Activity Of Ceftobiprole Research Articles

In Vitro Antibacterial Activity of Ceftobiprole and Comparator Compounds against Nation-Wide Bloodstream Isolates and Different Sequence Types of MRSA.

Bloodstream infections by bacteria, especially multidrug-resistant bacteria, remain a worldwide public health concern. We evaluated the antibacterial activity of ceftobiprole and comparable drugs against different bloodstream isolates and different sequence types of methicillin-resistant Staphylococcus aureus (MRSA) in China. We found that MRSA, methicillin-susceptible Staphylococcus aureus (MSSA), and methicillin-susceptible coagulase-negative Staphylococcus (MSCNS) displayed ceftobiprole sensitivity rates of >95%, which are similar to the rates for linezolid, daptomycin, and vancomycin. Of the tested MRCNS strains, 90.4% were sensitive to ceftobiprole. The sensitivities of ST59, ST398, and ST22 MRSA to ceftobiprole were higher than that of ST239. Ceftobiprole's MIC50/90 value against Enterococcus faecalis was 0.25/2 mg/L, whereas Enterococcus faecium was completely resistant to this drug. Ceftobiprole exhibited no activity against ESBL-positive Enterobacterales, with resistance rates between 78.6% and 100%. For ESBL-negative Enterobacterales, excluding Klebsiella oxytoca, the sensitivity to ceftobiprole was comparable to that of ceftazidime, ceftriaxone, and cefepime. The MIC50/90 value of ceftobiprole against Pseudomonas aeruginosa was 2/16 mg/L, and for Acinetobacter baumannii, it was 32/>32 mg/L. Thus, ceftobiprole shows excellent antimicrobial activity against ESBL-negative Enterobacterales and Pseudomonas aeruginosa (comparable to that of ceftazidime, ceftriaxone, and cefepime); however, it is not effective against ESBL-positive Enterobacterales and Acinetobacter baumannii. These results provide important information to clinicians.

2173. Activity of Ceftobiprole Against Enterococcus faecalis Clinical Isolates From the United States (2016–2020), Including Those From Difficult-to-Treat Infections

Abstract Background Ceftobiprole (BPR) is an advanced-generation cephalosporin that has in vitro and in vivo activity against clinically important Gram-positive organisms, including MRSA and Gram-negative organisms. While BPR does not have clinically relevant activity against Enterococcus faecium, BPR is active against E. faecalis, an opportunistic bacterial pathogen of increasing clinical relevance and a significant cause of infective endocarditis. This study evaluated the activity of BPR and comparator agents against E. faecalis isolated from patients hospitalized in US medical centers. Methods A total of 1,834 E. faecalis isolated from 34 US medical centers (2016–2020) were included. Isolates collected were responsible for bloodstream infections (40.8%), urinary tract infections (23.4%), skin and skin structure infections (22.0%), and other infection types (13.9%), including bone and joint infections (BJI; 1.6%), diabetic foot infections (DFI; 0.9%), and endocarditis (END; 0.8%). Isolates were tested for susceptibility using the CLSI broth microdilution method and MIC interpretations followed CLSI criteria. For BPR, the PK/PD non–species-related breakpoint of ≤4 mg/L was used. Results BPR inhibited 99.3% of all E. faecalis at ≤4 mg/L, whereas the comparator agents, ampicillin (AMP), daptomycin (DAP), linezolid (LZD), and vancomycin (VAN), inhibited between 97.0% to 100% of all isolates at their respective breakpoints. A total of 3% of all E. faecalis isolates were VAN resistant. BPR had similar MIC90 results of 2 mg/L and 4 mg/L when tested against VAN-susceptible and -resistant isolates, respectively. AMP, DAP, and LZD were also active against VAN-susceptible and -resistant E. faecalis. All (100%) isolates causing difficult-to-treat infections, such as bone/joint and diabetic foot infections and infective endocarditis, were inhibited by BPR at ≤4 mg/L in addition to AMP, DAP, and LZD at their respective breakpoints. Conclusion These data suggest that BPR represents a potential option for empirical and guided treatment of infections caused by E. faecalis in US hospitals, including isolates causing difficult-to-treat infections. Disclosures Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Leonard R. Duncan, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Helio S. Sader, MD, PhD, FIDSA, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Jennifer Smart, PhD, Basilea Pharmaceutica International Ltd, Allschwil, Switzerland: Stocks/Bonds Mark E. Jones, PhD, Astellas Pharma Global Development, Inc: Support for the present publication|Basilea Pharmaceutica International Ltd: Employee of Basilea Pharmaceutica International Ltd|Basilea Pharmaceutica International Ltd: Stocks/Bonds Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support

