Comparison of the efficacy and safety of standard- and high-dose daptomycin: A systematic review and meta-analysis.

AIMS: Standard doses of daptomycin at 4 and 6 mg/kg were used for the treatment of skin and soft tissue for infections and bacteraemia, respectively. However, increased doses of daptomycin are recommended for complicated infections by Gram-positive organisms. METHODS: A systematic review was conducted using 4 databases. We compared treatment success between standard-dose (SD, 4-6 mg/kg) and high-dose (HD, >6 mg/kg) daptomycin in patients with all-cause bacteraemia, complicated bacteraemia, infective endocarditis, osteomyelitis and foreign body/prosthetic infection as the primary outcome. We also compared the success between SD and HD2 (≥8 mg/kg) daptomycin treatments in patients with these diseases as the secondary outcome. The incidence of creatine phosphokinase (CPK) elevation was evaluated as safety. RESULTS: In patients with complicated bacteraemia and infective endocarditis, the treatment success was significantly lower in the SD group than in the HD group (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.30-0.76 and OR 0.50, 95% CI 0.30-0.82) and HD2 group (OR 0.38, 95% CI 0.21-0.69 and OR 0.30, 95% CI 0.15-0.60), respectively. A significant difference was demonstrated only in the HD2 group in patients with bacteraemia, including simple infection. SD did not decrease the success rate for the treatment of osteomyelitis and foreign body/prosthetic infection. The incidence of elevated CPK was significantly lower in SD group than in HD group. CONCLUSION: SD daptomycin was associated with significantly lower treatment success than HD in patients with complicated bacteraemia/infective endocarditis. The CPK elevation should be considered in patients treated with high daptomycin doses.

A pediatric case of ureterolithiasis due to cystinuria accompanied by acute appendicitis; a case report.

INTRODUCTION: Acute abdominal pain, a chief complaint frequently seen in the emergency department, can be triggered by a vast range of conditions. Although ureterolithiasis is a less common cause in children, renal colic can be caused by calculi due to hereditary metabolic diseases among patients in those age groups. PRESENTATION OF CASE: We report a 12-year-old girl with abdominal pain who was diagnosed with concurrent acute appendicitis and ureterolithiasis due to cystinuria. Acute appendicitis was successfully treated with cefmetazole, and the calculus was eliminated after adequate fluid loading. DISCUSSION: Synchronous acute appendicitis and ureterolithiasis is reported to be rare. Cystinuria is a hereditary metabolic stone-forming disease, and the first calculi can be detected in childhood. Increasing the solubility of cystine in the urine is required to prevent recurrent stone formation and accompanying complications. Urinalysis, ultrasound, and computed tomography coincidentally demonstrated two different acute pathological processes of ureterolithiasis and appendicitis. CONCLUSION: Careful physical and laboratory examination can help clinicians find coexisting etiologies of acute abdominal pain. Ureterolithiasis can be seen in children with hereditary disorders such as cystinuria. Early diagnosis of cystinuria and close monitoring may lead to a better long-term outcome.

A Case of Exacerbation of Haloperidol-Induced Rhabdomyolysis Following the Onset of COVID-19.

BACKGROUND Rhabdomyolysis is a condition in which intracellular components are released into the blood and urine. Rhabdomyolysis can be caused by drug-related complications and COVID-19; however, the underlying mechanism is not clear. In this study, we report a case of rhabdomyolysis complicated by COVID-19, in which we presumed that the cause of rhabdomyolysis was related to prior administration of haloperidol by assessment of the drug history and progression of myopathy. CASE REPORT A 52-year-old man with schizophrenia experienced worsening insomnia 10 days before admission. Thus, haloperidol was increased from 1.5 mg to 3 mg once daily, and 2 to 3 days later, he developed hand tremors and weakness. One day prior to admission, the patient suddenly developed severe back pain. Based on the examination, the patient was diagnosed with COVID-19 complicated with rhabdomyolysis. Laboratory findings on admission were as follows: creatine phosphokinase: 41 539 IU/L; urinary myoglobin, 190×10³ ng/mL; and hematuria scale, grade 4. On day 1, he was started on saline infusion; therefore, haloperidol was discontinued. On day 2, the hematuria resolved. On day 5, the tremor, weakness, and back pain had resolved. On day 7, his creatine kinase level was 242 IU/L, and saline was administered. CONCLUSIONS It has been suggested that the onset of COVID-19 can exacerbate haloperidol-induced rhabdomyolysis. Therefore, if there is a complication of rhabdomyolysis and COVID-19, it is important to review the drug history, specifically that of haloperidol. We recommend hydration and discontinuation of haloperidol to avoid acute kidney injury, in addition to treating COVID-19.

