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This first‐in‐human study evaluated the safety, tolerability, single‐ and multiple‐dose pharmacokinetic profiles with dietary influence, and pharmacodynamics (PD) of DFV890, an oral NLRP3 inhibitor, in healthy participants. In total, 122 participants were enrolled into a three‐part trial including single and 2‐week multiple ascending oral doses (SAD and MAD, respectively) of DFV890, and were randomized (3:1) to DFV890 or placebo (SAD [3–600 mg] and MAD [fasted: 10–200 mg, once‐daily or fed: 25 and 50 mg, twice‐daily]). DFV890 was generally well‐tolerated. Neither deaths nor serious adverse events were reported. A less than dose‐proportional increase in exposure was observed with the initially used crystalline suspension (3–300 mg); however, an adjusted suspension formulation using spray‐dried dispersion (SDD; 100–600 mg) confirmed dose‐proportional increase in exposure. Relative bioavailability between crystalline suspension and tablets, and food effect were evaluated at 100 mg. Under fasting conditions, Cmax of the tablet yielded 78% compared with the crystalline suspension, and both formulations showed comparable AUC. The fed condition led to a 2.05‐ and 1.49‐fold increase in Cmax and AUC0–last compared with the fasting condition. The median IC50 and IC90 for ex‐vivo lipopolysaccharide‐stimulated interleukin IL‐1β release inhibition (PD) were 61 (90% CI: 50, 70) and 1340 ng/mL (90% CI: 1190, 1490). Crystalline tablets of 100 mg once‐daily or 25 mg twice‐daily were sufficient to maintain ~90% of the IL‐1β release inhibition over 24 h at steady state. Data support dose and formulation selection for further development in diseases, in which an overactivated NLRP3 represents the underlying pathophysiology. [ABSTRACT FROM AUTHOR]

Purpose: Nacubactam (NAC) is a novel diazabicyclooctane β-lactamase inhibitor used in combination with cefepime (CFPM). In this study, we aimed to determine the target pharmacokinetics (PK) and pharmacodynamics (PD) values of CFPM/NAC in mice infected with β-lactamase-producing Enterobacterales, such as the carbapenemase-producing Enterobacterales. Methods: Three strains of β-lactamase-producing Enterobacterales, Klebsiella pneumoniae MSC 21444, Escherichia coli MSC 20662, and K. pneumoniae ATCC BAA-1898, were used for checkerboard assays and fractionation studies and dose-range studies. A PK study was performed in neutropenic mice. Additionally, PK/PD analysis was performed based on the instantaneous minimum inhibitory concentration (MICi) concept. Results: Checkerboard measurements revealed that higher NAC concentrations decreased the CFPM MIC in a concentration-dependent manner. In all tested strains, fT > MICi calculated from the PK experiments showed a high correlation with the mean change in the bacterial count of thigh-infected mice in the in vivo PD study, suggesting that fT > MICi is an optimal PK/PD parameter for monitoring the CFPM/NAC combination. The target fT > MICi values for CFPM/NAC to achieve a bacteriostatic effect, 1-log10-kill, and 2-log10-kill values were 30, 49, and 94%, respectively. Conclusions: Our results indicate that fT > MICi is a PK/PD parameter is suitable for monitoring the CFPM/NAC combination. The minimum target value for achieving a static effect against β-lactamase-producing Enterobacterales is 30%. [ABSTRACT FROM AUTHOR]

Purpose: Cefditoren, the active form of cefditoren pivoxil, is an oral cephalosporin antimicrobial drug. Although cefditoren exhibits high antimicrobial activity against Streptococcus pneumoniae, its pharmacokinetics/pharmacodynamics (PK/PD) characteristics remain unknown. This study aimed to determine its PK/PD parameter with target values for cefditoren against S. pneumoniae in S. pneumoniae lung-infected mice and to simulate MIC range of S. pneumoniae that can be expected to be treated at approved cefditoren doses in human using population pharmacokinetic (PPK) data from patients. Methods: Susceptibility testing and time-kill assays against S. pneumoniae ATCC® 49619 were performed for in vitro PD evaluation. Based on the results of a PK study in healthy mice and PD studies in S. pneumoniae lung-infected mice, optimal PK/PD parameters were determined using the correlation curve between the PK/PD parameters and lung bacterial count changes. The target value was calculated to achieve a 2 log10 reduction in the lung bacterial counts. Results: In vitro PD evaluation showed that cefditoren had a potent antimicrobial effect against S. pneumoniae in a time-dependent manner at concentrations above the MIC. In PK/PD analyses, both fAUC24/MIC and fCmax/MIC were well correlated with bactericidal efficacy, achieving 2 log10-kill with fAUC24/MIC ≥ 63 and fCmax/MIC ≥ 16. Conclusions: Cefditoren pivoxil has good therapeutic efficacy against acute pneumonia caused by S. pneumoniae with a MIC ≤ 0.031–0.063 mg/L at approved doses in adults and children. [ABSTRACT FROM AUTHOR]

