Endovascular Treatment May Be Effective in Preventing Recurrence of Ischemic Stroke in Vertebral Artery Stump Syndrome: A Case Series.

Vertebral artery stump syndrome (VASS) is a rare condition that can cause posterior circulation ischemic stroke due to occlusion of the ipsilateral vertebral artery (VA) orifice, resulting in blood flow stagnation and embolus formation. Although there is no established treatment for this condition, we observed 3 cases of VASS out of 326 acute ischemic stroke cases at a single institution from April 2021 to October 2022. Despite the best possible antithrombotic treatment, all 3 patients had recurrent ischemic strokes. One patient underwent drug-eluting stenting of the VA orifice to relieve occlusive flow. The other 2 patients received coil embolization, which resulted in the disappearance of their culprit collateral flow. None of the patients had recurrent ischemic strokes after endovascular intervention. Based on our observations, stenting and coil embolization are effective methods for preventing future recurrences of VASS.

In vivo Pharmacokinetic/Pharmacodynamic Analysis of the Efficacy of the Cefepime/Nacubactam Combination Against ß-Lactamase-Producing Enterobacterales based on the Instantaneous MIC Concept.

PURPOSE: Nacubactam (NAC) is a novel diazabicyclooctane ß-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 ß-lactamase-producing Enterobacterales, such as the carbapenemase-producing Enterobacterales. METHODS: Three strains of ß-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 ß-lactamase-producing Enterobacterales is 30%.

In vivo Pharmacokinetics/Pharmacodynamics Profiles for Appropriate Doses of Cefditoren pivoxil against S. pneumoniae in Murine Lung-Infection Model.

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.

Dilation of proximal internal carotid artery collapse due to severe distal stenosis after angioplasty for distal stenosis: A case report.

Background: We report a case of proximal internal carotid artery (ICA) collapse due to severe distal stenosis that dilated after angioplasty for distal stenosis. Case Description: A 69-year-old woman underwent thrombectomy for the left ICA occlusion due to stenosis of C3 portion and was discharged home with a modified Rankin Scale score of 0. One year later, she developed cerebral infarction due to progressive stenosis of the C3 portion of the left ICA with proximal ICA collapse and underwent emergency percutaneous transluminal angioplasty (PTA) for distal stenosis. Device guidance to the stenosis was difficult due to proximal ICA collapse. After PTA, blood flow in the left ICA increased, and proximal ICA collapse dilated over time. Due to severe residual stenosis, she underwent more aggressive PTA followed by Wingspan stenting. Device guidance to the residual stenosis was facilitated because proximal ICA collapse had already dilated. Six months later, proximal ICA collapse further dilated. Conclusion: PTA for severe distal stenosis with proximal ICA collapse may result in dilation of proximal ICA collapse over time.

Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae.

BACKGROUND: Nacubactam, a new ß-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 ß-lactam/ß-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 Imax 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.

Differences in Pharmacokinetic/Pharmacodynamic Parameters of Tedizolid Against VRE and MRSA.

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.

Efficacy of surgical skin preparation with chlorhexidine in alcohol according to the concentration required to prevent surgical site infection: meta-analysis.

BACKGROUND: A combination of chlorhexidine gluconate and alcohol (CHG-alcohol) is recommended for surgical skin preparation to prevent surgical site infection (SSI). Although more than 1 per cent CHG-alcohol is recommended to prevent catheter-related bloodstream infections, there is no consensus regarding the concentration of the CHG compound for the prevention of SSI. METHODS: A systematic review and meta-analysis was performed. Four electronic databases were searched on 5 November 2020. SSI rates were compared between CHG-alcohol and povidone-iodine (PVP-I) according to the concentration of CHG (0.5 per cent, 2.0 per cent, 2.5 per cent, and 4.0 per cent). RESULTS: In total, 106 of 2716 screened articles were retrieved for full-text review. The risk ratios (RRs) of SSI for 0.5 per cent (6 studies) and 2.0 per cent (4 studies) CHG-alcohol were significantly lower than those for PVP-I (RR = 0.71, 95 per cent confidence interval (c.i.) 0.52 to 0.97; RR = 0.52, 95 per cent c.i 0.31 to 0.86 respectively); however, no significant difference was observed in the compounds with a CHG concentration of more than 2.0 per cent. CONCLUSIONS: This meta-analysis is the first study that clarifies the usefulness of an alcohol-based CHG solution with a 0.5 per cent or higher CHG concentration for surgical skin preparation to prevent SSI.

