A systematic review and meta-analysis of antibiotic-loaded bone cement for prevention of deep surgical site infections following primary total joint replacement.

BACKGROUND: The use of antibiotic-loaded bone cement (ALBC) as a mean for preventing deep surgical site infections (SSI) after total joint replacement is controversial. Therefore, we have conducted a meta-analysis to evaluate the prophylactic effect of ALBC for SSI prevention in patients undergoing arthroplasty. This study was conducted to revise treatment guidelines for MRSA infections in Japan. METHODS: PubMed (Medline), Scopus, Embase, Web of Science and Cochrane library were searched for relevant articles comparing preventive effect of ALBC for patients undergoing primary total joint arthroplasty by August 2022. Primary outcome was the incidence of deep SSI. Subgroup analyses by type of surgery (total hip (THA) or knee (TKA) arthroplasty) and by causative pathogen (methicillin-resistant Staphylococcus aureus (MRSA)) were performed. RESULTS: Of the 3379 studies identified for screening, six studies involving 5745 patients were included. The use of ALBC significantly reduced the incidence of deep SSI in overall patients (risk ratio [RR] 0.60, 95% confidential interval [CI] 0.39-0.92), but the evidence level was very low. There was no significant preventive effect for ALBC compared with non-ALBC in both THA and TKA (THA, RR 0.52, 95% CI 0.23-1.16; TKA, RR 0.64, 95% CI 0.38-1.06), and for preventing MRSA-SSI (RR 0.27, 95% CI 0.03-2.41). CONCLUSIONS: Although the overall preventive effect of ALBC was significant, the evidence level was very low. Thus, the routine use of ALBC as a mean to prevent SSI in arthroplasty may not be suggested.

Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study.

INTRODUCTION: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. METHODS: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400-600 µg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). RESULTS: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400-600 µg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). CONCLUSION: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

Pharmacokinetics and Pharmacodynamics of Glucarpidase Rescue Treatment After High-dose Methotrexate Therapy Based on Modeling and Simulation.

BACKGROUND: Model-informed approaches are important in drug development, including for dose optimization and the collection of evidence in support of efficacy. MATERIALS AND METHODS: We developed a modified Michaelis-Menten pharmacokinetics/pharmacodynamics model and used it to conduct simulations of glucarpidase at doses between 10 and 80 U/kg rescue treatment after high-dose methotrexate therapy. We carried out a dose-finding modeling and simulation study before a phase II study of glucarpidase. Monte-Carlo simulations were conducted using the deSolve package of R software (version 4.1.2). The proportion of samples in which the plasma methotrexate concentration was less than 0.1 and 1.0 µmol/l at 70 and 120 h after methotrexate treatment was evaluated for each dosage of glucarpidase. RESULTS: The proportion of samples in which the plasma methotrexate concentration was less than 0.1 µmol/l at 70 h after methotrexate treatment was 71.8% and 89.6% at 20 and 50 U/kg of glucarpidase, respectively. The proportion of samples in which the plasma methotrexate concentration was less than 0.1 µmol/l at 120 h after methotrexate treatment was 46.4% and 59.0% at 20 and 50 U/kg of glucarpidase, respectively. CONCLUSION: We determined a recommended glucarpidase dose of 50 U/kg to be ethically acceptable. A rebound in the serum concentration of methotrexate may be observed in many patients after the administration of glucarpidase, and long-term monitoring (over 144 h) of the serum methotrexate concentration may be needed after the administration of glucarpidase. Its validity was confirmed in the phase II study and glucarpidase was approved for manufacturing in Japan.

Development of a population pharmacokinetics and pharmacodynamics model of glucarpidase rescue treatment after high-dose methotrexate therapy.

Introduction: Glucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation. Methods: In this study, a CPG2 population pharmacokinetics (popPK) analysis in healthy volunteers (phase 1 study) and a popPK-pharmacodynamics (popPK-PD) analysis in patients (phase 2 study, n = 15) who received 50 U/kg of CPG2 rescue for delayed MTX excretion were conducted. In the phase 2 study, the first CPG2 treatment at a dose of 50 U/kg was intravenously administered for 5 min within 12 h after the first confirmation of delayed MTX excretion. The second dose of CPG2, with a plasma MTX concentration >1 µmol/L, was administered to the patient more than 46 h after the start of CPG2 administration. Results: The population mean PK parameters (95% CI) of MTX, obtained from the final model post hoc, were estimated as follows: CLrMTX = 2.424 L/h (95% CI: 1.755-3.093), VcMTX = 12.6 L (95% CI: 10.8-14.3), VpMTX = 2.15 L (95% CI: 1.60-2.70), and α = 8.131 x 105 (4.864 x 105-11.398 x 105). The final model, including covariates, was CLrMTX (L/h): 3.248 x Body Weight/Serum creatinine/60 (CV 33.5%), VcMTX (L): 0.386 x Body Weight/body surface area (CV 29.1%), VpMTX (L):3.052 x Body Weight/60 (CV 90.6%), and α (L/h): 6.545 x 105 (CV 79.8%). Discussion: These results suggest that the pre-CPG2 dose and 24 h after CPG2 dosing were the most important sampling points in the Bayesian estimation of plasma MTX concentration prediction at 48 h. These CPG2-MTX popPK analysis and Bayesian estimation of rebound in plasma MTX concentrations are clinically important to estimate >1.0 µmol/L 48 h after the first CPG2 dosing. Clinical trial registration: https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2363, identifier JMA-IIA00078 and https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2782, identifier JMA-IIA00097.

Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan.

BACKGROUND: We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan. METHODS: DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32. RESULTS: We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy. CONCLUSIONS: Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.

A retrospective study on the risk factors for bleeding events in warfarin therapy, focusing on renal function.

PURPOSE: The anticoagulant effect of warfarin used to treat stroke has been shown to vary with the concomitant use of medications and comorbidity. Concomitant use of antithrombotic drugs and underlying chronic kidney disease (CKD) represent risk factors for bleeding events. We conducted a comprehensive investigation of the background characteristics and concomitant use of drugs to identify the risk factors for warfarin-related bleeding, focusing on renal function. METHODS: The study population consisted of patients prescribed warfarin at the Tokyo Women's Medical University Hospital. A retrospective review of the patient data, including bleeding events, bleeding sites, the patient's background, concomitant use of drugs, and laboratory data was carried out, and the incidence of bleeding events was compared in patient groups stratified according to CKD stage and antithrombotic drug use. Multivariate logistic regression analysis was performed to determine the risk factors for warfarin-related bleeding. RESULTS: Of the 3,831 patients included in the study, the incidence of warfarin-related bleeding was 3.0 events per 100 patient-years. The multivariate logistic regression analysis identified age > 65 years, body mass index (BMI), alanine aminotransferase (ALT), estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, prothrombin time-international normalized ratio (PT-INR), and concomitant use of antithrombotic drugs as risk factors for warfarin-related bleeding. CONCLUSIONS: The present analyses identified age > 65 years, BMI, ALT, eGFR <30 mL/min/1.73 m2, PT-INR, and concomitant use of antithrombotic drugs as independent risk factors for warfarin-related bleeding. We should pay attention to the risk factors associated with warfarin-related bleeding when prescribing warfarin in patients with renal impairment.

Clinical characteristics associated with mortality of patients with anaerobic bacteremia.

The presence of anaerobes in the blood stream is known to be associated with a higher rate of mortality. However, few prognostic risk factor analyses examining whether a patient's background characteristics are associated with the prognosis have been reported. We performed a retrospective case-controlled study to assess the prognostic factors associated with death from anaerobic bacteremia. Seventy-four patients with anaerobic bacteremia were treated between January 2005 and December 2014 at Aichi Medical University Hospital. The clinical information included drug susceptibility was used for analysis of prognostic factors for 30-day mortality. Multivariate logistic analyses revealed an association between the 30-day mortality rate and malignancy (OR: 3.64, 95% CI: 1.08-12.31) and clindamycin resistance (OR: 7.93, 95% CI: 2.33-27.94). The result of Kaplan-Meier analysis of mortality showed that the 30-day survival rate was 83% in clindamycin susceptible and 38.1% in clindamycin resistant anaerobes causing bacteremia. The result of log-rank test also showed that susceptibility to clindamycin affected mortality (P < 0.001). Our results indicated that malignancy and clindamycin susceptibility could be used to identify subgroups of patients with anaerobic bacteremia with a higher risk of 30-day mortality. The results of this study are important for the early and appropriate management of patients with anaerobic bacteremia.

Clinical experience with colistin in 9 Japanese patients with infection due to multi-drug resistance pathogens.

Colistin is a polypeptide antibiotic of the polymyxin family (polymyxin E) which has been reported to be active against many multidrug-resistant (MDR) Gram-negative aerobic bacteria collected across the globe. While this agent was not currently licensed in Japan, the emergence of MDR organisms has necessitated its off-label used in the country. However, colistin was approved in March, 2015. This retrospective observational report includes nine patients with MDR Gram-negative infections due to Pseudomonas aeruginosa (n=6) and Klebsiella spp. (n=3) who received intravenous colistin therapy as part of their antimicrobial regimen. The median age and duration of administration were 40 years (range 7-90) and 8 days (range 1-19). Clinical success was observed in all eight patients for whom efficacy could be evaluated. Two patients encountered colistin related adverse effects 22.2% (2/9). In both cases the nephrotoxicity and dysgeusia resolved after discontinuation of colistin therapy. In vitro studies conducted with these clinical isolates of P aeruginosa displayed synergy with the combination of colistin plus ceftazidime, rifampicin, meropenem or aztreonam. This report provides early evidence that colistin is generally safe, effective and demonstrates in vitro synergy when used in combination for the management of MDR Gram-negative pathogens derived from Japanese patients.

Investigation of the risk factors of anaerobic bacteremia in a case-control study.

