Exploring the Factors Affecting the Transferability of Vancomycin to Cerebrospinal Fluid in Postoperative Neurosurgical Patients with Bacterial Meningitis.

Vancomycin (VCM) is a standard treatment for bacterial meningitis. However, little is known about the transferability of VCM to cerebrospinal fluid (CSF), thus evidence of the transferability of VCM to CSF during bacterial meningitis is needed. In this study, we evaluated the concentration of VCM in the plasma and CSF of postoperative neurosurgical patients with bacterial meningitis and evaluated the factors that affect the transferability of VCM to CSF. The concentrations of VCM in plasma (trough) and CSF were determined in eight patients (four males and four females) with bacterial meningitis who were treated with VCM using HPLC. The ratio of the VCM concentrations in CSF/plasma was also calculated by estimating the blood VCM concentration at the same time as the VCM concentration in CSF was measured. The results showed that the VCM concentration in CSF was 0.9-12.7 µg/mL and the CSF/plasma VCM concentration ratio was 0.02-0.62. We examined the effect of drainage on the transferability of VCM to CSF, which showed that the VCM concentration in CSF and the CSF/plasma VCM concentration ratio were significantly higher in patients not undergoing drainage than in patients who were undergoing drainage. The CSF protein and glucose concentrations, which are diagnostic indicators of meningitis, were positively correlated with the VCM concentration in CSF and the CSF/plasma VCM concentration ratio. Thus, VCM transferability to CSF may be affected by changes in the status of the blood-brain barrier and blood-cerebrospinal fluid barrier due to drainage or meningitis.

Influences of protein levels on the cerebrospinal fluid distribution of ceftazidime & ceftriaxone in the cerebrospinal fluid of patients with inflamed meningitis.

INTRODUCTION: Ceftazidime and ceftriaxone are used to treat various gram-negative pathogens, such as Streptococcus pneumoniae and Pseudomonas aeruginosa, and have shown excellent therapeutic efficacy against bacterial meningitis. However, there is insufficient information on the pharmacokinetic characteristics of their cerebrospinal distribution. Here, we investigated the association of clinical laboratory data in cerebrospinal fluid with ceftazidime and ceftriaxone concentration in the cerebrospinal fluid of patients with inflamed meningitis. METHODS: Cerebrospinal fluid samples were collected from eight adult patients with inflamed meningitis who intravenously received either ceftazidime or ceftriaxone (ceftazidime: a total of 25 samples from three patients, ceftriaxone: a total of 12 samples from five patients). Total cell number, protein concentration, and glucose concentration in the cerebrospinal fluid were retrospectively collected from electronic medical charts. All ceftazidime and ceftriaxone concentrations in the cerebrospinal fluid were determined using high-performance liquid chromatography. RESULTS: Both ceftazidime and ceftriaxone concentrations in cerebrospinal fluid correlated with protein concentration in cerebrospinal fluid; however, no significant correlation was observed in total cell number and glucose concentration in cerebrospinal fluid. CONCLUSIONS: This is the first report on the relationship between the cerebrospinal distribution of these antibiotics and clinical laboratory data in cerebrospinal fluid of adult patients with meningitis.

False-negative rate of SARS-CoV-2 RT-PCR tests and its relationship to test timing and illness severity: A case series.

Objective: To determine the false-negative rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse-transcription polymerase chain reaction (RT-PCR) test results, and to describe the characteristics of coronavirus disease 2019 (COVID-19) patients with false-negative results. Methods: We validated SARS-CoV-2-positive RT-PCR test results performed in hospitalized patients between February 1 and August 31, 2020 and classified the patients according to disease severity. Results: In total, 2038 SARS-CoV-2 RT-PCR tests were performed on 1890 patients. Of these, 145 patients had positive results and were diagnosed with COVID-19. Among the 145 patients with COVID-19, the initial RT-PCR tests were negative in five patients. Of these, three had moderate illness and were initially tested in the early stage of disease, and two had severe illness and were initially tested in the late stage of disease, when RT-PCR testing has lower sensitivity due to viral clearance. Conclusions: These findings suggest that false-negative results can be caused by both observer errors and by low viral RNA levels in the later stages of disease, after the infection has cleared. Clinicians should be aware that patients with COVID-19 can have negative RT-PCR test results in the later stages of infection.

Pulmonary embolism after dexamethasone treatment for COVID-19: a case report.

