ppi-0903 and Staphylococcal-Infections

Ceftaroline and ceftobiprole are advanced generation cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA). This review summarizes their clinical efficacy for complicated skin and soft tissue infections (cSSTIs).. Both these agents retain excellent in vitro activity against both MRSA and Gram-negative isolates from patients with CSSTIs. Both these agents are registered for the management of cSSTIs based on the results of large scale phase III noninferiority trials. Ceftaroline and ceftobiprole are noninferior to the combination of vancomycin and aztreonam as this was assessed by their clinical cure rate at the test-of-cure visits. Furthermore, ceftobiprole is noninferior to comparators for the achievement of early clinical success at 72 h. Ceftaroline achieves 81% clinical cure against diabetic foot infections.. Ceftaroline and ceftobiprole can be used as monotherapy for the treatment of cSSTIs.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Soft Tissue Infections; Staphylococcal Infections

To develop the 'Stronger Towns Index': a deprivation index that took into account characteristics of areas encompassing towns that may be eligible for redevelopment funding and explore how this index was associated with self-rated health and migration within England between 2001 and 2011.. There were areas in the lowest deciles of Town Strength who did not receive funding. After multiple adjustment, LS members living in areas with higher deciles were significantly more likely (7% to 38%) to report good health than those in the lowest decile in 2001. Remaining in the same decile between 2001 and 2011 was associated with 7% lower odds of good self-rated health in 2011.. It is important to consider health in towns when allocating funding. Areas in the Midlands may have missed out on funding which might help mitigate poor health.. Ferritin levels <30µg/L were associated with unexplained infertility and might be screened in the future. Further studies with a focus on iron deficiency and iron treatment on women with unexplained infertility are warranted.. This EGM provides a valuable resource for researchers, policy-makers and the public to access the available evidence on the determinants of various COVID-19 health-related behaviours. The map can also be used to help guide research commissioning, by evidence synthesis teams and evidence intermediaries to inform policy during the ongoing pandemic and potential future outbreaks of COVID-19 or other respiratory infections. Evidence included in the map will be explored further through a series of systematic reviews examining the strength of the associations between malleable determinants and the uptake and maintenance of individual protective behaviours.. Patients with polymicrobial bloodstream infections are typically critically ill and harbor multidrug-resistant bacteria. Thus, to minimize mortality rate in critically ill patients, changes in infectious flora should be monitored, antibiotics selected reasonably, and invasive procedures reduced.. Altogether, these findings clearly revealed the great potential of the in vitro biological activity of linseed extract as a safe source for combatting multidrug-resistant. In this work, the capture of carbon dioxide using a dense hollow fiber membrane was studied experimentally and theoretically. The factors affecting the flux and recovery of carbon dioxide were studied using a lab-scale system. Experiments were conducted using a mixture of methane and carbon dioxide to simulate natural gas. The effect of changing the CO. Persistent gender and racial disparities in high-impact medical and critical care journals underscore the need to revise policies and strategies to encourage greater diversity in critical care research.. Thirty evaluable patients were enrolled. Median age was 60.5 years. Median follow-up for all patients was 17 months. Ten patients (33%) experienced grade ≥ 3 treatment-related adverse events, the most common being neutropenia and diarrhea; 50% required ≥ 1 dose reduction. The disease control rate was 90% (progressive disease: 10%, partial response: 23%, stable disease: 67%). There was zero treatment-related mortality. Twenty-two patients (73%, 90% CI 57-86; p = 0.008) completed all chemotherapy and surgery. Two patients (9%) who successfully underwent resection had minor postoperative complications. Median length of hospital stay was 4 days. Median RFS was 7.1 months. Median OS for the entire cohort was 24 months and was not reached in patients who underwent surgical resection.. Neoadjuvant treatment with gemcitabine, cisplatin, and nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes.

Topics: Acetogenins; Acute Disease; Acute Kidney Injury; Administration, Intravenous; Aged; Albumins; Alcoholism; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; alpha-Glucosidases; Anemia; Animals; Anthozoa; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bacterial; Antigens, Bacterial; Antihypertensive Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Ascites; Asthma; Bacteria; beta-Lactamases; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Binding Sites; Biological Availability; Biomass; Borderline Personality Disorder; Brain; Brucella abortus; Brucella melitensis; Brucellosis; Calcium; Carbapenems; Case-Control Studies; Caseins; Cattle; CD8-Positive T-Lymphocytes; Ceftaroline; Cell Line; Cell Line, Tumor; Cell Physiological Phenomena; Cell Proliferation; Cephalosporins; Chemotherapy, Adjuvant; China; Chitin; Chlorella; Chlorophyll; Chlorophyll A; Chlorophyta; Cholangiocarcinoma; Cisplatin; Conotoxins; Contrast Media; Conus Snail; Cross-Sectional Studies; Cytokines; Decapodiformes; Deoxycytidine; Diagnostic and Statistical Manual of Mental Disorders; Dietary Fiber; Diterpenes; DNA Methylation; Dogs; Double-Blind Method; Drug Design; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Screening Assays, Antitumor; Eicosapentaenoic Acid; Enzyme-Linked Immunosorbent Assay; Epidermis; Escherichia coli; Escherichia coli Infections; Extraintestinal Pathogenic Escherichia coli; Fatty Acids; Fatty Acids, Unsaturated; Fatty Acids, Volatile; Feasibility Studies; Feces; Female; Ferritins; Fluorodeoxyglucose F18; Gastrectomy; Gastrointestinal Microbiome; Gemcitabine; Glomerular Filtration Rate; Glucose; Glycerol; Granulocyte-Macrophage Colony-Stimulating Factor; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Immunoassay; Immunoglobulin G; India; Infant, Newborn; Infertility; Inflammation; Intensive Care Units; Iron; Iron Deficiencies; Kidney; Lacticaseibacillus rhamnosus; Laurencia; Leukocytes; Lipids; Liver Cirrhosis; Long Interspersed Nucleotide Elements; Longitudinal Studies; Male; Mesenchymal Stem Cells; Methicillin-Resistant Staphylococcus aureus; Mice; Microalgae; Microbial Sensitivity Tests; Microscopy; Middle Aged; Minerals; Molecular Conformation; Molecular Docking Simulation; Molecular Structure; Mycobacterium tuberculosis; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Nephropidae; Nicotinic Antagonists; Nitrogen; Obesity; Oxaliplatin; Paclitaxel; Panax; Pancreatic Neoplasms; Pancreatitis; Personality; Personality Disorders; Personality Inventory; Photobioreactors; Plant Extracts; Plasmalogens; Plasmids; Polymorphism, Genetic; Polynesia; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Prebiotics; Predictive Value of Tests; Prognosis; Prolyl-Hydroxylase Inhibitors; Rabbits; Radiopharmaceuticals; Rats; Rats, Wistar; Receptors, Nicotinic; Recombinant Proteins; Retrospective Studies; Rifampin; Risk Factors; RNA, Ribosomal, 16S; Salinity; Seaweed; Sensitivity and Specificity; Sepsis; Sesquiterpenes; Severity of Illness Index; Shock, Septic; Silicones; Single Photon Emission Computed Tomography Computed Tomography; Skin; Snails; Solubility; Solvents; Sputum; Staphylococcal Infections; Stomach Neoplasms; Stramenopiles; Structure-Activity Relationship; Technetium Tc 99m Exametazime; Technology; Terpenes; Tuberculosis; Tuberculosis, Multidrug-Resistant; Urinary Catheters; Urinary Tract Infections; Vascular Endothelial Growth Factor A; Virulence Factors; Water; Wound Healing

To assess the success rates of off-label uses of ceftaroline for infections caused by methicillin-resistant. We queried PubMed/MEDLINE, with the search term "Ceftaroline." Articles were restricted to the English language and year of publication (January 1, 2009-January 31, 2022).. Clinical trials, observational studies, and case reports that reported efficacy, safety, pharmacokinetics, use in MRSA infections other than acute bacterial skin infection and community-acquired pneumonia, and ceftaroline resistance were selected.. The search pooled 103 publications and all abstracts were reviewed. Forty-six articles that reported efficacy, safety, pharmacokinetics, or off-label use in multiple patients and 7 articles on ceftaroline resistance are used in this review. Ceftaroline has been approved for treatment of acute skin/soft tissue infection and community-acquired pneumonia. Ceftaroline's efficacy in off-label infections ranged from 66.7% to 87.3% depending on the types of infection. There were 14 documented cases of ceftaroline resistance associated with PBP2a changes.. Case series and observational studies have documented success with ceftaroline alone or in combination with vancomycin or daptomycin for treatment of MRSA bone and joint, endovascular, diabetic foot infections, and bacteremia from other causes.. Despite the lack of randomized controlled trials, ceftaroline is used as salvage therapy for different MRSA infections. The data from case series and observational studies are promising but ceftaroline should be used judiciously as ceftaroline-resistant MRSA begin to emerge.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Daptomycin; Drug Resistance; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin

Vancomycin and daptomycin are options for the initial treatment of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Treatment options for persistent MRSA bacteremia or bacteremia due to vancomycin-intermediate or vancomycin-resistant strains include daptomycin, ceftaroline, and combination therapies. There is a critical need for high-level evidence from clinical trials to allow optimally informed decisions in the treatment of MRSA bacteremia.

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Daptomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin

The development of resistance to antibiotics has been ignored for a long time. But nowadays, increasing resistance is an important topic. For a decade no new antibiotics had been developed and it is not possible to quickly close this gap of new resistance and no new drugs. This work presents six new antibiotics (ceftaroline, ceftobiprole, solithromycin, tedizolid, ceftolozane/tazobactam, ceftazidime/avibactam). In part, only expert opinions are given due to lack of study results.The two 5th generation cephalosporins ceftaroline and ceftobiprole have beside their equivalent efficacy to ceftriaxone (ceftaroline) and cefipim (ceftobiprole) high activity against MRSA. The fluoroketolide solithromycin should help against macrolide-resistant pathogens and has been shown to be noninferior to the fluorochinolones. The oxazolidinone tedizolid is effective against linezolid-resistant MRSA. The two cephalosporins ceftolozane/tazobactam and ceftazidime/avibactam are not only effective against gram-negative pathogens, but they have a very broad spectrum. Due to the efficacy against extended-spectrum β‑lactamases, they can relieve the selection pressure of the carbapenems. We benefit from all new antibiotics which can take the selection pressure from other often used antibiotics. The increasing number of resistant gram-negative pathogens worldwide is alarming. Thus, focusing on the development of new drugs is extremely important.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Infections; Ceftaroline; Ceftazidime; Cephalosporins; Clinical Trials as Topic; Drug Approval; Drug Combinations; Drug Resistance, Multiple, Bacterial; Ephedrine; Humans; Macrolides; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Penicillanic Acid; Phenobarbital; Staphylococcal Infections; Tazobactam; Theophylline; Triazoles

Tedizolid, the active moiety of tedizolid phosphate, is approved in the United States, the European Union, Canada and a number of other countries for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This network meta-analysis (NMA) evaluates the comparative effectiveness of tedizolid and other antibacterials indicated for the treatment of ABSSSI caused by MRSA.. Systematic review of 10 databases was undertaken to inform an NMA to estimate the relative effectiveness of tedizolid and established monotherapy comparators (ceftaroline, daptomycin, linezolid, teicoplanin, tigecycline, vancomycin) for treating MRSA-associated ABSSSI. Randomized controlled trials enrolling adults with ABSSSI or complicated skin and skin structure infections caused by suspected/documented MRSA were eligible for inclusion. Networks were developed based on similarity of study design, patient characteristics, outcome measures and available data. Outcomes of interest included clinical response at end of therapy (EOT), post-therapy evaluation (PTE) or test-of-cure assessment and treatment discontinuations resulting from adverse events (AEs). Bayesian NMA was conducted for each outcome using fixed-effects and random effects models.. Literature searches identified 3,618 records; 15 trials met the inclusion criteria and were considered suitable for NMA comparison. In fixed-effects models, tedizolid had higher odds of clinical response at EOT (odds ratio [OR], 1.7; credible interval, 1.0, 3.0) and PTE than vancomycin (OR, 1.6; credible interval, 1.1, 2.5). No differences in odds of clinical response at EOT or PTE were observed between tedizolid and other comparators. There was no evidence of a difference among treatments for discontinuation due to AEs. Results from random effects and fixed-effects models were generally consistent.. Tedizolid was superior to vancomycin for clinical response at EOT and PTE. There was no evidence of a difference between tedizolid and other comparators and no evidence of a difference between tedizolid and all comparators when evaluating discontinuation due to AEs. These findings suggest that tedizolid provides an alternative option for the management of serious skin infections caused by suspected or documented MRSA. This study is subject to the limitations inherent in all NMAs, and the results should be interpreted accordingly.

Topics: Anti-Bacterial Agents; Bayes Theorem; Ceftaroline; Cephalosporins; Daptomycin; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Oxazolidinones; Skin Diseases, Bacterial; Staphylococcal Infections; Tetrazoles; Vancomycin

The utility of ceftaroline for the treatment of methicillin-resistant. Ceftaroline was originally approved for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs) but recently received an additional approval for the treatment of. Ceftaroline has been used to successfully treat SAB, including endocarditis. Therapy with ceftaroline may be considered when antibiotic resistance or previous treatment failure precludes the use of first-line agents.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Retrospective Studies; Staphylococcal Infections; Treatment Outcome

This article reviews recent clinical evidence for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Vancomycin remains the initial antibiotic of choice for the treatment of patients with MRSA bacteremia and endocarditis due to isolates with vancomycin minimum inhibitory concentration ≤2 μg/mL, whereas daptomycin is an effective alternative, and ceftaroline seems promising. Treatment options for persistent MRSA bacteremia or bacteremia due to vancomycin-intermediate or vancomycin-resistant strains include daptomycin, ceftaroline, and combination therapies. There is a critical need for high-level evidence from clinical trials to allow optimally informed decisions in the treatment of MRSA bacteremia and endocarditis.

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Daptomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin

To summarize published data regarding the use of ceftaroline as salvage monotherapy for persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.. PubMed (January 1980-June 2016) was searched using combinations of the search terms methicillin-resistant Staphylococcus aureus, MRSA, bacteremia, ceftaroline, refractory, and persistent Supplemental references were generated through review of identified literature citations.. Available English-language, full-text articles pertaining to the use of ceftaroline for persistent MRSA bacteremia (MRSAB) were included.. The PubMed search yielded 23 articles for evaluation. There are no randomized controlled trials to date-only case series and reports. Four retrospective case series detailing the use of ceftaroline as monotherapy for persistent MRSAB were included. Most patients received at least 4 days of an appropriate anti-MRSA antimicrobial prior to ceftaroline and were able to clear bacteremia within 3 days. The most common rationales for ceftaroline use were progression of disease or nonresponse to current therapy. Higher off-label dosing of ceftaroline is often utilized to achieve optimal pharmacokinetic/pharmacodynamic parameters. Adverse events are not well described due to lack of follow-up; however, neutropenia has been associated with prolonged use.. Treatment options for persistent MRSAB remain few and far between. Ceftaroline is an effective agent for the salvage treatment of MRSAB. Off-label doses up to 600 mg every 8 hours are often used to achieve optimal pharmacokinetic/pharmacodynamic parameters. Because of lack of follow-up in these reports, the incidence of adverse effects of prolonged use of ceftaroline is not well defined.

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Female; Humans; Methicillin-Resistant Staphylococcus aureus; Salvage Therapy; Staphylococcal Infections

Ceftaroline fosamil was approved in 2010 by the United States Food and Drug Administration (USA-FDA) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). After approval, several studies and case reports have described the postmarketing clinical experience with ceftaroline in ABSSSIs and CABP and in patients with invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, many of whom had failed prior antibiotics. Successful clinical outcomes observed among the majority of these patients were supported by preapproval and postapproval in vitro surveillance of ceftaroline activity using breakpoint criteria that have been harmonized between the USA-FDA and CLSI. MIC90 values/percentage of strains susceptible to ceftaroline has remained stable over the period 2009-2012. Taken together, these postapproval studies support the use of ceftaroline for ABSSSI as well as CABP. Importantly, these data also suggest that ceftaroline can be effective in patients with serious invasive MRSA infections who have failed other therapies.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Drug Approval; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Product Surveillance, Postmarketing; Soft Tissue Infections; Staphylococcal Infections; Treatment Outcome; United States

We report a case of clearance of persistent bacteremia due to daptomycin non-susceptible, vancomycin-intermediate Staphylococcus aureus native mitral valve endocarditis with a combination of ceftaroline and daptomycin, in an 81-year-old medically complex patient who was not an operative candidate.

Topics: Aged, 80 and over; Bacteremia; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Bacterial; Drug Therapy, Combination; Endocarditis, Bacterial; Female; Humans; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

Staphylococcus aureus (S. aureus) has proven to be a major pathogen with the emergence of methicillin-resistant S. aureus (MRSA) infections and recently with heteroresistant vancomycin-intermediate S. aureus (hVISA) and vancomycin-intermediate S. aureus (VISA) infections. Although vancomycin is traditionally a first-line and relatively effective antibiotic, its continued use is under question because reports of heteroresistance in S. aureus isolates are increasing. Both hVISA and VISA infections are associated with complicated clinical courses and treatment failures. The prevalence, mechanism of resistance, clinical significance, and laboratory detection of hVISA and VISA infections are not conclusive, making it difficult to apply research findings to clinical situations. We provide an evidence-based review of S. aureus isolates expressing heterogenic and reduced susceptibility to vancomycin.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Linezolid; Risk Factors; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Skin infections have traditionally been classified by the US FDA as uncomplicated and complicated. In August 2010, the FDA released a new guidance document for the development of drugs to treat acute bacterial skin and skin structure infections (ABSSSI) and this was updated in 2013. Several new issues were addressed and henceforth skin infections in clinical trials were termed ABSSSI. In the USA, the annual prevalence of methicillin-resistant Staphylococcus aureus-related skin infections have continuously increased from 32.7% in 1998 to 53.8% in 2007. Ceftaroline fosamil is the only cephalosporin approved in the USA for monotherapy treatment of ABSSSI including infections caused by methicillin-resistant S. aureus. The efficacy of ceftaroline fosamil was shown in the CANVAS clinical trials. The CANVAS Day-3 analyses met an earlier, primary efficacy time point requested by the FDA. Ceftaroline has minimal drug-drug interactions, is well tolerated and possesses the safety profile associated with the cephalosporin class.

Topics: Acute Disease; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Approval; Drug Design; Drug Interactions; Humans; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Staphylococcal Infections; United States; United States Food and Drug Administration

Ceftaroline fosamil is a new subclass of cephalosporins with high intrinsic activity against various multi-resistant Gram-positive organisms, including Staphylococcus aureus and Streptococcus pneumoniae, as well as against Enterobacteriaceae causing bacteremia and infective endocarditis. Because of its pharmacokinetic profile and pharmacodynamic characteristics, this drug is a good therapeutic option for these infections. Experimental studies have shown good clinical efficacy for the treatment of endocarditis caused by S. aureus, regardless of their sensitivity to methicillin or vancomycin. Clinical experience is limited, although clinical trials and case series have reported a favorable clinical response in patients with bacteremia associated with skin and soft tissue infections, pneumonia, or infective endocarditis. Future studies should define more precisely the role of this new antibiotic in the treatment of these infections.

Topics: Animals; Bacteremia; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Disease Models, Animal; Endocarditis, Bacterial; Humans; Staphylococcal Infections

Ceftaroline is a fifth-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) that was recently launched in Singapore. It received approval from the United States (US) Food Drug Administration (FDA) and European Commission for the treatment of adult patients with community-acquired pneumonia (CAP) and complicated skin and soft tissue infections (cSSTI). This study aimed to review current published data and determine its clinical role, particularly in the local setting.. A literature review on published articles in English on ceftaroline, focusing in particular on clinical trials and other clinical reports. Susceptibility testing was also performed on a limited sample of local MRSA and Streptococcus pneumoniae isolates.. Ceftaroline has an extensive spectrum of activity, including coverage of MRSA and multidrug-resistant S. pneumoniae. However, it has limited activity against non-fermenting Gram-negative bacteria and is susceptible to hydrolysis by extended spectrum beta-lactamases. It is only available for intravenous delivery, with a reconstituted stability of just 6 hours, rendering it unavailable for use for outpatient antibiotic therapy. Clinical trials demonstrate non-inferiority compared to first-line comparators in the treatment of CAP and cSSTI. Published case reports/series suggest a potential greater role in the treatment of MRSA bacteremia and endocarditis. No resistance was found among local archived MRSA and S. pneumoniae isolates.. We believe ceftaroline will occupy primarily niche roles for culture-directed treatment of various infections--in particular those caused by MRSA--until further clinical trial data become available. A variety of factors render it less useful or appealing for empirical treatment of CAP or healthcare-associated infections.

Topics: Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Singapore; Staphylococcal Infections

Septic arthritis is a rheumatologic emergency as joint destruction occurs rapidly and can lead to significant morbidity and mortality. Accurate diagnosis can be particularly challenging in patients with underlying inflammatory joint disease. This review outlines the risk factors for septic arthritis and summarizes the causative bacterial organisms. We highlight advances in antibiotic management with a focus on new drugs for methicillin-resistant Staphylococcus aureus (MRSA) and discuss the use of adjunctive therapies for treatment of septic arthritis in adults.

Topics: Acetamides; Anti-Bacterial Agents; Arthritis, Infectious; Bacterial Infections; Ceftaroline; Cephalosporins; Daptomycin; Drug Therapy, Combination; Humans; Immunologic Factors; Linezolid; Methicillin-Resistant Staphylococcus aureus; Oxazolidinones; Risk Factors; Staphylococcal Infections; Treatment Outcome; Virginiamycin

Data regarding ceftaroline use for meticillin-resistant Staphylococcus aureus bacteraemia (MRSAB) are lacking. Here we review the outcomes of 31 patients with MRSAB treated with ceftaroline, including 9 patients with endocarditis. Clinical success was observed in 23 patients (74.2%). Adverse events associated with prolonged therapy were rare and included eosinophilic pneumonia, rash and diarrhoea. We conclude that ceftaroline can be used for MRSAB.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Staphylococcal Infections; Treatment Outcome; Young Adult

Ceftaroline is a cephalosporin with expanded gram-positive activity recently approved for clinical uses by the US Food and Drug Administration.. This article provides an overview of the in vitro and in vivo activities, mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of ceftaroline.. Relevant information was identified through a search of PubMed (1990-April 2011), EMBASE (1990-April 2011), International Pharmaceutical Abstracts (1970-April 2011), and Google Scholar using the key words ceftaroline, PPI-0903, PPI-0903M, T-91825, and TAK-599. A review of the reference lists of identified articles, a search of the US Food and Drug Administration Web site, and posters and abstracts from scientific meetings yielded additional publications.. In vitro, ceftaroline exhibits activity against most aerobic gram-positive isolates, common aerobic gram-negative respiratory pathogens, and some gram-positive anaerobes. The MIC range for most Staphylococcus aureus isolates, including vancomycin-resistant strains was between ≤0.008 and 4 μg/mL. In Phase III studies (CANVAS 1 and CANVAS 2), ceftaroline was found to be noninferior to vancomycin + aztreonam for the treatment of complicated skin and skin-structure infections, with a clinical cure rate of 91.6% among clinically evaluable patients (ceftaroline versus vancomycin + aztreonam: difference, -1.1; 95% CI, -4.2 to 2.0; P = NS). Ceftaroline's efficacy has also been assessed for the treatment of community-acquired pneumonia in 2 Phase III studies (FOCUS 1 and FOCUS 2) and was equivalent to ceftriaxone, with cure rates of 84.3% and 77.7%, respectively, among clinically evaluable patients in the combined analysis (ceftaroline versus ceftriaxone: difference, 6.7; 95% CI, 1.6 to 11.8). The recommended dosage for patients 18 years and older is 600 mg IV every 12 hours. Dosage adjustment is necessary in patients with renal impairment (creatinine clearance ≤50 mL/min). The pharmacokinetic properties of ceftaroline in patients with hepatic impairments are currently unavailable. Ceftaroline appeared to be well tolerated generally. The most frequently (>3%) reported adverse events were nausea, headaches, diarrhea, pruritus, rash, and insomnia; all were usually mild to moderate, self-limiting, and of little clinical significance.. Ceftaroline is a cephalosporin with broad gram-positive activity, including Methicillin-resistant S aureus and vancomycin-resistant S aureus. Its gram-negative activity includes common respiratory pathogens and members of the Enterobacteriaceae. Clinical trials have reported that ceftaroline was noninferior to ceftriaxone, and vancomycin + aztreonam for the treatment of community-acquired pneumonia and complicated skin and skin-structure infections, respectively.

Topics: Anti-Bacterial Agents; Area Under Curve; Ceftaroline; Cephalosporins; Half-Life; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections

The growing prevalence of resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus continues to pose a dilemma to clinicians. With strains developing reduced susceptibility to vancomycin, effective and well-tolerated antibiotics to combat these resistant pathogens are needed. Ceftaroline is a new parenteral cephalosporin that has been available in the USA for almost 2 years. Similar to other cephalosporins, it is well tolerated with mostly mild adverse events; however, compared with existing parenteral cephalosporins, ceftaroline has the unique attribute of being bactericidal against resistant Gram-positive aerobes including both hospital- and community-acquired methicillin-resistant S. aureus, S. aureus strains with reduced susceptibility or complete resistance to vancomycin, and resistant Streptococcus pneumoniae including multidrug-resistant strains. Current indications in the USA and Europe include treatment of adults with complicated skin, skin-structure infections and community-acquired pneumonia. This paper will review the properties of ceftaroline, its spectrum of activity, clinical use, safety profile and future role.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Gram-Positive Bacteria; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Pneumonia, Bacterial; Rabbits; Staphylococcal Infections

Ceftaroline (PPI 0903, formerly TAK-599), the active metabolite of a N-phosphono prodrug, ceftaroline fosamil, has been approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell wall synthesis and has a high affinity for PBP2a, which is associated with methicillin resistance. Ceftaroline is consistently active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, linezolid-resistant, and daptomycin-nonsusceptible strains. It possesses variable activity against Enterobacteriaceae and good activity against oral anaerobes. The drug is usually administrated intravenously at 600 mg every 12 h. Ceftaroline has low protein binding and is excreted by the kidneys and thus requires dose adjustments in individuals with renal failure. Clinical trials have demonstrated noninferiority when compared with vancomycin in the treatment of acute bacterial skin and skin structure infections and noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia. Ceftaroline demonstrated a safety profile similar to that of comparator drugs in clinical trials.

