1240. Ceftobiprole Activity against Drug-Resistant Staphylococcus aureus Clinical Isolates Collected in the United States from 2016 through 2020

Abstract Background Multidrug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA) present significant treatment challenges and can cause serious morbidity and mortality. Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced cephalosporin approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. Ceftobiprole is currently in phase 3 clinical development to support a New Drug Application in the United States for acute bacterial skin and skin structure infections and S. aureus bacteremia. Here, the activity of ceftobiprole and comparators was evaluated against recent MDR S. aureus and MRSA clinical isolates. Methods 13,868 S. aureus isolates were collected from patients with various infection types at 34 US medical centers from 2016–2020. Susceptibility to ceftobiprole and comparator agents was tested by CLSI methods. Current CLSI and EUCAST interpretive criteria were applied (Table). Isolates were categorized as MDR if they were non-susceptible (NS; CLSI criteria) to ≥3 of the following antimicrobials: clindamycin (CM), daptomycin (DAP), erythromycin (ERY), gentamicin (GM), levofloxacin (LEV), linezolid (LZD), tetracycline (TET), tigecycline (TGC), trimethoprim-sulfamethoxazole (TMP-SMX), or vancomycin (VAN). Isolates displaying oxacillin MIC values ≥4 mg/L were categorized as MRSA. Results Ceftobiprole was more active than ceftaroline (CPT) against MRSA (99.2% susceptible [S] versus 94.0% S, respectively) (Table). Ceftobiprole maintained activity against 88.0% of the CPT-NS isolates, but CPT was only active against 6.5% of the ceftobiprole-NS isolates. Ceftobiprole was also highly active (97.7–100.0% S) against isolates NS to CM, DAP, ERY, GM, LEV, LZD, TET, TGC, or TMP-SMX. No VAN-NS isolates were detected. Importantly, ceftobiprole was more active (97.7% S) than CPT (83.0% S) against the subset of MDR-MRSA isolates. Conclusion Conclusions: Ceftobiprole was highly active in vitro against MRSA and MDR S. aureus collected at US medical centers during 2016–2020. These results support the further development of ceftobiprole to treat S. aureus infections in the US. Disclosures Leonard R. Duncan, PhD, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Shionogi (Research Grant or Support) Kamal Hamed, MD, MPH, Basilea Pharmaceutica International, Ltd (Employee)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C) Jennifer Smart, PhD, Basilea Pharmaceutica International, Ltd. (Employee)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C) Michael A Pfaller, MD, Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cidara Therapeutics, Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Pfizer, Inc. (Research Grant or Support) Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)


Ceftaroline versus Vancomycin as First-Line Therapy for MRSA Bacteremia
Meghan Kamath, PharmD 1 ; Ariel Ma, PharmD 2 ; Scott T. Johns, PharmD 3 ; 1 VA San Diego Healthcare System, San Diego, California; 2 VA San Diego Medical Center, San Diego, California; 3 San Diego VA Healthcare System, San Diego, California Session: P-72. Resistance Mechanisms Background. Beta-lactams have demonstrated superior outcomes over vancomycin in MSSA bacteremia. Despite this, studies of the anti-MRSA beta-lactam ceftaroline in MRSA bacteremia (MRSAB) are largely limited in size or focus on combination or salvage regimens. This study sought to further examine ceftaroline as firstline therapy for MRSAB.
Methods. This was a retrospective matched cohort study at the San Diego VA Medical Center between November 2010 and June 2020. Patients had to have received at least 72 hours of ceftaroline or vancomycin for MRSAB and less than 72 hours of prior MRSA therapy. Adjunct MRSA therapy was allowed only if routinely indicated for the infection (e.g. rifampin for prosthesis). Patients in the vancomycin group were matched 1:1 to patients in the ceftaroline group by age (+/-10 years) and Pitt bacteremia score (+/-1 point). The primary outcome was duration of bacteremia after initiation of MRSA therapy, including time on prior MRSA therapy.
Results. Fifteen patients were included in each group, with a median age of 65 years and Pitt bacteremia score of 0. Patients in the ceftaroline group were more likely to have CKD; to have been on a different MRSA agent prior to initiation of the study drug, with a median of 1 day of prior treatment; and to have been on adjunctive rifampin or clindamycin. Though not significant, more patients in the ceftaroline group also had endovascular sources, uncontrolled sources, and longer durations of therapy. The median duration of bacteremia after initiation of MRSA therapy did not significantly differ between ceftaroline and vancomycin (4 vs. 3 days, p = 0.806). In addition, 30-day all-cause mortality, in-hospital mortality, 90-day readmission or treatment failure, inpatient length of stay, total duration of bacteremia, and rate of adverse events did not significantly differ between groups.
Conclusion. This study suggests ceftaroline may be an appropriate first-line agent for the treatment of MRSA bacteremia with similar outcomes between groups despite the ceftaroline group likely experiencing more difficult-to-treat infections. However, it was not powered to detect differences between groups, and its retrospective nature has the potential to introduce bias. Prospective comparative studies are needed to corroborate these findings.
Disclosures. Background. Multidrug-resistant (MDR) and methicillin-resistant Staphylococcus aureus (MRSA) present significant treatment challenges and can cause serious morbidity and mortality. Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced cephalosporin approved in many European and other countries for the treatment of adults with community-and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. Ceftobiprole is currently in phase 3 clinical development to support a New Drug Application in the United States for acute bacterial skin and skin structure infections and S. aureus bacteremia. Here, the activity of ceftobiprole and comparators was evaluated against recent MDR S. aureus and MRSA clinical isolates.
Conclusion. Conclusions: Ceftobiprole was highly active in vitro against MRSA and MDR S. aureus collected at US medical centers during 2016-2020. These results support the further development of ceftobiprole to treat S. aureus infections in the US.