P-1360. Restoring Efficacy against Ceftaroline-Resistant MRSA with Ceftaroline-Carbapenem Combinations

TL;DR

Combining ceftaroline with carbapenems can restore effectiveness against drug-resistant MRSA infections in both lab and animal studies.

Contribution

Demonstrates that ceftaroline-carbapenem combinations can overcome resistance in MRSA, particularly in high-inoculum, physiologically relevant conditions.

Findings

Ceftaroline-carbapenem combinations showed synergy against ceftaroline-resistant MRSA in checkerboard and time-kill assays.

In vivo, the combination reduced bacterial burden in a murine model despite minimal monotherapy efficacy.

The synergy was most effective under high-inoculum, physiological conditions resembling serious infections like endocarditis.

Abstract

Ceftaroline-resistant methicillin-resistant Staphylococcus aureus (MRSA) is an emerging threat, especially in patients with comorbidities requiring chronic antibiotic exposure. As one of the few β-lactams active against MRSA, ceftaroline's diminishing efficacy jeopardizes treatment options. Building on prior work showing ceftaroline-carbapenem synergy, we evaluated this approach against a ceftaroline-resistant strain—where its potential remains underexplored.

Carbapenems potentiate the antibacterial activity of ceftaroline against MRSA AR-0703Figure 1.Synergistic effects of ceftaroline-carbapenem combinations against methicillin-resistant Staphylococcus aureus (MRSA AR-0703) under various conditions. (A) Kill curves over 24 hours demonstrating the effect of subtherapeutic ceftaroline (CPT, 8 mg/L, 1/2 MIC) and ertapenem (ETP, 50 mg/L) or meropenem (MEM, 49 mg/L) at average serum concentrations, alone or in combination, against ceftaroline-resistant MRSA AR-0703. Experiments were conducted under standard (5×105 CFU/mL) and high (2×107 CFU/mL) inoculum conditions in CA-MHB or RPMI+5%LB media. Combination therapy with either carbapenem showed enhanced bacterial killing compared to monotherapy, particularly under high inoculum, physiological (RPMI+5%LB) conditions. (B) Efficacy of adjunctive carbapenem therapy in a murine bacteremia model. Bacterial counts from kidneys (CFU/g) after 24 hours of treatment with ceftaroline (12 mg/kg q8 h) or ertapenem (100 mg/kg q8 h), alone or in combination, versus no antibiotics (PBS control) are shown. Combination therapy with ceftaroline (CPT) and ertapenem (ETP) significantly reduced recoverable ceftaroline-resistant MRSA from kidneys compared to both monotherapies and the PBS control (n>5). Statistical significance was determined by unpaired two-tailed t-test (A) and one-way ANOVA with multiple comparisons (B). **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. Abbreviations: CA-MHB, cation-adjusted Mueller-Hinton broth; RPMI+5%LB, Roswell Park Memorial Institute physiological cell culture media supplemented with 5% Luria-Bertani; CFU, colony-forming units; PBS, phosphate-buffered saline.

Synergistic effects of ceftaroline-carbapenem combinations against methicillin-resistant Staphylococcus aureus (MRSA AR-0703) under various conditions. (A) Kill curves over 24 hours demonstrating the effect of subtherapeutic ceftaroline (CPT, 8 mg/L, 1/2 MIC) and ertapenem (ETP, 50 mg/L) or meropenem (MEM, 49 mg/L) at average serum concentrations, alone or in combination, against ceftaroline-resistant MRSA AR-0703. Experiments were conducted under standard (5×105 CFU/mL) and high (2×107 CFU/mL) inoculum conditions in CA-MHB or RPMI+5%LB media. Combination therapy with either carbapenem showed enhanced bacterial killing compared to monotherapy, particularly under high inoculum, physiological (RPMI+5%LB) conditions. (B) Efficacy of adjunctive carbapenem therapy in a murine bacteremia model. Bacterial counts from kidneys (CFU/g) after 24 hours of treatment with ceftaroline (12 mg/kg q8 h) or ertapenem (100 mg/kg q8 h), alone or in combination, versus no antibiotics (PBS control) are shown. Combination therapy with ceftaroline (CPT) and ertapenem (ETP) significantly reduced recoverable ceftaroline-resistant MRSA from kidneys compared to both monotherapies and the PBS control (n>5). Statistical significance was determined by unpaired two-tailed t-test (A) and one-way ANOVA with multiple comparisons (B). **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. Abbreviations: CA-MHB, cation-adjusted Mueller-Hinton broth; RPMI+5%LB, Roswell Park Memorial Institute physiological cell culture media supplemented with 5% Luria-Bertani; CFU, colony-forming units; PBS, phosphate-buffered saline.

We evaluated a well-characterized ceftaroline-resistant MRSA isolate (CDC AR-0703) using checkerboard synergy testing and time-kill assays under bacteriologic (CA-MHB) and physiologic (RPMI + 5% LB) conditions. Given the association between high-inoculum staphylococcal infections—such as infective endocarditis—and clinical treatment failures, antibiotic activity was assessed at both standard (5×10⁵ CFU/mL) and high (2×10⁷ CFU/mL) inocula. In vivo efficacy was assessed using a murine bacteremia model. Mice received humanized, subtherapeutic regimens of ceftaroline (12 mg/kg q8h) ± ertapenem (100 mg/kg q8h), and kidney bacterial burden was quantified at 26 hours.

Ceftaroline combined with ertapenem or meropenem exhibited synergy by checkerboard (FICI ≤0.5) at both standard and high inocula. In time-kill assays, combinations drove marked bacterial reductions versus monotherapy, especially in physiologic media under high-inoculum conditions. In vivo, ceftaroline plus ertapenem reduced kidney bacterial burden by ∼1 log10 (p< 0.05) compared to ceftaroline alone, despite minimal activity from either agent alone.

Ceftaroline-carbapenem combinations restored bactericidal activity against ceftaroline-resistant MRSA in vitro and in vivo, despite high MICs and limited monotherapy efficacy. These findings support their potential as a salvage strategy for serious, drug-resistant MRSA infections and warrant broader clinical investigation.

George Sakoulas, MD, Abbvie: Honoraria

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