In Vitro Activities of Ceftobiprole, Dalbavancin, Tedizolid and Comparators against Clinical Isolates of Methicillin-Resistant Staphylococcus aureus Associated with Skin and Soft Tissue Infections.

Skin and soft tissue infections (SSTIs) are associated with significant morbidity and healthcare costs, especially when caused by methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is a preferred antimicrobial therapy for the management of complicated SSTIs (cSSTIs) caused by MRSA, with linezolid and daptomycin regarded as alternative therapeutic options. Due to the increased rates of antimicrobial resistance in MRSA, several new antibiotics with activity against MRSA have been recently introduced in clinical practice, including ceftobiprole, dalbavancin, and tedizolid. We evaluated the in vitro activities of the aforementioned antibiotics against 124 clinical isolates of MRSA obtained from consecutive patients with SSTIs during the study period (2020-2022). Minimum inhibitory concentrations (MICs) for vancomycin, daptomycin, ceftobiprole, dalbavancin, linezolid and tedizolid were evaluated by the MIC Test Strip using Liofilchem strips. We found that when compared to the in vitro activity of vancomycin (MIC90 = 2 μg/mL), dalbavancin possessed the lowest MIC90 (MIC90 = 0.094 μg/mL), followed by tedizolid (MIC90 = 0.38 μg/mL), linezolid, ceftobiprole, and daptomycin (MIC90 = 1 μg/mL). Dalbavancin demonstrated significantly lower MIC50 and MIC90 values compared to vancomycin (0.064 vs. 1 and 0.094 vs. 2, respectively). Tedizolid exhibited an almost threefold greater level of in vitro activity than linezolid, and also had superior in vitro activity compared to ceftobiprole, daptomycin and vancomycin. Multidrug-resistant (MDR) phenotypes were detected among 71.8% of the isolates. In conclusion, ceftobiprole, dalbavancin and tedizolid exhibited potent activity against MRSA and are promising antimicrobials in the management of SSTIs caused by MRSA.

In vitro activity of ceftobiprole and dalbavancin against a collection of coagulase-negative staphylococci isolates from clinical samples with reduced susceptibility to daptomycin and/or resistant to linezolid or glycopeptides

IntroductionThe aim was to investigate the in vitro activity of ceftobiprole and dalbavancin against a collection of coagulase-negative staphylococci (CoNS) isolates with reduced susceptibility to daptomycin or resistant to linezolid and/or glycopeptides. MethodsA total of 228 CoNS were tested using the Vitek-2 AST-626 cards (bioMérieux) and MIC of daptomycin, linezolid, vancomycin and teicoplanin were confirmed by Etest Strips (bioMérieux). Susceptibility testing for ceftobiprole and dalbavancin were performed by CLSI broth microdilution methodology. Results were interpreted according to 2021 EUCAST clinical breakpoints. ResultsCeftobiprole and dalbavancin were active against 96.0% and 93.0% of CoNS, respectively, MIC90 were 2 and 0.125mg/L. MICs of ceptobiprole were higher against S. hominis and S. haemolyticus (MIC90 4mg/L). Dalbavancin exhibited higher MICs against S. haemolyticus and CoNS with reduced susceptibility to daptomycin and resistant to teicoplanin. ConclusionCeftobiprole and dalbavancin demonstrated a high in vitro activity against our collection of CoNS isolates.

