ppi-0903 and Gram-Negative-Bacterial-Infections

We conducted a national antimicrobial surveillance study of both gram-positive and gram-negative organisms isolated from hospitalized patients. This report presents data on antimicrobial susceptibility among 4998 organisms collected in China between 2012 and 2014.. The minimum inhibitory concentrations (MICs) and susceptibilities of ceftaroline/avibactam (CPA), ceftazidime/avibactam (CZA) and a range of comparative agents were determined according to guidelines established by the Clinical and Laboratory Standards Institute (CLSI).. The highest overall susceptibility levels for all Enterobacteriaceae during the study period were observed for CPA, CZA, doripenem (DOR), meropenem (MEM), and amikacin (AMK), which were all >90%. However, both CPT and CAZ alone and in combination with avibactam showed low activities for Acinetobacter spp., whereas CPA and CZA exhibited MIC90 values for Pseudomonas aeruginosa that were reduced by 4- and 8-fold, respectively, compared with those of CPT and CAZ. High susceptibilities of Acinetobacter spp. and P. aeruginosa to colistin and P. aeruginosa to AMK were observed. For the gram-positive strains, no significant activity changes were seen for Enterococcus, Staphylococcus, and viridans group streptococci to CPT or CAZ alone or in combination with avibactam, whereas Streptococcus pneumoniae and β-hemolytic Streptococcus showed almost 100% susceptibility to both CPT and CPA.. The addition of 4 mg/L avibactam greatly increased the activities of CPT and CAZ against most Enterobacteriaceae and P. aeruginosa isolates, whereas no significant changes were observed in Acinetobacter spp. or any of the gram-positive strains.

Topics: Acinetobacter; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftaroline; Ceftazidime; Cephalosporins; China; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hospitalization; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Public Health Surveillance

We report the structure-activity relationship analyses of 17 linear lipopeptide paenipeptin analogues. Analogues 7, 12, and 17 were more potent than the lead compound. Analogue 17 was active against carbapenem-resistant and polymyxin-resistant pathogens. This compound at 40 μg/mL resulted in 3 log and 2.6 log reductions of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, respectively, in catheter-associated biofilms in vitro. Analogue 17 showed little hemolysis at 32 μg/mL and lysed 11% of red blood cells at 64 μg/mL. Analogues 9 and 16 were nonhemolytic and retained potent P. aeruginosa-specific antimicrobial activity. These two analogues when used alone lacked activity against Acinetobacter baumannii and Klebsiella pneumoniae; however, analogue 9 and 16 at 4 μg/mL decreased the MIC of rifampicin and clarithromycin against the same pathogens from 16 to 32 μg/mL to nanomolar levels (sensitization factor: 2048-8192). Therefore, paenipeptins, alone or in combination with rifampicin or clarithromycin, are promising candidates for treating bacterial infections.

Topics: Anti-Bacterial Agents; Biofilms; Clarithromycin; Drug Synergism; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hemolysis; Humans; Lipopeptides; Microbial Sensitivity Tests; Paenibacillus; Rifampin; Structure-Activity Relationship

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

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

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