BACKGROUND: Although the RECOVERY trial showed that dexamethasone was efficacious for the treatment of coronavirus disease 2019 (COVID-19), its impact on the risk of pulmonary embolism (PE) and other serious procoagulant events was not assessed. CASE PRESENTATION: Here we report the case of a previously healthy 83-year-old woman with COVID-19, without any genetic predisposition to thrombosis. She developed moderate respiratory distress 12 days after symptom onset and a 10-day course of dexamethasone therapy was initiated. Her clinical condition and imaging findings improved initially; however, they deteriorated after the completion of dexamethasone therapy, despite the improvement in her pneumonia and viral clearance. Laboratory tests showed markedly raised serum D-dimer, ferritin, and sIL-2R levels, and contrast-enhanced computed tomography showed deep vein thrombosis (DVT) in the left iliac vein and PE of the right pulmonary artery. The DVT and PE were successfully treated using intravenous heparin administration. CONCLUSIONS: This case illustrates the potential risk of rebound inflammation and procoagulant events following dexamethasone withdrawal. We believe that COVID-19-induced DVT and PE can be affected by dexamethasone therapy. Although dexamethasone reduces procoagulant factors, increases anticoagulant factors, and modulates cytokines, which can suppress/delay thrombus formation during treatment, it confers the risk for rebound cytokine production after treatment completion, triggering cytokine and coagulation cascades that can lead to thromboembolic diseases. In this critical clinical period, the patient's deteriorating condition may be overlooked because of the masking effects of dexamethasone treatment on fever and other clinical conditions and laboratory changes. Clinicians should follow-up coagulation markers carefully and contrast-enhanced computed tomography is useful for detecting coagulation; and, if PE occurs, therapeutic heparin administration is essential because emboli can also generate cytokines.

Different intra-cerebrospinal distribution of linezolid in patients with inflammatory meningitis.

Linezolid has excellent antibiotic activity against gram-positive organisms and is expected to be an alternative to vancomycin for the treatment of bacterial meningitis. Accumulated evidence has shown the superior pharmacokinetic characteristics of linezolid to vancomycin, such as cerebrospinal fluid penetration. However, in the treatment of meningitis, pharmacokinetic information regarding the intra-cerebrospinal distribution of linezolid and the effects of drainage on the linezolid concentration in the cerebrospinal fluid are unclear. This report describes two patient cases, in which the linezolid concentrations in the cerebrospinal fluid were in the following order: subarachnoid space (cisternal drainage and lumbar puncture) ≥ third ventricle > lateral ventricle. In addition, the linezolid concentration in the cerebrospinal fluid, collected via lumbar puncture, tended to increase after removal of the drainage. This report is novel in presenting two cases of meningitis that showed different intra-cerebrospinal distribution of linezolid in various parts of the central nervous system and an increased linezolid concentration in the cerebrospinal fluid after removal of the drainage.

Case studies of SARS-CoV-2 treated with favipiravir among patients in critical or severe condition.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is rising globally. However, clinically effective antiviral treatments are not established. Favipiravir may prevent pneumonia and acute respiratory distress syndrome aggravation. We describe SARS-CoV-2-positive patients, two of whom were in a critical condition and one of whom was in a severe condition, who were administered favipiravir for their deteriorating conditions and cured.

Evaluation for optimal dosing of vancomycin in patients with different physical types.

The sufficient dose to obtain an optimal trough concentration of vancomycin (VCM) in patients with non-standard physical types remains controversial. In this study, we examined the relationship between the dose and physical type in patients in whom an optimal trough concentration was obtained among VCM-treated patients. We retrospectively investigated the dose of VCM and physical type in patients treated with VCM between January 2012 and January 2017 at two medical institutions (n = 272). The physical type was classified using the body mass index (BMI). Patients with a BMI of <18.5 kg/m2 were assigned to the lean group, those with a BMI of 18.5-24.9 kg/m2 were assigned to the standard group, and those with a BMI of ≥25 kg/m2 were assigned to the obesity group. The mean doses of VCM per time (mg/kg) to achieve the target trough concentration of VCM, 15-20 µg/mL, were 19.8 ± 4.3, 16.5 ± 3.7, and 13.7 ± 2.7 mg/kg in the lean, standard, and obesity groups, respectively. The dose per time to achieve the target trough concentration decreased significantly in association with an increase of BMI. The upper limit of the recommended dose (15-20 mg/kg) or higher in lean patients, and the lower dose in obese patients than the recommended dose might be appropriate to achieve the target trough concentration when we calculated the dose per time based on actual body weight.