Antimicrobial activity of ceftobiprole and comparator agents when tested against gram-positive and -negative organisms collected across China (2016–2018)

BackgroundCeftobiprole is a fifth-generation cephalosporin which has been reported to have broad antibacterial spectrum when tested against bacteria collected from other countries except China. This study evaluated the in vitro activity of ceftobiprole in comparison with other comparators against clinically significant isolates collected across from China.ResultsSusceptibility testing of ceftobiprole and comparators against 1163 clinically isolated Gram-positive and Gram-negative bacteria was performed with broth micro dilution method following the CLSI guidelines. All 110 S. aureus were susceptible to ceftobiprole with MIC50/90 of 1/2 mg/L for MRSA and 0.5/1 mg/L for MSSA. For Coagulase-negative staphylococci (CNS), MIC50/90 of ceftobiprole for MRCNS and MSCNS was 1/2 mg/L and 0.25/0.5 mg/L. Ceftobiprole demonstrated good potency against E. faecalis (MIC50/90 of 0.5/1 mg/L) but limited activity against E. faecium (MIC50/90 of > 32/ > 32 mg/L). Ceftobiprole demonstrated potent activity against all 39 β-hemolytic Streptococcus spp. with MIC50/90 ≤ 0.015/ ≤ 0.015–2 mg/L and 110 of PSSP with 98.2% susceptibility. Ceftobiprole inhibited all isolates of H. influenzae and M. catarrhalis at ≤ 1 mg/L. 91.8% and 98.2% of the ESBL-negative E. coli and K. pneumoniae were susceptible to ceftobiprole, but most of the ESBL-positive or carbapenem-resistant strains were also resistant to ceftobiprole. Ceftobiprole inhibited 84.2% of carbapenem-susceptible P. aeruginosa and 94.1% of carbapenem-susceptible A. baumannii at ≤ 8 mg/L, but only 52.6% of carbapenem-resistant P. aeruginosa and 5.3% of carbapenem-resistant A. baumannii.ConclusionCeftobiprole demonstrated good in vitro activity against a broad range of clinically relevant contemporary Gram-positive and Gram-negative bacterial isolates.

In vitro activity of ceftobiprole and dalbavancin against a collection of coagulase-negative staphylococci isolates from clinical samples with reduced susceptibility to daptomycin and/or resistant to linezolid or glycopeptides

IntroductionThe aim was to investigate the in vitro activity of ceftobiprole and dalbavancin against a collection of coagulase-negative staphylococci (CoNS) isolates with reduced susceptibility to daptomycin or resistant to linezolid and/or glycopeptides. MethodsA total of 228 CoNS were tested using the Vitek-2 AST-626 cards (bioMérieux) and MIC of daptomycin, linezolid, vancomycin and teicoplanin were confirmed by Etest Strips (bioMérieux). Susceptibility testing for ceftobiprole and dalbavancin were performed by CLSI broth microdilution methodology. Results were interpreted according to 2021 EUCAST clinical breakpoints. ResultsCeftobiprole and dalbavancin were active against 96.0% and 93.0% of CoNS, respectively, MIC90 were 2 and 0.125mg/L. MICs of ceptobiprole were higher against S. hominis and S. haemolyticus (MIC90 4mg/L). Dalbavancin exhibited higher MICs against S. haemolyticus and CoNS with reduced susceptibility to daptomycin and resistant to teicoplanin. ConclusionCeftobiprole and dalbavancin demonstrated a high in vitro activity against our collection of CoNS isolates.