Topics: Adult; Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Bacterial; Rabbits; Staphylococcal Infections; Streptococcus pneumoniae

To review the pharmacology, microbiology, chemistry, in vitro activity, pharmacokinetics, clinical efficacy, safety, dosage, and administration of ceftaroline fosamil (Teflaro, Forest Laboratories, Inc.), a novel parenteral broad-spectrum cephalosporin approved by the Food and Drug Administration (FDA) on October 29, 2010, for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).. A search of MEDLINE (1966-July 2011) using the search terms ceftaroline fosamil, ceftaroline, TAK-599, PPI-0903, PPI-0903M, and T-91825 was performed. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, European Congress on Clinical Microbiology and Infectious Diseases, and the Infectious Diseases Society of America from 2005 to 2010, as well as information available from the manufacturer's Web site.. All English-language articles identified from the data sources were evaluated. In vitro, preclinical, and Phase 1, 2, and 3 clinical trials were included.. Clinical trials have been conducted evaluating use of ceftaroline for treatment of ABSSSI and CABP. Safety data from Phase 1, 2, and 3 clinical trials suggest that it is well tolerated and has a safety and tolerability profile common to the cephalosporin class. Ceftaroline has excellent in vitro activity against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), which makes it an attractive monotherapy for the treatment of ABSSSI. However, it lacks activity against problem gram-negative bacteria (eg, Pseudomonas spp.), which will likely limit its use for serious health care-associated infections. While its role in treating CABP is supported by excellent in vitro activity against Streptococcus pneumoniae and clinical efficacy data, currently available comparators may offer some advantages over ceftaroline. Finally, data are lacking to assess its role in the treatment of serious infections due to MRSA (eg, pneumonia, bacteremia).. These considerations should be part of the formulary review process; however, when considering the significant role MRSA plays in ABSSSI in both the community and hospital settings, we believe that ceftaroline will provide clinicians with a welcome option in addition to currently available anti-MRSA therapies for the treatment of ABSSSI.

Topics: Animals; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Drug Evaluation, Preclinical; Humans; Methicillin-Resistant Staphylococcus aureus; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Staphylococcal Infections

There is a choice of anti-MRSA antibiotic available with proven efficacy in the treatment of complicated skin and skin structure infection (cSSSI). Additional anti-MRSA antibiotics are in development, which have the potential to influence how such infections are managed. The emergence of resistance to current anti-MRSA agents, toxicity, and general lack of oral agents with proven efficacy for deep seated infection justify the development of new agents. However, there is a relative dearth of information specific to patients with orthopaedic-related infection. Combination therapy is often used in these patients, although there is a paucity of controlled trial data to support particular antibiotic combinations. As the choice of anti-MRSA agents increases, so does the need to identify which are best for the large variety of infections included in the group of cSSSIs. This is particular true for infections occurring in orthopaedic patients where poorly vascularised tissue, trauma or implanted prosthetic material, pose specific challenges.

Topics: Aminoglycosides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Glycopeptides; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Teicoplanin

Ceftaroline is a novel, broad-spectrum, advanced-generation cephalosporin whose action is mediated by binding to penicillin-binding proteins in bacteria, consistent with other beta-lactam antibiotics. Ceftaroline is distinct in that it has antimicrobial activity against multidrug-resistant Staphylococcus aureus (including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus [VISA], heteroresistant VISA, and vancomycin-resistant S. aureus), Streptococcus pneumonia (including drug-resistant strains), and respiratory gram-negative pathogens such as Moraxella catarrhalis and Haemophilus influenzae (including beta-lactamase-positive strains). Development of resistance to ceftaroline occurs rarely in gram-positive bacteria and at a similar rate to that of other oxyimino-cephalosporins in gram-negative bacteria. The inactive prodrug, ceftaroline fosamil, is administered by intravenous infusion and rapidly undergoes biotransformation to ceftaroline. Ceftaroline then follows a two-compartment pharmacokinetic model and is eliminated primarily by renal excretion, with a half-life of approximately 3 hours. Similar to other cephalosporins, time above the minimum inhibitory concentration is the pharmacodynamic parameter that best predicts efficacy for ceftaroline. Ceftaroline 600 mg intravenously every 12 hours has been shown to have similar efficacy to vancomycin plus aztreonam for the treatment of complicated skin and skin structure infections and to ceftriaxone for the treatment of community-acquired bacterial pneumonia in phase III clinical trials. Ceftaroline displayed a safety profile similar to that of other cephalosporins in clinical trials. Dosage adjustment is required for moderate renal impairment and for patients receiving hemodialysis. Ceftaroline breakpoints have been proposed but not confirmed. Ceftaroline is a renally excreted broad-spectrum cephalosporin that is clinically effective for the treatment of complicated skin and skin structure infections and community-acquired bacterial pneumonia, and it has distinctive activity against some difficult-to-treat multidrug-resistant gram-positive organisms.

Topics: Ceftaroline; Cephalosporins; Gram-Positive Bacteria; Humans; Methicillin Resistance; Staphylococcal Infections; Staphylococcus aureus

Current antibiotics available for the treatment of healthcare-associated pneumonia (HCAP) may result in clinical failure due to resistance development, side effect intolerance, or poor pharmacokinetic-pharmacodynamic profiles. New agents active against common HCAP pathogens are needed. The mechanism of action, spectrum of activity, pharmacokinetics, adverse effects, and clinical efficacy of seven new agents in clinical development or recently approved with either methicillin-resistant Staphylococcus aureus (MRSA) or pseudomonal activity are reviewed. They include doripenem, a new antipseudomonal carbapenem; ceftobiprole and ceftaroline, two anti-MRSA cephalosporins; iclaprim, a selective dihydrofolate reductase antagonist; and three glycopeptides, dalbavancin, telavancin, and oritavancin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Ceftaroline; Cephalosporins; Cross Infection; Doripenem; Glycopeptides; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pseudomonas Infections; Pyrimidines; Staphylococcal Infections; Teicoplanin

Ceftaroline is a broad-spectrum cephalosporin currently under clinical investigation for the treatment of complicated skin and skin-structure infections (cSSSI), including those caused by meticillin-resistant Staphylococcus aureus (MRSA), and community-acquired pneumonia (CAP). Ceftaroline has the ability to bind to penicillin-binding protein (PBP)2a, an MRSA-specific PBP that has low affinity for most other beta-lactam antibacterials. The high binding affinity of ceftaroline to PBP2a (median inhibitory concentration 0.90 microg/mL) correlates well with its low minimum inhibitory concentration for MRSA. Ceftaroline is active in vitro against Gram-positive cocci, including MRSA, meticillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococcus faecalis (not E. faecium). The broad-spectrum activity of ceftaroline includes many Gram-negative pathogens but does not extend to extended-spectrum beta-lactamase-producing or AmpC-derepressed Enterobacteriaceae or most nonfermentative Gram-negative bacilli. Ceftaroline demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. Limited data show that ceftaroline has a low propensity to select for resistant subpopulations. Ceftaroline fosamil (prodrug) is rapidly converted by plasma phosphatases to active ceftaroline. For multiple intravenous doses of 600 mg given over 1 h every 12 hours for 14 days, the maximum plasma concentration was 19.0 microg/mL and 21.0 microg/mL for first and last dose, respectively. Ceftaroline has a volume of distribution of 0.37 L/kg (28.3 L), low protein binding (<20%) and a serum half-life of 2.6 hours. No drug accumulation occurs with multiple doses and elimination occurs primarily through renal excretion (49.6%). Based on Monte Carlo simulations, dosage adjustment is recommended for patients with moderate renal impairment (creatinine clearance 30-50 mL/min); no adjustment is needed for mild renal impairment. Currently, limited clinical trial data are available for ceftaroline. A phase II study randomized 100 patients with cSSSI to intravenous ceftaroline 600 mg every 12 hours or intravenous vancomycin 1 g every 12 hours with or without intravenous aztreonam 1 g every 8 hours (standard therapy) for 7-14 days. Clinical cure rates were 96.7% for ceftaroline compared with 88.9% for standard therapy. Adverse events were similar between groups and generally mild in nature. I

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections

In bacterial and fungal infections, optimal outcomes are obtained through the timely provision of adequate antimicrobial coverage in an initial anti-infective treatment regimen. However, selecting appropriate antimicrobial regimens to treat infections in the intensive care unit is challenging because of the expansion of antibiotic resistance. Multidrug anti-infective regimens are typically needed to adequately cover common important pathogens in ICUs. Here, we describe novel antibacterial agents in the late stages of clinical development that show potential for treating methicillin-resistant Staphylococcus aureus (MRSA) infections. These include the fifth-generation cephalosporins, ceftaroline and ceftobiprole; the glycopeptides, dalbavancin, oritavancin, and telavancin; and iclaprim.

Topics: Aminoglycosides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Glycopeptides; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pyrimidines; Staphylococcal Infections; Teicoplanin

To develop the 'Stronger Towns Index': a deprivation index that took into account characteristics of areas encompassing towns that may be eligible for redevelopment funding and explore how this index was associated with self-rated health and migration within England between 2001 and 2011.. There were areas in the lowest deciles of Town Strength who did not receive funding. After multiple adjustment, LS members living in areas with higher deciles were significantly more likely (7% to 38%) to report good health than those in the lowest decile in 2001. Remaining in the same decile between 2001 and 2011 was associated with 7% lower odds of good self-rated health in 2011.. It is important to consider health in towns when allocating funding. Areas in the Midlands may have missed out on funding which might help mitigate poor health.. Ferritin levels <30µg/L were associated with unexplained infertility and might be screened in the future. Further studies with a focus on iron deficiency and iron treatment on women with unexplained infertility are warranted.. This EGM provides a valuable resource for researchers, policy-makers and the public to access the available evidence on the determinants of various COVID-19 health-related behaviours. The map can also be used to help guide research commissioning, by evidence synthesis teams and evidence intermediaries to inform policy during the ongoing pandemic and potential future outbreaks of COVID-19 or other respiratory infections. Evidence included in the map will be explored further through a series of systematic reviews examining the strength of the associations between malleable determinants and the uptake and maintenance of individual protective behaviours.. Patients with polymicrobial bloodstream infections are typically critically ill and harbor multidrug-resistant bacteria. Thus, to minimize mortality rate in critically ill patients, changes in infectious flora should be monitored, antibiotics selected reasonably, and invasive procedures reduced.. Altogether, these findings clearly revealed the great potential of the in vitro biological activity of linseed extract as a safe source for combatting multidrug-resistant. In this work, the capture of carbon dioxide using a dense hollow fiber membrane was studied experimentally and theoretically. The factors affecting the flux and recovery of carbon dioxide were studied using a lab-scale system. Experiments were conducted using a mixture of methane and carbon dioxide to simulate natural gas. The effect of changing the CO. Persistent gender and racial disparities in high-impact medical and critical care journals underscore the need to revise policies and strategies to encourage greater diversity in critical care research.. Thirty evaluable patients were enrolled. Median age was 60.5 years. Median follow-up for all patients was 17 months. Ten patients (33%) experienced grade ≥ 3 treatment-related adverse events, the most common being neutropenia and diarrhea; 50% required ≥ 1 dose reduction. The disease control rate was 90% (progressive disease: 10%, partial response: 23%, stable disease: 67%). There was zero treatment-related mortality. Twenty-two patients (73%, 90% CI 57-86; p = 0.008) completed all chemotherapy and surgery. Two patients (9%) who successfully underwent resection had minor postoperative complications. Median length of hospital stay was 4 days. Median RFS was 7.1 months. Median OS for the entire cohort was 24 months and was not reached in patients who underwent surgical resection.. Neoadjuvant treatment with gemcitabine, cisplatin, and nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes.

Topics: Acetogenins; Acute Disease; Acute Kidney Injury; Administration, Intravenous; Aged; Albumins; Alcoholism; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; alpha-Glucosidases; Anemia; Animals; Anthozoa; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bacterial; Antigens, Bacterial; Antihypertensive Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Ascites; Asthma; Bacteria; beta-Lactamases; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Binding Sites; Biological Availability; Biomass; Borderline Personality Disorder; Brain; Brucella abortus; Brucella melitensis; Brucellosis; Calcium; Carbapenems; Case-Control Studies; Caseins; Cattle; CD8-Positive T-Lymphocytes; Ceftaroline; Cell Line; Cell Line, Tumor; Cell Physiological Phenomena; Cell Proliferation; Cephalosporins; Chemotherapy, Adjuvant; China; Chitin; Chlorella; Chlorophyll; Chlorophyll A; Chlorophyta; Cholangiocarcinoma; Cisplatin; Conotoxins; Contrast Media; Conus Snail; Cross-Sectional Studies; Cytokines; Decapodiformes; Deoxycytidine; Diagnostic and Statistical Manual of Mental Disorders; Dietary Fiber; Diterpenes; DNA Methylation; Dogs; Double-Blind Method; Drug Design; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Screening Assays, Antitumor; Eicosapentaenoic Acid; Enzyme-Linked Immunosorbent Assay; Epidermis; Escherichia coli; Escherichia coli Infections; Extraintestinal Pathogenic Escherichia coli; Fatty Acids; Fatty Acids, Unsaturated; Fatty Acids, Volatile; Feasibility Studies; Feces; Female; Ferritins; Fluorodeoxyglucose F18; Gastrectomy; Gastrointestinal Microbiome; Gemcitabine; Glomerular Filtration Rate; Glucose; Glycerol; Granulocyte-Macrophage Colony-Stimulating Factor; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Immunoassay; Immunoglobulin G; India; Infant, Newborn; Infertility; Inflammation; Intensive Care Units; Iron; Iron Deficiencies; Kidney; Lacticaseibacillus rhamnosus; Laurencia; Leukocytes; Lipids; Liver Cirrhosis; Long Interspersed Nucleotide Elements; Longitudinal Studies; Male; Mesenchymal Stem Cells; Methicillin-Resistant Staphylococcus aureus; Mice; Microalgae; Microbial Sensitivity Tests; Microscopy; Middle Aged; Minerals; Molecular Conformation; Molecular Docking Simulation; Molecular Structure; Mycobacterium tuberculosis; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Nephropidae; Nicotinic Antagonists; Nitrogen; Obesity; Oxaliplatin; Paclitaxel; Panax; Pancreatic Neoplasms; Pancreatitis; Personality; Personality Disorders; Personality Inventory; Photobioreactors; Plant Extracts; Plasmalogens; Plasmids; Polymorphism, Genetic; Polynesia; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Prebiotics; Predictive Value of Tests; Prognosis; Prolyl-Hydroxylase Inhibitors; Rabbits; Radiopharmaceuticals; Rats; Rats, Wistar; Receptors, Nicotinic; Recombinant Proteins; Retrospective Studies; Rifampin; Risk Factors; RNA, Ribosomal, 16S; Salinity; Seaweed; Sensitivity and Specificity; Sepsis; Sesquiterpenes; Severity of Illness Index; Shock, Septic; Silicones; Single Photon Emission Computed Tomography Computed Tomography; Skin; Snails; Solubility; Solvents; Sputum; Staphylococcal Infections; Stomach Neoplasms; Stramenopiles; Structure-Activity Relationship; Technetium Tc 99m Exametazime; Technology; Terpenes; Tuberculosis; Tuberculosis, Multidrug-Resistant; Urinary Catheters; Urinary Tract Infections; Vascular Endothelial Growth Factor A; Virulence Factors; Water; Wound Healing

The recommended adult dose of ceftaroline fosamil is 600 mg q12h by 1 h intravenous (iv) infusion for 5-14 days in complicated skin and soft tissue infection (cSSTI) and 5-7 days in community-acquired pneumonia (CAP). A dosage of 600 mg q8h by 2 h iv infusion is approved in some regions for cSSTI patients with Staphylococcus aureus infection where the ceftaroline MIC is 2 or 4 mg/L. This analysis compares the safety profiles of the q8h and q12h regimens.. Safety data from six Phase III, randomized, double-blind clinical trials were collated into the q8h cSSTI pool (ceftaroline fosamil n = 506; NCT01499277) and the q12h pool {ceftaroline fosamil n = 1686; comprising five studies [two cSSTI (NCT00424190 and NCT00423657) and three CAP (NCT01371838, NCT00621504 and NCT00509106)]}.. The pattern and incidence of adverse events were similar between the q8h and q12h ceftaroline fosamil pools. Most were gastrointestinal and of mild or moderate intensity. Overall, rash intensity was similar between the q8h pool and the q12h pool. For the q8h regimen, there was a higher frequency of rash in some Asian study sites, associated with longer duration of therapy (≥7 days); most cases were mild and resolved following treatment discontinuation. No dose-related vital sign or ECG abnormalities were detected with either regimen.. The q8h regimen in cSSTI was generally well tolerated; the observed safety profile was consistent with the known safety profile of ceftaroline fosamil, reflective of the cephalosporin class and qualitatively consistent with the q12h regimen.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Administration Schedule; Female; Humans; Male; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a common cause of complicated skin and skin structure infections (cSSSIs). Increasing antibiotic resistance and significant morbidity in cSSSIs have led to a need for new effective and safe therapies. Ceftaroline fosamil, a novel parenteral cephalosporin with excellent in vitro activity against Gram-positive pathogens, including MRSA, and many Gram-negative pathogens, was evaluated as therapy for cSSSIs in a large multicentre study. The primary study objective was to determine non-inferiority [lower limit of 95% confidence interval (CI), -10%] in the clinical cure rate achieved with ceftaroline fosamil monotherapy compared with that achieved with vancomycin plus aztreonam in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations.. Adult patients with cSSSIs requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5-14 days (randomized 1 : 1). Clinical and microbiological response, adverse events (AEs) and laboratory tests were assessed. Registration number NCT00424190 (http://clinicaltrials.gov/ct2/show/NCT00424190).. Of 702 enrolled patients, 353 received ceftaroline fosamil and 349 received vancomycin plus aztreonam. Baseline characteristics of treatment groups were comparable. Clinical cure rates were similar for ceftaroline fosamil and vancomycin plus aztreonam in the CE (91.1%, 288/316 versus 93.3%, 280/300; 95% CI, -6.6, 2.1) and MITT (86.6%, 304/351 versus 85.6%, 297/347; 95% CI, -4.2, 6.2) populations, respectively. The clinical cure rate for MRSA cSSSIs was 95.1% (78/82) for ceftaroline fosamil and 95.2% (59/62) for vancomycin plus aztreonam. The microbiological success rate was also similar for ceftaroline fosamil and vancomycin overall, and for MRSA. The rates of AEs, serious AEs, deaths and discontinuations because of an AE were similar for ceftaroline fosamil and vancomycin plus aztreonam. The most common AEs for ceftaroline fosamil and vancomycin plus aztreonam were diarrhoea (3.4% versus 3.2%), nausea (5.7% versus 4.6%), headache (5.1% versus 3.7%) and pruritus (3.1% versus 8.4%), respectively.. Ceftaroline fosamil achieved high clinical cure and microbiological success rates, was efficacious for cSSSIs caused by MRSA and other common cSSSI pathogens and was generally well tolerated. Ceftaroline fosamil has the potential to provide a monotherapy alternative for treatment of cSSSIs.

Topics: Adult; Aged; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Double-Blind Method; Drug Therapy, Combination; Humans; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Treatment Outcome; Vancomycin; Young Adult

New therapies for complicated skin and skin structure infections (cSSSIs) are needed because of significant morbidity and increasing antimicrobial resistance. Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of cSSSIs. Ceftaroline fosamil, a novel parenteral cephalosporin with excellent in vitro activity against Gram-positive pathogens, including MRSA, and many Gram-negative pathogens, was evaluated as therapy for cSSSIs in a multinational Phase III study. The primary study objective was to determine non-inferiority [lower limit of 95% confidence interval (CI), -10%] in the clinical cure rate of ceftaroline fosamil monotherapy to that achieved with vancomycin plus aztreonam combination therapy in the clinically evaluable (CE) and modified intent-to-treat (MITT) analysis populations.. Adult patients with cSSSIs requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5-14 days (randomized 1 : 1). Clinical and microbiological response, adverse events (AEs) and laboratory tests were assessed. Registration number NCT00423657 (http://clinicaltrials.gov/ct2/show/NCT00423657).. The study enrolled 694 patients, 348 of whom received ceftaroline fosamil and 346 of whom received vancomycin plus aztreonam. The treatment groups had comparable baseline characteristics. Clinical cure rates for the ceftaroline fosamil and vancomycin plus aztreonam groups were similar in the CE (92.2%, 271/294 versus 92.1%, 269/292; 95% CI, -4.4, 4.5) and MITT (85.1%, 291/342 versus 85.5%, 289/338; 95% CI, -5.8, 5.0) populations, respectively. MRSA cSSSIs were cured in 91.4% (64/70) of patients in the ceftaroline fosamil group and 93.3% (56/60) of patients in the vancomycin plus aztreonam group. The microbiological success rate in the microbiologically evaluable population was 92.9% and 95.0% for ceftaroline fosamil and vancomycin plus aztreonam, respectively. Ceftaroline fosamil and vancomycin plus aztreonam had similar rates of AEs, serious AEs and discontinuations because of an AE. The most common AEs for ceftaroline fosamil and vancomycin plus aztreonam included diarrhoea (6.5% versus 4.4%), nausea (6.2% versus 5.6%), headache (5.3% versus 5.3%) and pruritus (3.8% versus 8.3%), respectively.. Ceftaroline fosamil demonstrated high clinical cure and microbiological success rates, was efficacious against cSSSIs caused by MRSA and other common cSSSI pathogens and was generally well tolerated. Monotherapy with ceftaroline fosamil has the potential to provide an alternative treatment for cSSSIs.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Double-Blind Method; Drug Therapy, Combination; Humans; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Treatment Outcome; Vancomycin; Young Adult

Treatment of complicated skin and skin structure infections (cSSSIs) requires therapy that is effective against a range of Gram-positive and Gram-negative bacteria, including resistant pathogens such as methicillin-resistant Staphylococcus aureus. Equally important is the need to provide therapy that is safe and well tolerated. Ceftaroline fosamil is a new-generation, parenteral cephalosporin that was developed for the treatment of moderate to severe bacterial infections, including cSSSIs. This report provides an integrated safety summary of the CeftAroliNe Versus VAncomycin in Skin and Skin Structure Infections (CANVAS) 1 and 2 studies (registration numbers NCT00424190 and NCT00423657).. Adult patients with cSSSIs requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5-14 days (randomized 1 : 1). All patients were followed for treatment-emergent adverse events (TEAEs) occurring from the start of the initial study drug infusion up to the test-of-cure visit, ∼1 week following the last dose of study medication; serious adverse events (SAEs) that occurred within 30 days after the last dose were recorded.. A total of 1378 patients received any amount of study drug and were included in the safety analysis. The percentage of patients with an SAE was similar between the ceftaroline fosamil and the vancomycin plus aztreonam groups (4.3% versus 4.1%). The majority of patients (>75%) had either no or mild TEAEs and the distribution of TEAEs based on severity was comparable between the groups. The most commonly reported TEAEs in patients treated with ceftaroline fosamil included nausea (5.9%), headache (5.2%), diarrhoea (4.9%) and pruritus (3.5%).. Ceftaroline fosamil was well tolerated and did not result in any unexpected safety concerns. The data from the CANVAS trials suggest that ceftaroline fosamil has the expected safety and tolerability profile common to the cephalosporin class.

Topics: Adult; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Double-Blind Method; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Treatment Outcome; Vancomycin

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Hospitals; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; United States

The preferred antibiotic salvage regimen for persistent methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) is unclear. We sought to evaluate the effectiveness and safety of vancomycin plus ceftaroline for persistent MRSAB. The primary outcome was time to MRSAB clearance post-ceftaroline initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90-day readmission for MRSAB, 90-day all-cause mortality, MRSAB-related mortality, and incidence of antibiotic-associated adverse effects.. Single-center, retrospective cohort study between January 1, 2016, and December 31, 2021.. State University of New York Upstate University Hospital, a 748-bed tertiary care, academic medical center in Syracuse, NY.. Adult patients were included if they had blood cultures positive for MRSA ≥72 h, received vancomycin monotherapy initially, and received vancomycin plus ceftaroline for ≥24 h. Patients were excluded if they received other anti-MRSA antibiotics, were pregnant, or were incarcerated. Of the 178 patients identified, 30 unique patients were evaluated.. Patients were medically complex with a median Pitt bacteremia score of 3, 63.3% (19/30) were admitted to the intensive care unit, and 66.7% (20/30) had infective endocarditis. Vancomycin-associated acute kidney injury was observed in 10% (3/30) of patients, which resulted in dose adjustments. No patients experienced ceftaroline-associated neutropenia or Clostridioides difficile infection, but 6.7% (2/30) developed a rash attributed to ceftaroline. Median time to MRSAB clearance post-ceftaroline initiation was 2.6 days. Microbiologic cure occurred in nearly all patients 96.7% (29/30). Median hospital length of stay was 19.5 days, and 6.7% (2/30) of patients had 90-day readmission for MRSAB. 90-day all-cause mortality and MRSAB-related mortality occurred in 26.7% (8/30) and 13.3% (4/30) of patients, respectively.. Vancomycin plus ceftaroline may represent an effective and well-tolerated salvage regimen option for persistent MRSAB.

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Retrospective Studies; Staphylococcal Infections; Vancomycin

New strategies are urgently needed to address the public health threat of antimicrobial resistance. Synergistic agent combinations provide one possible pathway toward addressing this need and are also of fundamental mechanistic interest. Effective methods for comprehensively identifying synergistic agent combinations are required for such efforts. In this study, an FDA-approved drug library was screened against methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) in the absence and presence of sub-MIC levels of ceftobiprole, a PBP2a-targeted anti-MRSA β-lactam. This screening identified numerous potential synergistic agent combinations, which were then confirmed and characterized for synergy using checkerboard analyses. The initial group of synergistic agents (sum of the minimum fractional inhibitory concentration ∑FIC

Topics: Anti-Bacterial Agents; beta-Lactams; Ceftaroline; Cloxacillin; Floxacillin; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections

This study aimed to evaluate both efficacy and safety of combination therapy with daptomycin plus ceftaroline (DAP/CPT) versus alternative therapy in the treatment of persistent methicillin-resistant Staphylococcus aureus bacteraemia (MRSAB).. This retrospective, single-centre study investigated adult patients who underwent a change in antibiotic therapy for persistent MRSAB. Daptomycin plus ceftaroline was compared with alternative therapy after initial treatment with vancomycin or DAP monotherapy was modified. The primary outcome was in-hospital mortality, and several secondary efficacy and safety outcomes were evaluated.. A total of 68 patients with persistent MRSAB had initial therapy switched to DAP/CPT (n = 43) or alternative therapy (n = 25). In-hospital mortality was similar with DAP/CPT versus alternative therapy (16.3% vs. 16%; P = 1.0). On average, the total duration of bacteraemia was numerically 1 day less in patients switched to DAP/CPT (11.4 days vs. 12.5 days; P = 0.5). Daptomycin plus ceftaroline was de-escalated in 81% of patients after receiving combination therapy for an average of 12.5 days. Secondary outcomes, including rates of adverse events and emergence of antimicrobial resistance, were similar between the two groups.. Switching to DAP/CPT after approximately 1 week of persistent MRSA bacteraemia may result in similar clinical outcomes when compared with alternative therapy. Rates of adverse events and emergence of antimicrobial resistance were low without a statistically significant difference observed between DAP/CPT and alternative therapy. These findings, as well as the impact of earlier switch or prolonged treatment with the combination, require further investigation.

