ppi-0903 and Enterobacteriaceae-Infections

The widespread diffusion of extended-spectrum β-lactamases (ESBLs)-producing Enterobacteriales currently represents a major threat for public health worldwide. Carbapenems are currently considered the first-line choice for serious ESBL infections. However, the dramatic global increase in ESBL prevalence has led to a significant overuse of carbapenems that has promoted the selection and spread of carbapenemases, which might further prejudicated our ability to treat infections due to multidrug-resistant pathogens. Therefore, strategies to limit the use of carbapenems should be implemented.. Although piperacillin-tazobactam should no longer be considered an alternative to carbapenems for definitive treatment of bloodstream infections due to ESBL-producing strains, it might still represent an alternative for step-down therapy or for low-to-moderate severity infection originating from urinary or biliary sources and when piperacillin-tazobactam minimum inhibitory concentration of 4 mg/l or less. Ceftazidime-avibactam and ceftolozane-tazobactam are both carbapenem sparing agents that appear interesting alternatives for treatment of serious ESBL infections. New β-lactams/β-lactamase inhibitors (BL/BLI), including cefepime-enmetazobactam, ceftaroline fosamil-avibactam, aztreonam-avibactam and cefepime-zidebactam, are also promising agents for treatment of ESBL infections, but further clinical data are needed to establish their efficacy relative to carbapenems. The role of carbapenems/β-lactamase inhibitors remain to be clarified.. New BL/BLI have distinctive specificities and limitations that require further investigations. Future randomized clinical trials are required to define the best strategy for their administering for ESBL infections.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Carbapenems; Ceftaroline; Ceftazidime; Cephalosporins; Cyclooctanes; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Public Health; Sepsis; Tazobactam

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

Pharmacodynamics of β-lactamase inhibitors are an area of intense interest as new β-lactam/β-lactamase inhibitor combinations enter clinical development and clinical practice. Avibactam, a non-β-lactam β-lactamase inhibitor, has been combined with ceftaroline or ceftazidime but these two combinations have not been directly compared.. Using an in vitro pharmacokinetic model we simulated human drug concentration-time courses associated with ceftaroline 600 mg every 8 h and ceftazidime 2000 mg every 8 h. Avibactam was given by continuous infusion at a range of concentrations up to 10 mg/L and antibacterial effect assessed against a CTX-M-producing Escherichia coli , AmpC-hyperproducing Enterobacter cloacae and KPC-producing Klebsiella pneumoniae. Simulations were performed over 72 h.. Avibactam, at a concentration of 1-2 mg/L, produced maximum bacterial clearance over 72 h for the E. coli and E. cloacae strains with both ceftaroline and ceftazidime. Avibactam (4 mg/L) was required for maximum reduction in bacterial load with the KPC-producing K. pneumoniae. A series of dose fractionation experiments were performed with avibactam against each of the three strains and AUC, C max or T  >   avibactam concentration of 1, 2 or 4 mg/L related to antibacterial effect as measured by change in bacterial count at 24 h. AUC or C max were best related to 24 h antibacterial effect for avibactam though there was no consistent pattern favouring one over the other.. As AUC is a much easier and more reliable pharmacokinetic measure than C max , it would be useful to explore how AUC-based indices for avibactam exposures could be used for translating the results of the present study into patients' therapy.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Ceftaroline; Ceftazidime; Cephalosporins; Computer Simulation; Drug Therapy, Combination; Enterobacter cloacae; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests

Dose-ranging experiments were performed to study the pharmacodynamics of ceftaroline against Enterobacteriaceae.. A range of fT>MIC values (0%-100%) were simulated over 96 h using a single-compartment dilutional in vitro pharmacokinetic model using Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Citrobacter koseri and Serratia marcescens (n = 16). Antibacterial effect was assessed by change in viable count and population profiles by growth on ceftaroline MIC ×2, ×4 and ×8 agar plates. The fT>MIC (%) was related to antibacterial effect using a sigmoid Emax model.. The 24 h bacteriostatic effect fT>MIC was 39.7% ± 15.7% and 43.2% ± 15.6% for a -1 log drop for all strains. E. coli required lower exposures than K. pneumoniae, i.e. 24 h fT>MIC for a -3 log drop in viable count was 40.0% ± 9.6% and 84.8% ± 15.2% for K. pneumoniae. Similarly at 96 h, fT>MIC was >100% for K. pneumoniae (for four of five strains), 27.2%-66.2% for E. coli and 16.2%-86.6% for P. mirabilis. Strain-to-strain variation within species in the fT>MIC for static and cidal effect was marked; the 24 h bacteriostatic range was 14.1%-73.4% for P. mirabilis, 34.2%-44.6% for E. coli and 42.2%-62.5% for K. pneumoniae. Changes in ceftaroline population analysis profiles were observed with E. coli, K. pneumoniae and C. koseri, especially at fT>MIC values just below the bacteriostatic effect exposures.. The pharmacodynamics of ceftaroline against the species within the Enterobacteriaceae group are different. K. pneumoniae requires higher drug exposures than E. coli, and P. mirabilis strains are highly variable, which may have important clinical correlates. Translational extrapolations from preclinical observations using E. coli to other Enterobacteriaceae species may not be optimal.