[Confusion Over the Term "Contamination Rate" as It Pertains to Blood Cultures].

The blood culture contamination rate is often used to validate specimen-collection procedures. CUMITECH has set its optimal target to be 2% to 3%. However, the term "contamination rate" has been defined in many ways, limiting its generalizability. The definitions used in earlier studies can be divided into two categories; definitions based on clinical judgements, and those based on preset rules. According to each principle, the equation must be composed of a defined numerator and denominator. The problem with clinical definitions is that the decision is inevitably subjective, and the process is too cumbersome. Also, if the number of positive cultures is used as the denominator, the value would be equivalent to the positive predictive value, given that contamination is regarded as a "positive case." Thus, the value would not be useful for validating a procedure. On the other hand, when the preset algorithm was adopted, true infection would, to some degree, inevitably be classified as contamination. Also, if the algorithm adopted the number of blood culture sets as the denominator and contamination was defined as the identification of 1 or more specified organisms in only 1 of multiple sets of blood cultures, its theoretical maximum value would not be 100%. This is a problem because the value is a mixture of several numbers with different scales. In other words, whether the blood cultures are collected once, twice, or thrice or more a day would affect the result. The study cited by CUMITECH aimed to evaluate the equivalence between the clinical definition and the laboratory definition with preset rules, rather than to establish a benchmark for the contamination rate. It is undesirable for the number to be perceived as a benchmark. "A Guide to Blood Culture" (2013) by the Japanese Society for Clinical Microbiology introduced a calculation for the contamination rate, but the definition of the term "number of specimens" in the formula is ambiguous. In addition, the references cited in the guide do not concern contamination and do not even mention the definition of contamination rate. Thus, it is impossible to confirm the definition. In view of the weaknesses of these previous works, we defined the contamination rate as a benchmark for the validation of blood culture procedures as follows. [number of series in which 1 or more specified organisms (*) were identified in only 1 of multiple sets of blood cultures]/[total number of multiple sets of blood cultures in the series] *coagulase-negative staphylococci, Propionibacterium acnes, Micrococcus spp., Viridans-group streptococci, Corynebacterium spp., and Bacillus spp., but not B. anthracis.

Liberation of actin from actomyosin in meats heated to 65°C.

This study investigated whether actin liberation from myofibrils occurs during the heating of various muscles, as well as squid mantle muscle at temperatures, such as 60°C, employed for vacuum cooking of meats. Actin liberation was demonstrated in scallop striated adductor muscle, but not in beef, pork, or chicken, using the detection method previously employed with squid muscle, in which liberated actin was detected with SDS-PAGE, in the supernatant obtained by centrifugation of the homogenate of heated muscle in 0.2M KCl at a neutral pH. However, actin liberation was demonstrated in beef, pork and chicken by a new detection method, in which heated muscle was homogenized in 0.6M KCl or NaCl at a slightly alkaline pH and maintained at 4°C for 16h with stirring, after which the homogenate was diluted three times with water and centrifuged to obtain the supernatant containing the liberated actin. This new method indicated that actin liberation in beef, pork, and chicken was marked by heating at 65°C, but scarcely induced at 80°C. Thus, the liberation of actin from myofibrils may contribute to the greater tenderness of vacuum-cooked meat (meat heated at a low temperature for long time), as compared with meat prepared by cooking at a higher temperature.

AMP and IMP dissociate actomyosin into actin and myosin.

We investigated to determine why heating of squid muscle at 60 degrees C induced the liberation of actin from myofibrils. When a mixture of a myofibrillar fraction and a low-molecular sarcoplasmic fraction prepared from squid muscle was heated at 60 degrees C, actin liberation occurred. When a myofibrillar fraction was heated with ATP, AMP, or IMP, actin liberation occurred. Hence, AMP is perhaps one of the factors causing actin liberation in postmortem squid muscle. It was found that AMP and IMP reversibly dissociated actomyosin of chicken, bovine, and porcine skeletal muscles into actin and myosin on incubation at 0 degrees C at pH 7.2 in 0.2 M KCl. These results led us to conclude that AMP and IMP were the most responsible factors causing actin liberation from myofibrils in the heated muscle and causing reversible dissociation of actomyosin on storage of skeletal muscle at a low temperature. Hence, AMP and IMP are possible factors causing the resolution of rigor mortis in muscles.