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Daptomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus

Methicillin-resistant Staphylococcus epidermidis (MRSE) endocarditis failing conventional therapy has been successfully treated with nafcillin plus daptomycin in the clinic. In vitro studies showed that nafcillin enhanced daptomycin killing of MRSE in both planktonic cells and biofilm. Nafcillin exposure also sensitized MRSE to killing by human neutrophils and cathelicidin antimicrobial peptide LL-37. Fluorescent microscopy showed increased daptomycin and LL-37 binding to the MRSE bacterial surface upon nafcillin treatment. Ceftaroline also increased MRSE killing by daptomycin in planktonic cultures and biofilms, as well as daptomycin and LL-37 binding on the bacterial surface. Nafcillin, ceftaroline, and possibly other β-lactams, may serve an important role in the therapy of MRSE endocarditis through augmentation of cationic peptide, the innate immune system, and daptomycin killing. Clinical studies will be needed to determine how early these regimens should be deployed to optimize clinical outcome.

Topics: Anti-Bacterial Agents; Cathelicidins; Ceftaroline; Daptomycin; Endocarditis; Humans; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Nafcillin; Staphylococcal Infections; Staphylococcus epidermidis

The combination of daptomycin and ceftaroline used as salvage therapy is associated with higher survival and decreased clinical failure in complicated methicillin-resistant Staphylococcus aureus (MRSA) infections that are resistant to standard MRSA treatment. This study aimed to evaluate dosing regimens for coadministration of daptomycin and ceftaroline in special populations including paediatrics, renally impaired (RI), obese and geriatrics that generate sufficient coverage against daptomycin-resistant MRSA.. Physiologically based pharmacokinetic models were developed from pharmacokinetic studies of healthy adults, geriatric, paediatric, obese and RI patients. The predicted profiles were used to evaluate joint probability of target attainment (PTA), as well as tissue-to-plasma ratios.. The adult dosing regimens of 6 mg/kg every (q)24h or q48h daptomycin and 300-600 mg q12h ceftaroline fosamil by RI categories achieved ≥90% joint PTA when the minimum inhibitory concentrations in the combination are at or below 1 and 4 μg/mL against MRSA. In paediatrics, wherein there is no recommended daptomycin dosing regimen for S. aureus bacteraemia, ≥90% joint PTA is achieved when the minimum inhibitory concentrations in the combination are up to 0.5 and 2 μg/mL for standard paediatric dosing regimens of 7 mg/kg q24h daptomycin and 12 mg/kg q8h ceftaroline fosamil. Model predicted tissue-to-plasma ratios of 0.3 and 0.7 in the skin and lung, respectively, for ceftaroline and 0.8 in the skin for daptomycin.. Our work illustrates how physiologically based pharmacokinetic modelling can inform appropriate dosing of adult and paediatric patients and thereby enable prediction of target attainment in the patients during multitherapies.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Child; Daptomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections

Treatment of late-onset neonatal staphylococcal sepsis is sometimes challenging with feared side effects of vancomycin, increasing minimal inhibitory concentrations and questions about catheter management. In case of failure, ceftaroline was administered as a compassionate treatment in 16 infants (gestational age of less than 32 weeks and less than 28 postnatal days), whose first-line treatment failed. We report 11 successes and no severe adverse drug reactions. Larger data are required to confirm these encouraging results.

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Humans; Infant; Infant, Newborn; Neonatal Sepsis; Sepsis; Staphylococcal Infections; Vancomycin

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Communicable Diseases; Daptomycin; Humans; Pharmacists; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus

The purpose of this study is to evaluate the in-hospital mortality of community-acquired pneumonia (CAP) treated with ceftaroline in comparison with standard therapy. This was a retrospective observational study in two centers. Hospitalized patients with CAP were grouped according to the empiric regimen (ceftaroline versus standard therapy) and analyzed using a propensity score matching (PSM) method to reduce confounding factors. Out of the 6981 patients enrolled, 5640 met the inclusion criteria, and 89 of these received ceftaroline. After PSM, 78 patients were considered in the ceftaroline group (cases) and 78 in the standard group (controls). Ceftaroline was mainly prescribed in cases with severe pneumonia (67% vs. 56%, p = 0.215) with high suspicion of Staphylococcus aureus infection (9% vs. 0%, p = 0.026). Cases had a longer length of hospital stay (13 days vs. 10 days, p = 0.007), while an increased risk of in-hospital mortality was observed in the control group compared to the case group (13% vs. 21%, HR 0.41; 95% CI 0.18 to 0.62, p = 0.003). The empiric use of ceftaroline in hospitalized patients with severe CAP was associated with a decreased risk of in-hospital mortality.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Female; Hospital Mortality; Humans; Male; Middle Aged; Retrospective Studies; Standard of Care; Staphylococcal Infections

Vancomycin remains a first-line treatment for methicillin-resistant Staphylococcus aureus (MRSA)-mediated acute pulmonary exacerbations (APEs) in adult cystic fibrosis (CF) patients; however, optimal alternatives remain poorly defined. The aim of this study was to determine the safety and efficacy of ceftaroline for MRSA-mediated APEs of CF in adults.. We conducted a retrospective, observational cohort study comparing ceftaroline with vancomycin for the treatment of MRSA-mediated APEs in adult CF patients. The primary endpoint was the return to at least 90% of baseline lung function measured by discharge FEV. A total of 55 patients were included in the analysis (22 receiving ceftaroline and 33 receiving vancomycin). Of the patients included in the analysis, 13 patients (59%) in the ceftaroline group and 24 patients (73%) in the vancomycin group met the primary outcome (P = 0.38). FEV. Our small cohort study supports ceftaroline as an alternative treatment option for MRSA-mediated APE of CF in adults.

Topics: Adult; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Cohort Studies; Cystic Fibrosis; Humans; Lung; Methicillin-Resistant Staphylococcus aureus; Retrospective Studies; Staphylococcal Infections; Vancomycin

We aimed to determine the synergistic effects of ceftaroline (CPT) in combination with daptomycin (DAP), vancomycin (VAN), or linezolid (LNZ) against various methicillin-resistant Staphylococcus aureus (MRSA) strains.. MRSA strains randomly selected from 2014 to 2018 were studied. Checkerboard titration and in vitro time-kill analyses were used to determine the synergistic activities of the antibiotic combinations.. A total of 10 genetically distinct MRSA strains were included in this study. The checkerboard titration analysis revealed that the CPT-DAP, CPT-VAN, and CPT-LNZ combinations had a synergistic effect against 30%, 10%, and 10% of the selected MRSA strains, respectively. Using time-kill analysis, we showed that CPT-DAP exhibited a significant synergistic and sustained bactericidal effect against both DAP-susceptible (Δ colony-forming units/ml, -5.79; P = 0.0495) and DAP-resistant (Δ colony-forming units/ml, -6.40; P = 0.0463) MRSA strains at a concentration of 0.5 × the minimum inhibitory concentration of CPT plus 0.5 × the minimum inhibitory concentration of DAP. No synergistic bactericidal effects were observed for the CPT-VAN and CPT-LNZ combinations against the selected strains.. The CPT-DAP combination showed better synergistic activity than the CPT-VAN and CPT-LNZ combinations against the enrolled MRSA strains. DAP, rather than VAN or LNZ, might be a better choice for CPT combination in the treatment of MRSA infections.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Hospitals; Humans; Linezolid; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus epidermidis

Ceftaroline represents an attractive therapy option for methicillin-resistant Staphylococcus aureus (MRSA). Little data is available, however, regarding the frequency of reduced susceptibility (RS) to ceftaroline among pediatric MRSA infections. We screened invasive MRSA isolates at a tertiary children's hospital for ceftaroline RS. Ceftaroline RS occurred in 2.9% of isolates and only among health care associated infections. Ceftaroline RS isolates were more often clindamycin-resistant. Sequencing data indicated the predominance of the CC5 lineage among ceftaroline RS isolates.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Clindamycin; Genomics; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections

Infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) are still associated with significant morbidity and mortality. Treatment failures of cefazolin (CFZ) have been reported and probably related to the inoculum effect. New treatments for severe MSSA infections are needed and ceftaroline fosamil (CPT) could be an option. Our aim was to describe the clinical characteristics of five patients with complicated MSSA bacteremia failing CFZ and successfully treated with CPT. We performed a retrospective chart review in a Hospital in Buenos Aires, Argentina; in a 12-month period, five patients (24%) of 21 with MSSA bacteremia experienced CFZ failure and were salvaged with CPT. The median time of CFZ therapy was 10 days before changing to CPT; four patients had evidence of metastatic spread and 2 had endocarditis. All patients experienced microbiological and clinical cure with CPT, which was used as monotherapy in 4 and in combination with daptomycin in another. One patient discontinued CPT due to neutropenia on day 23 of treatment. In patients with MSSA BSI failing current therapy, CPT could be a good therapeutic option.. Las infecciones causadas por Staphylococcus aureus sensible a la meticilina (SASM) todavía se asocian con una morbilidad y mortalidad significativas. Se han informado fallas en el tratamiento de cefazolina (CFZ) probablemente relacionadas con efecto inóculo. Nuevos tratamientos son necesarios para estas infecciones y ceftarolina fosamil (CPT) podría ser una opción. Nuestro objetivo fue describir las características clínicas de cinco pacientes con bacteriemia por SASM complicada con falla a CFZ y que fueron exitosamente tratados con CPT. Realizamos una revisión retrospectiva de historias clínicas en un hospital de Buenos Aires, Argentina; en un período de 12 meses, cinco pacientes (24%) de 21 con bacteriemia por SASM experimentaron falla a CFZ y fueron tratados con CPT. La mediana de tiempo de la terapia con CFZ fue de 10 días antes de cambiar a CPT; cuatro pacientes presentaban evidencia de diseminación metastásica y 2 tenían endocarditis. Todos los pacientes experimentaron curación microbiológica y clínica con CPT, que se utilizó como monoterapia en 4 y en combinación con daptomicina en otro. Un paciente interrumpió CPT debido a neutropenia el día 23 de tratamiento. En enfermos con infecciones graves por SASM que fallan en la terapia actual, CPT podría ser una buena opción terapéutica.

Topics: Anti-Bacterial Agents; Bacteremia; Cefazolin; Ceftaroline; Cephalosporins; Daptomycin; Humans; Methicillin; Retrospective Studies; Salvage Therapy; Staphylococcal Infections; Staphylococcus aureus

To evaluate the activity of fosfomycin against a group of MRSA strains, including isolates with reduced susceptibility or resistance to vancomycin, daptomycin, linezolid and ceftaroline and to determine the effect of combining various combinations of antimicrobial agents used in the therapy of serious Gram-positive infections.. Broth microdilution testing was used to determine the MICs of fosfomycin, vancomycin, daptomycin, linezolid, ceftaroline and cefazolin. Isolates were selected for further evaluations to determine in vitro synergy between fosfomycin and select antimicrobial agents using chequerboard broth microdilution testing. Fosfomycin was tested in combination with vancomycin, linezolid, daptomycin, ceftaroline and cefazolin.. Fosfomycin maintained activity against 100% of strains of vancomycin-resistant Staphylococcus aureus (VRSA) and linezolid-resistant S. aureus (LRSA), 86% of VISA and 95% of daptomycin-resistant S. aureus (DRSA) strains. The combination of fosfomycin with ceftaroline consistently demonstrated synergy among all 18 isolates against the strains tested. The next most potent combination regimen was linezolid with fosfomycin, which demonstrated synergy in 16 of the 18 strains. Daptomycin demonstrated synergy in only 7 of the 18 strains tested when combined with fosfomycin. Cefazolin demonstrated synergy in 6 of 6 strains and vancomycin demonstrated no interaction in 6 of 6 strains tested.. Fosfomycin demonstrated excellent activity against MRSA as well as isolates with resistance or reduced activity to other anti-MRSA drugs including vancomycin, daptomycin and linezolid. When combined with linezolid or daptomycin, fosfomycin demonstrated synergy for all or most strains tested. Thus, these combinations may have potential clinical utility when treating patients with serious infections caused by MRSA.

Topics: Anti-Bacterial Agents; Cefazolin; Ceftaroline; Daptomycin; Fosfomycin; Humans; Linezolid; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Our objective is to report a paediatric case of high-level ceftaroline resistance without previous ceftaroline exposure.. A 20-month-old, 12 kg, female with invasive MRSA infection presented with high-level ceftaroline resistance with no previous ceftaroline exposure.. To our knowledge, our case is the first report of high-level ceftaroline resistance evident in a paediatric patient with invasive infection due to MRSA, without history of prior ceftaroline exposure. This case illustrates the importance of weighing the risk of resistance with the benefits of use when starting therapy empirically prior to susceptibility results, even in patients without previous drug exposure.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Infant; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin

Complicated methicillin-resistant Staphylococcus aureus bloodstream infections (MRSA-BSIs), particularly those with delayed culture clearance, are associated with high mortality. Combination therapy with daptomycin and ceftaroline (DAP+CPT) represents a novel therapeutic approach to MRSA-BSI owing to synergistic bactericidal activity. This study aimed to compare DAP+CPT with historical standard of care (SoC) for treatment of complicated MRSA-BSI. This single-centre retrospective cohort study included patients with complicated MRSA-BSI at University of Colorado Hospital. Patients receiving DAP+CPT for ≥48 h between November 2013 and March 2020 or SoC with vancomycin or DAP ± gentamicin and/or rifampicin from November 2011 to December 2013 were compared. The primary outcome was clinical failure defined as a composite of MRSA-related mortality and recurrent infection at 60 days. A total of 60 patients received DAP+CPT (n = 30) or SoC (n = 30). Median age was 56 years and median Pitt bacteremia score was 3. Common infectious sites were endovascular (63%) and musculoskeletal (40%). DAP+CPT was associated with a numerically lower incidence of clinical failure compared with SoC (20% vs. 43%; P = 0.052). Multivariable analysis controlling for immunocompromised status (OR, 6.90, 95% CI 1.08-44.15), Charlson comorbidity index (OR, 1.12, 95% CI 0.90-1.39) and source control (OR, 0.35, 95% CI 0.08-1.46) associated DAP+CPT with 77% lower odds of clinical failure (OR, 0.23, 95% CI 0.06-0.89). In patients with complicated MRSA-BSI with delayed clearance, DAP+CPT trended towards lower rates of clinical failure than SoC and was significantly associated with decreased clinical failure after adjustment for baseline differences.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Daptomycin; Drug Synergism; Drug Therapy, Combination; Female; Gentamicins; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Rifampin; Salvage Therapy; Standard of Care; Staphylococcal Infections; Treatment Outcome; Vancomycin

Ceftaroline is a novel cephalosporin able to bind to and inhibit PBP2a, and thus active against methicillin-resistant Staphylococcus aureus. In the present study we assessed the in vitro activity of ceftaroline and comparators against a large sample of methicillin-resistant and methicillin-susceptible S. aureus isolates collected at our hospital. Overall, both MRSA and MSSA isolates in our study were sensitive to ceftaroline, even though the MIC range was higher for MRSAs (0.12-2 mg/L against ≤0.06-0.5 mg/L for MSSAs). Our results indicate that ceftaroline may be considered a reliable alternative for the treatment of MRSA.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Greece; Humans; Methicillin; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Tertiary Care Centers

Topics: Anti-Bacterial Agents; Bacteremia; Bacterial Typing Techniques; Ceftaroline; Cephalosporins; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Gene Expression; Genes, Bacterial; Humans; Linezolid; Methicillin; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Phylogeny; Rifampin; Staphylococcal Infections; Tetracycline; Turkey; Vancomycin; Vancomycin Resistance; Virginiamycin

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; United States

Ventriculostomy-related infection with multidrug-negative strains are challenging to treat. We report the use of new antibiotics in such a case.. We report the case of a neurosurgical intensive care unit patient who developed ventriculostomy-related infection with a multidrug-resistant Staphylococcus epidermidis. Vancomycin, recommended in such cases, was not used due to high minimal inhibitory concentrations and concerns for lack of pharmacokinetic/pharmacodynamic target attainment. Daptomycin and ceftaroline remained the only treatment options. Daptomycin was shown microbiologically ineffective after 10 treatment days, with undetectable cerebrospinal fluid (CSF) concentration. Ceftaroline, a novel beta-lactam agent to which the strain showed susceptibility, was thus used. Serum and CSF samples were assessed for antibiotic concentrations. Our results show that CSF bacterial clearance was obtained after 6 days of such treatment. Serum and CSF samplings showed low penetration ratios (2.6%-4.8%), probably due to mild inflammatory CSF profile, with CSF concentration at minimal inhibitory concentration level.. We observed than even in the case of mild meningeal inflammation, ceftaroline penetration in CSF, although moderate, enabled efficient bacterial clearance and clinical efficacy, in adjunction to correct ventriculoperitoneal shunt management.

Topics: Administration, Intravenous; Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Multiple, Bacterial; Female; Humans; Retreatment; Staphylococcal Infections; Staphylococcus epidermidis; Surgical Wound Infection; Ventriculostomy

Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC.. Steady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI.. Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively.. Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

Topics: Anti-Bacterial Agents; Bacteremia; Brazil; Ceftaroline; Cephalosporins; Daptomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Monte Carlo Method; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Ceftaroline is one of latest additions to the armamentarium for treating community-acquired pneumonia (CAP). This study aimed to describe the outcome of severe CAP (SCAP) in a cohort of hospitalised patients treated with ceftaroline.. A retrospective, observational study of patients with SCAP treated with ceftaroline in two hospitals in Spain and Italy. The primary objective was to explore 30-day mortality after diagnosis of SCAP.. During the study period the following were observed: there were 89 cases of SCAP treated with ceftaroline and 53 cases used in combination with other antibiotics (60%). Overall, 30-day mortality and clinical failure were 20% (18 of 89) and 36% (32 of 89), respectively. Independent predictors of 30-day mortality were: increasing age (OR for 1 year increase 1.0, 95% CI 1.0-1.1, P 0.043), presence of solid neoplasm (OR 4.0, 95% CI 1.0-15.1, P 0.044) and concomitant therapy with oseltamivir (OR 8.5, 95% CI 1.2°57.3, P 0.029). The only independent predictor of clinical failure was the time elapsing from SCAP diagnosis to ceftaroline therapy (OR for each passing day 1.5, 95% CI 1.1-1.9, P 0.003). The clinical success rate was 64% (57 of 89). In the subgroups of patients with proven Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) infection, clinical success was 83% (10 of 12), 75% (three of four) and 56% (five of nine), respectively.. Considering its spectrum of activity, ceftaroline could represent an important therapeutic option for SCAP. Further studies are needed to identify the precise clinical success rate against MRSA in a larger cohort of patients with SCAP.

Topics: Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Female; Humans; Italy; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Oseltamivir; Pneumococcal Infections; Pneumonia; Retrospective Studies; Spain; Staphylococcal Infections; Streptococcus pneumoniae

The aim of this study was to compare the antibacterial activity of ceftaroline versus vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) meningitis in an experimental rabbit meningitis model.. The antibacterial activity of ceftaroline was compared with vancomycin in the treatment of meningitis induced by MRSA strain ATCC 43300 in an experimental rabbit meningitis model. Quantitative cerebrospinal fluid (CSF) cultures were performed at the beginning of antibiotic treatment and 24h and 73h after the first antibiotic dose. Furthermore, in vitro time-kill data were investigated at 0, 2, 4, 6, 8, 12 and 24h in sterile human serum.. The difference between the control group versus both treatment groups was significant when comparing the decrease in colony counts in CSF both at 24h and 73h after the first antibiotic dose (P<0.05). At the end of the experiment, there was a significant difference in survival between both the ceftaroline-treated group and the vancomycin-treated group versus the control group, but not between the two treatment groups.. These results suggest that the antibacterial activity of both ceftaroline and vancomycin are similar in the treatment of MRSA meningitis in an experimental rabbit meningitis model.

Topics: Animals; Ceftaroline; Cephalosporins; Meningitis; Methicillin-Resistant Staphylococcus aureus; Rabbits; Staphylococcal Infections; Vancomycin

We characterised 80 Staphylococcus aureus strains isolated from human patients with SSTIs at a rural hospital in Ethiopia. Susceptibility to antibiotic of all strains was tested. The MLST method was used to type and a phylogenetic analysis was conducted employing the sequences of 7 housekeeping genes. PCR amplification was used to investigate the presence of the following virulence genes in all strains: hla (α-haemolysin), tstH (toxic shock syndrome toxin), luk PV (Panton-Valentine leukocidin), fnbA (fibronectin binding protein A) and mecA (methicillin resistance). Most of the strains were resistant to penicillin and ampicillin, but only 3 strains were resistant to oxacillin, and 1 of them was a true MRSA. The MLST results showed a high diversity of sequence types (ST), 55% of which were new, and ST152 was the most prevalent. A phylogeny study showed that many of the new STs were phylogenetically related to other previously described STs, but bore little relationship to the only ST from Ethiopia described in the database. Virulence gene detection showed a high prevalence of strains encoding the hla, fnbA and pvl genes (98.77%, 96.3% and 72.84%, respectively), a low prevalence of the tst gene (13.58%) and a markedly low prevalence of MRSA (1.25%). S. aureus strains isolated from patients in a rural area in Ethiopia showed low levels of antibiotic resistance, except to penicillin. Moreover, this study reveals new STs in Eastern Africa that are phylogenetically related to other previously described STs, and confirm the high prevalence of the pvl gene and the low prevalence of MRSA on the continent.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bacterial Toxins; Ceftaroline; Cephalosporins; Drug Resistance, Bacterial; Ethiopia; Exotoxins; Hospitals, Rural; Humans; Leukocidins; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Multilocus Sequence Typing; Penicillins; Phylogeny; Staphylococcal Infections; Staphylococcus aureus; Virulence

The use of daptomycin (DAP) in septic pulmonary emboli (SPE) remains controversial. We analyzed 29 cases of MRSA bacteremia complicated by SPE treated with DAP (n = 14) or DAP-ceftaroline fosamil (CPT; n = 15). Initial treatment with DAP monotherapy was found to have a success rate comparable with DAP-CPT (71% vs. 80%; p = 0.68).

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Cohort Studies; Daptomycin; Drug Therapy, Combination; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Staphylococcal Infections; Treatment Outcome

Respiratory infection with methicillin-resistant Staphylococcus aureus (MRSA) is an increasing complication in cystic fibrosis (CF) that results in accelerated lung function decline and mortality. Vancomycin is considered a first-line intravenous treatment agent for MRSA associated acute pulmonary exacerbations (APEs); however, rates of vancomycin intolerance and resistance have been observed. These factors have led to the exploration of additional treatment options for treating MRSA associated APEs.. This is a retrospective chart review conducted at a CF center including patients 0 to 21 years of age with CF admitted for an APE and treated with either vancomycin or ceftaroline between January 2016 and August 2018. The primary endpoint was to determine ceftaroline efficacy compared to vancomycin in the treatment of MRSA associated APEs.. There were 180 patients included in the study with 90 patients in each antibiotic group. Admission to discharge forced expiratory volume in 1 second (FEV. In this retrospective study, no difference existed between ceftaroline and vancomycin with regard to observed improvement in lung function from admission to discharge. Additionally, no difference was observed in mean FEV

Topics: Administration, Intravenous; Adolescent; Adult; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Child, Preschool; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Infant; Infant, Newborn; Male; Methicillin-Resistant Staphylococcus aureus; Retrospective Studies; Staphylococcal Infections; Vancomycin; Young Adult

Ceftaroline fosamil has been approved by the US Food and Drug Administration for the treatment of skin and soft tissue infections, including those caused by methicillin-resistant Staphylococcus aureus and community-acquired bacterial pneumonia. We evaluated the in-vitro activity of not-in-use ceftaroline against clinical isolates of methicillin- resistant (MRSA) and methicillin-susceptible (MSSA) S. aureus isolates. A total of 453 single-patient S. aureus isolates were tested for susceptibility to ceftaroline. The minimum inhibitory concentration (MIC) was determined using the MIC Evaluator. Disk diffusion test was performed using 30 μg ceftaroline disk according to the Clinical Laboratory Standards Institute criteria. In total, 410 (90.5%) of the 453 strains were susceptible to ceftaroline at MIC of 1 mg/L while 9.8% isolates had MIC of 2-3 mg/L. Among the MSSA, 92.5% of the isolates were susceptible with MIC: 1 mg/L while 36 (7.9%) strains expressed intermediate resistance (MIC range of 2-3 mg/L). None of the strains was resistant (MIC: 4 mg/L). Ceftaroline showed good in-vitro activity against MSSA and MRSA which can serve as an effective alternative to vancomycin in treating infections caused by MRSA.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Hospitals; Humans; Kuwait; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

The combination of vancomycin or daptomycin plus ceftaroline has showed synergistic results in vitro. This study aimed to investigate in vitro synergy of vancomycin or daptomycin plus ceftaroline for seven patients with daptomycin non-susceptible Staphylococcus aureus (SA) bacteremia Thirteen isolates from seven patients were evaluated: two methicillin-susceptible and five methicillin-resistant SA infections. All patients were treated with daptomycin and became non-susceptible (minimum inhibitory concentration (MIC) >1 μg/mL) with therapy or had resistant strains initially. Time kill experiments were completed with 0.25 × MIC, 0.5 × MIC, and 0.75 × MIC concentrations. No synergy was seen at 0.25 × MIC. Synergy was observed for 4 isolates with vancomycin plus ceftaroline and with daptomycin plus ceftaroline for 2 isolates at 0.5 × MIC. These results are in accordance with literature that supports synergistic combinations of daptomycin or vancomycin with ceftaroline for SA bacteremia. Daptomycin non-susceptible SA bacteremia presents a treatment challenge.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Chronic airways infection with methicillin-resistant Staphylococcus aureus (MRSA) is associated with worse respiratory disease cystic fibrosis (CF) patients. Ceftaroline is a cephalosporin that inhibits the penicillin-binding protein (PBP2a) uniquely produced by MRSA. We analyzed 335 S. aureus isolates from CF sputum samples collected at three US centers between 2015-2018. Molecular relationships demonstrated that high-level resistance of preceding isolates to carbapenems were associated with subsequent isolation of ceftaroline resistant CF MRSA. In vitro evolution experiments showed that pre-exposure of CF MRSA to meropenem with further selection with ceftaroline implied mutations in mecA and additional mutations in pbp1 and pbp2, targets of carbapenems; no effects were achieved by other β-lactams. An in vivo pneumonia mouse model showed the potential therapeutic efficacy of ceftaroline/meropenem combination against ceftaroline-resistant CF MRSA infections. Thus, the present findings highlight risk factors and potential therapeutic strategies offering an opportunity to both prevent and address antibiotic resistance in this patient population.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbapenems; Ceftaroline; Cephalosporins; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Genome, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mutation; Staphylococcal Infections

Persistent bacteremia occurs in at least 30% of patients with Staphylococcus aureus bloodstream infection (SAB) and may be attributable to a dysregulated host immune response. Neutrophils interact with a variety of S. aureus microbial factors, including lipoteichoic acid (LTA), to activate phagocytic function in a concentration-dependent manner. Antibiotics have been shown to exert both direct antimicrobial action as well as immunomodulatory effects. In this study, we compared the effects of different anti-staphylococcal antibiotics on LTA-mediated immune activation of neutrophils.. Neutrophils obtained from healthy volunteers were exposed to two levels of LTA (1 and 10 μg/ml) with or without addition of antibiotics from different pharmacologic classes (vancomycin, daptomycin, ceftaroline). Neutrophil function was assessed by examining phagocytic response, activation (CD11b, CD62L expression), Toll-like receptor-2 expression, cell survival and apoptosis, and CXCL8 release.. Differential LTA-mediated antibiotic effects on neutrophil function were observed primarily at the high LTA exposure level. Ceftaroline in the presence of 10 μg/ml LTA had the most prominent effects on phagocytosis and CD11b and CD62L expression, with trends towards increased neutrophil survival and preservation of CXCL8 release when compared to daptomycin and vancomycin with the latter significantly dampening PMN CXCL8 release.. Select antimicrobial agents, such as ceftaroline, exert immunostimulatory effects on neutrophils exposed to S. aureus LTA, which when confirmed in vivo, could be leveraged for its dual immunomodulatory and antibacterial actions for the treatment of persistent SAB mediated by a dysregulated host response.

