ppi-0903 and Pneumonia--Staphylococcal

Staphylococcus aureus (S. aureus), including methicillin-resistant S. aureus (MRSA), is an important aetiological cause of community-acquired pneumonia (CAP) and associated with significant morbidity and mortality. Empiric therapy for CAP frequently consists of β-lactam monotherapy or β-lactam/macrolide combination therapy. However, such agents are often ineffective against S. aureus and do not reflect the emergence and increasing prevalence of MRSA in the community setting. Ceftaroline fosamil is a fifth-generation parenteral cephalosporin with broad-spectrum activity against Gram-positive pathogens - such as S. aureus (including MRSA), Streptococcus pneumoniae and Streptococcus pyogenes - and typical Gram-negative pathogens, including Haemophilus influenzae and Moraxella catarrhalis. The approval of ceftaroline fosamil in the United States and Europe for the treatment of adults with moderate-to-severe CAP was based on two phase 3 trials (FOCUS 1 and 2), which demonstrated that ceftaroline fosamil was non-inferior to ceftriaxone, a standard empiric treatment for CAP, while exhibiting a comparable safety profile. Although head-to-head trials of ceftaroline fosamil versus comparators against MRSA CAP are lacking, the effectiveness of ceftaroline fosamil in subpopulations of patients not covered by phase 3 trials (e.g. those with MRSA CAP or severe renal impairment) has been demonstrated in the Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) study. As ineffective empiric therapy is associated with adverse outcomes, including mortality and increased costs, ceftaroline fosamil, with its extended spectrum of activity, is an attractive alternative to standard antibiotic CAP regimens.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Clinical Trials, Phase III as Topic; Community-Acquired Infections; Drug-Related Side Effects and Adverse Reactions; Humans; Pneumonia, Staphylococcal; Staphylococcus aureus; Treatment Outcome

Ceftriaxone is an empirical antibiotic commonly used to treat pneumonia. However, its use to treat infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) is controversial given limited evidence of its clinical efficacy. The objective of this study was to compare the clinical efficacy of ceftriaxone with either ceftaroline or ceftobiprole in the treatment of pneumonia caused by MSSA. A systematic review and meta-analysis of randomised controlled trials (RCTs) comparing clinical cure in patients with pneumonia who received ceftriaxone versus those who received either ceftaroline or ceftobiprole was conducted. Patients who received ceftriaxone plus vancomycin were excluded. The PubMed, Embase and Cochrane Library databases as well as clinical trial registries were searched up to 8 June 2018. Risk differences (RDs) with 95% confidence intervals (CIs) were estimated using a random-effects model and assessing for heterogeneity (I

Topics: Adolescent; Adult; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Pneumonia, Staphylococcal; Randomized Controlled Trials as Topic; Staphylococcus aureus; Treatment Outcome; Young Adult

Over the last 50 years methicillin-resistant S. aureus (MRSA) spread globally. Vancomycin is still the most recommended antibiotic for MRSA-infections. Teicoplanin is an alternative glycopeptide with longer elimination half-life. Telavancin is a more recently developed derivative of vancomycin with similar clinical efficacy as vancomycin. It is not recommended for treatment of patients with renal insufficiency. Nephrotoxicity limits the therapeutic use of glycopeptide antibiotics. The oxazolidinone linezolid exhibits similar to superior therapeutic efficacy. Hematologic controls are necessary during treatment with this antibacterial agent. Neurotoxic effects have been observed mainly in patients who received prolonged linezolid treatment. Attention must be paid to possible interactions with concomitantly given drugs acting on the serotonergic system. New therapeutic options arise with ceftaroline, the first β-lactam antibiotic with activity against MRSA. However, controlled clinical trials with pulmonary MRSA infections have not been conducted with ceftaroline. Daptomycin, a lipopeptide, and tigecycline, a glycylcyclin are active in vitro against MRSA as well, but are also not indicated in pulmonary MRSA infections. These antibiotics show in an exemplary manner that antibacterial activity in vitro is an important prerequisite, but relevant data for a therapeutic decision should be derived from randomized controlled clinical double-blind trials.