Ceftobiprole activity against Gram-positive and Gram-negative pathogens causing bone and joint infections in the United States from 2016 to 2020

Bone and joint infections (BJIs) present significant treatment challenges. Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus, is approved in many European and other countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. In this study, the in vitro activity of ceftobiprole and comparators was evaluated against clinical isolates collected from BJIs in the USA from 2016 to 2020. Gram-positive pathogens made up 70.6% of all BJI isolates and included S. aureus (47.4% of all isolates), β-hemolytic streptococci, coagulase-negative staphylococci, and Enterococcus faecalis. Ceftobiprole was highly active against S. aureus (MIC50/90 values, 0.5/1 mg/L; 99.6% susceptible using the European Committee on Antimicrobial Susceptibility Testing susceptibility breakpoint of ≤2 mg/L for the treatment of pneumonia patients) and exhibited potent activity against the other Gram-positive cocci and the predominant BJI Gram-negative groups. These results support the further evaluation of ceftobiprole for this potential indication.

In vitro activity of ceftobiprole and comparator antibiotics against contemporary European isolates (2016-19).

ObjectivesTo evaluate the susceptibility to ceftobiprole of clinical bacterial isolates obtained from hospitalized patients in Europe.MethodsA total of 20 000 non-duplicate bacterial isolates were collected in 2016–19 from patients with documented infections at medical centres located in 17 countries in Europe. Bacterial identification was confirmed and susceptibility to ceftobiprole and comparator agents was tested using the EUCAST broth microdilution methodology and interpretive criteria by a central microbiology laboratory.ResultsOf the 20 000 isolates, 10 007 (50.0%) were Gram-positive and 9993 (50.0%) were Gram-negative. The most common species was Staphylococcus aureus (35.0%), followed by Streptococcus pneumoniae (15.0%), Klebsiella pneumoniae (11.1%), Pseudomonas aeruginosa (11.0%), Escherichia coli (9.7%) and Haemophilus influenzae (3.0%). Overall, 99.7% (6981/7000) of S. aureus, including 99.5% (3483/3502) of MRSA, 97.8% (2941/3007) of S. pneumoniae, 100% (605/605) of H. influenzae and 76.3% (5492/7197) of Enterobacterales isolates were susceptible to ceftobiprole. Susceptibility to ceftobiprole was higher for isolates from northern and western Europe as compared with eastern and southern Europe.ConclusionsCeftobiprole continues to exhibit potent and broad-spectrum activity against Gram-positive and Gram-negative clinical isolates from Europe, and as expected, with a slight north-to-south and west-to-east susceptibility gradient.

The antimicrobial activity of ceftobiprole against Methicillin-resistant Staphylococcus aureus and multi-drug resistant Pseudomonas aeruginosa: A large tertiary care university hospital experience in Riyadh, Saudi Arabia.

Objectives:To assess the antibacterial activity of ceftobiprole against Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa) from various body specimen types and different patterns of resistance.Methods:A retrospective cohort study with a total of 49 MRSA and 99 P. aeruginosa isolated in the Microbiology Laboratory at King Saud University Medical City, Riyadh, Saudi Arabia, between 2018-2019, were used. Isolates were randomly selected from various specimen types. The minimum inhibition concentration (MIC) of ceftobiprole was determined by E-test. Breakpoints carried out by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were used to assess antibiotic susceptibility.Results:Approximately 100% of the MRSA isolates were susceptible with MIC50/90 value of 1/1.5 mg/L while 69.8% of multi-drug resistant (MDR) P. aeruginosa isolates were resistant with MIC50/90 value of 16/32 mg/L.Conclusion:The excellent activity of ceftobiprole against MRSA would have major implications in management of the patients with serious infections, as an empirical treatment or alternative to vancomycin. Ceftobiprole has a very low activity against MDR P. aeruginosa, and its susceptibility should be tested prior to use for treatment.

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

BackgroundMultidrug-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.Methods13,868 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.ResultsCeftobiprole 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)

Ceftobiprole Perspective: Current and Potential Future Indications.