Topics: Anti-Bacterial Agents; CD11b Antigen; Ceftaroline; Cephalosporins; Daptomycin; Humans; L-Selectin; Lipopolysaccharides; Neutrophils; Phagocytosis; Staphylococcal Infections; Staphylococcus aureus; Teichoic Acids; Vancomycin

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major pathogens in Iran with a high prevalence and a high level of antibiotic resistance. Ceftaroline is a fifth generation cephalosporin binding and inhibiting penicillin binding protein (PBP2a).. In the present study, 228 clinical MRSA isolates were collected from four cities of Iran and their susceptibility to ceftaroline was evaluated by E-test and the disk diffusion method.. Our results showed a high susceptibility rate (97.3%) to ceftaroline in MRSA strains from Iran. Six isolates were found to be ceftaroline non-susceptible (CPT-NS) with Minimum inhibitory concentration (MIC) ≥2 µg/mL. All CPT-NS isolates were isolated from blood and tracheal aspirate and belonged to SCCmec type III as well as agr type I and were all susceptible to vancomycin. Out of six isolates, three, two and one belonged to spa type t030, t4864, and t969, respectively. Vancomycin, quinupristin/dalfopristin, linezolid, chloramphenicol, and tigecycline were the most active agents against CPT-NS isolates.. Due to the broad-spectrum activity and low toxicity of ceftaroline as well as the increased rate of vancomycin resistance among MRSA strains in recent years, ceftaroline can be considered as a novel approach to treat MRSA-induced infections.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; DNA, Bacterial; Humans; Iran; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Prevalence; Staphylococcal Infections

Topics: Bacteremia; Ceftaroline; Cephalosporins; Daptomycin; Humans; Methicillin; Methicillin-Resistant Staphylococcus aureus; Standard of Care; Staphylococcal Infections; Staphylococcus aureus

Topics: Bacteremia; Ceftaroline; Cephalosporins; Daptomycin; Humans; Methicillin; Methicillin-Resistant Staphylococcus aureus; Standard of Care; Staphylococcal Infections; Staphylococcus aureus

To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L).. A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT>MIC for stasis, 31% fT>MIC for 1 log10 kill and 35% fT>MIC for 2 log10 kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study.. The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600 mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ≤2 mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600 mg q8h dosage regimen against S. aureus with ceftaroline MICs ≤4 mg/L.. The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Clinical Trials as Topic; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Soft Tissue Infections; Staphylococcal Infections; Staphylococcal Skin Infections; Staphylococcus aureus; Young Adult

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Multiple, Bacterial; Evolution, Molecular; Female; Genomics; Humans; Inpatients; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Mutation; Polymorphism, Single Nucleotide; Staphylococcal Infections; Vancomycin

Osteomyelitis is often challenging to treat. This analysis examined the clinical experience of patients with gram-positive osteomyelitis treated with ceftaroline fosamil in the phase 4 Clinical Assessment Program and Teflaro® Utilization Registry (CAPTURE) study.. Data including patient demographics, past illnesses, risk factors, disease characteristics, antibiotic use, pathogens isolated, and clinical outcome were collected between September 2013 and February 2015 by review of randomly ordered patient charts from participating sites in the United States. Clinical success was defined as discontinuation of ceftaroline fosamil following clinical cure with no further need for antibiotics or clinical improvement with switch to another antibiotic treatment.. A total of 150 patients with gram-positive osteomyelitis were treated with ceftaroline fosamil. Most patients (117/150; 78.0%) were treated with 600 mg ceftaroline fosamil per dose; 143/150 patients (95.3%) received a dose every 12 h. The majority (89/150 patients; 59.3%) had been previously diagnosed with diabetes mellitus or peripheral arterial disease. Osteomyelitis was associated with hardware in 32/150 patients (21.3%). Methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA; MSSA) were the most commonly isolated pathogens, observed in 93/150 (62.0%) and 21/150 (14.0%) patients, respectively. Clinical success with ceftaroline fosamil therapy was observed in 139/150 (92.7%) patients overall, 81/89 (91.0%) patients with diabetes or peripheral arterial disease, and 18/20 (90.0%) patients who had hardware implanted before ceftaroline fosamil therapy (none had hardware removed during therapy). Patients who received prior antibiotic therapy or ceftaroline fosamil as monotherapy experienced clinical success rates of 93.9% (107/114) and 91% (91/100), respectively. Among patients who received concurrent antibiotic therapy, the clinical success rate was 96.0% (48/50). Patients who were infected with MRSA or MSSA had clinical success rates of 92.5% (86/93) and 100% (21/21), respectively. A total of 2/150 (1.3%) patients discontinued ceftaroline fosamil therapy because of adverse events.. Clinical success rates with ceftaroline fosamil were high in patients with gram-positive osteomyelitis, including those with diabetes or peripheral arterial disease and those with MRSA or MSSA.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Multicenter Studies as Topic; Osteomyelitis; Registries; Retrospective Studies; Risk Factors; Staphylococcal Infections; Staphylococcus aureus; Young Adult

Topics: Anti-Bacterial Agents; Bacterial Infections; Ceftaroline; Cephalosporins; Daptomycin; Humans; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Neoplasms; Staphylococcal Infections; Vancomycin

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) is a major cause of morbidity and mortality in hospitalized patients. Ceftaroline fosamil (CPT) is the only available beta-lactam antibiotic with in vitro and in vivo activities against MRSA. There is currently limited clinical experience with CPT in complicated MRSA BSI.. We report a series of eight patients, including three whose strains had reduced susceptibility to vancomycin.. CPT monotherapy was successfully used as salvage therapy for complicated MRSA BSI. The median time to documented clearance was 7 days.. Ceftaroline monotherapy is effective for clearance of refractory MRSA BSI related to implanted devices, endocarditis, and orthopedic infections.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; New Jersey; Salvage Therapy; Staphylococcal Infections; Treatment Failure

The aim of this study was to address the involvement of PBP mutations in the bactericidal activity to novel cephalosporins, alone and in combination with daptomycin, in not-related multidrug-resistant methicillin-resistant Staphylococcus aureus strains isolated during a nationwide Italian survey. MICs determination and time-killing assays were performed and mecA, pbp1, pbp2, pbp3, pbp4, and gdpP genes were sequenced. Ten strains showed low-level resistance to ceftaroline and ceftobiprole. PBP2a sequence analysis identified four different mutations (N146K; N204K; T235I; E239K) uniquely present in the non-penicillin-binding domain (nPBD). Epidemiologically, this resistance was associated with the most widespread MDR Italian clone ST228-SCCmecI-t001/t041, confirming its proclivity to accumulate mutations, and it is also associated to substitutions in the GdpP signaling protein, involved in the maintenance of di-AMP balance, recently associated with resistance to beta-lactams. Despite these mutations, both drugs retained their potent in vitro bactericidal activity and showed a synergistic effect towards difficult-to-treat isolates.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Genotype; Humans; Italy; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mutation; Penicillin-Binding Proteins; Staphylococcal Infections

The best therapeutic approach for treating MRSA endocarditis remains unknown, particularly in cases of high vancomycin MICs. We report here a case of daptomycin-non-susceptible, ceftaroline-resistant and fosfomycin-resistant MRSA native left valve endocarditis that was successfully treated with valve repair and a combination of high-dose daptomycin and ceftaroline.. Antimicrobial testing of the clinical strain was performed using Etest and microdilution broth methods. Time-kill and chequerboard methodologies were used to test the activity of antibiotic combinations.. By Etest, the MIC of vancomycin was 2 mg/L, the MIC of daptomycin was 2 mg/L, the MIC of fosfomycin was 1024 mg/L and the MIC of ceftaroline was 1.5 mg/L. At the standard inoculum (105 cfu/mL), the three combinations of daptomycin plus ceftaroline, cloxacillin or fosfomycin were synergistic and bactericidal. However, when these combinations were tested using a higher inoculum (108 cfu/mL), all combinations were synergistic, but only daptomycin plus ceftaroline had bactericidal activity.. These results confirmed a synergistic effect between daptomycin plus ceftaroline and increased bactericidal activity against MRSA, suggesting that this combination may be effective for the treatment of invasive MRSA infection. Our experience highlights the potential clinical use of synergy testing to guide difficult treatment decisions in patients with MDR MRSA infection.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Daptomycin; Drug Synergism; Endocarditis; Fosfomycin; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Pneumonia, Bacterial; Pseudomonas; Staphylococcal Infections; Staphylococcus aureus

Despite limited clinical data, ceftaroline is commonly used for treatment of complicated, invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA). A retrospective chart review was conducted of adult patients receiving ceftaroline for MRSA osteomyelitis admitted between April 2011 and March 2016 at a five-hospital system. Twelve patients met the inclusion criteria. All patients received prior antimicrobial therapy with a median time to switch to ceftaroline of 45.5 days. Five of the 12 patients (41.7%) met criteria for ceftaroline failure. Patients with vertebral osteomyelitis (58%) had a longer length of stay, longer ceftaroline treatment, but similar success rates to those with non-vertebral osteomyelitis (57% vs. 60%). Ceftaroline is a viable alternative for a challenging patient population that has failed or are unable to receive other therapies.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Resistance, Microbial; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Osteomyelitis; Prognosis; Retrospective Studies; Staphylococcal Infections; United States

Ceftaroline is a broad-spectrum, methicillin-resistant Staphylococcus aureus (MRSA)-active β-lactam approved for acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired pneumonia. Because of its favorable spectrum and pharmacokinetics, ceftaroline is frequently utilized for infections such as osteomyelitis and endocarditis. Ceftaroline has been associated with neutropenia, but evaluation of other adverse events remains limited.. To describe the rates and types of ceftaroline-associated adverse events and determine if patients' baseline allergies affect the rates of an adverse event.. A single-center, retrospective, observational analysis was conducted of all patients who received ceftaroline between November 4, 2011, and March 28, 2017, at the VA Saint Louis Health Care System. The Naranjo algorithm was utilized as a standardized method to evaluate likelihood that the adverse events were caused by ceftaroline therapy. Ceftaroline dose, duration, indication, and baseline allergy information were collected for all patients.. There were 75 patients who received 78 courses of ceftaroline identified for inclusion. The most common indications were osteomyelitis (51.3%) and ABSSSI (16.7%). Overall, 13/75 (17.3%) patients developed an adverse event, and 10/75 (13.3%) required discontinuation of ceftaroline. Rash was the most common adverse reaction and occurred in 7/75 (9.3%) patients, followed by neutropenia in 3/75 (4.0%) patients. There were no differences in baseline allergy characteristics between patients who experienced an adverse reaction to ceftaroline and those who did not.. When compared with clinical trials, ceftaroline use appears to be associated with an increased rate of overall adverse events, which is driven by cutaneous reactions.

Topics: Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Exanthema; Female; Humans; Hypersensitivity; Incidence; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Neutropenia; Staphylococcal Infections

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporin Resistance; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Russia; Staphylococcal Infections

Ceftaroline is often used in durations greater than that studied in clinical trials. Several retrospective, non-comparative studies have suggested a higher than anticipated incidence of neutropenia in patients receiving prolonged treatment with ceftaroline. We sought to determine if ceftaroline was associated with neutropenia by comparing the incidence with ceftaroline treatment with treatment with several comparative antibiotics.. Patients receiving 14 or more consecutive days of treatment with ceftaroline were compared with patients receiving cefazolin, daptomycin, linezolid, nafcillin or vancomycin (control group). The primary outcome was the development of neutropenia. Multivariate logistic regression and propensity score weighting using inverse probability weights with regression adjustment were used to control for confounding variables.. A total of 753 patients were included (53 that received ceftaroline and 700 that received a comparative antibiotic). Ceftaroline was associated with a greater incidence of neutropenia as compared with the control group (17.0% versus 3.9%, P < 0.001). Several covariates were also associated with neutropenia and included younger age, lower baseline absolute neutrophil count, liver disease and bone and joint infections. After controlling for these confounders, receipt of ceftaroline continued to be associated with the development of neutropenia (adjusted OR 3.97, P = 0.003). Analysis after propensity score weighting confirmed this finding.. The results of this study suggest that prolonged treatment with ceftaroline is associated with a greater incidence of neutropenia as compared with other antibiotics that are often used for treatment of staphylococcal infections. Careful monitoring of absolute neutrophil count is recommended in patients receiving >14 days of ceftaroline.

Topics: Adult; Aged; Anti-Bacterial Agents; Cefazolin; Ceftaroline; Cephalosporins; Daptomycin; Female; Humans; Incidence; Leukocyte Count; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Neutropenia; Retrospective Studies; Staphylococcal Infections; Vancomycin

Infections of the spine lead to considerable morbidity and a high cost to the global healthcare system. Currently, evidence for using ceftaroline, an advanced-generation cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA), in spine infections is limited.. Describing Infections of the Spine treated with Ceftaroline (DISC) is a multicentre, retrospective, cohort study that evaluated ceftaroline for treating spine infections. Patients were included if they were aged ≥18 years, diagnosed with a spine infection and treated with ceftaroline for ≥28 days. A control group was identified with the same inclusion criteria as the study population except they were treated with a comparator antibiotic for ≥28 days.. Thirty-seven patients were included each in the ceftaroline and control groups. MRSA was the most commonly identified pathogen. With no differences between groups in age, sex, race or co-morbidities (with the exception of chronic kidney disease), treatment with ceftaroline led to similar clinical success compared with the control group. Multivariate regression analysis did not show a significant difference between the two groups in terms of clinical success after controlling for other covariates (adjusted odds ratio=1.49; P=0.711). More patients who received ceftaroline were discharged to an extended-care or rehabilitation facility than home compared with controls (81% vs. 54%, respectively; P=0.024). Side effects and toxicities were rare, including one case of eosinophilic pneumonia in the ceftaroline group.. Ceftaroline appears to be a safe and effective therapy for infections of the spine, including from MRSA.

Topics: Adult; Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Male; Middle Aged; Osteomyelitis; Retrospective Studies; Spinal Diseases; Staphylococcal Infections

To describe the ceftaroline pharmacokinetics in critically ill children treated for suspected or confirmed methicillin-resistant Staphylococcus aureus infections, including blood stream infection and describe the microbiological and clinical outcomes.. Retrospective electronic medical record review.. Free-standing tertiary/quaternary pediatric children's hospital.. Critically ill children receiving ceftaroline monotherapy or combination therapy for suspected or confirmed methicillin-resistant S. aureus infections in the PICU.. None.. Seven patients, three females (43%), and four males (57%), accounted for 33 ceftaroline samples for therapeutic drug management. A median of four samples for therapeutic drug management was collected per patient (range, 2-9 samples). The median age was 7 years (range, 1-13 yr) with a median weight of 25.5 kg (range, 12.6-40.1 kg). Six of seven patients (86%) demonstrated an increase in volume of distribution, five of seven patients (71%) demonstrated an increase in clearance, and 100% of patients demonstrated a shorter half-life estimate as compared with the package insert estimate. Six of seven patients (85.7%) had documented methicillin-resistant S. aureus growth from a normally sterile site with five of six (83.3%) having documented BSI, allowing six total patients to be evaluated for the secondary objective of microbiological and clinical response. All six patients achieved a positive microbiological and clinical response for a response rate of 100%.. These data suggest the pharmacokinetics of ceftaroline in PICU patients is different than healthy pediatric and adult patients, most notably a faster clearance and larger volume of distribution. A higher mg/kg dose and a more frequent dosing interval for ceftaroline may be needed in PICU patients to provide appropriate pharmacodynamic exposures. Larger pharmacokinetic, pharmacodynamic, and interventional treatment trials in the PICU population are warranted.

Topics: Adolescent; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Child, Preschool; Critical Illness; Female; Humans; Infant; Intensive Care Units, Pediatric; Male; Methicillin-Resistant Staphylococcus aureus; Prospective Studies; Retrospective Studies; Staphylococcal Infections; Treatment Outcome

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Daptomycin; Humans; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Salvage Therapy; Staphylococcal Infections

Increasing utilization of vancomycin due to the high prevalence of methicillin-resistant

Topics: beta-Lactams; Cefazolin; Cefepime; Ceftaroline; Cephalosporins; Drug Synergism; Drug Therapy, Combination; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Nafcillin; Staphylococcal Infections; Vancomycin

As antibiotic resistance rises, there is a need for strategies such as antibiotic adjuvants to conserve already-established antibiotics. A family of bacterial kinases known as the penicillin-binding-protein and serine/threonine kinase-associated (PASTA) kinases has attracted attention as targets for antibiotic adjuvants for β-lactams. Here, we report that the pyrazolopyridazine GW779439X sensitizes methicillin-resistant Staphylococcus aureus (MRSA) to various β-lactams through inhibition of the PASTA kinase Stk1. GW779439X potentiates β-lactam activity against multiple MRSA and MSSA isolates, including the sensitization of a ceftaroline-resistant isolate to ceftaroline. In silico modeling was used to guide the synthesis of GW779439X derivatives. The presence and orientation of GW779439X's methylpiperazine moiety was crucial for robust biochemical and microbiologic activity. Taken together, our data provide a proof of concept for developing the pyrazolopyridazines as selective Stk1 inhibitors which act across S. aureus isolates.

Topics: Adjuvants, Pharmaceutic; Autoradiography; beta-Lactam Resistance; Ceftaroline; Cephalosporins; Drug Synergism; fms-Like Tyrosine Kinase 3; Methicillin-Resistant Staphylococcus aureus; Oxacillin; Protein Kinase Inhibitors; Pyridazines; Small Molecule Libraries; Staphylococcal Infections

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mutation; Penicillin-Binding Proteins; Reference Standards; Staphylococcal Infections

Topics: Ceftaroline; Cephalosporins; Drug Resistance, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Spain; Staphylococcal Infections; Tertiary Care Centers

The risk of developing pericarditis secondary to Methicillin-Resistant

Topics: Adult; Ceftaroline; Cephalosporins; Female; Humans; Methicillin-Resistant Staphylococcus aureus; Pericarditis; Prednisolone; Staphylococcal Infections; Treatment Outcome

Ceftaroline fosamil has recently received US Food and Drug Administration approval for treatment of acute bacterial skin/skin structure infections (SSSIs), including those caused by methicillin-resistant Staphylococcus aureus and community-acquired bacterial pneumonia for pediatric patients ≥2 months old. We evaluated the potency and spectrum of ceftaroline and comparators when tested against community-acquired respiratory tract infection (CARTI) and SSSI pathogens from pediatric patients. A total of 3141 consecutive, unique pediatric patient isolates of clinical significance (1460 CARTI and 1681 SSSI isolates) were collected from 29 US medical centers and tested for susceptibility to ceftaroline and comparators by broth microdilution methods. The organism collection included Streptococcus pneumoniae (n = 754), Haemophilus influenzae (487), S. aureus (1399), β-hemolytic streptococci (214), Enterobacteriaceae (112), Pseudomonas aeruginosa (58), Klebsiella spp. (39), Escherichia coli (26) and miscellaneous other bacteria (52). Susceptibility results were analyzed according to patient age as follows: ≤1, 2-5, 6-12 and 13-17 years old. Overall, 99%-100% of Gram-positive isolates and H. influenzae were susceptible to ceftaroline according to Clinical and Laboratory Standards Institute clinical breakpoint criteria. Ceftaroline exhibited potent in vitro activity against bacterial pathogens from CARTI and SSSI recently (2012-2014) collected from pediatric patients in US medical centers. Ceftaroline was particularly active against methicillin-resistant S. aureus from SSSI ([minimum inhibitory concentration for 50% and 90% of isolates (MIC50/90,)] and ceftriaxone-nonsusceptible isolates of S. pneumoniae from CARTI (MIC50/90, 0.25/0.5 μg/mL; 98.3% susceptible).

Topics: Adolescent; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Child; Child, Preschool; Community-Acquired Infections; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Haemophilus influenzae; Hospitals; Humans; Infant; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Respiratory Tract Infections; Retrospective Studies; Skin Diseases, Bacterial; Staphylococcal Infections; Streptococcus pneumoniae; United States

The medical treatment of periprosthetic joint infection (PJI) involves prolonged systemic antibiotic courses, often with suboptimal clinical outcomes including increased morbidity and health-care costs. Oral and intravenous monotherapies and combination antibiotic regimens were evaluated in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) PJI.. Oral linezolid with or without oral rifampin, intravenous vancomycin with oral rifampin, intravenous daptomycin or ceftaroline with or without oral rifampin, oral doxycycline, or sham treatment were administered at human-exposure doses for 6 weeks in a mouse model of PJI. Bacterial burden was assessed by in vivo bioluminescent imaging and ex vivo counting of colony-forming units (CFUs), and reactive bone changes were evaluated with radiographs and micro-computed tomography (μCT) imaging.. Oral-only linezolid-rifampin and all intravenous antibiotic-rifampin combinations resulted in no recoverable bacteria and minimized reactive bone changes. Although oral linezolid was the most effective monotherapy, all oral and intravenous antibiotic monotherapies failed to clear infection or prevent reactive bone changes.. Combination antibiotic-rifampin regimens, including oral-only linezolid-rifampin and the newer ceftaroline-rifampin combinations, were highly effective and more efficacious than monotherapies when used against a preclinical MRSA PJI.. This study provides important preclinical evidence to better optimize future antibiotic therapy against PJIs. In particular, the oral-only linezolid-rifampin option might reduce venous access complications and health-care costs.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Disease Models, Animal; Doxycycline; Drug Combinations; Linezolid; Methicillin-Resistant Staphylococcus aureus; Mice; Prosthesis-Related Infections; Rifampin; Staphylococcal Infections; Treatment Outcome

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bone Diseases, Infectious; Ceftaroline; Cephalosporins; Female; Humans; Joint Diseases; Male; Middle Aged; Prosthesis-Related Infections; Retrospective Studies; Salvage Therapy; Staphylococcal Infections; Treatment Outcome

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Echocardiography, Transesophageal; Endocarditis, Bacterial; Heart Ventricles; Humans; Immunocompetence; Magnetic Resonance Imaging; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Staphylococcal Infections; Stroke Volume; Treatment Refusal

A previously healthy 48-year-old active duty man, who had been treated for an elbow abscess 3 weeks earlier, presented to an emergency department in Bahrain with tachycardia, pericardial friction rub and jugular venous distention. Cardiac tamponade was confirmed on transthoracic echocardiogram and he was taken for emergent pericardiocentesis. Pericardial fluid cultures grew community-acquired methicillin-resistant

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Hypersensitivity Syndrome; Drug Therapy, Combination; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Myocarditis; Pericardial Effusion; Pericardiectomy; Pericarditis; Postoperative Complications; Staphylococcal Infections; Steroids; Treatment Outcome; Vancomycin

The current CLSI and EUCAST clinical susceptible breakpoint for 600 mg q12h dosing of ceftaroline (active metabolite of ceftaroline fosamil) for Staphylococcus aureus is ≤1 mg/L. Efficacy data for S. aureus infections with ceftaroline MIC ≥2 mg/L are limited. This study was designed to generate in-depth pharmacokinetic/pharmacodynamics (PK/PD) understanding of S. aureus isolates inhibited by ≥ 2 mg/L ceftaroline using an in vitro hollow-fibre infection model (HFIM).. The PK/PD target of ceftaroline was investigated against 12 diverse characterized clinical MRSA isolates with ceftaroline MICs of 2 or 4 mg/L using q8h dosing for 24 h. These isolates carried substitutions in the penicillin-binding domain (PBD) and/or the non-PBD. Additionally, PD responses of mutants with ceftaroline MICs ranging from 2 to 32 mg/L were evaluated against the mean 600 mg q8h human-simulated dose over 72 h.. The mean stasis, 1 log10-kill and 2 log10-kill PK/PD targets were 29%, 32% and 35% f T>MIC, respectively. In addition, these data suggest that the PK/PD target for MRSA is not impacted by the presence of substitutions in the non-PBD commonly found in isolates with ceftaroline MIC values of ≤ 2 mg/L. HFIM studies with 600 mg q8h dosing demonstrated a sustained long-term bacterial suppression for isolates with ceftaroline MICs of 2 and 4 mg/L.. Overall, efficacy was demonstrated against a diverse collection of clinical isolates using HFIM indicating the utility of 600 mg ceftaroline fosamil for S. aureus isolates with MIC ≤4 mg/L using q8h dosing.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Humans; Membranes, Artificial; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Models, Biological; Staphylococcal Infections; Staphylococcus aureus