Correlation of Scoring Systems with the Requirement of an External Ventricular Drain in Intraventricular Hemorrhage.

BACKGROUND: External ventricular drainage (EVD) is required to resolve acute hydrocephalus associated with intraventricular hemorrhage (IVH). The correlation of scoring systems of IVH with indications for EVD for acute hydrocephalus related to IVH is currently unknown. METHODS: We identified 213 hypertensive patients with IVH and divided them into 2 groups according to treatment method: 187 patients receiving blood pressure control alone and 26 patients undergoing EVD. The following patients were excluded: pediatric patients, patients undergoing intracranial hematoma removal, patients with fetal status, and patients without sufficient clinical data. We compared the Glasgow Coma Scale score, Graeb score, LeRoux score, Evans index, and bicaudate index values between the 2 groups and determined the prognostication accuracy of each scoring system. RESULTS: There were significant differences in all 4 scoring systems between the 2 groups (P < 0.001). The cutoff values (sensitivity and specificity) of each scoring system were as follows: Glasgow Coma Scale, 8 (65.4%, 87.7%); Graeb score, 6 (80.8%, 75.4%); LeRoux score, 9 (80.8%, 76.5%); Evans index, 0.245 (80.8%, 67.9%); and bicaudate index, 0.186 (76.9%, 76.5%). The value of the area under the curve of each scoring system (95% confidence interval) was as follows: Glasgow Coma Scale, 0.806 (0.705-0.907); Graeb score, 0.852 (0.779-0.925); LeRoux score, 0.875 (0.812-0.937); Evans index, 0.788 (0.702-0.875); and bicaudate index, 0.778 (0.673-0.883). CONCLUSIONS: The LeRoux score is better for identifying patients with IVH who are more likely to have EVD.

Subjective and objective evaluation of swallowing in lateral decubitus positions examined in healthy volunteers.

BACKGROUND: Dysphagia can result from shock, trauma, aging, head and neck neoplasms, and some cerebrovascular diseases or neuromotor degenerative disorders. Swallowing rehabilitation therapy combined with postural control of the neck, head, and body can be effective for patients with dysphagia. Though the lateral decubitus posture has been a favorable option for swallowing rehabilitation therapy, available clinical data pertaining to it are scarce. METHODS: Twenty-seven healthy volunteers were enrolled in this study. The subjects underwent a repetitive saliva swallowing test, food swallowing test, and water swallowing test. The trials were performed in four different positions: upright sitting position, lateral decubitus position with the head raised to 60°, lateral decubitus position with the head raised to 30°, and complete lateral decubitus position. After each trial, the subjects were asked to declare the swallowing difficulty utilizing a visual analogue scale. Swallowing time and swallowing sound level were recorded simultaneously, as objective evaluation in each trial. We analyzed the visual analogue scale scores, swallowing time, and swallowing sound levels for all the four positions. RESULTS: The results of the visual analogue scale of the water swallowing test in the sitting position were significantly lower than those of the complete lateral decubitus position (p < 0.01). However, statistical significance was not detected in swallowing time or the swallowing sound level among the four different positions. Although subjective discomfort in swallowing was identified, difficulty of swallowing was not objectively evident in the trials, irrespective of the position. CONCLUSIONS: A complete lateral decubitus position can be an effective and safe position in swallowing.

Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments.

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.