Background A randomized, double-blind, multicenter trial involving patients with a broad range of complicated skin and skin-structure infections due to either gram-positive or gram-negative bacteria was conducted to compare ceftobiprole monotherapy with treatment with vancomycin plus ceftazidime. Methods Patients were randomized 2:1 to receive ceftobiprole or to receive vancomycin plus ceftazidime. Outcomes were determined at a test-of-cure visit (7-14 days after completion of therapy) and were analyzed for all patients with complicated skin and skin-structure infections, as well as for subgroups, on the basis of major types of infections and severity of disease. Results Among the clinically evaluable and the intent-to-treat populations, clinical cure rates at the test-of-cure visit were similar in the ceftobiprole and comparator treatment arms (clinical cure rate, 90.5% [439 of 485 patients] and 90.2% [220 of 244 patients] in the clinically evaluable population, respectively; 81.9% [448 of 547 patients] and 80.8% [227 of 281 patients] in the intent-to-treat population, respectively). Clinical cure rates in ceftobiprole-treated patients ranged from 86.2% (125 of 145 patients) among those with diabetes who had foot infections to 93.0% (80 of 86 patients) among those with cellulitis. Among patients treated with ceftobiprole, clinical cure rates were similar among patients from whom gram-negative bacteria were isolated (87.9% [109 of 124 patients]) and among patients from whom gram-positive bacteria were isolated (91.8% [292 of 318 patients]) and were not statistically different from the clinical cure rates among comparator-treated patients (89.7% [61 of 68 patients] and 90.3% [149 of 165 patients], respectively). Rates of adverse events and serious adverse events in the 2 treatment groups were similar. Conclusions Ceftobiprole monotherapy is as effective as vancomycin plus ceftazidime for treating patients with a broad range of complicated skin and skin-structure infections and infections due to gram-positive and gram-negative bacteria.

https://www.jstor.org/stable/pdfplus/40307067.pdf

A Randomized, Double-Blind Trial Comparing Ceftobiprole Medocaril with Vancomycin plus Ceftazidime for the Treatment of Patients with Complicated Skin and Skin-Structure Infections

Staphylococcal cassette chromosome mec (SCCmec) is a mobile genetic element characterized by flanking terminal direct and, in most cases, inverted repeat sequences, the mec and ccr gene complexes, and their surrounding DNA regions. Unique combinations of the mec and ccr gene complexes generate various SCCmec types. Six SCCmec types have been reported to date. We describe here a novel SCCmec type identified in a Canadian methicillin-resistant Staphylococcus aureus (MRSA) epidemic strain. MRSA clinical isolates were screened for known SCCmec types by multiplex and conventional PCR methods. Three phenotypically and genotypically identical MRSA clinical isolates with a pulsotype identical to CMRSA9 were identified locally and found to be nontypeable by available SCCmec typing schemes. Complete sequencing of the SCCmec element revealed a nucleotide fragment of 32,168 bp integrated at an identical chromosomal integration site (attBscc) at the 3' end of the orfX gene. The nucleotide sequences at the chromosome-SCCmec junction regions were typical of other SCCmec types, but the element harbored a unique combination of class A mec and type 4 ccr gene complexes. Sequence recombination analysis suggested that this unique SCCmec type may be derived from homologous recombination between the previously described SCC(RP62A) of S. epidermidis strain RP62A and SCC composite island of S. epidermidis ATCC 12228, respectively, or via recombination of other staphylococcal strains that carry the same or similar mobile cassettes. We identified a previously undescribed type of SCCmec from isolate C10682, tentatively designated type VIII, and we provide compelling evidence supporting the ability of SCC elements to transfer horizontally or undergo recombination to generate new SCCmec types.

Novel Staphylococcal Cassette Chromosome mec Type, Tentatively Designated Type VIII, Harboring Class A mec and Type 4 ccr Gene Complexes in a Canadian Epidemic Strain of Methicillin-Resistant Staphylococcus aureus

Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, -4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, -8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n = 17) of the ceftobiprole-treated patients and 6% (n = 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.

Results of a Double-Blind, Randomized Trial of Ceftobiprole Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria

The implementation of routine whole-genome sequencing (WGS) promises to transform our ability to monitor the emergence and spread of bacterial pathogens. Here we combined WGS data from 308 invasive Staphylococcus aureus isolates corresponding to a pan-European population snapshot, with epidemiological and resistance data. Geospatial visualization of the data is made possible by a generic software tool designed for public health purposes that is available at the project URL (http://www.microreact.org/project/EkUvg9uY?tt=rc). Our analysis demonstrates that high-risk clones can be identified on the basis of population level properties such as clonal relatedness, abundance, and spatial structuring and by inferring virulence and resistance properties on the basis of gene content. We also show that in silico predictions of antibiotic resistance profiles are at least as reliable as phenotypic testing. We argue that this work provides a comprehensive road map illustrating the three vital components for future molecular epidemiological surveillance: (i) large-scale structured surveys, (ii) WGS, and (iii) community-oriented database infrastructure and analysis tools. IMPORTANCE The spread of antibiotic-resistant bacteria is a public health emergency of global concern, threatening medical intervention at every level of health care delivery. Several recent studies have demonstrated the promise of routine whole-genome sequencing (WGS) of bacterial pathogens for epidemiological surveillance, outbreak detection, and infection control. However, as this technology becomes more widely adopted, the key challenges of generating representative national and international data sets and the development of bioinformatic tools to manage and interpret the data become increasingly pertinent. This study provides a road map for the integration of WGS data into routine pathogen surveillance. We emphasize the importance of large-scale routine surveys to provide the population context for more targeted or localized investigation and the development of open-access bioinformatic tools to provide the means to combine and compare independently generated data with publicly available data sets.

/pdf/whole-genome-sequencing-for-routine-pathogen-surveillance-in-3qaizkk7x9.pdf

Whole-Genome Sequencing for Routine Pathogen Surveillance in Public Health: a Population Snapshot of Invasive Staphylococcus aureus in Europe

Heterogeneity among methicillin-resistant Staphylococcus aureus from Italian pig finishing holdings.

We developed a new multiplex PCR assay for detection of Panton-Valentine leukocidin virulence genes and simultaneous discrimination of methicillin-susceptible from -resistant staphylococci. This assay is simple, rapid, and accurate and offers the potential for prompt detection of newly emerging community-associated methicillin-resistant Staphylococcus aureus.

Novel Multiplex PCR Assay for Detection of the Staphylococcal Virulence Marker Panton-Valentine Leukocidin Genes and Simultaneous Discrimination of Methicillin-Susceptible from -Resistant Staphylococci

Wendy Hutchins

Papers

Novel Multiplex PCR Assay for Detection of the Staphylococcal Virulence Marker Panton-Valentine Leukocidin Genes and Simultaneous Discrimination of Methicillin-Susceptible from -Resistant Staphylococci