Ceftobiprole combines an excellent spectrum for community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) pathogens, with a low/medium MDR risk, and the β-lactams’ safety in frail patients admitted to the hospital in internal medicine wards which may be at high risk of adverse events by anti-MRSA coverage as oxazolidinones or glycopeptides. We aimed to report the available evidence regarding ceftobiprole use in pneumonia and invasive bacterial infections, shedding light on ceftobiprole stewardship. The clinical application and real-life experiences of using ceftobiprole for bloodstream infections, including infective endocarditis, are limited but nevertheless promising. In addition, extended-spectrum ceftobiprole activity, including Enterococcus faecalis, Enterobacteriaceae, and Pseudomonas aeruginosa, has theoretical advantages for use as empirical therapy in bacteremia potentially caused by a broad spectrum of microorganisms, such as catheter-related bacteremia. In the future, the desirable approach to sepsis and severe infections will be administered to patients according to their clinical situation, the intrinsic host characteristics, the susceptibility profile, and local epidemiology, while the “universal antibiotic strategy” will no longer be adequate.

1595. Ceftobiprole Activity against Gram-Positive Pathogens Causing Bone and Joint Infections in the United States from 2016 through 2019

BackgroundBone and joint infections (BJIs) cause serious morbidity and mortality and present significant treatment challenges. Ceftobiprole medocaril, the prodrug of ceftobiprole, is an advanced cephalosporin approved in many European and non-European countries for the treatment of adults with community- and hospital-acquired pneumonia, excluding ventilator-associated pneumonia. Ceftobiprole medocaril is not approved in the United States (USA) but has qualified infectious disease product (QIDP) status, and is being evaluated in two phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (completed) or Staphylococcus aureus bacteremia (ongoing). In this study, the activity of ceftobiprole and comparators was evaluated against recent Gram-positive clinical isolates collected from BJIs in the USA.Methods306 Gram-positive pathogens were collected from patients with BJIs at 27 US medical centers from 2016 through 2019. Susceptibility to ceftobiprole and comparator agents was tested using current CLSI methods. CLSI and EUCAST interpretive criteria were applied according to current guidelines.ResultsThe major Gram-positive species and pathogen groups included S. aureus (67.0%; methicillin-resistant S. aureus [MRSA], 35.1%), β-hemolytic streptococci (BHS; 13.7%), coagulase-negative staphylococci (CoNS; 9.5%), and Enterococcus faecalis (6.9%). Ceftobiprole was highly active against S. aureus (MIC50/90 values, 0.5/1 mg/L; 100.0% susceptible by EUCAST criteria), including MRSA (MIC50/90 values, 1/2 mg/L). Ceftobiprole also exhibited potent activity against other Gram-positive cocci, including BHS (MIC50/90 values, 0.015/0.03 mg/L; 100% inhibited at ≤ 4 mg/L, which is the EUCAST PK-PD non-species-related breakpoint), CoNS (MIC50/90 values, 1/4 mg/L; 100% inhibited at ≤4 mg/L), and E. faecalis (MIC50/90 values, 0.5/2 mg/L; 100.0% inhibited at ≤ 4 mg/L).ConclusionCeftobiprole was highly active against clinical BJI isolates from the major Gram-positive pathogen groups collected at US medical centers during 2016–2019. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for this potential indication.DisclosuresLeonard R. Duncan, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Dept of Health and Human Services (Research Grant or Support) Kamal Hamed, n/a, Basilea Pharmaceutica International Ltd. (Employee) Jennifer Smart, PhD, Basilea Pharmaceutica International, Ltd (Employee)Department of Health and Human Services (Research Grant or Support) Michael A. Pfaller, MD, Amplyx Pharmaceuticals (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support) Robert K. Flamm, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support) Rodrigo E. Mendes, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Pfizer (Research Grant or Support)

Ceftobiprole Activity against Bacteria from Skin and Skin Structure Infections in the United States from 2016 through 2018.