BACKGROUND: Many case series studies have reported risk factors of infection with anaerobic bacteria, but few factor analysis studies have been conducted. OBJECTIVE: We conducted a case-control study to identify the risk factors of anaerobic bacteremia. METHODS: We compared a number of characteristics of patients with anaerobic bacteremia with those with aerobic bacteremia. Clinical information for 71 patients of anaerobic bacteremia was collected from January 1999 to December 2012 in Aichi Medical University Hospital. For each case, we identified up to four controls matched by the time of the positive blood culture. RESULTS: Multivariate logistic analyses revealed an association between anaerobic bacteremia and malignancy (OR: 3.35, 95% CI: 1.85-6.09), Douglas' pouch drains (OR: 25.90, 95% CI: 2.90-25.00) and chest drains (OR: 3.35, 95% CI: 1.19-9.43) as the primary causative disease, as well as associations between anaerobic bacteremia and the gastrointestinal tract (OR: 3.29, 95% CI: 1.38-7.81), genitourinary tract (OR: 4.98, 95% CI: 2.06-12.05), Douglas' pouch drains (OR: 16.95, 95% CI: 1.82-166.67) and chest drains (OR: 3.62, 95% CI: 1.29-10.20) as the primary causative organs. On the other hand, our study showed that having a central venous catheter was not associated with anaerobic bacteremia. CONCLUSIONS: We demonstrated an association between anaerobic bacteremia and malignancy, gastrointestinal and genitourinary tracts, patients having a Douglas' pouch drains or chest drains. These findings may be useful for developing early appropriate management for anaerobic bacteremia.

Motor-dominant polyneuropathy due to IgM monoclonal antibody against disialosyl gangliosides in a patient with mantle cell lymphoma.

A rapidly progressive motor-dominant neuropathy associated with IgM monoclonal antibody against gangliosides with disialosyl residues, GD3, GD1b, GT1b, and GQ1b, in a 60-year-old Japanese man with mantle cell lymphoma is reported. Plasma exchange and chemotherapy for mantle cell lymphoma were performed for the neuropathy and mantle cell lymphoma. After therapy, the motor neuropathy dramatically improved concurrently with substantial reduction of the antibody activities especially in reaction to GD1b. This is the first case report of neuropathy with anti-disialosyl IgM antibodies associated with mantle cell lymphoma, and plasma exchange and chemotherapy were effective.

Details of treatment-related difficulties in men with anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody-associated encephalitis is an immunologic disease characterized by a female preponderance. Males are infrequently affected. The clinical symptoms of affected boys as well as girls have been summarized, and they have some clinical features distinct from those of adults. However, the characteristics of men have been described in only a few reports. We describe in detail four men with anti-NMDAR encephalitis who presented with several clinical features that complicated disease management and recovery, including venous thrombosis, bilateral hippocampal involvement, hypersexuality, and joint contracture. We also report the first detailed clinical information about a male patient who died of this disease. In addition, we summarize the clinical characteristics of five patients previously reported by others.

Phase II study of radiation therapy combined with weekly nedaplatin in locally advanced uterine cervical carcinoma: Kitasato Gynecologic Radiation Oncology Group (KGROG 0501).

In order to evaluate the safety and efficacy of chemoradiotherapy using nedaplatin for locally advanced uterine cervical carcinoma in Japanese patients, we have started a single-institute phase II trial. Eligibility criteria include: (i) pathologically proven squamous cell carcinoma or adenocarcinoma, (ii) clinical FIGO stage Ib, IIa, or IIb with bulky tumor (> 40 mm) or pelvic lymph node swelling, or (iii) clinical FIGO stage IIIa, IIIb and IVa, (iv) no para-aortic lymph node swelling. A combination of external beam radiation and high dose rate intracavitary irradiation is given. Nedaplatin (30 mg/m2) is intravenously infused on a weekly basis for five times. The primary endpoint is 3-year overall survival, and the secondary endpoints are tumor response, 2-year overall survival, 3-year progression-free survival, acute adverse events, protocol treatment compliance, and late adverse events. We plan to recruit 45 patients within 3 years.

[A case of Parkinson's disease with neuroleptic malignant syndrome induced by paroxetine].

We present a first case of Parkinson's disease with neuroleptic malignant syndrome by Paroxetine, one of the selective serotonin reuptake inhibitor (SSRI). The patient was a 73-year-old woman who had been diagnosed as Parkinson's disease for one and half year. The severity of her disease was categorized as Hoehn & Yahr 2nd degree and she had taken 0.25 mg/day of Pramipexole. Four days after the addition of 10 mg/day of Paroxetine for the treatment of her depression, she developed consciousness disturbance, severe muscular rigidity, tremor, fever, hyperhidrosis, incontinence and elevated serum creatine kinase level. According to diagnostic criteria, she was diagnosed as neuroleptic malignant syndrome probably induced by Paroxetine. Her clinical symptoms and laboratory data were improved seven days after intravenous drip infusion. We should recognize that SSRI could induce neuroleptic malignant syndrome in patients with Parkinson's disease.