Topics: Acetamides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Evidence-Based Medicine; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Oxazolidinones; Pneumonia, Staphylococcal; Treatment Outcome; Vancomycin

We report here the first pharmacokinetic-pharmacodynamic relationship for ceftaroline in a preterm infant born at <28 weeks' gestational age who was given ceftaroline (8.5 mg/kg every 8 hours) for pneumonia attributable to methicillin-resistant Staphyloccocus aureus. This dose of ceftaroline was adequate to achieve the pharmacodynamic endpoint associated with efficacy for methicillin-resistant Staphyloccocus aureus.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Therapy, Combination; Fatal Outcome; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Staphylococcal; Rifampin

To compare the concordance of ceftaroline MIC values by reference broth microdilution (BMD) and Etest (bioMérieux, France) for MSSA and MRSA isolates obtained from PREMIUM (D372SL00001), a European multicentre study.. Ceftaroline MICs were determined by reference BMD and by Etest for 1242 MSSA and MRSA isolates collected between February and May 2012 from adult patients with community-acquired pneumonia or complicated skin and soft tissue infections; tests were performed across six European laboratories. Selected isolates with ceftaroline resistance in broth (MIC >1 mg/L) were retested in three central laboratories to confirm their behaviour.. Overall concordance between BMD and Etest was good, with >97% essential agreement and >95% categorical agreement. Nevertheless, 12 of the 26 MRSA isolates found resistant by BMD scored as susceptible by Etest, with MICs ≤1 mg/L, thus counting as very major errors, whereas only 5 of 380 MRSA isolates found ceftaroline susceptible in BMD were miscategorized as resistant by Etest. Twenty-one of the 26 isolates with MICs of 2 mg/L by BMD were then retested twice by each of three central laboratories: BMD MICs of 2 mg/L were consistently found for 19 of the 21 isolates. Among 147 Etest results for these 21 isolates (original plus six repeats per isolate) 112 were >1 mg/L.. BMD and Etest have good overall agreement for ceftaroline against Staphylococcus aureus; nevertheless, reliable Etest-based discrimination of the minority of ceftaroline-resistant (MIC 2 mg/L) MRSA is extremely challenging, requiring careful reading of strips, ideally with duplicate testing.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Europe; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Staphylococcal; Staphylococcal Skin Infections; Staphylococcus aureus; Young Adult

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 common nosocomial pneumonia (NP) pathogen in US ICUs. Ceftaroline fosamil is a novel cephalosporin with activity against MRSA.. We retrospectively reviewed patients (pts) who received ceftaroline therapy for MRSA NP.. A total of 10 pts received ceftaroline from September 2011 to September 2012 for MRSA NP. Nine pts received prior anti-MRSA therapy before initiation of ceftaroline. Ceftaroline duration of therapy ranged from 4 to 28 days. Three pts pursued palliative care prior to completion of therapy and expired off antibiotics. Of the remaining seven pts, six pts were considered to have clinical cure or improvement either at the end of therapy with ceftaroline or total antibiotic treatment. One pt had a relapse 1 week after ceftaroline treatment.. This case series suggests the potential of ceftaroline as an alternative agent for the treatment of MRSA NP and warrants further investigation.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Cross Infection; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Pneumonia, Staphylococcal; Retrospective Studies

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Cross Infection; Daptomycin; Humans; Linezolid; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Minocycline; Oxazolidinones; Pneumonia, Staphylococcal; Tigecycline; Vancomycin; Virginiamycin