Ceftobiprole medocaril is an advanced-generation cephalosporin prodrug that has qualified infectious disease product status granted by the US FDA and is currently being evaluated in phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSIs) and in patients with Staphylococcus aureus bacteremia. In this study, the activity of ceftobiprole and comparators was evaluated against more than 7,300 clinical isolates collected in the United States from 2016 through 2018 from patients with skin and skin structure infections. The major species/pathogen groups were S. aureus (53%), Enterobacterales (23%), Pseudomonas aeruginosa (7%), beta-hemolytic streptococci (6%), Enterococcus spp. (4%), and coagulase-negative staphylococci (2%). Ceftobiprole was highly active against S. aureus (MIC50/90, 0.5/1 mg/liter; 99.7% susceptible by EUCAST criteria; 42% methicillin-resistant S. aureus [MRSA]). Ceftobiprole also exhibited potent activity against other Gram-positive cocci. The overall susceptibility of Enterobacterales to ceftobiprole was 84.8% (>99.0% susceptible for isolate subsets that exhibited a non-extended-spectrum β-lactamase [ESBL] phenotype). A total of 74.4% of P. aeruginosa, 100% of beta-hemolytic streptococci and coagulase-negative staphylococci, and 99.6% of Enterococcus faecalis isolates were inhibited by ceftobiprole at ≤4 mg/liter. As expected, ceftobiprole was largely inactive against Enterobacterales that contained ESBL genes and Enterococcus faecium Overall, ceftobiprole was highly active against most clinical isolates from the major Gram-positive and Gram-negative skin and skin structure pathogen groups collected at U.S. medical centers participating in the SENTRY Antimicrobial Surveillance Program during 2016 to 2018. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for a potential ABSSSI indication.

Staphylococcus aureus from hospital-acquired pneumonia from an Italian nationwide survey: activity of ceftobiprole and other anti-staphylococcal agents, and molecular epidemiology of methicillin-resistant isolates.

To determine the prevalence of Staphylococcus aureus from hospital-acquired pneumonia (HAP) in Italy and the susceptibility to ceftobiprole and comparators of MSSA and MRSA isolates. A secondary objective was to characterize the clonality and acquired resistance and virulence genes of MRSA. Consecutive non-replicate isolates from HAP were collected from 13 laboratories distributed across Italy, from January to May 2016. Antimicrobial susceptibility testing was performed by broth microdilution, and results were interpreted according to the EUCAST breakpoints. All MRSA isolates were subjected to WGS using an Illumina platform. Clonality and resistance and virulence gene content were investigated with bioinformatics tools. Among 333 isolates from HAP, S. aureus was the third most common pathogen (18.6%). The proportion of MRSA was 40.3%. Susceptibility to ceftobiprole was 100% for MSSA and 95.5% for MRSA. Lower susceptibility rates of 78.4% and 94.6% in MSSA and 36.4% and 12.1% in MRSA isolates were observed for erythromycin and levofloxacin, respectively. The MRSA from HAP mostly belonged to clonal complex (CC) 22 (47.0%), CC5 (25.8%) and CC8 (15.2%), with a minority of other lineages (ST1, ST6, ST7, ST30, ST152 and ST398). Acquired resistance and virulence genes in most cases exhibited a clonal distribution. The three ceftobiprole-resistant isolates exhibited an MIC of 4 mg/L and belonged to ST228-MRSA-I of CC5. S. aureus is an important cause of HAP in Italy. Ceftobiprole exhibited good in vitro activity against S. aureus isolated from HAP, including MRSA. A trend to replacement of ST228 with ST22 was noticed compared with previous studies.