Topics: Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Microbial Sensitivity Tests; Microbial Viability; Models, Biological; Models, Theoretical

Contemporary (2012) β-lactamase-producing isolates (n=493) from U.S. hospitals were tested against ceftaroline-avibactam. Klebsiella spp., Escherichia coli and Proteus mirabilis isolates displaying the Clinical and Laboratory Standards Institute (CLSI) screening criteria for extended spectrum β-lactamase (ESBL) production were evaluated. Isolates carried genes encoding CTX-M (n=316, CTX-M-14-like and -15-like), KPC (n=45), CMY-2-like (n=54), or SHV enzyme with ESBL activity (n=78). Ceftaroline-avibactam inhibited 98.2% of the isolates at ≤0.5 μg/mL, and all strains were inhibited by ≤2 μg/mL of this novel β-lactamase-inhibitor combination. These results confirm that ceftaroline-avibactam could be a useful therapeutic option for Enterobacteriaceae isolates producing β-lactamases that are prevalent in the United States.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Ceftaroline; Cephalosporins; Drug Combinations; Enterobacteriaceae Infections; Escherichia coli; Humans; Klebsiella; Microbial Sensitivity Tests; Prevalence; Proteus mirabilis; United States

Previous in vivo studies using a human-simulated regimen of ceftaroline/avibactam 600/600mg every 8h (q8h) showed activity against extended-spectrum β-lactamase-, AmpC- and KPC-producing Enterobacteriaceae with minimum inhibitory concentrations (MICs) ≤ 1 μg/mL. Here we sought to determine the efficacy of this human-simulated regimen against organisms with MICs ≥ 1 μg/mL to help determine a breakpoint value that would reliability predict efficacy in humans. In total, 31 isolates (1 Escherichia coli, 9 Klebsiella pneumoniae, 9 Enterobacter cloacae, 1 Citrobacter koseri, 2 Serratia marcescens, 1 Klebsiella oxytoca and 8 Pseudomonas aeruginosa) with ceftaroline/avibactam MICs of 1 to 16 μg/mL were tested in a murine immunocompromised thigh infection model; 15 isolates were also tested in an immunocompetent model. Doses were given to simulate human free drug exposures of ceftaroline fosamil/avibactam 600/600 mg q8h over 24h as a 1-h infusion by targeting the fT>MIC profile. Efficacy was evaluated as the change in log10 CFU compared with 0-h controls after 24h. Reductions in bacterial CFU in the neutropenic model were seen against a majority of isolates tested with MICs ≤ 4 μg/mL, where fT>MIC was >55%. More variable efficacy was seen in isolates with MICs ≥ 8 μg/mL, where fT>MIC drops below 40%. Overall activity was enhanced in the immunocompetent model. The humanised regimen of ceftaroline fosamil/avibactam 600/600 mg q8h as a 1-h infusion showed predictable efficacy against isolates with various genotypic and phenotypic profiles and MICs ≤ 4 μg/mL. These data provide valuable information to help determine a ceftaroline/avibactam breakpoint for Enterobacteriaceae.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Ceftaroline; Cephalosporins; Disease Models, Animal; Enterobacter cloacae; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Reproducibility of Results; Thigh

New broad-spectrum β-lactamases such as KPC enzymes and CTX-M-15 enzymes threaten to markedly reduce the utility of our armamentarium of β-lactam agents, even our most potent drugs, such as carbapenems. NXL104 is a broad-spectrum non-β-lactam β-lactamase inhibitor. In this evaluation, we examined organisms carrying defined β-lactamases and identified doses and schedules of NXL104 in combination with the new cephalosporin ceftaroline, which would maintain good bacterial cell kill and suppress resistance emergence for a clinically relevant period of 10 days in our hollow-fiber infection model. We examined three strains of Klebsiella pneumoniae and one isolate of Enterobacter cloacae. K. pneumoniae 27-908M carried KPC-2, SHV-27, and TEM-1 β-lactamases. Its isogenic mutant, K. pneumoniae 4207J, was "cured" of the plasmid expressing the KPC-2 enzyme. K. pneumoniae 24-1318A carried a CTX-M-15 enzyme, and E. cloacae 2-77C expressed a stably derepressed AmpC chromosomal β-lactamase. Dose-ranging experiments for NXL104 administered as a continuous infusion with ceftaroline at 600 mg every 8 h allowed identification of a 24-h area under the concentration-time curve (AUC) for NXL104 that mediated bactericidal activity and resistance suppression. Dose fractionation experiments identified that "time > threshold" was the pharmacodynamic index linked to cell kill and resistance suppression. Given these results, we conclude that NXL104 combined with ceftaroline on an 8-hourly administration schedule would be optimal for circumstances in which highly resistant pathogens are likely to be encountered. This combination dosing regimen should allow for optimal bacterial cell kill (highest likelihood of successful clinical outcome) and the suppression of resistance emergence.