Community-acquired pneumonia (CAP) is a common infection in developed countries and causes a large number of hospital admissions and deaths. In recent years, the incidence of this disease has increased, caused by progressive population aging. Following the introduction of the conjugate vaccine against Streptococcus pneumoniae, there have been significant epidemiological changes that require close monitoring because of the possible emergence of new patterns of resistance. This article aims to review the role of ceftaroline fosamil, a new parenteral cephalosporin with antibacterial activity against Gram-negative and Gram-positive pathogens, in the treatment of pneumonia. Several in vitro and in vivo studies have shown the efficacy of ceftaroline fosamil against penicillin-resistant S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). Additionally, ceftaroline has shown similar efficacy and safety to ceftriaxone in the treatment of community-acquired pneumonia with severe prognosis (prognostic severity index III and IV) in two phase III clinical trials. Although a non-inferiority design was used for these clinical trials, some data suggest a superior efficacy of ceftaroline, with earlier clinical response and higher cure rate in infections caused by S. pneumoniae, making this drug particularly interesting for critically-ill patients admitted to the intensive care unit. Ceftaroline may also be considered for empirical and directed treatment of MRSA pneumonia.

Topics: Animals; Ceftaroline; Cephalosporins; Clinical Trials as Topic; Community-Acquired Infections; Cross Infection; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Pneumonia, Staphylococcal; Streptococcus pneumoniae

Methicillin-resistant Staphylococcus aureus (MRSA) hospital-acquired pneumonia (HAP) and healthcare-associated pneumonia (HCAP) patients treated with current antibiotic therapies have exhibited poor outcomes, increased hospital length of stay, and higher costs of care. The optimal management of these infections is undetermined; thus, it is critical to look at ways to improve outcomes in these patients. There is insufficient data on clinical efficacy in patients with MRSA HAP or HCAP infection treated with ceftaroline-fosamil. In a recent pilot study, nearly 90% of patients treated with ceftaroline-fosamil survived, despite the difficulties associated with administrating bactericidal antimicrobial therapy for this increasingly resistant pathogen. These data suggest a possible benefit in the use of ceftaroline-fosamil for MRSA pneumonia. Presently, we have identified cases over a two-year period treated with ceftaroline-fosamil, and will conduct a comparative analysis to controls (those treated with vancomycin and/or cefepime, and linezolid) to determine optimal therapeutic agents; these findings will have important implications for control of further spread of infection, recurrence, readmission, and mortality attributable to MRSA HAP and HCAP.

Topics: Ceftaroline; Cephalosporins; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Staphylococcal; Treatment Outcome

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

Ceftaroline fosamil is a cephalosporin with activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to characterize the dose-response relationship of ceftaroline fosamil against S. aureus in an immunocompromised murine pneumonia model, as well as to evaluate the efficacy of the humanized regimen of 600 mg intravenously (i.v.) every 12 h. Seventeen S. aureus (2 methicillin-susceptible Staphylococcus aureus [MSSA], 15 MRSA) isolates with ceftaroline MICs of 0.5 to 4 μg/ml were utilized. The pharmacokinetics of ceftaroline in serum and epithelial lining fluid (ELF) were evaluated to determine bronchopulmonary exposure profiles in infected and uninfected animals, using single and human-simulated doses. Serum fT>MIC (the percentage of time that free drug concentrations remain above the MIC) of 17% to 43% was required to produce a 1-log(10) kill in the dose-ranging studies. These targets were readily achieved with the humanized exposure profile, where decreases of 0.64 to 1.95 log(10) CFU were observed against 13 MRSA and both MSSA isolates tested. When taken as a composite, the fT>MICs required for stasis and a 1-log(10) kill were 16% and 41%, respectively. ELF concentrations were similar to serum concentrations across the dosing interval in infected and uninfected animals. The serum fT>MIC targets required in this lung infection model were similar to those observed with ceftaroline against S. aureus in a murine thigh infection model. Exposures simulating the human dose of 600 mg i.v. every 12 h achieved pharmacodynamic targets against MRSA and MSSA considered susceptible by current U.S. FDA breakpoints.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Dose-Response Relationship, Drug; Female; Humans; Immunocompromised Host; Lung; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Neutropenia; Pneumonia, Staphylococcal; Protein Binding