In vitro evidence of the synergistic interaction of ceftopibrole and other antibiotics against multidrug-resistant Gram-negative isolates

The purpose of the present study was to investigate the in vitro activity of ceftobiprole in combination with other antimicrobials against 27 selected Gram-negative isolates, including ESBL-producing E. coli and KPC-OXA-48-producing K. pneumoniae. Ceftobiprole activity in combination with amikacin, colistin, levofloxacin, piperacillin/tazobactam and rifampin was evaluated by time-kill curves and gradient-cross method (except colistin).Among the 27 strains tested with gradient strips most were resistant to ceftobiprole. Synergy was observed in some cases with piperacillin/tazobactam. There was at least one synergistic combination towards 9 isolates belonging to different species. No antagonism was observed with any of the antibiotic tested. In time-kill curves, performed for 12 selected isolates, synergistic interaction was more frequent, occurring with 32/60 combinations. The most interesting results of our study are the bactericidal effects of ceftobiprole in combination with colistin or piperacillin/tazobactam tested against Gram-negative isolates, including KPC and OXA-48-producing K. pneumoniae.

Ceftobiprole activity when tested against contemporary bacteria causing bloodstream infections in the United States (2016–2017)

Ceftobiprole medocaril, the prodrug of ceftobiprole, is an advanced-generation cephalosporin that is approved in many European and non-European countries for the treatment of adults with hospital-acquired pneumonia (excluding ventilator-associated pneumonia) and community-acquired pneumonia and is currently being evaluated in a global phase 3 clinical trial of patients with Staphylococcus aureus bacteremia. This study investigated the in vitro activity of ceftobiprole and comparators against a total of 5466 gram-positive and -negative isolates from bloodstream infections (BSIs) that were collected in the United States during 2016 and 2017 as part of the SENTRY Antimicrobial Surveillance Program. Ceftobiprole was highly active (isolates were >99% susceptible) against S. aureus (including methicillin-resistant S. aureus), coagulase-negative staphylococci, Enterococcus faecalis, streptococci, and non–extended-spectrum β-lactamase (non-ESBL) phenotype Enterobacteriaceae. As expected, lower activities were observed against Enterococcus faecium, ESBL-phenotype Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. These results support further clinical evaluation of ceftobiprole for the treatment of BSIs caused by susceptible organisms.

Ceftobiprole Activity against Gram-Positive and -Negative Pathogens Collected from the United States in 2006 and 2016.

Ceftobiprole is an advanced cephalosporin with potent activity against Gram-positive and Gram-negative bacteria that has been approved in many European and non-European countries to treat community- and hospital-acquired pneumonia (excluding ventilator-associated pneumonia). This study reports on the activity of ceftobiprole against a large set of clinical isolates obtained from hospitalized patients in the United States in 2016 that caused serious infections, including pneumonia, bacteremia, and skin and skin structure infections. To assess any potential temporal changes in ceftobiprole activity, the 2016 results were compared to corresponding MIC data from a 2006 U.S. survey that included key target pathogens. Ceftobiprole exhibited potent activity against Staphylococcus aureus (including methicillin-resistant S. aureus isolates, which were 99.3% susceptible), coagulase-negative staphylococci (100% susceptible), Enterococcus faecalis (100% susceptible), Streptococcus pneumoniae (99.7% susceptible), and other tested streptococci. Similarly, ceftobiprole was highly active against Enterobacteriaceae isolates that did not exhibit an extended-spectrum β-lactamase (ESBL) phenotype, including Escherichia coli (99.8% susceptible) and Klebsiella pneumoniae (99.6% susceptible). A total of 99.6% of all Haemophilus influenzae and Moraxella catarrhalis isolates were inhibited at ≤1 mg/liter ceftobiprole, and 72.7% of the Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. With the exception of decreased cephalosporin susceptibility among Enterobacteriaceae isolates, which correlates with an increased prevalence of ESBL-producing isolates, ceftobiprole had similar activities against the isolate sets collected in 2006 and 2016. Therefore, ceftobiprole remains highly active when tested in vitro against a large number of current Gram-positive or Gram-negative pathogens that cause serious infections.

