Dataset Information

Ceftobiprole versus daptomycin in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, Phase III trial.

ABSTRACT: Although Staphylococcus aureus is a common cause of bacteremia, treatment options are limited. The need for new therapies is particularly urgent for methicillin-resistant S. aureus bacteremia (SAB). Ceftobiprole is an advanced-generation, broad-spectrum cephalosporin with activity against both methicillin-susceptible and -resistant S. aureus. This is a Phase III, randomized, double-blind, active-controlled, parallel-group, multicenter, two-part study to establish the efficacy and safety of ceftobiprole compared with daptomycin in the treatment of SAB, including infective endocarditis. Anticipated enrollment is 390 hospitalized adult patients, aged ?18 years, with confirmed or suspected complicated SAB. The primary end point is overall success rate. Target completion of the study is in the second half of 2021. Clinicaltrials.gov identifier: NCT03138733.

SUBMITTER: Hamed K

PROVIDER: S-EPMC7046132 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Ceftobiprole versus daptomycin in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, Phase III trial.

Hamed Kamal K Engelhardt Marc M Jones Mark E ME Saulay Mikael M Holland Thomas L TL Seifert Harald H Fowler Vance G VG

Future microbiology 20200110

Although Staphylococcus aureus is a common cause of bacteremia, treatment options are limited. The need for new therapies is particularly urgent for methicillin-resistant S. aureus bacteremia (SAB). Ceftobiprole is an advanced-generation, broad-spectrum cephalosporin with activity against both methicillin-susceptible and -resistant S. aureus. This is a Phase III, randomized, double-blind, active-controlled, parallel-group, multicenter, two-part study to establish the efficac ...[more]

PMID: 31918579

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Project description:New treatment modalities are needed for the treatment of infections due to multidrug-resistant Staphylococcus aureus. S. aureus capsular polysaccharide immune globulin (Altastaph) is a polyclonal immune globulin preparation that is being developed as adjunctive therapy for persons with S. aureus infections complicated by bacteremia. In a phase II, multicenter, randomized, double-blind, placebo-controlled trial, 40 subjects with documented S. aureus bacteremia received standard therapy plus either Altastaph at 200 mg/kg of body weight in each of two infusions 24 h apart or placebo. During the 42-day observation period, antibody pharmacokinetics and safety were the primary characteristics studied. Information regarding the resolution of bacteremia and fever was also analyzed. Anti-type-5 and anti-type-8 capsular antibody levels peaked after the second infusion at 550 mug/ml and 419 mug/ml, respectively, and remained above 100 mug/ml at day 28. A total of 316 adverse events were noted in 39 of 40 subjects. Infusion-related adverse events in Altastaph recipients were infrequent and similar to those among recipients of commercial intravenously administered immunoglobulin G products. Five of 21 (23%) subjects in the Altastaph group died, whereas 2 of 18 (11%) subjects in the placebo group died (P = 0.42). Compared to the control patients, the Altastaph recipients had a shorter median time to the resolution of fever (2 days and 7 days, respectively; P = 0.09) and a shorter length of hospital stay (9 days and 14 days, respectively; P = 0.03). However, these findings are exploratory, and there were few differences in the other variables measured. High levels of opsonizing antibodies were maintained for the initial 4 weeks. Although the study was not powered to show efficacy, these preliminary findings and safety profile suggest that Altastaph may be an effective adjunct to antibiotics and warrants further investigation (ClinicalTrials.gov number NCT00063089).

Project description:The genomic evolution in vivo in persistent infection was critical information for understanding how methicillin-resistant Staphylococcus aureus (MRSA) was adapted to host environments with high antibiotic selective pressure. Thirty-two successive MRSA blood isolates with incremental non-susceptibility to vancomycin (VISA), daptomycin (DRSA), and/or linezolid (LRSA) were isolated from a patient failing multiple courses of antimicrobial therapy during 1,356 days of bacteremia. Whole genome sequencing (WGS) for all consecutive isolates were conducted to characterize the evolutionary pathways, resistance-associated mutations and their temporal relationship with antimicrobial treatment. The WGS-based phylogeny categorized the isogenic strains into three major clades, I (22 isolates), II (7 isolates), and III (3 isolates), respectively, harboring a median (range) of 7 (1-30), 62 (53-65), and 118 (100-130) non-synonymous mutations when compared to the very first isolate. Clade I strains were further grouped into early and late subclades, which, respectively, shared the most recent common ancestor with Clade III strains at day 393.7 and Clade II strain at day 662.5. Clade I and Clade III strains were characterized, respectively, with high rates of VISA (9/22, 40.9%) and VISA-and-DRSA phenotype (2/3, 66.7%). Linezolid-resistance including VISA-DRSA-and-LRSA phenotype was exclusively identified in Clade II strains after eight courses of linezolid treatment. The LRSA displayed a small colony variant phenotype and were associated with G2576T mutations in domain V region of 23S rRNA. Substantial loss of mobile elements or alleles mediating resistance or virulence were identified during the evolution of multi-resistance. However, the gene loss might not be correlated to the development of VISA, DRSA, or LRSA phenotype. In conclusion, MRSA in persistent bacteremia was adapted to harsh host environment through multiple pathways involving both resistance-associated mutations and extensive gene loss.

Dataset Information

Ceftobiprole versus daptomycin in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, Phase III trial.

Publications

Ceftobiprole versus daptomycin in <i>Staphylococcus aureus</i> bacteremia: a novel protocol for a double-blind, Phase III trial.

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