ppi-0903 and Gram-Positive-Bacterial-Infections

Infections caused by resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are now posing a major health risk for patients in hospital and community settings. There is a need to evaluate new antibiotics that would offer reliable clinical efficacy combined with a favorable safety profile for the treatment of such infections. Ceftaroline is a new member of the cephalosporin class of antibiotics with expanded activity against Gram-positive pathogens such as MRSA, vancomycin-intermediate S. aureus, vancomycin-resistant S. aureus and multidrug-resistant Streptococcus pneumoniae, while retaining good activity against common Gram-negative organisms. Phase II and III studies have shown ceftaroline to be an effective and well-tolerated treatment for complicated skin and skin-structure infections compared with standard therapy. Trials are ongoing in the treatment of community-acquired pneumonia.

Topics: Adult; Animals; Ceftaroline; Cephalosporins; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Mice; Skin Diseases, Bacterial; Treatment Outcome

Ceftaroline is a broad-spectrum cephalosporin antibiotic with activity against drug-resistant bacteria, including strains of methicillin-resistant Staphylococcus aureus (MRSA), and may be useful to prevent and treat ventriculostomy-related infections (VRIs). The purpose of this study was to analyze the pharmacokinetics and pharmacodynamics of prophylactic ceftaroline in neurosurgical patients with an external ventricular drain (EVD).. Adult patients in the neurosurgical intensive care unit with an EVD were given prolonged prophylaxis with ceftaroline. Serum and cerebral spinal fluid (CSF) were obtained simultaneously at 2, 6, and 12 h after initiation of the fourth dose of ceftaroline and concentrations were measured by a liquid chromatography tandem mass spectrometry assay. Time-kill curves against isolates of coagulase-negative S. aureus, methicillin-sensitive S. aureus, MRSA, and Streptococcus pneumoniae were determined in serum and CSF at each collection time point.. A total of five patients with a mean age of 63 y and mean weight of 83 kg were enrolled. The mean CSF:serum penetration ratios of ceftaroline were 0.005 (0.5%), 0.021 (2.1%), and 0.043 (4.3%) at 2, 6, and 12 h, respectively. The mean ceftaroline exposure ratio area under the curve (AUC)csf/AUCserum) was 0.011 (1.1%). Bactericidal activity at each collection time point was observed against each strain of staphylococci from serum samples and a penicillin-sensitive strain of S. pneumoniae from CSF samples.. This investigation suggests that ceftaroline could have clinical utility for the prevention of VRIs in patients with EVDs.

Topics: Aged; Anti-Bacterial Agents; Antibiotic Prophylaxis; Ceftaroline; Cephalosporins; Drainage; Female; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Neurosurgical Procedures; Prosthesis-Related Infections; Staphylococcus; Streptococcus pneumoniae

Ceftaroline, with a unique activity against methicillin-resistant Staphylococcus aureus (MRSA), was not launched in Taiwan before 2019. The in vitro susceptibility data of ceftaroline against important Taiwanese pathogens are lacking.. The in vitro susceptibility of ceftaroline against important pathogens collected from 2012 through 2018 were extracted from the Antimicrobial Testing Leadership and Surveillance program. Broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) to ceftaroline against all isolates.. From the pharmacodynamic perspectives, the ceftaroline dosage of 600 mg as a 2-h intravenous infusion every 8 h is effective against all S. aureus and other Gram-positive isolates regardless of acquisition sites in Taiwan. Before ceftaroline is prescribed in treatment of the patient with Gram-negative infection, a cautious evaluation about patient's healthcare-associated factor is warranted.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Haemophilus; Humans; Klebsiella pneumoniae; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Respiratory Tract Infections; Soft Tissue Infections; Staphylococcus aureus; Taiwan

The unfavourable safety profile of aminoglycosides and the synergistic effects observed in vitro have prompted the development of novel dual β-lactam therapies, e.g. ampicillin/ceftriaxone or ampicillin/ceftaroline, for the treatment of Enterococcus faecalis endocarditis.. For comparison with in vitro chequerboard assay results, a partial chequerboard setup of ampicillin/gentamicin, ampicillin/ceftriaxone and ampicillin/ceftaroline against E. faecalis was established in the Galleria mellonella larval infection model.. Discrimination of synergistic and additive interactions was based on the evaluation of larval survival, bacterial quantity in the haemolymph and a pathology score index (internal to the workgroup). Single and multiple dosing schemes based on the half-life of ampicillin were applied. Pharmacokinetic data of the antibiotics in the larvae were determined via agar plate diffusion assays.. Ampicillin and ceftriaxone exhibited strain-specific synergistic interactions in the larvae under both dosing regimens, while the other two combinations showed additive effects. Ampicillin/ceftaroline was inferior to ampicillin/ ceftriaxone. Not all synergistic effects observed in vitro could be replicated in the larvae.. Our results suggest superior efficacy of ampicillin/ceftriaxone for the treatment of high-inoculum enterococcal infections, for at least some strains, but question the benefit of the current standard of adding the nephrotoxic gentamicin compared with the safer ceftriaxone. This is the first study to develop a scheme for differentiation between additive and synergistic effects in larvae and apply a multiple-antibiotic dosing scheme based on the pharmacokinetics of ampicillin. The model allows the analysis of synergistic effects of antimicrobials in an in vivo setting, but the clinical correlation warrants further study.