[Suppurative Thrombophlebitis of the Posterior Neck Caused by Streptococcus constellatus: A Case Report and Literature Review].

We report a rare case of suppurative thrombophlebitis of the posterior neck caused by Streptococcus constellatus. A 69-year-old female patient was admitted to the hospital with neck pain and fever, which had persisted for 16 days prior to hospitalization. On day 1 (day of admission), blood cultures (later identifying S. constellatus) were performed, and ceftriaxone (CTRX) IV (2 g SID) was started. On day 3, suppurative thrombophlebitis of the posterior neck was diagnosed by CT scan. The antimicrobials were changed from CTRX to ampicillin/sulbactam IV (12 g QID) to guard against the possibility of complicated infection with Fusobacterium spp. or Prevotella spp. On day 17, a CT scan revealed that the thrombus remained. Therefore, oral edoxaban (30 mg SID) was started. On day 27, the patient was discharged after her medication was changed to oral amoxicillin/clavulanate (1500 mg/375 mg TID). On day 33, the amoxicillin/clavulanate was changed to oral cefaclor (1500 mg TID) and edoxaban was discontinued due to itching. On day 45, the course of cefaclor was completed. The patient went on to follow an uneventful course with no relapses or complications for two years since the conclusion of treatment. These results suggest that when a patient presents with persistent neck pain accompanied by fever, suppurative thrombophlebitis of the posterior neck should be considered. In antimicrobial therapy, the treatment could be switched from intravenous to oral. In addition, direct-acting oral anticoagulants may be an alternative to other forms of anticoagulants.

Incidence of elevated creatine phosphokinase between daptomycin alone and concomitant daptomycin and statins: A systematic review and meta-analysis.

AIMS: The present systematic review and meta-analysis evaluated the incidence of elevated creatine phosphokinase (CPK) levels between daptomycin alone and concomitant daptomycin and statin use. METHODS: We searched the PubMed, Web of Sciences, Cochrane Library and ClinicalTrials.gov databases. We analysed the incidence of elevated CPK between daptomycin alone and concomitant daptomycin and statins among studies defining CPK elevation as levels ≥ the upper limit of normal (ULN) or ≥5× ULN. We also analysed the incidence of rhabdomyolysis between the groups. We then calculated the odds ratios (ORs) and 95% confidence intervals (CIs) based on the included studies. RESULTS: Comparing CPK elevation defined as CPK levels ≥ULN, a significantly higher incidence of CPK elevation was observed with concomitant daptomycin and statin use than with daptomycin alone (OR = 2.55, 95% CI 1.78-3.64, P < .00001, I2  = 0%). Likewise, when CPK elevation was defined as CPK levels ≥5× ULN, a significantly higher incidence of CPK elevation was detected with concomitant daptomycin and statin use than with daptomycin alone (OR = 1.89, 95% CI 1.06-3.35, P = .03, I2  = 48%). The incidence of rhabdomyolysis was significantly higher following concomitant daptomycin and statin use than with daptomycin alone (OR = 11.60, 95% CI 1.81-74.37, P = .01, I2  = 0%). CONCLUSION: The combined use of daptomycin and statins were significant risk factors for the incidence of CPK elevation defined as levels ≥ULN or ≥5× ULN and rhabdomyolysis.

Identification of Risk Factors for Daptomycin-Associated Creatine Phosphokinase Elevation and Development of a Risk Prediction Model for Incidence Probability.

BACKGROUND: In this study, we investigated the risk factors for daptomycin-associated creatine phosphokinase (CPK) elevation and established a risk score for CPK elevation. METHODS: Patients who received daptomycin at our hospital were classified into the non-elevated or elevated CPK group based on their peak CPK levels during daptomycin therapy. Univariable and multivariable analyses were performed, and a risk score and prediction model for the incidence probability of CPK elevation were calculated based on logistic regression analysis. RESULTS: The non-elevated and elevated CPK groups included 181 and 17 patients, respectively. Logistic regression analysis revealed that concomitant statin use (odds ratio [OR], 4.45 [95% confidence interval {CI}, 1.40-14.47]; risk score 4), concomitant antihistamine use (OR, 5.66 [95% CI, 1.58-20.75]; risk score 4), and trough concentration (Cmin) between 20 and <30 µg/mL (OR, 14.48 [95% CI, 2.90-87.13]; risk score 5) and ≥30.0 µg/mL (OR, 24.64 [95% CI, 3.21-204.53]; risk score 5) were risk factors for daptomycin-associated CPK elevation. The predicted incidence probabilities of CPK elevation were <10% (low risk), 10%-<25% (moderate risk), and ≥25% (high risk) with total risk scores of ≤4, 5-6, and ≥8, respectively. The risk prediction model exhibited a good fit (area under the receiver operating characteristic curve, 0.85 [95% CI, .74-.95]). CONCLUSIONS: These results suggested that concomitant use of statins with antihistamines and Cmin ≥20 µg/mL were risk factors for daptomycin-associated CPK elevation. Our prediction model might aid in reducing the incidence of daptomycin-associated CPK elevation.

