Further investigation is warranted to assess the full
impact of carbapenem use on patient and community resistance patterns.
Questions remain regarding the choice between ASP as compared to
cefazolin in the setting of risk of acute kidney injury versus efficacy
with inoculum conditions. Lastly and perhaps most importantly, further
research is needed to capture whether rapid blood sterilization offers a
patient-centered outcome benefit.