Topics: Ceftaroline; Cephalosporins; Coagulase; Humans; Italy; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus

The aim of this study was to estimate the in vitro activity of ceftaroline against clinical Staphylococcus aureus isolates collected during national surveillance in Belgian acute-care hospitals. Ceftaroline-resistant isolates were further investigated for their resistance mechanisms.. From October 2013 to March 2014, 155 laboratories of Belgian acute-care hospitals were invited to send to the National Reference Centre-Staphylococcus aureus (Belgium) up to five non-duplicate S. aureus including three MRSA and two MSSA from hospitalized patients. Isolates were analysed by spa typing, SCCmec typing (for MRSA) and PCR for detection of 16S-mecA-nuc and 16S-mecC. MICs of oxacillin, cefoxitin and ceftaroline were determined by the broth microdilution method. The nucleotide sequences of mecA, native pbp and gdpP genes of isolates with reduced susceptibility to ceftaroline were analysed for the presence of mutations responsible for amino acid substitutions.. Ninety-nine percent of isolates, including MRSA (n = 284) and MSSA (n = 131), were susceptible to ceftaroline. Only four MRSA isolates showed resistance to ceftaroline (MIC = 2 mg/L). These four isolates belonged to lineages CC5 (n = 1), CC22 (n = 2) and CC8 (n = 1). Two isolates (CC22 and CC8) carried mutations in mecA, as well as in other pbp genes. The remaining isolates carried mutations in native pbp genes or in gdpP.. This is the first Belgian in vitro survey on ceftaroline activity against S. aureus. This antibiotic showed excellent activity against MRSA and MSSA, and only a few MRSA isolates with resistance were found. Reduced susceptibility to ceftaroline seems a complex phenomenon due to the accumulation of mutations in genes involved in β-lactam tolerance.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Belgium; Ceftaroline; Cephalosporins; DNA, Bacterial; Drug Resistance, Bacterial; Female; Genotype; Hospitals; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Typing; Prevalence; Sequence Analysis, DNA; Staphylococcal Infections; Staphylococcus aureus

Ceftaroline is a broad-spectrum antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Ceftaroline susceptibility of an MRSA set archived between 1994 and 2003 in the Geneva University Hospitals detected a high percentage (66 %) of ceftaroline resistance in clonotypes ST228 and ST247 and correlated with mutations in PBP2a. The ceftaroline mechanism of action is based on the inhibition of PBP2a; thus, the identification of PBP2a mutations of recently circulating clonotypes in our institution was investigated. We analyzed ceftaroline susceptibility in MRSA isolates (2013 and 2014) and established that resistant strains correlated with PBP2a mutations and specific clonotypes. Ninety-six MRSA strains were analyzed from independent patients and were isolated from blood cultures (23 %), deep infections (38.5 %), and superficial (skin or wound) infections (38.5 %). This sample showed a ceftaroline minimum inhibitory concentration (MIC) range between 0.25 and 2 μg/ml and disk diameters ranging from 10 to 30 mm, with a majority of strains showing diameters ≥20 mm. Based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, 76 % (73/96) of isolates showed susceptibility to ceftaroline. Nevertheless, we still observed 24 % (23/96) of resistant isolates (MIC = 2 μg/ml). All resistant isolates were assigned to clonotype ST228 and carried the N146K mutation in PBP2a. Only two ST228 isolates showed ceftaroline susceptibility. The decreasing percentage of ceftaroline-resistant isolates in our hospital can be explained by the decline of ST228 clonotype circulating in our hospital since 2008. We present evidence that ceftaroline is active against recent MRSA strains from our hospital; however, the presence of PBP2a variants in particular clonotypes may affect ceftaroline efficacy.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Ceftaroline; Cephalosporins; Drug Resistance, Bacterial; Genotype; Hospitals, University; Humans; Italy; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Typing; Mutation; Penicillin-Binding Proteins; Prevalence; Staphylococcal Infections

Novel therapies for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) are needed in the setting of reduced antibiotic susceptibilities and therapeutic failure. Ceftaroline is a cephalosporin antibiotic with MRSA activity. Although not FDA approved for MRSA BSI, ceftaroline has generated much interest as a potential treatment option. However, detailed descriptions of its use in this setting remain limited. To address this, we conducted a retrospective, multicenter, observational study of adult patients with MRSA BSI treated with at least 72 h of ceftaroline from 2011 to 2015. Safety outcomes were examined in the overall cohort, while efficacy outcomes were examined among patients who had not cleared their BSI prior to ceftaroline initiation. Data were also stratified by ceftaroline monotherapy or combination therapy. Predictors of clinical failure on ceftaroline treatment were also sought. Overall, 211 patients were included in the safety population; Clostridium difficile infection, rash, and neutropenia occurred in 6 patients (2.8%), 7 patients (3.3%), and 3 patients (1.4%), respectively. Clinical success was observed in 86 (68.3%) of the 126 patients included in the efficacy population. The monotherapy and combination therapy subgroups had similar proportions of patients experiencing success (69.7 and 64.9%, respectively). The median BSI durations post-ceftaroline treatment were 2 days (interquartile range, 1 to 4 days) for monotherapy and 3 days (interquartile range, 1.5 to 5 days) for combination therapy. Higher acute physiology and chronic health evaluation II scores and comorbid malignancy independently predicted treatment failure. Ceftaroline appears effective for MRSA BSI as both monotherapy and combination therapy. However, comparative studies are needed to further delineate the role of ceftaroline in MRSA BSI treatment.

Topics: Aged; Bacteremia; Ceftaroline; Cephalosporins; Daptomycin; Endocarditis; Female; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Staphylococcal Infections; Vancomycin

Although vancomycin has been the mainstay of therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections, its effectiveness has been challenged. Combination therapy may be used for patients with persistent MRSA bacteremia refractory to initial therapy. Studies have reported in vitro synergy between vancomycin and ceftaroline; however, clinical experience with this therapy is limited. Here, we report our experience with 5 cases of vancomycin-refractory MRSA bacteremia treated with the combination of vancomycin and ceftaroline.. Between January 2014 and August 2016, 5 patients were identified who received vancomycin and ceftaroline combination therapy due to persistent bacteremia or deterioration of their clinical status on vancomycin alone (despite a vancomycin MIC within the susceptible range).. Five patients presented with MRSA bacteremia secondary to endocarditis (n = 2), epidural abscess (n = 2), or left iliopsoas abscess (n = 1). Four of the 5 patients experienced microbiologic cure, and 1 patient transitioned to palliative care.. This case series serves to describe additional clinical experience with vancomycin and ceftaroline combination therapy. This combination may be considered when vancomycin monotherapy does not lead to microbiological and/or clinical improvement in patients with metastatic MRSA bacteremia. Additional studies are warranted to further define its role in salvage therapy for persistent MRSA bacteremia.

Topics: Abscess; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Salvage Therapy; Staphylococcal Infections; Vancomycin

Vancomycin is the treatment of choice for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia; however, its use has been subject to scrutiny due to failure in severe infections. Ceftaroline fosamil (CPT-F) is approved for MRSA acute bacterial skin and skin structure infections, but not for bloodstream infections. The clinical outcomes of treatment with CPT-F in patients with MRSA bacteremia were evaluated.. Patients diagnosed with MRSA bacteremia at Henry Ford Hospital in Detroit, Michigan, USA, involving isolates with a vancomycin minimum inhibitory concentration ≥1.0mg/l and susceptible in vitro to CPT-F, were systematically reviewed retrospectively. Ceftaroline fosamil-treated patients were matched with at least two vancomycin- and/or one daptomycin-treated control patient based on age-patients age 65 years or greater or less than 65 years of age. Outcomes evaluated included the duration of hospitalization, duration of therapy, adverse events, relapse, hospital readmission, and death.. Thirty consecutive cases of MRSA bacteremia treated with CPT-F during the period May 2011 to June 2013 were identified; these patients were matched to 56 MRSA bacteremia patients treated with vancomycin and 46 MRSA bacteremia patients treated with daptomycin. The primary source of MRSA bacteremia in the cohort treated with CPT-F was endocarditis (n=7, 23%), skin/wound (n=9, 30%), and bone/joint (n=8, 27%). The MRSA bacteremia in those treated with CPT-F was community-acquired in 43% of cases, healthcare-associated in 43%, and hospital-acquired in 13%. The mean length of hospital stay for these patients was 22 days. The overall 30-day mortality rate was 13% (n=4) in CPT-F patients versus 24% (n=11) in daptomycin patients and 11% (n=6) in vancomycin patients (p=0.188).. CPT-F demonstrated comparable clinical outcomes in MRSA bacteremia patients compared with the other agents, especially as salvage therapy.

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Daptomycin; Female; Hospitalization; Humans; Length of Stay; Male; Methicillin-Resistant Staphylococcus aureus; Michigan; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Salvage Therapy; Staphylococcal Infections; Treatment Outcome; Vancomycin

We report a case of infective endocarditis (IE) caused by ceftaroline-resistant, daptomycin-tolerant, and heterogeneous vancomycin-intermediate methicillin-resistant

Topics: Adult; Amino Acid Substitution; Anti-Bacterial Agents; Bacterial Proteins; Ceftaroline; Cephalosporins; Cross Infection; Daptomycin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Endocarditis, Bacterial; Gene Expression; Humans; Male; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Penicillin-Binding Proteins; Staphylococcal Infections; Vancomycin

Ceftaroline and ceftobiprole are new cephalosporins, which are active against MRSA by inhibiting PBP2a. Recently, high rates of resistance to ceftaroline were reported from Ghana. The objective of this study was to assess rates of resistance to ceftaroline and ceftobiprole in MRSA from Africa and to describe potential missense mutations of PBP2a.. MRSA isolates derived from Staphylococcus aureus colonization (n = 37) and infection (n = 23) and were collected in Côte d'Ivoire (n = 17), DR Congo (n = 6), Gabon (n = 21) and Nigeria (n = 16). The MICs were determined by the broth microdilution method. The mecA gene was sequenced and missense mutations were associated with the corresponding MLST ST.. In total, 16.7% (n = 10) and 15% (n = 9) of isolates were resistant to ceftaroline and ceftobiprole, respectively. The corresponding MICs of ceftaroline and ceftobiprole correlated significantly (r = 0.92). Isolates belonging to ST241 harboured a triple mutation of PBP2a (N146K-N204K-G246E), which was associated with high rates of resistance to ceftaroline (90.9%) and ceftobiprole (81.8%).. Resistances to ceftaroline and ceftobiprole were only detected in Nigeria and were associated with ST241 and a triple mutation of PBP2a.

Topics: Africa; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; Carrier State; Ceftaroline; Cephalosporins; Genotype; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Multilocus Sequence Typing; Mutation, Missense; Penicillin-Binding Proteins; Sequence Analysis, DNA; Staphylococcal Infections

Topics: Amino Acid Substitution; Animals; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Penicillin-Binding Proteins; Staphylococcal Infections; United Kingdom

Ceftaroline is a fifth-generation cephalosporin with potent antimicrobial activity against Gram-positive and Gram-negative pathogens. Neutropenia is a rare serious adverse event for the class of cephalosporins; however, we observed several cases of severe neutropenia in our outpatient infectious disease practice believed to be associated with ceftaroline use. The aim of this study was to determine the incidence of neutropenia among patients receiving ceftaroline therapy for more than 7 days. We conducted a retrospective cohort analysis of patients admitted to an 800-bed regional medical center between June 2012 and December 2014 who received ceftaroline for more than 7 days to assess the incidence of developing clinically significant neutropenia. Demographic and patient care data points as well as underlying admitting and chronic diagnoses were retrospectively collected from the medical record. Clinically significant neutropenia was defined as an absolute neutrophil count (ANC) less than 1,500 cells/mm(3). Analysis was performed to determine the incidence, severity, and outcome of neutropenia following ceftaroline administration. A total of 39 patients were included in the cohort. The median duration of therapy was 27 days. Seven patients (18%) developed neutropenia while on ceftaroline therapy. Four (10%) of the neutropenic patients had an ANC of <500 cells/mm(3). The median first neutropenic day was day 17, with the median ANC nadir of 432 cells/mm(3) on day 24. We determined that extended ceftaroline infusion is associated with the development of neutropenia. We recommend obtaining a complete blood count (CBC) with differential at the onset of therapy and weekly thereafter. Should the ANC fall below 2,500 cells/mm(3), then twice-weekly CBCs should be monitored for the duration of ceftaroline therapy, and therapy should be discontinued if the ANC falls to 1,500 cells/mm(3) or less.

Topics: Adult; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Leukocyte Count; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Neutropenia; Neutrophils; Retrospective Studies; Staphylococcal Infections; Time Factors

Ceftaroline, the active metabolite of the prodrug ceftaroline-fosamil, is an advanced-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). This investigation provides in vitro susceptibility data for ceftaroline against 1,971 S. aureus isolates collected in 2012 from seven countries (26 centers) in the Asia-Pacific region as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program. Broth microdilution as recommended by the CLSI was used to determine susceptibility. In all, 62% of the isolates studied were MRSA, and the ceftaroline MIC90 for all S. aureus isolates was 2 μg/ml (interpretive criteria: susceptible, ≤1 μg/ml). The overall ceftaroline susceptibility rate for S. aureus was 86.9%, with 100% of methicillin-sensitive S. aureus isolates and 78.8% of MRSA isolates susceptible to this agent. The highest percentages of ceftaroline-nonsusceptible MRSA isolates came from China (47.6%), all of which showed intermediate susceptibility, and Thailand (37.1%), where over half (52.8%) of isolates were resistant to ceftaroline (MIC, 4 μg/ml). Thirty-eight ceftaroline-nonsusceptible isolates (MIC values of 2 to 4 μg/ml) were selected for molecular characterization. Among the isolates analyzed, sequence type 5 (ST-5) was the most common sequence type encountered; however, all isolates analyzed from Thailand were ST-228. Penicillin-binding protein 2a (PBP2a) substitution patterns varied by country, but all isolates from Thailand had the Glu239Lys substitution, and 12 of these also carried an additional Glu447Lys substitution. Ceftaroline-fosamil is a useful addition to the antimicrobial agents that can be used to treat S. aureus infections. However, with the capability of this species to develop resistance to new agents, it is important to recognize and monitor regional differences in trends as they emerge.

Topics: Amino Acid Substitution; Anti-Bacterial Agents; Asia, Southeastern; Bacterial Proteins; beta-Lactam Resistance; Ceftaroline; Cephalosporins; Epidemiological Monitoring; Gene Expression; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Epidemiology; Multilocus Sequence Typing; Penicillin-Binding Proteins; Staphylococcal Infections

We tested the in vitro activity of ceftaroline by Etest against staphylococci recovered from patients with prosthetic joint infection, including 97 Staphylococcus aureus isolates (36%, oxacillin resistant) and 74 Staphylococcus epidermidis isolates (74%, oxacillin resistant). Ceftaroline inhibited all staphylococci at ≤0.5 μg/mL. The ceftaroline MIC(90/50) values for methicillin-susceptible S. aureus, methicillin-susceptible S. epidermidis, methicillin-resistant S. aureus, and methicillin-resistant S. epidermidis were 0.19/0.125, 0.094/0.047, 0.5/0.38, and 0.38/0.19 μg/mL, respectively. Based on these in vitro findings, ceftaroline should be further evaluated as a potential therapeutic option for the treatment of prosthetic joint infection caused by methicillin-susceptible and methicillin-resistant S. aureus and S. epidermidis.

Topics: Anti-Bacterial Agents; Arthritis; Ceftaroline; Cephalosporins; Disk Diffusion Antimicrobial Tests; Humans; Prosthesis-Related Infections; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis

We previously determined the extent to which mutations of different Staphylococcus aureus regulatory loci impact biofilm formation as assessed under in vitro conditions. Here we extend these studies to determine the extent to which those regulatory loci that had the greatest effect on biofilm formation also impact antibiotic susceptibility. The experiments were done under in vitro and in vivo conditions using two clinical isolates of S. aureus (LAC and UAMS-1) and two functionally diverse antibiotics (daptomycin and ceftaroline). Mutation of the staphylococcal accessory regulator (sarA) or sigB was found to significantly increase susceptibilities to both antibiotics and in both strains in a manner that could not be explained by changes in the MICs. The impact of a mutation in sarA was comparable to that of a mutation in sigB and greater than the impact observed with any other mutant. These results suggest that therapeutic strategies targeting sarA and/or sigB have the greatest potential to facilitate the ability to overcome the intrinsic antibiotic resistance that defines S. aureus biofilm-associated infections.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Biofilms; Catheter-Related Infections; Catheters; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Bacterial; Humans; Mice; Microbial Sensitivity Tests; Sigma Factor; Staphylococcal Infections; Staphylococcus aureus

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; India; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

HY-133 is a recombinant bacteriophage endolysin with bactericidal activity againstStaphylococcus aureus Here, HY-133 showedin vitroactivity against major African methicillin-susceptible and methicillin-resistantS. aureuslineages and ceftaroline/ceftobiprole- and borderline oxacillin-resistant isolates. HY-133 was also active againstStaphylococcus schweitzeri, a recently described species of theS. aureuscomplex. The activity of HY-133 on the tested isolates (MIC50, 0.25 μg/ml; MIC90, 0.5 μg/ml; range, 0.125 to 0.5 μg/ml) was independent of the species and strain background or antibiotic resistance.

Topics: Africa; Anti-Bacterial Agents; beta-Lactam Resistance; Ceftaroline; Cephalosporins; Endopeptidases; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Recombinant Proteins; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Staphylococcus Phages

Oritavancin possesses activity against vancomycin-resistant enterococci (VRE) and methicillin-resistantStaphylococcus aureus(MRSA).In vitrodata suggest synergy between beta-lactams (BLs) and vancomycin or daptomycin, agents similar to oritavancin. We evaluated the activities of BLs combined with oritavancin against MRSA and VRE. Oritavancin MICs were determined for 30 strains, 5 each of MRSA, daptomycin-nonsusceptible (DNS) MRSA, vancomycin-intermediate MRSA (VISA), heteroresistant VISA (hVISA), vancomycin-resistantEnterococcus faecalis, and vancomycin-resistantEnterococcus faecium Oritavancin MICs were determined in the presence of subinhibitory concentrations of BLs. Oritavancin combined with ceftaroline, cefazolin, or nafcillin was evaluated for lethal synergy against MRSA, and oritavancin combined with ceftaroline, ampicillin, or ertapenem was evaluated for lethal synergy against VRE in 24-h time-kill assays. Oritavancin at 0.5× the MIC was combined with BLs at 0.5× the MIC or the biological free peak concentration, whichever one was lower. Synergy was defined as a ≥2-log10-CFU/ml difference between the killing achieved with the combination and that achieved with the most active single agent at 24 h. Oritavancin MICs were ≤0.125 μg/ml for all MRSA isolates except three VISA isolates with MICs of 0.25 μg/ml. Oritavancin MICs for VRE ranged from 0.03 to 0.125 μg/ml. Oritavancin in combination with ceftaroline was synergistic against all MRSA phenotypes and statistically superior to all other combinations against DNS MRSA, hVISA, and MRSA isolates (P< 0.02). Oritavancin in combination with cefazolin and oritavancin in combination with nafcillin were also synergistic against all MRSA strains. Synergy between oritavancin and all BLs was revealed against VRE strain 8019, while synergy between oritavancin and ampicillin or ertapenem but not ceftaroline was demonstrated against VRE strain R7164. The data support the potential use of oritavancin in combination with BLs, especially oritavancin in combination with ceftaroline, for the treatment of infections caused by MRSA. The data from the present study are not as strong for oritavancin in combination with BLs for VRE. Further study of both MRSA and VRE in more complex models is warranted.

Topics: Anti-Bacterial Agents; beta-Lactams; Cefazolin; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Ertapenem; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Nafcillin; Staphylococcal Infections; Vancomycin; Vancomycin-Resistant Enterococci

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporin Resistance; Cephalosporins; Genes, Bacterial; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Mutation; Sequence Analysis, DNA; Spondylitis; Staphylococcal Infections

A total of 1593 coagulase-negative staphylococci (CoNS) considered clinically significant were collected from 71 US medical centers in 2013-2014 and tested for susceptibility by CLSI broth microdilution methods. Species identification was performed by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Overall, 59.7% of isolates were oxacillin resistant (MRCoNS). Ceftaroline (MIC50/90, 0.25/0.5μg/mL) inhibited 99.2% of CoNS at ≤1μg/mL (susceptible breakpoint for Staphylococcus aureus), including 98.7% of MRCoNS, and the highest ceftaroline MIC value was 2μg/mL (13 isolates). Staphylococcus epidermidis represented 60.3% of the CoNS collection and was highly susceptible to ceftaroline (MIC50/90, 0.25/0.5μg/mL, 99.9% inhibited at ≤1μg/mL). All isolates of Staphylococcus capitis, Staphylococcus caprae, Staphylococcus hominis, Staphylococcus lugdunensis, Staphylococcus pettenkoferi, Staphylococcus simulans, and Staphylococcus warneri (MIC50/90, 0.06-0.25/0.25-0.5μg/mL) were inhibited at ceftaroline MIC of ≤1μg/mL. Staphylococcus haemolyticus represented only 4.8%, was atypically less susceptible to ceftaroline (MIC50/90, 0.5/2μg/mL, 87.0% inhibited at ≤1μg/mL), and accounted for 76.9% (10/13) of isolates with ceftaroline MIC >1μg/mL.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Cross Infection; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staphylococcal Infections; Staphylococcus; United States

Ceftaroline fosamil is a novel cephalosporin approved by the United States Food and Drug Administration (US FDA) for treatment of acute bacterial skin and skin structure infection, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the activity of ceftaroline and comparator agents tested against S. aureus isolated from surgical skin and skin structure infections (SSSI).. Clinically substantial isolates (one/patient episode) from SSSI were consecutively collected from 64 medical centers in the United States over a 6-y period (2008-2013) and tested for susceptibility by broth microdilution methods against ceftaroline and several comparator agents.. Among 794 strains tested, 50.5% were MRSA. Ceftaroline was active against all methicillin-susceptible Staphylococcus aureus (MSSA; minimal inhibitory concentration [MIC]90, 0.25 mcg/mL) and nearly all MRSA (MIC90, 1 mcg/mL). Against MSSA, ceftaroline was 16-fold more potent than ceftriaxone (MIC90, 4 mcg/mL) and the highest ceftaroline MIC was 0.5 mcg/mL. Among MRSA, 97.5% and 100.0% of strains were inhibited at ≤1 and ≤2 mcg/mL of ceftaroline. Furthermore, 27.4% and 67.5% of MRSA were resistant to clindamycin and levofloxacin, respectively. Daptomycin (MIC50/90, 0.25/0.5 mcg/mL), linezolid (MIC50/90, 1/2 mcg/mL), tigecycline (MIC50/90, 0.06/0.12 mcg/mL) and vancomycin (MIC50/90, 1/2 mcg/mL) were also highly active against S. aureus strains.. Ceftaroline exhibited potent in vitro activity against S. aureus causing SSSI in a large number of US hospitals, including MRSA. On the basis of this in vitro data, ceftaroline fosamil may represent a valuable option for treatment of surgical SSSI, and should be further evaluated as an agent for surgical prophylaxis that would cover MRSA.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Skin Diseases, Bacterial; Staphylococcal Infections; Staphylococcus aureus

Foot infections are a major cause of morbidity in people with diabetes and the most common cause of diabetes-related hospitalization and lower extremity amputation. Staphylococcus aureus is by far the most frequent species isolated from these infections. In particular, methicillin-resistant S. aureus (MRSA) has emerged as a major clinical and epidemiological problem in hospitals. MRSA strains have the ability to be resistant to most β-lactam antibiotics, but also to a wide range of other antimicrobials, making infections difficult to manage and very costly to treat. To date, there are two fifth-generation cephalosporins generally efficacious against MRSA, ceftaroline and ceftobripole, sharing a similar spectrum. Biofilm formation is one of the most important virulence traits of S. aureus. Biofilm growth plays an important role during infection by providing defence against several antagonistic mechanisms. In this study, we analysed the antimicrobial susceptibility patterns of biofilm-producing S. aureus strains isolated from diabetic foot infections. The antibiotic minimum inhibitory concentration (MIC) was determined for ten antimicrobial compounds, along with the minimum biofilm inhibitory concentration (MBIC) and minimum biofilm eradication concentration (MBEC), followed by PCR identification of genetic determinants of biofilm production and antimicrobial resistance.. Results demonstrate that very high concentrations of the most used antibiotics in treating diabetic foot infections (DFI) are required to inhibit S. aureus biofilms in vitro, which may explain why monotherapy with these agents frequently fails to eradicate biofilm infections. In fact, biofilms were resistant to antibiotics at concentrations 10-1000 times greater than the ones required to kill free-living or planktonic cells. The only antibiotics able to inhibit biofilm eradication on 50 % of isolates were ceftaroline and gentamicin.. The results suggest that the antibiotic susceptibility patterns cannot be applied to biofilm established infections. Selection of antimicrobial therapy is a critical step in DFI and should aim at overcoming biofilm disease in order to optimize the outcomes of this complex pathology.

Topics: Anti-Bacterial Agents; beta-Lactams; Biofilms; Ceftaroline; Cephalosporins; Diabetic Foot; Gentamicins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Polymerase Chain Reaction; Staphylococcal Infections; Staphylococcus aureus

Among 8437 methicillin-resistant Staphylococcus aureus (MRSA) isolates collected from 143 medical centers in the United States (2012-2014), 7116 and 1321 were reported as community-acquired (CA) and hospital-acquired (HA) MRSA, respectively. CA-/HA-MRSA were most often isolated from patients with skin and skin structure infections (SSSI; 68.4/26.9%), pneumonia (13.7/49.0%) and bacteremia (10.0/17.7%). Overall, susceptibility rates were generally lower among HA-MRSA compared to CA-MRSA strains, especially for clindamycin (44.6 vs. 66.1%) and levofloxacin (21.4 vs. 35.5%). Also, susceptibility rates were lower for these two compounds among isolates from pneumonia compared to SSSI and bacteremia. Ceftaroline was broadly active against 98.0% of CA-MRSA and 94.3% of HA-MRSA (MIC50/90, 1μg/mL for both; no resistant isolate) overall, with little variation among infection type subsets.