Topics: Anti-Bacterial Agents; Area Under Curve; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Ceftaroline; Cephalosporins; Chromatography, Liquid; Drug Administration Schedule; Drug Dosage Calculations; Drug Resistance, Bacterial; Drug Synergism; Enterobacter cloacae; Enterobacteriaceae Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Models, Biological; Tandem Mass Spectrometry

Ceftaroline fosamil, a new broad-spectrum cephalosporin, exhibits potent bactericidal activity against common Gram-negative pathogens, including Enterobacteriaceae, and Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The purpose of this study was to evaluate the efficacy of a human simulated dose of ceftaroline fosamil against clinical Enterobacteriaceae in both neutropenic and immunocompetent mouse thigh infection models. Thirty-five Enterobacteriaceae isolates with ceftaroline MICs ranging from 0.25 to 32 μg/ml were selected for the neutropenic model, and five Escherichia coli isolates were also tested in the immunocompetent model. Two hours after inoculation, the ceftaroline fosamil human simulated regimen of 600 mg intravenously (i.v.) every 12 h was administered. The change in log(10) CFU after 24 h was compared to that in 0 h controls. The human simulated regimen produced predictable efficacy against 18 of 20 isolates with a MIC of ≤ 1 μg/ml. Similar efficacy was seen in the immunocompetent model against isolates with a MIC of ≤ 2 μg/ml, and enhanced efficacy was observed against the isolate with a MIC of 4 μg/ml. Human simulated exposures to ceftaroline fosamil at 600 mg every 12 h provided predictable efficacy against Enterobacteriaceae with MICs of ≤ 1 μg/ml and enhanced efficacy within the immunocompetent model, supporting the clinical utility of ceftaroline fosamil against these organisms.

Topics: Animals; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Drug Administration Schedule; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Female; Humans; Immunocompetence; Injections, Intravenous; Klebsiella; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Phenotype; Thigh

Ceftaroline exhibits in vitro activity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producing Enterobacteriaceae when combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 against Enterobacteriaceae in a murine thigh infection model. Twelve Enterobacteriaceae isolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log(10) CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to ≥ 2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤ 1 μg/ml and could be useful in combating the growing threat of resistant Enterobacteriaceae.

Topics: Animals; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Ceftaroline; Cephalosporins; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Thigh

Ceftaroline (PPI-0903M, T-91825) is a novel cephalosporin, administered as an N-phosphono prodrug. We investigated its in vitro activity and resistance selection potential.. MICs were determined by CLSI agar dilution, but with varied inocula. Mutant selection was investigated in single- and multi-step procedures.. MICs for methicillin-resistant Staphylococcus aureus (MRSA) were 0.5-2 mg/L, compared with 0.12-0.25 mg/L for methicillin-susceptible S. aureus; corresponding values for coagulase-negative staphylococci were 0.25-2 and 0.06-0.12 mg/L, respectively. Even with 2% NaCl added, all MRSA were susceptible at 2 mg/L. MICs for Enterococcus faecalis were from 0.25 to 8 mg/L; E. faecium was resistant. MICs for Escherichia coli, Klebsiella spp., Morganella morganii and Proteeae without acquired resistance were 0.06-0.5 mg/L versus 0.12-1 mg/L for Enterobacter, Serratia and Citrobacter spp. and 2-8 mg/L for Acinetobacter spp. MICs rose to 1-2 mg/L for many Enterobacteriaceae with classical TEM beta-lactamases, and were much higher for those with extended-spectrum beta-lactamases (ESBLs), hyperproduced AmpC or K1 enzymes. MICs for strains with classical TEM/SHV beta-lactamases rose if the inoculum was increased to 10(6) cfu/spot; this effect was even more marked for those with ESBLs. Resistance due to Class A beta-lactamases was reversed by clavulanate. Geometric mean MICs were 0.005, 0.05 and 0.09 mg/L for penicillin-susceptible, -intermediate and -resistant Streptococcus pneumoniae strains, respectively-lower than for any comparator beta-lactam. Haemophilus influenzae and Moraxella catarrhalis were very susceptible, although with marginally raised MICs for beta-lactamase-positive Moraxella strains and for haemophili with chromosomal ampicillin resistance. Ceftaroline selected AmpC-derepressed Enterobacter mutants similarly to cefotaxime in single-step experiments; in multi-step procedures it selected ESBL variants of blaTEM in E. coli. Resistance selection was not seen with S. aureus, H. influenzae or pneumococci.. Ceftaroline has impressive anti-MRSA and anti-pneumococcal activity. Slight lability to classical TEM and SHV beta-lactamases is exceptional for an oxyimino-cephalosporin, but was reversible with clavulanate, as was the greater resistance mediated by ESBLs. Resistance selection occurred with Enterobacteriaceae, not MRSA.

Topics: Acinetobacter; Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Bacteroides; beta-Lactamases; Ceftaroline; Cephalosporins; Clavulanic Acid; Conjugation, Genetic; Drug Combinations; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Enterococcus; Escherichia coli; Gram-Negative Bacteria; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Mutation; Phenotype; Respiratory Tract Diseases; Staphylococcus