ppi-0903 and Skin-Diseases--Infectious

Skin and soft tissue infections (SSTIs) are a common cause of hospital admission among elderly patients, and traditionally have been divided into complicated and uncomplicated SSTIs. In 2010, the FDA provided a new classification of these infections, and a new category of disease, named acute bacterial skin and skin structure infections (ABSSSIs), has been proposed as an independent clinical entity. ABSSSIs include three entities: cellulitis and erysipelas, wound infections, and major cutaneous abscesses This paper revises the epidemiology of SSTIs and ABSSSIs with regard to etiologies, diagnostic techniques, and clinical presentation in the hospital settings. Particular attention is owed to frail patients with multiple comorbidities and underlying significant disease states, hospitalized on internal medicine wards or residing in nursing homes, who appear to be at increased risk of infection due to multi-drug resistant pathogens and treatment failures. Management of ABSSSIs and SSTIs, including evaluation of the hemodynamic state, surgical intervention and treatment with appropriate antibiotic therapy are extensively discussed.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenems; Ceftaroline; Cephalosporins; Daptomycin; Female; Fluoroquinolones; Glycopeptides; Hospitalization; Humans; Iatrogenic Disease; Internal Medicine; Linezolid; Lipoglycopeptides; Male; Minocycline; Oxazolidinones; Skin Diseases, Infectious; Soft Tissue Infections; Teicoplanin; Tigecycline; Vancomycin

Only a parenteral formulation of ceftaroline is commercially available, and the prodrug, ceftaroline fosamil, is hydrolyzed quickly and completely upon intravenous administration. Ceftaroline is relatively minimally bound to plasma proteins (15-28 %), with a volume of distribution of 30-40 L. Ceftaroline undergoes minimal metabolism and does not appear to be a cytochrome P450 substrate. Its renal clearance (e.g. 4-7 L/h after multiple dosing) approximates glomerular filtration rate, with a terminal half-life of ~2.6 h in healthy subjects. The pharmacokinetics of ceftaroline have been described thoroughly in clinical investigations primarily conducted by the manufacturer. Despite its indications for treating skin and skin structure infections (SSSI) or community-acquired pneumonia (CAP), some studies that contributed data to the final drug labelling were conducted only in healthy volunteers. A significant amount of data have been contributed by the drug maker, and the overall quality of the pharmacodynamics and clinical data, based on our critical analysis provided in this review, is strong. Ceftaroline can be considered as a therapeutic alternative for complicated SSSI and CAP (Pneumonia Outcome Research Team Class III-IV). The current dosing regimen of ceftaroline 600 mg intravenously every 12 h appears sufficient to establish pharmacokinetic-pharmacodynamic relationships and achieve optimal clinical efficacy. More clinical studies are needed to define the place of ceftaroline in therapy for SSSI, CAP, and other indications such as osteomyelitis, endocarditis, and other types of pneumonia. Moreover, continued development in population modelling incorporating more patient-specific data would allow further analysis to identify intrinsic and extrinsic factors that influence the pharmacokinetics of ceftaroline in humans.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Drug Administration Schedule; Humans; Pneumonia; Precision Medicine; Skin Diseases, Infectious

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil (Zinforo, Teflaro), is an advanced-generation, parenteral cephalosporin with broad-spectrum antibacterial activity in vitro against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant Streptococcus pneumoniae and Gram-negative bacteria, including Haemophilus influenzae and Moraxella catarrhalis, but not Pseudomonas aeruginosa. Ceftaroline has demonstrated a low potential for the selection of resistance in vitro for drug-resistant Gram-positive organisms, including MRSA, as well as for Gram-negative respiratory pathogens. In pivotal phase III studies, intravenous ceftaroline fosamil demonstrated noninferiority to intravenous vancomycin plus aztreonam in patients hospitalized with complicated skin and soft tissue infections (cSSTIs) and intravenous ceftriaxone in patients hospitalized with community-acquired pneumonia (CAP) [Pneumonia Outcomes Research Team (PORT) risk class III or IV]; however, patients with CAP admitted to the intensive care unit were not evaluated. Ceftaroline fosamil was generally well tolerated in these trials, with an adverse event profile similar to that of other cephalosporins. Diarrhoea was the most commonly reported adverse event; however, the risk of Clostridium difficile-associated diarrhoea with ceftaroline fosamil appeared to be low. Potential limitations of the drug include the lack of an oral formulation and the requirement for twice-daily administration. Nonetheless, ceftaroline fosamil represents an attractive option (either alone or in combination with other agents) for the initial empirical treatment of patients hospitalized with cSSTIs (including those with suspected MRSA infection) or CAP (PORT risk class III or IV) who require intravenous antimicrobial therapy. As with all antibacterial agents, ceftaroline fosamil should be used in accordance with good antimicrobial stewardship.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Humans; Pneumonia; Skin Diseases, Infectious; Soft Tissue Infections

Ceftaroline, the bioactive metabolite of ceftaroline fosamil (previously PPI-0903, TAK-599), is a broad-spectrum cephalosporin with potent in vitro activity against multidrug-resistant gram-positive aerobic pathogens, including methicillin-resistant Staphylococcus aureus. A randomized, observer-blinded study to evaluate the safety and efficacy of ceftaroline versus standard therapy in treating complicated skin and skin structure infections (cSSSI) was performed. Adults with cSSSI, including at least one systemic marker of inflammation, were randomized (2:1) to receive intravenous (i.v.) ceftaroline (600 mg every 12 h) or i.v. vancomycin (1 g every 12 h) with or without adjunctive i.v. aztreonam (1 g every 8 h) for 7 to 14 days. The primary outcome measure was the clinical cure rate at a test-of-cure (TOC) visit 8 to 14 days after treatment. Secondary outcomes included the microbiological success rate (eradication or presumed eradication) at TOC and the clinical relapse rate 21 to 28 days following treatment. Of 100 subjects enrolled, 88 were clinically evaluable; the clinical cure rate was 96.7% (59/61) for ceftaroline versus 88.9% (24/27) for standard therapy. Among the microbiologically evaluable subjects (i.e., clinically evaluable and having had at least one susceptible pathogen isolated at baseline), the microbiological success rate was 95.2% (40/42) for ceftaroline versus 85.7% (18/21) for standard therapy. Relapse occurred in one subject in each group (ceftaroline, 1.8%; standard therapy, 4.3%). Ceftaroline exhibited a very favorable safety and tolerability profile, consistent with that of marketed cephalosporins. Most adverse events from ceftaroline were mild and not related to treatment. Ceftaroline holds promise as a new therapy for treatment of cSSSI and other serious polymicrobial infections.

Topics: Adult; Anti-Bacterial Agents; Aztreonam; Ceftaroline; Cephalosporins; Female; Humans; Male; Methicillin Resistance; Middle Aged; Recurrence; Skin Diseases, Infectious; Streptococcus agalactiae; Treatment Outcome; 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