Cefazolin and Ertapenem, a Synergistic Combination Used To Clear Persistent Staphylococcus aureus Bacteremia

Abstract

Ertapenem and cefazolin were used in combination to successfully clear refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. In addition, recent work has demonstrated activity of combination therapy with beta-lactams from different classes against methicillin-resistant S. aureus (MRSA). The ertapenem-plus-cefazolin combination was evaluated for synergy in vitro and in vivo in a murine skin infection model using an index MSSA bloodstream isolate from a patient in whom persistent bacteremia was cleared with this combination and against a cadre of well-described research strains and clinical strains of MSSA and MRSA. Against the index MSSA bloodstream isolate, ertapenem and cefazolin showed synergy using both checkerboard (fractional inhibitory concentration [FIC] index = 0.375) and time-kill assays. Using a disk diffusion ertapenem potentiation assay, the MSSA isolate showed a cefazolin disk zone increased from 34 to 40 mm. In vitro pharmacokinetic/pharmacodynamic modeling at clinically relevant drug concentrations demonstrated bactericidal activity (>3 log10-CFU/ml reduction) of the combination but bacteriostatic activity of ether drug alone at 48 h. A disk diffusion potentiation assay showed that ertapenem increased the cefazolin zone of inhibition by >3 mm for 34/35 (97%) MSSA and 10/15 (67%) MRSA strains. A murine skin infection model of MSSA showed enhanced activity of cefazolin plus ertapenem compared to monotherapy with these agents. After successful use in clearance of MSSA bacteremia, the combination of ertapenem and cefazolin showed synergy against MSSA in vitro and in vivo. This combination may warrant consideration for future clinical study in MSSA bacteremia.

Beta-lactam combination therapy for the treatment of Staphylococcus aureus and Enterococcus species bacteremia: A summary and appraisal of the evidence

“…Compared to MRSA, there is less clinical data on combination therapy for the treatment of persistent MSSA bacteremia, perhaps due to the improved clearance with standard of care antibiotic therapy (Kim et al, 2008;Chang et al, 2003). A recent case report described the addition of ertapenem to cefazolin after cefazolin therapy alone failed to clear blood cultures after 5 days of therapy (Sakoulas et al, 2016). The day following the addition of ertapenem, blood cultures cleared (Sakoulas et al, 2016).…”

“…A recent case report described the addition of ertapenem to cefazolin after cefazolin therapy alone failed to clear blood cultures after 5 days of therapy (Sakoulas et al, 2016). The day following the addition of ertapenem, blood cultures cleared (Sakoulas et al, 2016). Additionally, there was no evidence of relapse at 90 days of follow-up (Sakoulas et al, 2016).…”

Comparison of methods for the detection of in vitro synergy in multidrug-resistant gram-negative bacteria

“…In addition, some studies have shown the benefit of combined therapy despite the resistance of the microorganism to some antimicrobials in the scheme [24]. Synergism has also been described using DA and MIC: MIC methods against Gram-positive organisms-especially S. aureus [25][26][27]; these are likely useful methods against Gram-positive organisms. Unfortunately, for logistical reasons, we could not evaluate in vitro synergy against Gram-positive standard organisms.…”

Comparison of methods for the detection of in vitro synergy in multidrug-resistant Gram-negative bacteria

“…In addition, some studies have shown the benefit of combined therapy despite the resistance of the microorganism to some antimicrobials in the scheme [34]. Synergism has also been described using DA and MIC:MIC methods against Gram-positive organisms -especially S. aureus [35][36][37]; these are likely useful methods against Gram-positive organisms.…”