Topics: Ampicillin; Anti-Bacterial Agents; Ceftaroline; Ceftriaxone; Cephalosporins; Drug Synergism; Drug Therapy, Combination; Enterococcus faecalis; Gentamicins; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests

The combination of daptomycin (DAP) plus ampicillin (AMP), ertapenem (ERT), or ceftaroline has been demonstrated to be efficacious against a DAP-tolerant Enterococcus faecium strain (HOU503). However, the mechanism for the efficacy of these combinations against DAP-resistant (DAP-R) E. faecium strains is unknown.. We investigated the efficacy of DAP in combination with AMP, ERT, ceftaroline, ceftriaxone, or amoxicillin against DAP-R E. faecium R497 using established in vitro and in vivo models. We evaluated pbp expression, levels of penicillin-binding protein (PBP) 5 (PBP5) and β-lactam binding affinity in HOU503 versus R497.. DAP plus AMP was the only efficacious regimen against DAP-R R497 and prevented emergence of resistance. DAP at 8, 6, and 4 mg/kg in combination with AMP was efficacious but showed delayed killing compared with 10 mg/kg. PBP5 of HOU503 exhibited amino acid substitutions in the penicillin-binding domain relative to R497. No difference in pbp mRNA or PBP5 levels was detected between HOU503 and R497. labeling of PBPs with Bocillin FL, a fluorescent penicillin derivative, showed increased β-lactam binding affinity of PBP5 of HOU503 compared with that of R497.. Only DAP (10 mg/kg) plus AMP or amoxicillin was efficacious against a DAP-R E. faecium strain, and pbp5 alleles may be important contributors to efficacy of DAP plus β-lactam therapy.

Topics: Ampicillin; Animals; Anti-Bacterial Agents; beta-Lactams; Ceftaroline; Cephalosporins; Daptomycin; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Endocarditis, Bacterial; Enterococcus faecium; Ertapenem; Gram-Positive Bacterial Infections; Microbial Sensitivity Tests; Rats; Sequence Alignment; Transcriptome

The clinical experience of ceftaroline fosamil (CPT-F) therapy for Gram-positive infective endocarditis is reported from CAPTURE, a retrospective study conducted in the USA.. Data, including patient demographics, medical history, risk factors, microbiological aetiology and clinical outcomes, were collected by review of patient charts between September 2013 and February 2015.. Patients (n=55) with Gram-positive endocarditis were treated with CPT-F. The most common risk factors were intravascular devices (43.6%), diabetes mellitus (40.0%) and injection drug use (38.2%). The most commonly isolated pathogens were meticillin-resistant Staphylococcus aureus (MRSA; 80%), meticillin-susceptible S. aureus (MSSA; 7.3%) and coagulase-negative staphylococci (7.3%). CPT-F was given as first-line therapy in 7.3% of patients and as second-line or later therapy in 92.7% of patients, and as monotherapy in 41.8% of patients and as concurrent therapy in 58.2% of patients. Clinical success was observed in 82.6% (19/23) of patients treated with CPT-F as monotherapy. In patients treated with CPT-F as first-line therapy or second-line or later therapy, 75.0% (3/4) and 70.6% (36/51) achieved success, respectively. Clinical success was observed in 77.3% (34/44) of patients with MRSA and 25% (1/4) of patients with MSSA. Two patients discontinued treatment with CPT-F due to an adverse event.. CPT-F treatment was associated with a high rate of clinical success in patients with Gram-positive infective endocarditis, including those with risk factors and infections caused by MRSA. A high rate of clinical success was observed in patients treated with CPT-F used as first- line therapy or second-line or later therapy, or as monotherapy or in combination with other antibiotics.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Endocarditis, Bacterial; Female; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Retrospective Studies; Treatment Outcome; United States; Young Adult