Background Nacubactam, a new β-lactamase inhibitor with antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. However, determining pharmacokinetics/pharmacodynamics (PK/PD) parameters in β-lactam/β-lactamase inhibitor combinations remains challenging. We aimed to establish a practical PK/PD analysis method for aztreonam/nacubactam that incorporates instantaneous MIC (MICi). Methods Based on chequerboard MIC measurements, MICi of aztreonam against carbapenemase-producing Klebsiella pneumoniae in the presence of nacubactam was simulated. Results The mean change in the bacterial count of thigh-infected mice in an in vivo PD study was plotted based on % fT >MICi and analysed using the inhibitory effect sigmoid I max model. fT >MICi calculated from the PK experiments showed a high correlation with the in vivo bactericidal effect, suggesting that fT >MICi is the optimal PK/PD parameter for aztreonam/nacubactam. The target values of fT >MICi achieving growth inhibition, 1 log10 kill and 2 log10 kill, were 22, 38% and 75%, respectively. Conclusions The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in combination therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivo therapeutic effect against NDM-producing K. pneumoniae. [ABSTRACT FROM AUTHOR]

Purpose: Vancomycin-resistant enterococci (VRE) have recently become a major cause of nosocomial infections and a global public health concern. Tedizolid exhibits powerful antibacterial activity against VRE in vitro, but its pharmacokinetic/pharmacodynamic (PK/PD) parameters remain unclear. Therefore, we aimed to determine the PK/PD indices of tedizolid action on VRE and the mechanisms underlying the PK/PD indices differences of tedizolid against VRE and methicillin-resistant Staphylococcus aureus (MRSA). Methods: Optimal PK/PD target values of tedizolid were determined in vitro, based on time-kill curves and post-antibiotic effects (PAEs), and in vivo, using mouse models of thigh infection with VRE and MRSA strains. Results: The tedizolid bactericidal activity on VRE and MRSA was time-dependent. Correlations were closest between fAUC24/MIC and the tedizolid PK/PD index against MRSA and VRE. To achieve 1 log10 kill tedizolid fAUC24/MIC in neutropenic mouse models of thigh infection with VRE and MRSA should be 14.2 and 138.5, respectively. The PAEs of tedizolid against VRE and MRSA were 2.39 and 0.99 h, respectively. Conclusion: Tedizolid showed bactericidal effects against VRE even in neutropenic mice unlike MRSA, which could be attributed to its longer PAE against VRE. Hence, we hypothesize that tedizolid treatment against VRE infections is promising for achieving therapeutic success in clinical. [ABSTRACT FROM AUTHOR]

Purpose: Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC. Methods: The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice. Results: The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time–kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4–64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively. Conclusion: CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve "fT>MIC" ≥ 69.6% for the treatment of ESBL-EC infections. [ABSTRACT FROM AUTHOR]

Tedizolid (TZD) is an oxazolidinone anti-methicillin-resistant Staphylococcus aureus (MRSA) drug. Linezolid (LZD), another oxazolidinone, has been shown to have an anti-inflammatory effect. TZD has been shown to exhibit an anti-inflammatory effect in a murine model of hematogenous pulmonary infection. In this study, we further investigated the anti-inflammatory effect of TZDs using a carrageenan-induced rat footpad edema model. TZD was administered at 0, 10, 20, and 40 mg/kg to the carrageenan-induced rat footpad edema model, and the edema rate was measured over time up to 9 h later. The area under the time curve of the edema rate profile (AUC edema0→9) decreased in a TZD dose-dependent manner. In addition, the correlation between AUC edema0→9 and the area under the time curve of free TZD plasma concentration (f AUC blood) obtained from the pharmacokinetic study of TZD in the carrageenan-induced rat footpad edema model was examined. f AUC blood and AUC edema0→9 showed a good negative correlation. These results indicate that TZD suppresses carrageenan-induced footpad edema and that TZD exerts its anti-inflammatory effects in a plasma concentration-dependent manner. [ABSTRACT FROM AUTHOR]