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Community-Acquired Infections; Cross Infection; Epidemiological Monitoring; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pneumonia, Staphylococcal; Staphylococcal Infections; Staphylococcal Skin Infections; United States

Methicillin-resistant Staphylococcus aureus (MRSA) is a public health problem worldwide. The aim of the present study was to investigate the molecular epidemiology and antimicrobial susceptibilities of MRSA strains in Stockholm, Sweden in 2014. Pulsed-field gel electrophoresis (PFGE) was used to characterise the strains. Antimicrobial susceptibilities to ceftaroline, linezolid and mupirocin were determined by the disc diffusion method. Etest was used to determine vancomycin susceptibility and to confirm resistance to ceftaroline, mupirocin and linezolid in non-susceptible strains. High-level ceftaroline-resistant strains [minimum inhibitory concentration (MIC)≥4mg/L] were confirmed by the broth microdilution method. spa typing was carried out on strains that were non-susceptible to the antibiotics tested. In total, 743 consecutive non-duplicate MRSA strains recovered in Stockholm in 2014 were investigated. PFGE analysis of the isolates revealed a population with 271 different PFGE patterns and three non-typeable strains. No PFGE type accounted for >10% of all strains. The most common PFGE types were MRSA-00-02 (6.9%) and MRSA-05-02 (4.6%). MRSA-05-02 is a USA300-like strain. The antimicrobial susceptibilities of the strains were as follows: ceftaroline, 98.5%; linezolid, 100%; mupirocin, 99.3%; and vancomycin, 100%. Two strains with spa t001 displayed ceftaroline MICs of 4mg/L. Three strains with spa types t002, t064 and t437 showed high-level mupirocin resistance (MIC>1024mg/L). In conclusion, there was a diverse genetic population among the MRSA isolates and no predominant genotype was found. This study identified a few strains with high-level ceftaroline resistance, high-level mupirocin resistance and high-risk genotypes.

Topics: Anti-Bacterial Agents; Bacterial Typing Techniques; Ceftaroline; Cephalosporins; Genotype; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Epidemiology; Mupirocin; Staphylococcal Infections; Sweden; Vancomycin

We studied in vitro ceftaroline combinations against 61 meticillin-resistant Staphylococcus aureus isolates; 18 of them were also resistant to linezolid, using overlapping E-test method. Daptomycin-ceftaroline combination obtained lower fractional inhibitory concentration values, in comparison with those including vancomycin or linezolid against meticillin-resistant S. aureus (P<0.05). All meticillin- and linezolid-resistant S. aureus strains were resistant to ceftaroline; nevertheless, combinations with vancomycin or daptomycin showed higher synergy or addition rates than those with linezolid.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Drug Therapy, Combination; Humans; Linezolid; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin

In this study, the efficacy of ceftaroline versus vancomycin against biofilm-producing methicillin-resistant Staphylococcus epidermidis (MRSE) in a murine model of foreign-body and systemic infection was compared. Two bacteraemic biofilm-producing MRSE strains were used (SE284 and SE385). The minimum inhibitory concentrations (MICs) for strains SE284 and SE385, were, respectively, 0.25 mg/L and 0.5 mg/L for ceftaroline and 4 mg/L and 2 mg/L for vancomycin. The in vitro bactericidal activities of ceftaroline and vancomycin were evaluated using time-kill curves. A foreign-body and systemic infection model in neutropenic female C57BL/6 mice was used to ascertain in vivo efficacy. Animals were randomly allocated into three groups (n = 15) without treatment (controls) or treated with ceftaroline 50 mg/kg every 8 h or vancomycin 110 mg/kg every 6 h. In vitro, ceftaroline showed concentration-dependent bactericidal activity, whilst vancomycin presented time-dependent activity. In the experimental in vivo model, ceftaroline and vancomycin decreased the liver and catheter bacterial concentrations (P <0.05) and increased survival (P <0.05) for both strains. In conclusion, ceftaroline is as effective as vancomycin in the treatment of experimental foreign-body and systemic infection caused by biofilm-producing MRSE.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Biofilms; Ceftaroline; Cephalosporins; Disease Models, Animal; Female; Foreign Bodies; Methicillin Resistance; Mice, Inbred C57BL; Microbial Sensitivity Tests; Random Allocation; Sepsis; Soft Tissue Infections; Staphylococcal Infections; Staphylococcus epidermidis; Treatment Outcome; Vancomycin

Topics: Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Staphylococcal Infections; Treatment Outcome; Vancomycin

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Meningitis, Bacterial; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Staphylococcal Infections; Surgical Wound Infection; Treatment Outcome

To examine the activity of ceftaroline against reduced-vancomycin-susceptible MRSA isolates.. One-hundred and three MRSA blood culture isolates (predominantly ST239-MRSA-III), with varying vancomycin phenotypes, had their ceftaroline MICs determined by broth microdilution and MIC Evaluator strip (Oxoid-Thermo Fisher). Statistical analyses were performed that examined relationships with vancomycin and daptomycin MICs. Mutations in mecA were also examined.. All 103 isolates (including 60 heteroresistant vancomycin-intermediate Staphylococcus aureus/vancomycin-intermediate S. aureus) were susceptible to ceftaroline, with one isolate displaying heteroresistance that may be related to a mecA mutation. Higher ceftaroline MICs were associated with vancomycin-susceptible S. aureus isolates.. This study highlights that ceftaroline fosamil is an option for salvage therapy based on in vitro activity.

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Drug Tolerance; Female; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Salvage Therapy; Staphylococcal Infections; Vancomycin

To ascertain which demographic, clinical, and microbiological factors might affect clinical outcomes of patients with diabetic foot infections, excluding known osteomyelitis, by analysing Clinical Assessment Program and Teflaro® Utilization Registry study data of patients treated with ceftaroline fosamil.. At participating study centres, we collected data by randomized selection and chart review, including patient demographics, co-morbidities, infecting pathogens, antibiotic use, surgical interventions, and clinical response. Evaluable patients were those with data sufficient to determine clinical outcome. Clinical success was defined as clinical cure with no use of other antibiotics or clinical improvement with a switch to oral antibiotic therapy at the end of intravenous ceftaroline fosamil treatment.. Among 201 patients (mean age 61.7 years, mean body mass index 33.2 and 57% male patients), 40% had peripheral vascular disease. Prior antibiotic therapy had been given to 161 (80%) of the patients, most commonly with vancomycin and/or piperacillin-tazobactam. Patients received ceftaroline fosamil for mean duration of 6.1 days (range 1-30), as monotherapy in 130 (65%) patients and concurrently with other antibiotics in 71 (35%). Bacterial pathogens were identified in 114 (57%) of the patients; methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus were isolated from 56 (49%) and 28 (25%) of culture-positive patients respectively. Clinical success was noted in 81% of patients and was not significantly associated with co-morbidities, pathogen type, or need for surgical intervention.. Ceftaroline fosamil treatment of diabetic foot infections was associated with high clinical success, including inpatients with obesity, co-morbidities, or methicillin-resistant Staphylococcus aureus or mixed infections or requiring surgical intervention.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Body Mass Index; Ceftaroline; Cephalosporins; Cohort Studies; Comorbidity; Diabetic Foot; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Obesity; Overweight; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus

The development and maintenance of an arsenal of antibiotics is a major health care challenge. Ceftaroline is a new cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA); however, no reports concerning MRSA ceftaroline susceptibility have been reported in Switzerland. We tested the in vitro activity of ceftaroline against an archived set of 60 MRSA strains from the University Hospital of Geneva collected from 1994 to 2003. Our results surprisingly revealed ceftaroline-resistant strains (MIC, >1 μg/ml in 40/60 strains; EUCAST breakpoints, susceptible [S], ≤1 μg/ml; resistant [R], >1 μg/ml) were present from 1998 to 2003. The detected resistant strains predominantly belonged to sequence type 228 (ST228) (South German clonotype) but also to ST247 (Iberian clonotype). A sequence analysis of these strains revealed missense mutations in the penicillin-binding protein 2A (PBP2A) allosteric domain (N146K or E239K and N146K-E150K-G246E). The majority of our ST228 PBP2A mutations (N146K or E150K) were distinct from ST228 PBP2A allosteric domain mutations (primarily E239K) recently described for MRSA strains collected in Thailand and Spain during the 2010 Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) global surveillance program. We also found that similar allosteric domain PBP2A mutations (N146K) correlated with ceftaroline resistance in an independent external ST228 MRSA set obtained from the nearby University Hospital of Lausanne, Lausanne, Switzerland, collected from 2003 to 2008. Thus, ceftaroline resistance was observed in our archived strains (including two examples of an MIC of 4 µg/ml for the Iberian ST247 clonotype with the triple mutation N146K/E150K/G246E), at least as far back as 1998, considerably predating the commercial introduction of ceftaroline. Our results reinforce the notion that unknown parameters can potentially exert selective pressure on PBP2A that can subsequently modulate ceftaroline resistance.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Ceftaroline; Cephalosporins; Cross Infection; Drug Resistance, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mutation, Missense; Penicillin-Binding Proteins; Staphylococcal Infections; Switzerland

The case of a patient with multiple medication hypersensitivity reactions and a methicillin-resistant Staphylococcus aureus (MRSA) infection who underwent desensitization to ceftaroline is reported.. A 32-year-old Caucasian woman with asthma, gastroesophageal reflux disease, heart murmur, and major depression was admitted for MRSA cellulitis with a subcutaneous abscess along the left sternomanubrial joint and clavicular osteomyelitis secondary to port placement after gastric bypass surgery. The patient had an extensive history of hypersensitivity reactions. Pertinent documented allergies were as follows: penicillin (anaphylaxis), daptomycin (anaphylaxis), vancomycin (hives), linezolid (hives), ertapenem (rash), ciprofloxacin (rash), and tigecycline (rash). The patient also reported previous reactions to aztreonam (unknown) and gentamicin (hives). The pharmacy was consulted to develop a desensitization protocol for ceftaroline. The desensitization protocol used three serial dilutions of ceftaroline to make 14 sequential infusions with escalating doses. Intramuscular epinephrine, i.v. diphenhydramine, and i.v. methylprednisolone were ordered as needed for the development of immediate hypersensitivity reactions during or after administration of ceftaroline. The cumulative dose (574.94 mg) was administered intravenously over 225 minutes with no breakthrough symptoms reported during or after the desensitization protocol. Ceftaroline fosamil 600 mg i.v. every 12 hours was continued for six weeks.. Desensitization to ceftaroline was conducted for a patient with extensive history of hypersensitivity reactions to other drugs, including penicillin-induced anaphylaxis. Desensitization and subsequent treatment with full doses of ceftaroline were accomplished without apparent adverse effects.

Topics: Adult; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Desensitization, Immunologic; Drug Hypersensitivity; Female; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections

The objective of this study was to evaluate the in vitro antimicrobial activity of ceftaroline and comparator agents tested against Staphylococcus aureus isolates causing bloodstream infection (BSI).. A total of 4426 S. aureus isolates from patients with BSI were collected in 150 medical centres in the USA in 2009-13 and tested for susceptibility to ceftaroline and comparators by the CLSI broth microdilution method.. Overall, 45.5% of isolates were MRSA. Ceftaroline (MIC50/90, 0.25/1 mg/L) was active against 97.9% of S. aureus isolates at ≤1 mg/L (highest MIC, 2 mg/L). Daptomycin (MIC50/90, 0.25/0.5 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L) were active against ≥99.8% of isolates at the respective susceptible breakpoints. Susceptibility rates for clindamycin (MIC50/90, ≤0.25/>2 mg/L) and levofloxacin (MIC50/90, ≤0.5/>4 mg/L) were 80.8% and 59.2%, respectively. Against MSSA, ceftaroline (MIC50/90, 0.25/0.25 mg/L; 100.0% susceptible) was 16-, 4-8- and 4-fold more active in vitro (based on MIC50/90) than ceftriaxone (MIC50/90, 4/4 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L), respectively, and slightly more potent than daptomycin (MIC50/90, 0.25/0.5 mg/L). When tested against MRSA, ceftaroline was active against 95.4% and 100.0% of isolates at ≤1 and ≤2 mg/L, respectively. Moreover, ceftaroline retained significant activity against S. aureus with reduced susceptibility to vancomycin, daptomycin, clindamycin, levofloxacin and trimethoprim/sulfamethoxazole.. Ceftaroline demonstrated potent in vitro activity when tested against a large collection of contemporary (2009-13) S. aureus isolates causing BSI in US hospitals.

Topics: Academic Medical Centers; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Microbial Sensitivity Tests; Sepsis; Staphylococcal Infections; Staphylococcus aureus; United States

To compare the in vitro antimicrobial efficacy of ceftaroline with linezolid against Staphylococcus aureus and methicillin resistant Staphylococcus aureus.. Quasi-experimental study.. Microbiology Department, Army Medical College, Rawalpindi, from January to December 2013.. Clinical samples from respiratory tract, blood, pus and various catheter tips routinely received in the Department of Microbiology, Army Medical College, Rawalpindi were innoculated on blood and MacConkey agar. Staphylococcus aureus was identified by colony morphology, Gram reaction, catalase test and coagulase test. Methicillin resistant Staphylococcus aureus detection was done by modified Kirby Bauer disc diffusion method using cefoxitin disc (30 μg) and the isolates were considered methicillin resistant if the zone of inhibition around cefoxitin disc was ≤ 21 mm. Bacterial suspensions of 56 Staphylococcus aureus isolates and 50 MRSA isolates were prepared, which were standardized equal to 0.5 McFarland's turbidity standard and inoculated on Mueller-Hinton agar plates followed by application of ceftaroline and linezolid disc (Oxoid, UK), according to manufacturer's instructions. The plates were then incubated at 37 °C aerobically for 18 - 24 hours. Diameters of inhibition zone were measured and interpretated as per Clinical and Laboratory Standards Institute (CLSI) guidelines.. Out of 106 isolates all of the 56 Staphylococcus aureus (100%) were sensitive to ceftaroline and linezolid. However, out of 50 methicillin resistant Staphylococcus aureus, 48 (96%) were sensitive to ceftaroline whereas, 49 (98%) were sensitive to linezolid.. Ceftaroline is equally effective as linezolid against Staphylococcus aureus and methicillin resistant Staphylococcus aureus.

Topics: Acetamides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus

Ceftaroline is a new cephalosporin active against Methicillin-resistant Staphylococcus aureus (MRSA). Based on a representative collection of clinical S. aureus isolates from Germany, supplemented with isolates of clonal lineages ST228 and ST239, we demonstrate the in-vitro susceptibility towards ceftaroline prior to its introduction into clinical use for a total of 219 isolates. Susceptibility testing was performed by broth microdilution, disc diffusion and Etest, respectively. Results were interpreted according to EUCAST guidelines and showed considerable variance in dependence on clonal affiliation of the isolates tested. Among isolates of widespread hospital-associated lineages we found a high proportion of clinical isolates with MICs close to the EUCAST breakpoint (MIC50/90 1.0/1.5 mg/L); currently, interpretation of these "borderline" MICs is complicated by a lack of concordant susceptibility testing methods and reasonable breakpoint determination. Isolates of clonal lineages ST228 and ST239 demonstrated increased MIC50/90 values of 2.5/3.33 mg/L. Sequencing of mecA revealed no association of resistance to a specific mecA polymorphism, but rather reveals two regions in the non-penicillin-binding domain of PbP2a which displayed different combinations of mutations putatively involved in resistance development. This study provides national baseline data to (i) adjust susceptibility testing methods and current breakpoints to clinical and epidemiological requirements, (ii) evaluate current breakpoints with respect to therapeutic outcome and (iii) monitor further resistance evolution.

Topics: Ceftaroline; Cephalosporins; Genes, Bacterial; Germany; Humans; Microbial Sensitivity Tests; Phylogeny; Prevalence; Staphylococcal Infections; Staphylococcus aureus

Topics: Anti-Bacterial Agents; Australia; Ceftaroline; Cephalosporin Resistance; Cephalosporins; Cross Infection; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Prospective Studies; Staphylococcal Infections

Topics: Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Humans; Male; Methicillin Resistance; Middle Aged; Prodrugs; Prosthesis-Related Infections; Staphylococcal Infections; Surgical Procedures, Operative; Surgical Wound Infection; Treatment Outcome

The only clinically available cephalosporin with in vivo and in vitro activity against methicillin-resistant Staphylococcus aureus is ceftaroline, which is approved for the treatment of soft tissue infection and community-acquired pneumonia in doses of 600 mg intravenously every 12 hours for 2 weeks or less. However, many clinicians use ceftaroline to treat more serious infections and dose more frequently (every 8 hours) for longer periods of time.. A retrospective medication safety assessment was performed at two centers where agranulocytosis was observed in four patients (two at each center) who were treated with ceftaroline. The cases were reviewed by the treating physicians for common features, and the frequency of agranulocytosis was calculated based on the total number of treated patients.. We report four cases of agranulocytosis associated with ceftaroline use, highlighted by prolonged use (more than 14 days) and 8-hour dosing intervals or 12-hour dosing intervals with concomitant clindamycin therapy. When ceftaroline (600 mg every 12 hours) and clindamycin (900 mg every 8 hours) were coadministered for more than 2 weeks, the frequency of agranulocytosis was 18% (2 of 18 patients treated). When ceftaroline alone was administered for more than 2 weeks at 600 mg every 8 hours, agranulocytosis occurred in 5.4% (2 of 37 treated patients). No cases of ceftaroline-related agranulocytosis were seen that did not have these features. In these patients, granulocyte-colony stimulating factor therapy usually resulted in rapid myeloid recovery.. Clinicians should have a heightened awareness of agranulocytosis when using ceftaroline in such settings and monitor complete blood counts at least once/week.

Topics: Adult; Agranulocytosis; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clindamycin; Drug Therapy, Combination; Female; Fournier Gangrene; Humans; Male; Meningitis, Bacterial; Middle Aged; Retrospective Studies; Staphylococcal Infections; Surgical Wound Infection; Young Adult

The objectives of this study were to characterize contemporary MRSA isolates and understand the prevalence and impact of sequence variability in PBP2a on ceftaroline susceptibility.. A total of 184 MRSA isolates collected from 28 countries were collected and characterized.. WT PBP2a proteins were found in MRSA distributed evenly over the ceftaroline MIC range of 0.5-2 mg/L (n=56). PBP2a variations found in 124 isolates fell into two categories: (i) 12 isolates contained a substitution in the transpeptidase pocket located in the penicillin-binding domain and exhibited significantly decreased ceftaroline susceptibility (typically 8 mg/L); and (ii) isolates with substitutions in the non-penicillin-binding domain (nPBD) in a region proposed to be functionally important for cell wall biogenesis. The majority (71%) of isolates containing only nPBD variations were inhibited by 2 mg/L ceftaroline, 23% by ≤1 mg/L and 6% by 4 mg/L. These data suggest that the WT MRSA distribution extends beyond the current EUCAST and CLSI susceptible breakpoints and includes isolates inhibited by 2 mg/L ceftaroline. SCCmec type IV was the predominant type in the ceftaroline-susceptible population (68%), whereas it only represented 6% of the non-susceptible population. The variations of MLST lineages were fewer among the non-susceptible group.. This study suggests that MRSA populations with a WT PBP2a and those with nPBD variations overlap significantly and that PBP2a sequence-independent factors contribute to ceftaroline susceptibility. Whereas characterization of isolates with a ceftaroline MIC of 2 mg/L enriched for isolates with nPBD variations, it was not a discrete population. In contrast, the rare isolates containing a substitution in the transpeptidase-binding pocket were readily differentiated.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Ceftaroline; Cephalosporins; Genetic Variation; Genotype; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Penicillin-Binding Proteins; Staphylococcal Infections

Topics: Aged; Anti-Bacterial Agents; Aortic Valve; Bicuspid Aortic Valve Disease; Ceftaroline; Cephalosporins; Daptomycin; Endocarditis; Heart Defects, Congenital; Heart Valve Diseases; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbial Viability; Staphylococcal Infections; Treatment Outcome

Coagulase negative Staphylococcus continues generating interest in critically ill patients, due to their infections in extended admissions, in instrumented patients and due to their described multidrug resistance, which include glycopeptide heterorresistance and the increase in oxazolidinone resistance. Ceftaroline is a new cephalosporin with activity against resistant gram-positives, which, being betalactam, may provide adequate safety profile in the critical ill patient. The aim of this study was to determine the activity of ceftaroline and other antimicrobial agents against methicillin and linezolid-resistant Staphylococcus epidermidis.. We studied susceptibility of ceftaroline, tigecycline, daptomycin and vancomycin in a total of sixty-eight methicillin and linezolid-resistant S. epidermidis isolates with clinical significance from an Intensive Care Unit, using E-test.. All strains were susceptible to the four antimicrobial agents, regardless of the level of resistance to linezolid.. Ceftaroline could be an alternative in the treatment of methicillin and linezolid-resistant S. epidermidis infections in critically ill patients.

Topics: Anti-Bacterial Agents; Bacteremia; Body Fluids; Catheter-Related Infections; Ceftaroline; Cephalosporins; Critical Care; Cross Infection; Daptomycin; Drug Resistance, Multiple, Bacterial; Exudates and Transudates; Humans; Linezolid; Methicillin; Minocycline; Staphylococcal Infections; Staphylococcus epidermidis; Tigecycline; Vancomycin

A total of 421 methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates were tested for ceftaroline susceptibility by Etest (bioMérieux). A multidrug resistant phenotype was found in 40.9%, and clonal complex 239 (CC239) was found in 33.5%. Ceftaroline nonsusceptibility (MIC, >1.0 μg/ml) was 16.9% overall. Nonsusceptibility was significantly higher in CC239 (41.1%, 58/141) and in isolates with a multidrug resistant phenotype (35.5%, 61/172) compared with comparators (P < 0.0001). Nonsusceptibility of common multidrug resistant MRSA clones limits the empirical use of ceftaroline for these infections.

Topics: Anti-Bacterial Agents; Australia; Ceftaroline; Cephalosporins; Clone Cells; Drug Resistance, Multiple, Bacterial; Humans; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Phenotype; Staphylococcal Infections

The in vitro activities of ceftaroline and comparators, using broth microdilution, were determined against 1,066 Staphylococcus aureus isolates from hospitalized patients. Seventeen medical centers from Latin American countries contributed isolates. Methicillin-resistant S. aureus (MRSA) percentages ranged from 46% (Brazil) to 62% (Argentina). All methicillin-susceptible S. aureus (MSSA) isolates were susceptible to ceftaroline. Ceftaroline activity against MRSA varied with MIC90s of 0.5 (Venezuela) to 2 (Brazil, Chile, and Colombia) μg/ml, which was the highest MIC value. ST-5 was the most common sequence type.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Hospitalization; Humans; Latin America; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Public Health Surveillance; Staphylococcal Infections

Right-sided infective endocarditis (RIE) is commonly due to Staphylococcus aureus and often involves the tricuspid valve (TV). A 31-year-old man with prior intravenous drug use presented with substernal pain, cough, dyspnoea and fever. Examination revealed a febrile, tachycardic male with peripheral infective endocarditis stigmata and right-heart failure. Laboratory parameters demonstrated leucocytosis, lactic acidosis and methicillin-resistant S. aureus (MRSA) bacteraemia. Echocardiography demonstrated multiple TV echodensities and chest imaging confirmed septic emboli. The MRSA species demonstrated 'vancomycin-creep', necessitating therapy with daptomycin and ceftaroline. Owing to persistent bacteraemia and septic shock, the patient underwent TV surgery, but continued to have a poor postoperative course with subsequent death. Indications for surgical therapy of RIE are limited to the European guidelines and most data are extrapolated from left-heart disease. MRSA exhibiting vancomycin-creep portends a poorer prognosis and requires aggressive therapy. We advocate the use of ceftaroline salvage therapy with daptomycin, pending further trials.

Topics: Adult; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Multiple, Bacterial; Endocarditis, Bacterial; Fatal Outcome; Heart Valve Diseases; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Mitral Valve; Staphylococcal Infections; Tricuspid Valve; Vancomycin

Topics: Administration, Intravenous; Aged; Bacteremia; Ceftaroline; Cephalosporins; Discitis; Drug Administration Schedule; Endocarditis; Humans; Kidney Failure, Chronic; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Renal Dialysis; Staphylococcal Infections

Forty-two medical centers from throughout the United States participating in a longitudinal surveillance program were asked to submit 100 consecutive Staphylococcus aureus isolates during July to December 2011. Susceptibility testing using CLSI broth microdilution and mecA detection by PCR analysis was performed on the 4,131 isolates collected. Methods employing Etest glycopeptide resistance detection (GRD; bioMérieux) and brain heart infusion agar containing 4 μg/ml vancomycin (BHIV) were used to screen methicillin-resistant S. aureus (MRSA) isolates for heterogeneous intermediate-level resistance to vancomycin (hVISA). Isolates with positive hVISA screen results were confirmed by population analysis profiling-area under the curve (PAP-AUC) determinations. The genetic relatedness of hVISA, ceftaroline-nonsusceptible, or high-level (HL) mupirocin resistance MRSA isolates was assessed by pulsed-field gel electrophoresis (PFGE). Among 2,093 MRSA isolates, the hVISA screen results were positive with 47 isolates by Etest GRD and 30 isolates by BHIV agar screen. Twenty-five of the GRD- or BHIV screen-positive isolates were confirmed as hVISA by PAP-AUC testing. Results of the current study were compared to results obtained from prior surveillance performed in 2009. The prevalence of hVISA among MRSA isolates was higher in 2011 than in 2009 (1.2% versus 0.4%, P = 0.003), especially for isolates with a vancomycin MIC of 2 (45.4% versus 14.3%, P = 0.01). The overall rate of ceftaroline susceptibility in the current study was 99.4% (one hVISA isolate had an intermediate ceftaroline MIC). HL mupirocin resistance increased from 2.2% in 2009 to 3.2% in 2011 (P = 0.006). Although overall rates of hVISA and HL mupirocin resistance are low, they have increased since 2009.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Electrophoresis, Gel, Pulsed-Field; Epidemiological Monitoring; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mupirocin; Staphylococcal Infections; United States; Vancomycin; Vancomycin Resistance

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Cross Infection; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections

A case of a patient who received ceftaroline fosamil as salvage therapy for a methicillin-resistant Staphylococcus aureus (MRSA) epidural abscess is reported.. A 48-year-old white woman arrived at the emergency department (ED) with an altered mental status. She had been to the ED two days prior with complaints of sudden-onset and worsening neck pain. She had a history of compacted disks in her neck secondary to a motor vehicle accident that occurred three years prior but that did not require surgical intervention. Computed tomography and magnetic resonance imaging scans confirmed an epidural abscess with wound cultures growing MRSA. The admitting physician indicated that the patient was severely septic. Acyclovir, ceftriaxone, and vancomycin were initiated for empirical treatment due to suspected meningitis. Paired blood cultures also continued to grow MRSA in four of four bottles collected four days after admission. This indicated that antimicrobial therapy was not successfully eradicating the MRSA found in the blood and the patient's clinical status was deteriorating. Ceftaroline was used as salvage therapy, resulting in rapid clearance of MRSA from the blood and the patient becoming afebrile in 24 hours. Blood culture tests on hospital day 11-one day after ceftaroline initiation-were clear of MRSA. The patient was discharged to a long-term-care facility and ordered ceftaroline fosamil 600 mg i.v. every 12 hours for four weeks.. A MRSA epidural abscess in a 48-year-old woman was successfully treated with ceftaroline fosamil 600 mg every 12 hours as salvage therapy.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Therapy, Combination; Emergency Medical Services; Epidural Abscess; Female; Humans; Laminectomy; Long-Term Care; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Neck Pain; Salvage Therapy; Staphylococcal Infections; Thrombocytopenia; Tomography, X-Ray Computed

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with broad-spectrum in vitro activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae (MDRSP), and common Gram-negative pathogens. This study investigated the in vivo activity of ceftaroline fosamil compared with clindamycin, linezolid, and vancomycin in a severe pneumonia model due to MRSA-producing Panton-Valentine leukocidin (PVL). A USA300 PVL-positive clone was used to induce pneumonia in rabbits. Infected rabbits were randomly assigned to no treatment or simulated human-equivalent dosing with ceftaroline fosamil, clindamycin, linezolid, or vancomycin. Residual bacterial concentrations in the lungs and spleen were assessed after 48 h of treatment. PVL expression was measured using a specific enzyme-linked immunosorbent assay (ELISA). Ceftaroline, clindamycin, and linezolid considerably reduced mortality rates compared with the control, whereas vancomycin did not. Pulmonary and splenic bacterial titers and PVL concentrations were greatly reduced by ceftaroline, clindamycin, and linezolid. Ceftaroline, clindamycin, and linezolid were associated with reduced pulmonary tissue damage based on significantly lower macroscopic scores. Ceftaroline fosamil, clindamycin, and, to a lesser extent, linezolid were efficient in reducing bacterial titers in both the lungs and spleen and decreasing macroscopic scores and PVL production compared with the control.