Enterococci frequently cause severe biofilm-associated infections such as endocarditis. The combination of ampicillin/ceftriaxone has recently been clinically evaluated as non-inferior compared with the standard therapy of ampicillin/gentamicin for treatment of Enterococcus faecalis endocarditis. Ceftaroline is a novel cephalosporin with enhanced activity against Gram-positive bacteria.. To compare the in vitro effectiveness of the ceftaroline/ampicillin combination with those of gentamicin/ampicillin and ceftriaxone/ampicillin in planktonic and biofilm cultures of clinical E. faecalis isolates.. Synergistic effects at the planktonic level were analysed by chequerboard assays in 20 E. faecalis isolates. Biofilm-eradicating and biofilm-preventing activities of the antibiotics and their combinations were determined by confocal laser scanning microscopy with quantification by quantitative biofilm analysis (qBA) algorithm and cfu/mL determination.. Comparable synergistic effects were observed for both β-lactam combinations in most isolates, in contrast to gentamicin/ampicillin. However, none of the antibiotic combinations succeeded in eradicating mature biofilms. Gentamicin showed promising biofilm-preventing activity, but at concentrations above those clinically tolerable. The β-lactams showed a U-shape dose-response relationship in biofilm prevention. Only exposure to cephalosporins caused alterations in cell morphology, which resulted in cell elongation and reclustering in a concentration-dependent manner. Reclustering was associated with high occurrences of small colony variants (SCVs), especially at high ceftriaxone concentrations.. This study suggests that combinations of cephalosporins or gentamicin with ampicillin may be advantageous only while bacteraemia persists, whereas combinations have no advantage over monotherapy regarding the treatment of mature biofilms. The selection of SCVs at high ceftriaxone concentrations is worth further study.

Topics: Adult; Aged; Aged, 80 and over; Ampicillin; Anti-Bacterial Agents; Biofilms; Ceftaroline; Ceftriaxone; Cephalosporins; Cohort Studies; Drug Synergism; Endocarditis, Bacterial; Enterococcus faecalis; Female; Gentamicins; Gram-Positive Bacterial Infections; Humans; Male; Microbial Sensitivity Tests; Middle Aged

In an era of increasing drug resistance and limited numbers of antimicrobials in the drug production pipeline, healthcare-associated infections represent a growing public health threat. When therapeutic options are limited, clinicians often resort to using antimicrobial combinations that produce a synergistic effect on the target pathogen. Novel antibiotics are therefore welcome in the daily practice of medicine. For example, ceftaroline is a broad-spectrum cephalosporin active against a variety of bacteria, including methicillin-resistant Staphylococcus aureus, but with limited activity against enterococci, particularly Enterococcus faecium. In this study, we tested the efficacy of ceftaroline against clinical isolates of gram-positive bacteria (S. aureus, Enterococcus faecalis, and E. faecium) by the broth microdilution and E-test assays, and then evaluated the synergistic effect of ceftaroline and ampicillin using the E-test method. The time-kill assay was used to confirm the data on selected strains. This drug combination has been recently shown to be effective against E. faecalis and could offer the advantage of cost-effectiveness (compared to other synergistic associations) as well as good tolerability. The E-test was chosen because of its relative simplicity of use that makes it suitable for routine clinical laboratories as a quick tool to guide clinicians when confronted with difficult-to-treat infections that may require an empirical approach. Our results indicate the presence of a synergistic effect of ceftaroline and ampicillin on most of the strains used, especially E. faecium and E. faecalis. The fact that two of those Enterococcus strains were vancomycin resistant suggests that the possible use of this combination for combating the spread of vancomycin-resistant enterococci should be explored.

Topics: Ampicillin; Anti-Bacterial Agents; Biological Assay; Ceftaroline; Cephalosporins; Drug Combinations; Drug Synergism; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Vancomycin Resistance

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: Ampicillin; Anti-Bacterial Agents; Bacteremia; Ceftaroline; Cephalosporins; Colony Count, Microbial; Drug Synergism; Enterococcus faecalis; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Microbial Viability

Ceftaroline was tested against 1859 clinically significant Gram-positive organisms from uncommonly isolated species. The organisms (31 species/groups) were collected from 133 medical centres worldwide over a 4-year period (2008-2011). Coagulase-negative staphylococci were generally susceptible to ceftaroline, with MIC50 values (minimum inhibitory concentration required to inhibit 50% of the isolates) of 0.06-0.5mg/L. Ceftaroline was active against Micrococcus spp. [minimum inhibitory concentration required to inhibit 90% of the isolates (MIC90)=0.06 mg/L], but showed more limited potency versus some Corynebacterium spp. and Listeria monocytogenes isolates. Ceftaroline was active against all β-haemolytic streptococci and viridans group streptococcal species/groups listed, with MIC50 and MIC90 values ranging from ≤ 0.015 mg/L to 0.03 mg/L and from ≤ 0.015 mg/L to 0.5mg/L, respectively. Based on these in vitro findings, ceftaroline may have a potential role in the treatment of infections caused by these rarer species as guided by reference MIC test results.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Epidemiological Monitoring; Global Health; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests

Topics: Ceftaroline; Ceftriaxone; Cephalosporins; Community-Acquired Infections; Cross Infection; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests

The in vitro activities of ceftaroline-avibactam, ceftaroline, and comparative agents were determined for a collection of bacterial pathogens frequently isolated from patients seeking care at 15 Canadian hospitals from January 2010 to December 2012. In total, 9,758 isolates were tested by using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (document M07-A9, 2012), with MICs interpreted by using CLSI breakpoints (document M100-S23, 2013). Ceftaroline-avibactam demonstrated potent activity (MIC90, ≤ 0.5 μg/ml) against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Morganella morganii, Citrobacter freundii, and Haemophilus influenzae; >99% of isolates of E. coli, K. pneumoniae, K. oxytoca, P. mirabilis, M. morganii, C. freundii, and H. influenzae were susceptible to ceftaroline-avibactam according to CLSI MIC interpretative criteria for ceftaroline. Ceftaroline was less active than ceftaroline-avibactam against all species of Enterobacteriaceae tested, with rates of susceptibility ranging from 93.9% (P. mirabilis) to 54.0% (S. marcescens). All isolates of methicillin-susceptible Staphylococcus aureus (MIC90, 0.25 μg/ml) and 99.6% of methicillin-resistant S. aureus isolates (MIC90, 1 μg/ml) were susceptible to ceftaroline; the addition of avibactam to ceftaroline did not alter its activity against staphylococci or streptococci. All isolates of Streptococcus pneumoniae (MIC90, 0.03 μg/ml), Streptococcus pyogenes (MIC90, ≤ 0.03 μg/ml), and Streptococcus agalactiae (MIC90, 0.015 μg/ml) tested were susceptible to ceftaroline. We conclude that combining avibactam with ceftaroline expanded its spectrum of activity to include most isolates of Enterobacteriaceae resistant to third-generation cephalosporins, including extended-spectrum β-lactamase (ESBL)- and AmpC-producing E. coli and ESBL-producing K. pneumoniae, while maintaining potent activity against staphylococci and streptococci.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Canada; Ceftaroline; Cephalosporins; Cross Infection; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Public Health Surveillance; Retrospective Studies

Although Gram-positive cocci are the most common pathogens in diabetic foot infections, these infections often are polymicrobial. The objective of this study was to assess the efficacy of a simulated human dose of 600 mg ceftaroline fosamil-600 mg avibactam every 8 h as a 1-h infusion in a polymicrobial in vivo murine model. Seven isolates were used (3 methicillin-resistant Staphylococcus aureus [MRSA] isolates, 1 methicillin-susceptible S. aureus [MSSA] isolate, 1 Escherichia coli isolate, 1 Enterobacter cloacae isolate, and 1 Bacteroides fragilis isolate) in various combinations in an immunocompromised polymicrobial tissue infection to assess the efficacy of the simulated regimen. Each infection was comprised of at least one S. aureus isolate with a MIC of 0.25 to 1 μg/ml and one Enterobacteriaceae isolate with a MIC of 1 or 4 μg/ml. Eight of 16 infections also included B. fragilis, with a MIC of 0.5 μg/ml, as a third organism. Efficacy was evaluated after 24 h as the change in log10 CFU from the level of 0-h controls. Efficacy was seen against all isolate combinations, with at least a 1-log kill against Enterobacteriaceae and a minimum of a 2-log kill against S. aureus and B. fragilis isolates. These bacterial reductions correlate with free drug concentration above the MIC (fT>MIC) produced by the humanized regimen of 100, 86, and 56% at MICs of 1, 2, and 4 μg/ml, respectively. The humanized regimen of 600 mg ceftaroline fosamil-600 mg avibactam every 8 h as a 1-h infusion showed predictable efficacy against all infections tested in this model. These data support further clinical investigation of ceftaroline fosamil-avibactam for the treatment of polymicrobial tissue infections.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Bacteroides fragilis; Ceftaroline; Cephalosporins; Coinfection; Drug Administration Schedule; Drug Combinations; Enterobacter cloacae; Escherichia coli; Female; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Immunocompromised Host; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Treatment Outcome