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.