Bactericidal activity of ceftobiprole combined with different antibiotics against selected Gram-positive isolates

This study investigated the in vitro susceptibility of ceftobiprole and its potential synergistic activity in combination with other antimicrobials against 46 selected Gram-positive pathogens displaying resistance or decrease susceptibility to several drugs. The gradient-cross method was used to assess synergism between ceftobiprole and daptomycin, levofloxacin, linezolid, rifampicin and piperacillin/tazobactam. Time-kill curves were performed for seven representative isolates. Ceftobiprole MICs ranged from 0.25–6 mg/L for staphylococci; 4–≥32 mg/L for Enterococcus faecalis, and 0.38–≥32 mg/L for E. faecium. Ceftobiprole plus daptomycin was synergistic against all isolates. Ceftobiprole plus linezolid was synergistic against 4 isolates belonging to different species. Ceftobiprole plus levofloxacin was synergistic only against enterococci. In conclusion, ceftobiprole exhibited a potent in vitro antibacterial activity and exhibited synergy with daptomycin against all Gram-positive isolates, despite their antibiotic resistance phenotypes. The use of ceftobiprole in combination may provide a promising alternative therapy for the treatment of resistant Gram-positive infections.

Comparative activity of ceftobiprole against coagulase-negative staphylococci from the BSAC Bacteraemia Surveillance Programme, 2013\u20132015

Coagulase-negative staphylococci (CoNS) are a significant cause of bacteraemia, the treatment of which is becoming increasingly complex due to the emergence of multidrug-resistant strains. This study aimed to evaluate the in vitro activity of ceftobiprole, an advanced-generation cephalosporin, as compared with other antimicrobial agents against CoNS from patients with bacteraemia. As part of the British Society for Antimicrobial Chemotherapy (BSAC) Bacteraemia Surveillance Programme, 650 blood isolates of CoNS were obtained from patients with bacteraemia at 74 centres throughout the UK and Ireland for the years 2013–2015. Minimum inhibitory concentrations (MICs) of ceftobiprole and other antimicrobial agents were determined using the BSAC agar dilution method. Susceptibility was assessed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. The majority of the isolates (63.2%) were Staphylococcus epidermidis. Overall, methicillin resistance, as determined by oxacillin susceptibility testing, was observed in 64.2% of isolates. The MIC50/90 of ceftobiprole was 1/2 mg/L, and 100% of CoNS isolates were inhibited at the EUCAST ceftobiprole non-species-specific pharmacokinetic/pharmacodynamic breakpoint of 4 mg/L. Only one isolate was resistant to vancomycin. Overall rates of resistance to ciprofloxacin, clindamycin, erythromycin and teicoplanin were 50.5, 25.1, 68.2 and 20.9%, respectively. In S. epidermidis, resistance to oxacillin was associated with increased resistance to other antimicrobials. Ceftobiprole demonstrated in vitro activity against all CoNS species isolated from patients with bacteraemia and was active against species resistant to other antistaphylococcal antimicrobials. The collection of clinical data regarding the efficacy of ceftobiprole in treating CoNS bacteraemia is warranted.

Activity of ceftobiprole against Staphylococcus spec. isolates derived from foreign body associated infections

Antibiotic therapy is essential in foreign body associated infections. The treatment regime should aim at high tissue concentrations, high bioavailability, high biofilm penetration and good tolerance. We investigated whether the new cephalosporin ceftobiprole is active against clinical isolates from musculoskeletal foreign body associated infections. One hundred ninety-six staphylococci isolates (coagulase negative staphylococci and Staphylococcus aureus) derived from foreign body associated infections were tested towards susceptibility to ceftobiprole, using a test strip assay and broth microdilution. The MIC for all strains S. aureus indicated susceptibility to ceftobiprole. The MIC of only two strains of coagulase negative staphylococci was above 2 mg/L. Our results show that ceftobiprole might be considered as an off-label treatment option in foreign body associated infections.