Topics: Animals; Anti-Bacterial Agents; Bacterial Toxins; Ceftaroline; Cephalosporins; Exotoxins; Leukocidins; Male; Methicillin-Resistant Staphylococcus aureus; Pneumonia; Rabbits; Staphylococcal Infections

Due to the ongoing concern about the reliability of Staphylococcus breakpoints (interpretive criteria) for other β-lactam agents, the Clinical and Laboratory Standards Institute recently approved the elimination of all breakpoints for antistaphylococcal β-lactams except for penicillin, oxacillin or cefoxitin, and ceftaroline. Routine testing of penicillin and oxacillin or cefoxitin should be used to infer susceptibility for all β-lactams with approved clinical indications for staphylococcal infections. It is critical for laboratories to reject requests for susceptibility testing of other β-lactams against staphylococci and to indicate that susceptibility to these agents can be predicted from the penicillin and oxacillin or cefoxitin results. This article reviews β-lactam resistance mechanisms in staphylococci, current antimicrobial susceptibility testing and reporting recommendations for β-lactams and staphylococci, and microbiologic data and clinical data supporting the elimination of staphylococcal breakpoints for other β-lactam agents.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactams; Cefoxitin; Ceftaroline; Cephalosporins; Humans; Microbial Sensitivity Tests; Oxacillin; Penicillins; Staphylococcal Infections; Staphylococcus; United States; United States Food and Drug Administration

A case of eosinophilic pneumonia in a patient receiving ceftaroline for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is reported.. A 65-year-old woman was admitted to a medical intensive care unit after arriving at the emergency room with complaints of progressively worsening shortness of breath. Her medical history included chronic obstructive pulmonary disease, acute respiratory distress syndrome, recent traumatic brain injury, tobacco use, and alcohol abuse. Within the first few days of hospitalization, the patient was diagnosed with MRSA pneumonia based on microbiological data from bronchoscopy bronchial washings. Her renal function liver enzyme levels were within normal limits. Empirical antibiotic therapy included i.v. vancomycin and meropenem and was narrowed to i.v. linezolid monotherapy based on culture and sensitivity results. After 10 days of treatment with linezolid, the patient was persistently febrile, and cultures remained positive. It was decided to switch therapy to a course of i.v. ceftaroline, an anti-MRSA cephalosporin. On the fifth day of treatment with ceftaroline, the patient developed respiratory decompensation and peripheral eosinophilia of 40%. Bronchoalveolar lavage (BAL) results indicated the presence of pulmonary eosinophilia of 13%. Chest radiographs revealed pulmonary infiltrates, and the computed tomography angiography showed no evidence of pulmonary embolism. Ceftaroline was discontinued, and the patient was started on vancomycin and methylprednisolone. The patient responded to methylprednisolone therapy, with repeat BAL and peripheral blood counts showing resolved eosinophilia.. A patient with risk factors for respiratory disease developed eosinophilic pneumonia after receiving ceftaroline for the treatment of MRSA pneumonia. Eosinophilia resolved after ceftaroline was discontinued and i.v. methylprednisolone was initiated.

Topics: Aged; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Ceftaroline; Cephalosporins; Drug Hypersensitivity; Female; Humans; Hypoxia; Methicillin-Resistant Staphylococcus aureus; Methylprednisolone; Penicillins; Pulmonary Disease, Chronic Obstructive; Pulmonary Eosinophilia; Staphylococcal Infections

Heteroresistance refers to the presence, within a large population of antimicrobial-susceptible microorganisms, of subpopulations with lesser susceptibilities. Ceftaroline is a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). The aim of this study was to detect the prevalence of ceftaroline heteroresistance in vitro in a select group of S. aureus strains. There were 57 isolates selected for evaluation, 20 MRSA, 20 vancomycin-intermediate S. aureus (VISA), 7 daptomycin-nonsusceptible S. aureus (DNSSA), 6 linezolid-nonsusceptible S. aureus (LNSSA), and 4 heteroresistant VISA (hVISA) isolates. MICs and minimal bactericidal concentrations were determined using the broth microdilution method according to CLSI guidelines. All of the isolates were analyzed by pulsed-field gel electrophoresis. The staphylococcal cassette chromosome mec element (SCCmec) types were determined by a multiplex PCR. Population analysis profiles (PAPs) were performed to determine heteroresistance for all of the isolates using plates made by adding various amounts of ceftaroline to brain heart infusion agar. The frequencies of resistant subpopulations were 1 in 10(4) to 10(5) organisms. We determined that 12 of the 57 (21%) isolates tested were ceftaroline-heteroresistant S. aureus (CHSA). CHSA occurred among strains with reduced susceptibilities to vancomycin, daptomycin, and linezolid but occurred in none of the USA-300 isolates tested. Evaluation of the heteroresistant strains demonstrated that the phenotype was unstable. Further studies are needed to determine whether CHSA has a role in clinical failures and to determine the implications of our study findings.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Vancomycin Resistance

Infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin and daptomycin has few adequate therapeutic options. Ceftaroline (CPT) is bactericidal against daptomycin (DAP)-nonsusceptible (DNS) and vancomycin-intermediate MRSA, but supporting data are limited for IE. This study evaluated the activities of ceftaroline, vancomycin, daptomycin, and the combination of ceftaroline plus daptomycin against DNS MRSA in a pharmacokinetic/pharmacodynamic (PK/PD) model of simulated endocardial vegetations (SEVs). Simulations of ceftaroline-fosamil (600 mg) every 8 h (q8h) (maximum concentration of drug in serum [Cmax], 21.3 mg/liter; half-life [t1/2], 2.66 h), daptomycin (10 mg/kg of body weight/day) (Cmax, 129.7 mg/liter; t1/2, 8 h), vancomycin (1 g) q8h (minimum concentration of drug in serum [Cmin], 20 mg/liter; t1/2, 5 h), and ceftaroline plus daptomycin were evaluated against 3 clinical DNS, vancomycin-intermediate MRSA in a two-compartment, in vitro, PK/PD SEV model over 96 h with a starting inoculum of ∼8 log10 CFU/g. Bactericidal activity was defined as a ≥ 3-log10 CFU/g reduction from the starting inoculum. Therapeutic enhancement of combinations was defined as ≥ 2-log10 CFU/g reduction over the most active agent alone. MIC values for daptomycin, vancomycin, and ceftaroline were 4 mg/liter, 4 to 8 mg/liter, and 0.5 to 1 mg/liter, respectively, for all strains. At simulated exposures, vancomycin was bacteriostatic, but daptomycin and ceftaroline were bactericidal. By 96 h, ceftaroline monotherapy offered significantly improved killing compared to other agents against one strain. The combination of DAP plus CPT demonstrated therapeutic enhancement, resulting in significantly improved killing versus either agent alone against 2/3 (67%) strains. CPT demonstrated bactericidal activity against DNS, vancomycin-intermediate MRSA at high bacterial densities. Ceftaroline plus daptomycin may offer more rapid and sustained activity against some MRSA in the setting of high-inoculum infections like IE and should also be considered.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Computer Simulation; Daptomycin; Drug Combinations; Endocarditis, Bacterial; Half-Life; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Endocarditis, Bacterial; Female; Humans; Male; Methicillin Resistance; Middle Aged; Salvage Therapy; Staphylococcal Infections; Staphylococcus; Treatment Outcome

Antimicrobial resistance has increased during the last few years, representing a public health concern. Among Gram-positive organisms, methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae are paradigms of resistance and of the dispersion of multiresistant clones. Ceftaroline, a broad-spectrum cephalosporin that includes MRSA and penicillin-resistant S. pneumoniae, is the first β-lactam antibiotic useful in infections due to MRSA. Phase-III clinical trials have demonstrated its efficacy in the treatment of community-acquired pneumonia and in skin and soft tissue infections, which are the current indications for ceftaroline. Due to its microbiological and pharmacological (PK/PD) profiles, these indications could be expanded to include bacteremia, endocarditis, and even osteoarticular infections. Another notable feature is the activity of this drug against Gram-negative bacilli susceptible to third generation cephalosporins, indicating that ceftaroline could be useful when these organisms are suspected or demonstrated in polymicrobial infections. Clinical follow-up of ceftaroline use will more clearly define future ceftaroline indications.

Topics: Ceftaroline; Cephalosporins; Drug Resistance, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections

Osteoarticular infections (OAI) include a wide-usually complex-spectrum of clinical scenarios. The approach is usually medical-surgical. In addition to this complexity, there is a low grade of evidence in the medical literature on these infections. Nevertheless, it is possible-and necessary-to integrate microbiological, pharmacological, experimental and clinical information to achieve the best possible clinical results. The most appropriate choice of antibiotic therapy largely depends on the clinical scenario and, obviously, on the microorganisms involved. Given the protagonism of staphylococci in OAI, it is appropriate to elucidate the role that could be played by a new antistaphylococcic agent in these infections. For clinicians who manage OAI, the incorporation of ceftaroline represents the recovery of a beta-lactam to treat methicillin-resistant staphylococci. This perspective can be used to guide the potential role of this new antibiotic for the management of OAI in various scenarios and the clinical research required for its introduction in clinical practice.

Topics: Arthritis; Bone Diseases, Infectious; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections

Ceftaroline, approved in Europe in 2012, has activity against methicillin-resistant Staphylococcus aureus (MRSA), with MIC90 values of 1-2 mg/L depending on geographical location. During a global 2010 surveillance programme, conducted prior to the European launch, 4 S. aureus isolates, out of 8037 tested, possessing ceftaroline MIC values of >2 mg/L were identified. The objective of this study was to characterize these four isolates to elucidate the mechanism of ceftaroline resistance.. MIC determinations were performed using broth microdilution and whole genome sequencing was performed to enable sequence-based analyses.. The only changes in proteins known to be required for full expression of methicillin resistance that correlated with the ceftaroline MIC were in penicillin-binding protein 2a (PBP2a). Isolates with a ceftaroline MIC of 2 mg/L had a Glu239Lys mutation in the non-penicillin-binding domain whereas the four isolates with ceftaroline MIC values of 8 mg/L carried an additional Glu447Lys mutation in the penicillin-binding domain. The impact of these mutations was analysed using the known X-ray structure of S. aureus PBP2a and a model for ceftaroline resistance proposed. Analysis of the core genomes showed that the isolates with reduced susceptibility to ceftaroline were epidemiologically related.. Mutations in PBP2a can affect the activity of ceftaroline against MRSA. Although a rare event, based on surveillance studies, it appears a first-step change in the non-penicillin-binding domain together with a second-step in the penicillin-binding domain may result in elevation of the ceftaroline MIC to >2 mg/L.

Topics: Amino Acid Substitution; Anti-Bacterial Agents; Bacterial Typing Techniques; Base Sequence; Ceftaroline; Cephalosporins; DNA, Bacterial; Drug Resistance, Bacterial; Genome, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Models, Molecular; Penicillin-Binding Proteins; Sequence Analysis, DNA; Staphylococcal Infections

Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin.. All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed.. Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis). Bacteremia persisted for a median of 10 days (range, 3-23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1-6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model.. Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacteremia; Cathelicidins; Ceftaroline; Cephalosporins; Daptomycin; Drug Therapy, Combination; Female; Humans; Male; Mice; Middle Aged; Salvage Therapy; Staphylococcal Infections; Staphylococcus

The case is described of a frail patient who developed prosthetic valve endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA). Conventional antimicrobial treatments either failed or were contraindicated, and the patient was judged unsuitable for a further valve replacement. A salvage therapy with high doses of a new cephalosporin, ceftaroline, given three times daily was undertaken; subsequently, the patient had not relapsed at two months after completing a six-week course of ceftaroline. Ceftaroline deserves major attention as an alternative choice in difficult-to-treat MRSA endocarditis.

Topics: Aged; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Endocarditis, Bacterial; Frail Elderly; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Prosthesis-Related Infections; Staphylococcal Infections; Treatment Outcome

In light of the in vivo/in vitro discordance among beta-lactams against Gram-negative pathogens, we compared the in vivo pharmacodynamics of humanized ceftaroline against 9 Staphylococcus aureus strains (MICs of 0.13 to 1 mg/liter) from published in vitro studies using standard and high inocula in the murine thigh infection model. Consistent with the in vitro findings, mean reductions of ≥1 log10 CFU were observed for ceftaroline against all strains using both standard and high inocula. These results suggest in vivo/in vitro concordance with no observed inoculum effect.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Female; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Penicillin-Binding Proteins; Staphylococcal Infections; Staphylococcus aureus

Ceftaroline (CPT), the active metabolite of the prodrug ceftaroline-fosamil (CPT-F), demonstrates in vitro bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and is effective in rabbit models of difficult-to-treat MRSA endocarditis and acute osteomyelitis. However, its in vivo efficacy in a prosthetic joint infection (PJI) model is unknown. Using a MRSA-infected knee PJI model in rabbits, the efficacies of CPT-F or vancomycin (VAN) alone and combined with rifampin (RIF) were compared. After each partial knee replacement with a silicone implant that fit into the tibial intramedullary canal was performed, 5 × 10(7) MRSA CFU (MICs of 0.38, 0.006, and 1 mg/liter for CPT, RIF, and VAN, respectively) was injected into the knee. Infected animals were randomly assigned to receive no treatment (controls) or CPT-F (60 mg/kg of body weight intramuscularly [i.m.]), VAN (60 mg/kg i.m.), CPT-F plus RIF (10 mg/kg i.m.), or VAN plus RIF starting 7 days postinoculation and lasting for 7 days. Surviving bacteria in crushed tibias were counted 3 days after ending treatment. Although the in vivo mean log10 CFU/g of CPT-treated (3.0 ± 0.9, n = 12) and VAN-treated (3.5 ± 1.1, n = 12) crushed bones was significantly lower than those of controls (5.6 ± 1.1, n = 14) (P < 0.001), neither treatment fully sterilized the bones (3/12 were sterile with each treatment). The mean log10 CFU/g values for the antibiotics in combination with RIF were 1.9 ± 0.5 (12/14 were sterile) for CPT-F and 1.9 ± 0.5 (12/14 were sterile) for VAN. In this MRSA PJI model, the efficacies of CPT-F and VAN did not differ; thus, CPT appears to be a promising antimicrobial agent for the treatment of MRSA PJIs.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Disease Models, Animal; Drug Resistance, Bacterial; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Prosthesis-Related Infections; Rabbits; Staphylococcal Infections; Vancomycin

Ceftaroline is the first member of a novel class of cephalosporins approved for use in the United States. Although prior studies have identified eight ceftaroline-resistant methicillin-resistant Staphylococcus aureus (MRSA) isolates in Europe and Asia with MICs ranging from 4 to 8 mg/liter, high-level resistance to ceftaroline (>32 mg/liter) has not been described in MRSA strains isolated in the United States. We isolated a ceftaroline-resistant (MIC > 32 mg/liter) MRSA strain from the blood of a cystic fibrosis patient and five MRSA strains from the respiratory tract of this patient. Whole-genome sequencing identified two amino acid-altering mutations uniquely present in the ceftaroline-binding pocket of the transpeptidase region of penicillin-binding protein 2a (PBP2a) in ceftaroline-resistant isolates. Biochemical analyses and the study of isogenic mutant strains confirmed that these changes caused ceftaroline resistance. Thus, we identified the molecular mechanism of ceftaroline resistance in the first MRSA strain with high-level ceftaroline resistance isolated in the United States.

Topics: Adult; Amino Acid Substitution; Anti-Bacterial Agents; Base Sequence; Binding Sites; Ceftaroline; Cephalosporins; Cystic Fibrosis; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; MutS DNA Mismatch-Binding Protein; Penicillin-Binding Proteins; Sequence Analysis, DNA; Staphylococcal Infections; Young Adult

Elevated minimum inhibitory concentrations (MICs) of vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) and the emergence of heteroresistant S. aureus strains have led to increased use of anti-MRSA antibiotics other than vancomycin. Ceftaroline fosamil is a novel cephalosporin with activity against MRSA, but there are limited clinical data on its use for MRSA bacteraemia (MRSAB) and against strains exhibiting high vancomycin MICs (2-4 μg/mL). This multicentre, retrospective, case-control study compared the microbiological and clinical effectiveness of ceftaroline used after vancomycin failure with that of vancomycin-treated controls for the treatment of MRSA with vancomycin MICs ≥ 2 μg/mL. In total, 32 patients were matched 1:1 with respect to vancomycin MIC, age and origin of bacteraemia. In the ceftaroline group, patients received prior MRSA therapy for a median of 5 days [interquartile range (IQR), 3-15.8 days] prior to switching to ceftaroline. Median time to eradication of MRSA was significantly less after treatment with ceftaroline compared with vancomycin [4 days (IQR, 3-7.5 days) vs. 8 days (IQR, 5.8-19.5 days); P=0.02]. Both clinical success at the end of treatment and recurrence of MRSA at Day 7 were trending towards being inferior in the vancomycin group, although the results did not attain statistical significance [81% vs. 44% (P=0.06) and 6% vs. 38% (P=0.08), respectively]. Ceftaroline added at the point of vancomycin failure resolves MRSAB more rapidly and with a higher rate of clinical success, therefore ceftaroline should be considered as an alternative for these difficult-to-treat infections.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Case-Control Studies; Ceftaroline; Cephalosporins; Demography; Disease Eradication; Female; Glycopeptides; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Staphylococcal Infections; Time Factors; Treatment Failure; Vancomycin

Topics: Anti-Bacterial Agents; Bacterial Infections; Ceftaroline; Cephalosporins; Drug Approval; Drug Industry; Drug Resistance, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Translational Research, Biomedical

Topics: Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Cross Infection; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Staphylococcal Infections

Topics: Algorithms; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Opportunistic Infections; Postoperative Care; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections

Topics: Aged; Arthroplasty, Replacement, Hip; Ceftaroline; Cephalosporins; Dose-Response Relationship, Drug; Drug Therapy, Combination; Femoral Neck Fractures; Humans; Infusions, Intravenous; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Opportunistic Infections; Reoperation; Soft Tissue Infections; Staphylococcal Infections; Surgical Wound Infection

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections

An in vitro single-compartment dilutional pharmacokinetic model was used to study the pharmacodynamics of ceftaroline against Staphylococcus aureus (both methicillin-susceptible S. aureus [MSSA] and methicillin-resistant S. aureus [MRSA]). Mean serum free concentrations of ceftaroline (the active metabolite of the prodrug ceftaroline fosamil) dosed in humans at 600 mg every 12 h (q12h) were simulated, and activities against 12 S. aureus strains (3 MSSA strains and 9 MRSA strains, 3 of which had a vancomycin-intermediate phenotype) were determined. Ceftaroline produced 2.5- to 4.0-log10-unit reductions in viable counts by 24 h with all strains and a 0.5- to 4.0-log-unit drop in counts at 96 h. The antibacterial effect could not be related to the strain MIC across the ceftaroline MIC range from 0.12 to 2.0 μg/ml. In dose-ranging studies, the cumulative percentage of a 24-h period that the free drug concentration exceeded the MIC under steady-state pharmacokinetic conditions (fT(MIC)) of 24.5% ± 8.9% was associated with a 24-h bacteriostatic effect, one of 27.8% ± 9.5% was associated with a -1-log-unit drop, and one of 32.1% ± 8.1% was associated with a -2-log-unit drop. The MSSA and MRSA strains had similar fT(MIC) values. fT(MIC) values increased with increasing duration of exposure up to 96 h. Changes in ceftaroline population analysis profiles were related to fT(MIC). fT(MIC)s of <50% were associated with growth on 4× MIC recovery plates at 96 h of drug exposure. These data support the use of ceftaroline fosamil at doses of 600 mg q12h to treat S. aureus strains with MICs of ≤ 2 μg/ml. An fT(MIC) of 25 to 30% would make a suitable pharmacodynamic index target, but fTMIC values of ≥ 50% are needed to suppress the emergence of resistance and require clinical evaluation.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Humans; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Models, Biological; Staphylococcal Infections; Staphylococcus aureus

Vancomycin, linezolid, and daptomycin are very active against staphylococci, but isolates with decreased susceptibility to these antimicrobial agents are isolated sporadically. A total of 19,350 Staphylococcus aureus isolates (51% methicillin resistant [MRSA]) and 3,270 coagulase-negative staphylococci (CoNS) were collected consecutively from 82 U.S. medical centers from January 2008 to December 2011 and tested for susceptibility against ceftaroline and comparator agents by the reference broth microdilution method. Among S. aureus strains, 14 isolates (0.07%) exhibited decreased susceptibility to linezolid (MIC, ≥ 8 μg/ml), 18 (0.09%) to daptomycin (MIC, ≥ 2 μg/ml), and 369 (1.9%) to vancomycin (MIC, ≥ 2 μg/ml; 368 isolates at 2 μg/ml and 1 at 4 μg/ml). Fifty-one (1.6%) CoNS were linezolid resistant (MIC, ≥ 8 μg/ml), and four (0.12%) were daptomycin nonsusceptible (MIC, ≥ 2 μg/ml). Ceftaroline was very active against S. aureus overall (MIC50/90, 0.5/1 μg/ml; 98.5% susceptible), including MRSA (MIC50/90, 0.5/1 μg/ml; 97.2% susceptible). All daptomycin-nonsusceptible and 85.7% of linezolid-resistant S. aureus isolates were susceptible to ceftaroline. Against S. aureus isolates with a vancomycin MIC of ≥ 2 μg/ml, 91.9, 96.2, and 98.9% were susceptible to ceftaroline, daptomycin, and linezolid, respectively. CoNS strains were susceptible to ceftaroline (MIC50/90, 0.25/0.5 μg/ml; 99.1% inhibited at ≤ 1 μg/ml), including methicillin-resistant (MIC50/90, 0.25/0.5 μg/ml), linezolid-resistant (MIC50/90, 0.5/0.5 μg/ml), and daptomycin-nonsusceptible (4 isolates; MIC range, 0.03 to 0.12 μg/ml) strains. In conclusion, ceftaroline demonstrated potent in vitro activity against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin, and it may represent a valuable treatment option for infections caused by these multidrug-resistant staphylococci.

Topics: Acetamides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Hospitals; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

We present a case of eosinophilic pneumonia due to ceftaroline used for the treatment of methicillin-resistant Staphylococcus aureus bacteremia associated with a postoperative spinal infection. Our patient developed shortness of breath and hypoxemia on the fifth week of ceftaroline therapy. Chest imaging disclosed diffuse bilateral infiltrates. Laboratory abnormalities included peripheral eosinophilia and eosinophilic predominant bronchoalveolar lavage fluid. The combination of ceftaroline discontinuation plus initiation of steroid treatment resulted in complete resolution of signs, symptoms, and radiologic abnormalities. We speculate about possible mechanisms underlying this adverse event and diagnostic criteria for drug-induced eosinophilic pneumonia.

