Treating Persistent Methicillin-susceptible Staphylococcus aureus (MSSA) Bacteremia

Staphylococcus aureus is a significant pathogen commonly implicated in serious infections including endocarditis, osteomyelitis, and pneumonia. In the setting of bloodstream infections, 30-day infection-related mortality and 30-day mortality rates approximate 13% and 20%, respectively.^1,2 These rates may be even higher in patients with persistent MSSA bacteremia, defined as positive blood cultures for a period of 2 to 7 days despite appropriate antibiotics.³ Minejima and colleagues reported a significant difference in 30-mortality rates between patients with short (1–2 days) versus prolonged (≥7 days) Staphylococcus aureus bacteremia durations (5 vs 22%), with a 20% higher risk with each additional day of positivity.⁴ Therefore, this concerning infection requires special attention in regards to treatment in conjunction with effective source control measures.

In vitro Studies

Clinical failure of monotherapy with antibiotics despite reported in vitro susceptibility may be due to a multitude of reasons including virulence factors (eg, biofilm formation), underlying host factors, pharmacokinetic/ pharmacodynamic target nonattainment, and limited source control. Additionally, in the case of cefazolin and high-inoculum infection, it may be due to production of a type A beta-lactamase.⁵ As a result of treatment failure, experimental studies have been completed exploring the synergistic mechanisms of unique combinations. In these exploratory studies, the anti-staphylococcal beta-lactams (ASBLs) (eg, nafcillin, oxacillin, cefazolin) in combination with aminoglycosides, daptomycin, or other beta-lactams have demonstrated promising results.^6-10 Proposed mechanisms of synergy for dual beta-lactam therapy include complementary penicillin-binding protein (PBP) attachment profiles, with PBPs representing the enzyme molecules involved in peptidoglycan cross-linking to form the bacterial cell wall, and enhanced immune-mediated killing (see Figure 1).

Figure 1 – Proposed Mechanism of Synergy with Dual β-lactams⁶

Peptidoglycan (white circles) cross-linked within the cell wall (grey and black pentagons) to provide structure. Penicillin-binding proteins (PBP; green and purple shapes) assist with the peptidoglycan cross-linking (transpeptidation) process.

A. Ceftaroline and ertapenem inhibit PBP1 (green) to disrupt peptidoglycan cross-linking

B. Cefazolin, ceftaroline, nafcillin, and oxacillin inhibit PBP2 (purple) to disrupt peptidoglycan cross-linking

Other mechanisms include improved daptomycin binding as beta-lactams can lower the surface charge of bacteria, improving the ability for the daptomycin complex to adhere to the cell surface and exert bactericidal action. Finally, improved intracellular uptake of gentamicin into the bacterial cell when paired with a beta-lactam may improve killing due to complementary protein synthesis inhibition conferred by aminoglycosides. Despite these findings, additional investigation into the clinical translation of these data is needed.

Clinical Studies

To date, clinical outcomes with combination therapy for MSSA bacteremia have primarily been reported with ASBLs combined with one of the following: ceftaroline, daptomycin, ertapenem, fosfomycin (intravenous), gentamicin, levofloxacin, or rifampin. A comprehensive list of combinations studied and relevant findings was recently published by Chastain and colleagues.¹¹ Of the available literature, only a few case reports and series have reported outcomes in patient populations with persistently positive blood cultures, and are further summarized in Table 1. Notably, the addition of an aminoglycoside to standard of care was not associated with decreased rates of bacteremia recurrence.

Reported outcomes with cefazolin or oxacillin in combination with daptomycin or ertapenem based on limited data appear promising, with clearance often observed within 3 days of starting combination therapy. Given the time in which the switch occurred, it is difficult to ascertain if bacterial burden had been significantly reduced, and if clearance could have been observed within 3 days, even without antimicrobial adjustment. Concomitant source control measures may have affected these outcomes as well. Finally, dosing was not reported in several of these publications, and the impact of specific ASBL dosing strategies (eg, cefazolin 9 versus 6 grams per day) cannot be fully elucidated at this time.

Conclusions and Practice Application

Combinations of ASBLs with ertapenem, ceftaroline, or daptomycin may work synergistically to reduce bacterial burden in high inoculum disease and promote clearance of bloodstream infections. Based on available literature, an ASBL in combination with ertapenem may represent a preferred option amongst the combinations studied, but collateral effects (eg, changes to the gastrointestinal microbiota, resistance evolution) should be considered. Additionally, comparator studies are necessary to truly assess the benefit of antimicrobial escalation in persistent cases, considering that clearance may be impacted by an underlying nidus of infection as well as timing and adequacy of source control techniques. Effect on clinical outcomes (eg, recurrence and infection-related mortality) should also be further evaluated to inform practice.

Table 1– Persistent MSSA Bacteremia Treated with Combination Therapy

AG = aminoglycoside; BSI = bloodstream infection; CFZ = cefazolin; CNS = central nervous system; CPT = ceftaroline; DAP = daptomycin; ERT = ertapenem; EV = endovascular; IVDU = intravenous drug use; LVAD = left ventricular assist device; NAF = nafcillin; OA = osteoarticular; OXA = oxacillin; PNA = pneumonia; SOC = standard of care

References

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