Topics: Anti-Bacterial Agents; Bronchoalveolar Lavage Fluid; Ceftaroline; Cephalosporins; Glucocorticoids; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Pulmonary Eosinophilia; Staphylococcal Infections

Topics: Anti-Bacterial Agents; Blood Proteins; Ceftaroline; Ceftriaxone; Cephalosporins; Microbial Sensitivity Tests; Protein Binding; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

The Clinical Assessment Program and TEFLARO Utilization Registry (CAPTURE) is a multicentre retrospective cohort study in the USA describing treatment of acute bacterial skin and skin structure infection (ABSSSI) with ceftaroline fosamil (CPT-F). Charts for review were chosen by random selection. Among 647 evaluable patients, 52% were obese, 46% had diabetes mellitus (DM), and 19% had peripheral vascular disease (PVD). Methicillin-resistant Staphylococcus aureus (MRSA) was recovered in 28% and methicillin-susceptible S. aureus (MSSA), 11%. Antibiotics were administered prior to CPT-F treatment in 80%, and concurrently in 39%. Clinical success overall was 85%; in patients with DM, 83%; with PVD, 76%; and in obese patients, 88%. Clinical success was ≥ 79% across all infection types; 81% for MRSA and 83% for MSSA; and 86% for ceftaroline monotherapy and 84% for concurrent therapy. These high clinical success rates support CPT-F as an effective treatment option for ABSSSI, including infections due to MRSA and patients with significant co-morbidities.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ceftaroline; Cephalosporins; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Retrospective Studies; Skin; Skin Diseases, Bacterial; Skin Diseases, Infectious; Staphylococcal Infections; Young Adult

Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging pathogen that cause severe community- and hospital-acquired infections. Studies continue on searching alternatives due to the limited number of therapeutic options in MRSA infections. Ceftaroline is a wide-spectrum new generation cephalosporin which has been begun to be used in treatment of skin and respiratory tract infections caused by MRSA. The aim of this study was to investigate the in vitro activity of ceftaroline against MRSA strains isolated from various clinical specimens in microbiology laboratories of seven hospitals located at different provinces (Bolu, Samsun, Rize, Tekirdag, Sakarya, Amasya, Osmaniye) of Turkey. A total of 192 MRSA isolates (89 skin/wound/abscess, 38 blood, 36 respiratory tract, 29 urine/sterile body fluids/catheter) were included in the study, and ceftaroline susceptibilities of the strains were detected by broth microdilution method. MIC values of 181 (94.3%) isolates were determined as ≤ 1 µg/ml meaning of susceptible according to the criteria of CLSI, and MIC values of 11 (5.7%) isolates were found as 2 µg/mL indicating intermediate susceptibility. The range of MIC values of the isolates was found between 0.25-2 µg/ml. The rates of intermediate isolates have varied between 0-12.5% from the participating centers. MIC50 and MIC90 values of all the isolates were determined as 0.5 µg/ml and 1 µg/ml, respectively. No significant differences were found between the centers in terms of mean MIC values (p> 0.05). MIC50 and MIC90 values in Samsun and Bolu isolates were found to be the same with the whole group, however, MIC50 and MIC90 were 0.5 µg/ml and 0.5 µg/ml in Amasya isolates and 1 µg/ml and 1 µg/ml in Rize, Tekirdag, Osmaniye and Sakarya isolates, respectively. When evaluating MIC50 and MIC90 values and isolation rates of intermediate strains according to the specimen types, there were no significant differences (p> 0.05). Susceptibility rates to ceftaroline and the distribution profiles of MIC values of the isolates obtained from seven centers of Turkey have been detected similar with the previous American and European reports. With this study, initial data on the activity of ceftaroline against MRSA were obtained from Turkey. These preliminary findings indicate that ceftaroline is effective even on Turkish isolates and can be a suitable treatment in cases requiring wide-spectrum antimicrobiotic use, however further large-scaled studies are needed.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Turkey

There are many limitations to the current antibiotics used for the treatment of severe methicillin-resistant Staphylococcus aureus (MRSA) infections. Ceftaroline is a new fifth-generation cephalosporin approved for the treatment of skin and soft tissue infections caused by MRSA and community-acquired pneumonia. We propose that ceftaroline can also be used successfully in more severe MRSA infections, including endocarditis. We conducted a retrospective chart review in a university-affiliated Department of Veterans Affairs hospital in San Diego, California (USA) of ten inpatients treated with ceftaroline for severe MRSA infection, including five cases of probable endocarditis (including two endocardial pacemaker infections), one case of pyomyositis with possible endocarditis, two cases of pneumonia (including one case of empyema), two cases of septic arthritis (including one case of prosthetic joint infection), and two cases of osteomyelitis. Seven of the 10 patients achieved microbiological cure. Six of the 10 patients achieved clinical cure. Seven patients were discharged from the hospital. Three patients were placed on comfort care and expired in the hospital; one achieved microbiological cure before death, and two remained bacteremic at time of death. In most patients, ceftaroline was effective for treatment of MRSA bacteremia and other severe MRSA infections. Adverse effects seen included rash, eosinophilia, pruritus, and Clostridium difficile infection. Ceftaroline can be a safe and effective drug for treatment of severe MRSA infections, and further comparative studies are warranted.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Arthritis, Infectious; Bacteremia; Ceftaroline; Cephalosporins; Endocarditis, Bacterial; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Osteomyelitis; Pneumonia, Staphylococcal; Prodrugs; Retrospective Studies; Staphylococcal Infections; Treatment Outcome

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Debridement; Drug Resistance, Bacterial; Endocarditis, Bacterial; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Osteomyelitis; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin

One of the newest methicillin-resistant Staphylococcus aureus (MRSA) antibiotics to receive FDA approval is ceftaroline fosamil, a member of a new subclass of cephalosporins with unique activity against MRSA. However, ceftaroline is currently only FDA approved for complicated skin/soft tissue infections and community-acquired pneumonia; there are currently no clinical data regarding its use in MRSA bacteraemia and endocarditis. We report a series of six patients in which ceftaroline was utilized as salvage monotherapy in persistent MRSA bacteraemia or endocarditis.. Using pharmacy records, 11 ceftaroline-treated patients were identified between January 2011 and November 2011 at University Health System and the South Texas Veterans Health Care System in San Antonio, TX, USA. All cases were reviewed and six patients received ceftaroline therapy for MRSA bacteraemia or endocarditis due to persistent or recurrent bacteraemia while on standard antibiotics (vancomycin or daptomycin).. All six patients experienced rapid clearance of their bacteraemia after starting ceftaroline. In the case of endocarditis for which the patient subsequently developed heart failure and required valve replacement, there was no evidence of growth from cultures taken from the excised valve, suggesting sterilization within 13 days of starting ceftaroline.. Ceftaroline exhibits potent anti-MRSA activity in both in vitro and animal studies, including rabbit endocarditis models; however, the lack of clinical data has limited its use in bacteraemia and endovascular infections in humans. We hope that this series serves as an initial stepping stone for further evaluation of this compound for more invasive infections due to MRSA.

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Endocarditis, Bacterial; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Salvage Therapy; Staphylococcal Infections; Texas; Treatment Outcome

To characterize the mechanisms responsible for elevated MICs of ceftaroline for methicillin-resistant Staphylococcus aureus (MRSA).. During the 2008 Assessing Worldwide Antimicrobial Resistance Evaluation ('AWARE') surveillance programme, four S. aureus collected from separate patients in Athens, Greece, demonstrated ceftaroline MICs of 4 mg/L. These isolates were clonally related and one strain (13101) was selected for further characterization. Two strains (4981 and 4977) displaying ceftaroline MICs of 1 and 2 mg/L, respectively, were included for comparison. All strains originated from the same hospital. Penicillin-binding protein (PBP) affinities for ceftaroline and comparators were determined. Strains were typed by single-locus typing (i.e. spa typing), multilocus sequence typing ('MLST') and by multiple-locus variable-number tandem repeat fingerprinting (MLVF). The presence of Pantone-Valentine leucocidin and the staphylococcal cassette chromosome mec types was assessed. We also performed nucleotide sequencing of the mecA (encoding PBP2a) promoter and ribosomal binding site (rbs) regions and mecR1.. Ceftaroline demonstrated the highest PBP2a affinity with strain 4981 (ST5-MRSA-II) (IC(50) 0.06 mg/L; MIC 1 mg/L). Strains 4977 and 13101 (both ST239-MRSA-III) showed indistinguishable MLVF profiles. Ceftaroline PBP2a binding affinity in strains 4977 (IC(50) 0.25 mg/L; MIC 2 mg/L) and 13101 (IC(50) 1 mg/L; MIC 4 mg/L) was 4- and 16-fold lower than 4981, respectively. Strain 4981 contains a wild-type PBP2a, while strains 4977 and 13101 have N(146)K and E(150)K alterations in the non-penicillin-binding domain. Additionally, 13101 has one substitution (H(351)N) in the transpeptidase domain. Alterations in the mecR1, mecA promoter or rbs regions were not observed.. Increased ceftaroline MICs were associated with decreased PBP2a binding affinity and reflected alterations in PBP2a.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Bacterial Proteins; Bacterial Toxins; Ceftaroline; Cephalosporins; DNA Fingerprinting; Exotoxins; Genotype; Greece; Humans; Leukocidins; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Sequence Data; Molecular Typing; Penicillin-Binding Proteins; Protein Binding; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Staphylococcal Infections; Virulence Factors

Treatment failure of methicillin-resistant Staphylococcus aureus (MRSA) remains an important concern. In order to investigate new MRSA treatment modalities, we used standard time-kill assays to determine the in vitro killing rate of 22 strains of MRSA by vancomycin, telavancin, daptomycin, and ceftaroline. Studies were carried out with 7-10-times the minimum bactericidal concentrations of each antibiotic in broth culture for 24 h, with subculture at 4, 8, and 24 h. We found that killing by ceftaroline closely paralleled that of vancomycin. Telavancin killed bacteria significantly more slowly, whereas daptomycin killed significantly more rapidly.

Topics: Aminoglycosides; Analysis of Variance; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Daptomycin; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin

Ceftaroline is a new cephalosporin with broad-spectrum activity against Gram-positive and -negative organisms. The prodrug of ceftaroline, ceftaroline fosamil, combined with the β-lactamase inhibitor avibactam (formerly NXL104), was tested against Enterobacteriaceae strains producing Ambler class A, B, C, and D enzymes, including strains producing multiple enzymes, as well as Pseudomonas aeruginosa, Acinetobacter spp., and methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MRSA) strains. Isolates were collected from 1999 to 2008 from global surveillance programs, and susceptibility testing was performed by reference broth microdilution methods. Ceftaroline-avibactam exhibited potent activity against Enterobacteriaceae producing various β-lactamase types (MIC(90), 0.25 to 2 μg/ml, except for metalloenzymes), including 99 strains carrying multiple enzymes (2 to 4 β-lactamases; MIC(90), 2 μg/ml). All isolates were inhibited by ceftaroline-avibactam at ≤4 μg/ml. Ceftaroline-avibactam (MIC(90), 0.5 to 1 μg/ml) was more active than meropenem (MIC(90), >8 μg/ml) and other comparators when tested against KPC-producing strains. S. aureus strains, including MRSA with four staphylococcal cassette chromosome mec (SCCmec) types, were dominantly (99.1%) inhibited by ceftaroline-avibactam at ≤2 μg/ml, and the ceftaroline MIC was not adversely affected by the addition of the β-lactamase inhibitor (MIC(50/90), 1 and 2 μg/ml for ceftaroline with and without avibactam). Ceftaroline-avibactam demonstrated limited activity against Acinetobacter spp. and P. aeruginosa (MIC(50)s, 32 and 16 μg/ml, respectively). These results document that ceftaroline-avibactam has potent activity against Enterobacteriaceae that produce KPC, various ESBL types (CTX-M types), and AmpC (chromosomally derepressed or plasmid-mediated enzymes), as well as against those producing more than one of these β-lactamase types, and its development as a therapeutic option for the treatment of infections caused by multidrug-resistant Enterobacteriaceae as well as MRSA is warranted.

Topics: Acinetobacter; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Ceftaroline; Cephalosporins; Chromosomes, Bacterial; Drug Combinations; Gram-Negative Bacterial Infections; Humans; Isoenzymes; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Plasmids; Pseudomonas aeruginosa; Staphylococcal Infections

Antistaphylococcal beta-lactams enhance daptomycin activity and have been used successfully in combination for refractory methicillin-resistant Staphylococcus aureus (MRSA) infections. Ceftaroline possesses MRSA activity, but it is unknown if it improves the daptomycin potency comparably to other beta-lactams. We report a complex patient case of endocarditis who was treated with daptomycin in combination with ceftaroline, which resulted in clearance of a daptomycin-nonsusceptible strain. An in vitro pharmacokinetic/pharmacodynamic model of renal failure was used to simulate the development of daptomycin resistance and evaluate the microbiologic effects of daptomycin plus ceftaroline treatment. Combination therapy with daptomycin and ceftaroline restored daptomycin sensitivity in vivo and resulted in clearance of persistent blood cultures. Daptomycin susceptibility in vitro was increased in the presence of either ceftaroline or oxacillin. Daptomycin at 6 mg/kg of body weight every 48 h was bactericidal in the model but resulted in regrowth and daptomycin resistance (MIC, 2 to 4 μg/ml) with continued monotherapy. The addition of ceftaroline at 200 mg every 12 h after the emergence of daptomycin resistance enhanced bacterial killing. Importantly, daptomycin plus ceftaroline as the initial combination therapy produced rapid and sustained bactericidal activity and prevented daptomycin resistance. Both in vivo- and in vitro-derived daptomycin resistance resulted in bacteria with more fluid cell membranes. After ceftaroline was added in the model, fluidity was restored to the level of the initial in vivo isolate. Daptomycin-resistant isolates required high daptomycin exposures (at least 10 mg/kg) to optimize cell membrane damage with daptomycin alone. Ceftaroline combined with daptomycin was effective in eliminating daptomycin-resistant MRSA, and these results further justify the potential use of daptomycin plus beta-lactam therapy for these refractory infections.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Daptomycin; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Infections; Ceftaroline; Cephalosporins; Clostridioides difficile; Drug Resistance, Multiple, Bacterial; Enterocolitis, Pseudomembranous; Fidaxomicin; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Streptococcal Infections; Streptococcus pneumoniae; Streptococcus pyogenes

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Infusions, Intravenous; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Skin Diseases, Bacterial; Staphylococcal Infections

The aim of this study was to compare the in vivo activities of the new antistaphylococcal drugs ceftaroline fosamil, daptomycin and tigecycline at projected human therapeutic doses against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains in a rabbit model of endocarditis.. The efficacy of therapeutic regimens in our model was evaluated following 4 days of treatment by determining colony counts of infected vegetations. Emergence of resistant variants during therapy was assessed.. Using this model of infective endocarditis, ceftaroline fosamil and daptomycin demonstrated high bactericidal in vivo activity (reduction of >5 log(10) cfu/g of vegetation) after a 4 day treatment against MSSA, MRSA and GISA strains. Both drugs were more efficacious than tigecycline, which showed moderate activity but failed to exhibit a bactericidal effect. Ceftaroline was superior to daptomycin in terms of sterilization of the vegetations. Emergence of resistant variants during daptomycin therapy was observed in two animals (one in the MSSA group and one in the MRSA group) but was not observed in ceftaroline- or tigecycline-treated animals.. The novel β-lactam agent ceftaroline fosamil was the most active bactericidal drug in this model and is a promising therapeutic option for the treatment of severe S. aureus infections, including those caused by MRSA and GISA strains.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Daptomycin; Disease Models, Animal; Drug Resistance, Bacterial; Endocarditis, Bacterial; Female; Methicillin-Resistant Staphylococcus aureus; Microbial Viability; Minocycline; Rabbits; Rodent Diseases; Staphylococcal Infections; Tigecycline; Treatment Outcome

This study assessed the pharmacodynamics of ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA), heteroresistant (h) vancomycin-intermediate S. aureus (hVISA), VISA and vancomycin-resistant S. aureus (VRSA) using an in vitro model.. Two methicillin-susceptible S. aureus (MSSA), one community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, one hVISA, three VISA and two VRSA were studied. The pharmacodynamic model was inoculated with a concentration of 1 × 10⁶ cfu/mL and ceftaroline dosed every 12 h (at 0 and 12 h) to simulate the ƒC(max) and t(½) obtained after administering 600 mg intravenously every 12 h (ƒC(max), 16 mg/L; t(½), 2.6 h). Samples were collected over 24 h to assess viable growth and changes in ceftaroline MIC over time.. Ceftaroline ƒT(> MIC) of ≥ 92% (ceftaroline MICs, ≤ 1 mg/L) was bactericidal (≥ 3 log₁₀ killing) against MSSA, CA-MRSA, HA-MRSA, hVISA, VISA and VRSA at 12 and 24 h. No bacterial regrowth occurred over the study period and no change in ceftaroline MIC was observed.. Ceftaroline ƒT(> MIC) of ≥ 92% (ceftaroline MICs, ≤ 1 mg/L) was bactericidal (≥ 3 log₁₀ killing) against MSSA, CA-MRSA, HA-MRSA, hVISA, VISA and VRSA at 12 and 24 h.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Cross Infection; Humans; In Vitro Techniques; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbial Viability; Staphylococcal Infections; Vancomycin Resistance

Topics: Ceftaroline; Cephalosporins; Community-Acquired Infections; Guidelines as Topic; Humans; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pneumonia; Staphylococcal Infections

Ceftaroline exhibits bactericidal activity against Gram-positive pathogens, including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, as well as common Gram-negative pathogens. This study evaluated the efficacy of human simulated exposures of ceftaroline against S. aureus in both the neutropenic and immunocompetent mouse thigh infection models. Twenty-six S. aureus isolates (4 MSSA, 22 MRSA) with ceftaroline MICs ranging from 0.125 to 4 μg/ml were collected. All isolates were tested in the neutropenic model and a subset of 13 MRSA isolates were tested in the immunocompetent model. Two hours after inoculation, a ceftaroline regimen that simulated the percentage of the dosing interval that free-drug concentrations remained above the MIC of the infecting organism (fT>MIC) of humans administered ceftaroline at 600 mg every 12 h (q12h) infused over 1 h was given. The change in log(10) CFU/ml after 24 h of treatment was analyzed relative to the 0- and 24-h controls for neutropenic and immunocompetent mice, respectively. The human simulated regimen resulted in efficacy against all isolates tested in both infection models. In the neutropenic model, a 0.95 to 3.28 log(10) CFU/ml reduction was observed when compared with the 0-h control, whereas for the immunocompetent model, all isolates obtained a >1 log(10) CFU/ml reduction (log(10) CFU/ml reduction range: 1.06 to 2.43) in bacterial density. Irrespective of immune competency, a reduction in bacterial density was observed at the highest MIC of 4 μg/ml (fT>MIC of 27.5%). Human simulated exposures of ceftaroline 600 mg q12h provided predictable efficacy against all tested S. aureus isolates in the mouse thigh model independent of immune status. These data support the clinical utility of ceftaroline against S. aureus, including MRSA, with MICs of ≤4 μg/ml.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Female; Genotype; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Phenotype; Staphylococcal Infections; Staphylococcus aureus; Thigh

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Methicillin Resistance; Pneumonia, Bacterial; Skin Diseases, Bacterial; Staphylococcal Infections

The aim of this study was to evaluate the in vitro activity of ceftaroline and its potential for synergy with tobramycin in comparison with vancomycin against a collection of hospital-acquired meticillin-resistant Staphylococcus aureus (HA-MRSA), including isolates with reduced susceptibility to glycopeptides. Ceftaroline, vancomycin, daptomycin and linezolid susceptibilities were determined for 200 HA-MRSA isolates. Four randomly selected strains [including one vancomycin-intermediate S. aureus (VISA) and one heteroresistant VISA (hVISA)] were evaluated in time-kill experiments with ceftaroline and vancomycin alone or combined with tobramycin at 0.25 and 0.5 times the minimum inhibitory concentration (MIC). MICs for 50% and 90% of the organisms (MIC(50) and MIC(90), respectively) were both 1mg/L for ceftaroline and were 1 mg/L and 2 mg/L, respectively, for vancomycin. The same ceftaroline MIC ranges (0.25-2 mg/L) were observed for isolates recovered from respiratory tract samples, blood or skin. In time-kill experiments, no synergy was observed at 0.25 x MIC against any tested isolates with either ceftaroline or vancomycin. In contrast, the combination of ceftaroline plus tobramycin at 0.5 x MIC was synergistic against the two MRSA strains and the hVISA but was indifferent against the VISA isolate. In conclusion, ceftaroline demonstrated antimicrobial activity independently of the specimen source and exhibited lower MICs than vancomycin. Finally, at sub-MIC levels, ceftaroline plus tobramycin displayed significantly greater activity than vancomycin plus tobramycin against MRSA (P < 0.01).

Topics: Acetamides; Ceftaroline; Cephalosporins; Cross Infection; Daptomycin; Drug Synergism; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Tobramycin; Vancomycin

A dramatic increase in infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has been observed, in part as a result of the epidemic of community-associated MRSA skin and skin-structure infections (SSSIs). Simultaneously, decreasing sensitivities of S. aureus to vancomycin have been reported and invasive infections caused by these strains have been associated with worse clinical outcomes. Clearly, new agents active against MRSA are needed. Ceftaroline is a new cephalosporin active against MRSA and many Gram-negative bacteria, though it is not active against Pseudomonas spp. and extended spectrum beta-lactamase producers (ESBL).. In this review we focus on the properties of ceftaroline such as in vitro activity, the pharmacokinetic and pharmacodynamic characteristics, and its efficacy and safety observed in the clinical trials of patients with SSSI. Finally, we provide an overview of the possible future role of ceftaroline and other compounds in development for the treatment of SSSIs. The literature search was based on PubMed articles plus review of the abstracts presented in the most important international conferences in the field.. The reader will gain clear concepts to understand the value that ceftaroline might have in the treatment of SSSIs, including those caused by MRSA.. Ceftaroline has shown bactericidal activity against common pathogens associated with SSSIs including MRSA, noninferiority in clinical trials of patients with complicated SSSI (cSSSI), and a favorable safety profile.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Staphylococcal Infections

To evaluate the activity of a new cephalosporin, ceftaroline, in comparison with other antistaphylococcal drugs (linezolid and vancomycin) at projected human therapeutic doses against methicillin-resistant Staphylococcus aureus (MRSA) and glycopeptide-intermediate S. aureus (GISA) strains.. Using a rabbit experimental model of acute osteomyelitis, efficacy was assessed following 4 days of treatment by colony counts of infected bone tissues (joint fluid, femoral bone marrow and bone).. Although vancomycin remains the standard treatment for MRSA osteomyelitis, it was ineffective against the MRSA strain and poorly active against GISA infections in this model. Ceftaroline and linezolid demonstrated significant activity in bone marrow and bone, and were significantly better than vancomycin treatment. However, ceftaroline was the only drug to exhibit significant activity against MRSA in infected joint fluid.. The present study supports ceftaroline as a promising therapeutic option for the treatment of severe MRSA infections, including osteomyelitis.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Bone and Bones; Bone Marrow; Ceftaroline; Cephalosporins; Disease Models, Animal; Female; Linezolid; Methicillin-Resistant Staphylococcus aureus; Osteomyelitis; Oxazolidinones; Rabbits; Staphylococcal Infections; Treatment Outcome; Vancomycin

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Ceftaroline; Cephalosporins; Disease Models, Animal; Endocarditis, Bacterial; Endocardium; Female; Injections, Intramuscular; Methicillin-Resistant Staphylococcus aureus; Rabbits; Staphylococcal Infections; Treatment Outcome

Ceftaroline fosamil is a new β-lactam antibiotic with an altered 3' side chain that allows it to interact with penicillin-binding protein (PBP) 2a, resulting in lower MIC values for methicillin-resistant Staphylococcus aureus (MRSA). Large MRSA collections repeatedly demonstrate MIC₉₀ values of 1 mg/L. The pharmacokinetics for ceftaroline fosamil are straightforward and reminiscent of many other cephalosporin antibiotics, with a terminal half-life of ∼2.6 h. Pharmacodynamic evaluation demonstrates that relatively short free drug T  >  MIC results in stasis or 1 log₁₀ cfu/g bacterial kill (mean values for four S. aureus isolates of 26% and 33% of the dosing interval, respectively). Monte Carlo simulation demonstrated high expected target attainment rates (> 97%) and clinical trial data showed clinically evaluable and microbiologically evaluable cure rates (96.7%) that are highly concordant with the pharmacodynamic analyses. Clinical trial data for ceftaroline fosamil are in excellent concordance with the pharmacodynamic analysis. Ceftaroline fosamil at a dose of 600 mg administered intravenously every 12 h is highly likely to be successful in clinical practice for treatment of complicated skin and skin structure infections.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Half-Life; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Penicillin-Binding Proteins; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections

Two investigational anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) beta-lactams, ceftaroline (a cephalosporin) and ME1036 (a carbapenem), were subjected to susceptibility testing by reference broth microdilution methods using 152 strains of community-acquired MRSA from the United States (47 medical centers). Ceftaroline and ME1036 were 64- and >128-fold more potent than ceftriaxone, respectively. All isolates had the Panton-Valentine leukocidin genes and staphylococcal cassette chromosome mec type IV, while 67.8% of isolates displayed pulsed-field gel electrophoresis clonal type USA300-0114.

Topics: Anti-Bacterial Agents; beta-Lactams; Carbapenems; Ceftaroline; Cephalosporins; Community-Acquired Infections; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; United States

Forest Laboratories (following its acquisition of Cerexa Inc, a spin-out from Peninsula Pharmaceuticals Inc), under license from Takeda, is developing ceftaroline fosamil, an N-phosphono prodrug of ceftaroline, a derivative of a fourth-generation cephalosporin, for the potential treatment of methicillin-resistant Staphylococcus aureus infection. Phase III clinical trials evaluating ceftaroline fosamil for community acquired pneumonia and complicated skin and skin structure infections are underway.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Humans; Methicillin Resistance; Molecular Structure; Patents as Topic; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship

Using the rabbit endocarditis model, we compared the activity of a new broad-spectrum cephalosporin, ceftaroline, with those of linezolid and vancomycin against methicillin-resistant Staphylococcus aureus. After a 4-day treatment, ceftaroline exhibited superior bactericidal in vivo activity against resistant S. aureus strains and appeared to be the most effective drug against a heterogeneous glycopeptide-intermediate S. aureus strain.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Area Under Curve; Ceftaroline; Cephalosporins; Chromatography, High Pressure Liquid; Colony Count, Microbial; Endocarditis, Bacterial; Immunoenzyme Techniques; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Oxazolidinones; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin; Vancomycin Resistance

TAK-599 is a water-soluble prodrug of a cephalosporin compound, T-91825. In vitro and in vivo antibacterial activities of T-91825 and TAK-599, respectively, were examined. T-91825 was active against both gram-positive and gram-negative bacteria, unlike vancomycin and linezolid, which are inactive against gram-negative bacteria. The 90% minimum inhibitory concentration of T-91825 against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) was 2 micro g/ml. This activity was comparable to those of vancomycin, linezolid, teicoplanin, and arbekacin. T-91825 was similarly active against vancomycin-intermediate S. aureus. In a time-kill study, T-91825 showed more rapid and distinct decrease of viable cells of two MRSA strains than did vancomycin and linezolid in vitro. The effect of TAK-599 against systemic infection caused by clinical isolates of MRSA in mice was comparable or superior to that of vancomycin, linezolid, teicoplanin, and arbekacin. In addition, TAK-599 at a dose of 20 mg/kg significantly decreased bacterial counts in lungs of mice in an experimental pneumonia model caused by MRSA in which vancomycin and linezolid were totally ineffective at the same dose. These results suggest the usefulness of TAK-599 in the treatment of MRSA infections in humans.

Topics: Animals; Butyrates; Ceftaroline; Cephalosporins; Disease Models, Animal; Enterococcus; Male; Methicillin Resistance; Mice; Mice, Inbred CBA; Mice, Inbred ICR; Microbial Sensitivity Tests; Oxazoles; Pneumonia, Bacterial; Staphylococcal Infections; Staphylococcus