Population Pharmacokinetic Analysis and Dosing Optimization Based on Unbound Daptomycin Concentration and Cystatin C in Nonobese Elderly Patients with Hypoalbuminemia and Chronic Kidney Disease.

PURPOSE: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose. METHODS: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration-time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated. RESULTS: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05-0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20-60 mL/min and aged 65-95 years were calculated as 200-500 mg q24h. CONCLUSION: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.

Support for fungal infection treatment mediated by pharmacist-led antifungal stewardship activities.

OBJECTIVE: At the Yokohama General Hospital, pharmacist-led antimicrobial stewardship programs (ASP) including antifungal stewardship programs (AFP) were started in 2012. To investigate the efficacy of the programs, we compared several parameters that are recommended for the measurement of ASP in Japan based on pre- and post-AFP activities. PATIENTS AND METHODS: The subjects were inpatients who developed candidemia between April 2008 and March 2016. They were divided into two groups: pre-AFP (April 2008 until March 2012) and post-AFP (April 2012 until March 2016). The results were compared between the two groups. RESULTS: The cumulative optimal antifungal drug usage rate, as a process parameter, significantly increased in the post-AFP group (p = 0.025). Furthermore, the days of therapy of antifungal drugs in the pre- and post-AFP groups was median 6.0 (interquartile range [IQR] 0.3-15.7) and median 3.4 (IQR 1.9-3.4) per 1,000 patient-days, respectively; there was a significant decrease in the post-AFP group (p < 0.001). Expenditure on antifungal drugs, as an outcome parameter, in the pre- and post-AFP groups was 9390.5 ± 5687.1 and 5930.8 ± 4687.0 US dollars, respectively; there was a significant decrease in the post-AFP group (p = 0.002). CONCLUSIONS: These results suggest that pharmacist-led antifungal stewardship activities improve both outcome and process parameters.

Derivation of gender and age-specific reference intervals from fully normal Japanese individuals and the implications for health screening.

BACKGROUND: With nationwide standardization of laboratory tests among institutions for health screening in Japan, common reference intervals (RIs) were derived from records of 1,500,000 health check attendees. METHODS: Targets were 20 basic laboratory tests including body mass index (BMI) and systolic and diastolic blood pressures (SBP, DBP). Individuals fulfilling the following strict criteria were chosen: SBP<130, DBP<85mmHg, BMI<25kg/m(2), non-smoking, ethanol consumption<20g/day and under no mediation with no remarkable current/past illnesses. The latent abnormal values exclusion (LAVE) method was applied to ensure fully normal results. RIs were derived by parametric method using modified Box-Cox power transformation. RESULTS: Among all attendees, 23% fulfilled the criteria. Application of the LAVE method further reduced the dataset by 40%-50%. Age-related charts of test results differed greatly between genders in almost all tests. Comparison of derived RIs with clinical decision limits (CDLs) revealed that the upper limits of RIs differed from CDLs according to gender and age. CONCLUSIONS: Implementation of gender and age-specific RIs derived from individuals with fully normal health attributes will (1) enable appropriate interpretation of test results in health screening and (2) promote judicious application of CDLs for therapeutic intervention, taking into account gender, age and other health attributes.

Organocatalytic asymmetric nitroaldol reaction: cooperative effects of guanidine and thiourea functional groups.

Catalytic enantio- and diastereoselective nitroaldol reactions were explored by using designed guanidine-thiourea bifunctional organocatalysts under mild and operationally simple biphasic conditions. These catalytic asymmetric reactions have a broad substrate generality with respect to the variety of aldehydes and nitroalkanes. Based on this catalytic nitroaldol process, straightforward syntheses of cytoxazone and 4-epi-cytoxazone were achieved. These catalytic nitroaldol reactions require KI as an additive for highly asymmetric induction; it operates by inhibiting the retro mode of the reaction. On the basis of studies of structure and catalytic-activity relationships, a plausible guanidine-thiourea cooperative mechanism and a transition state of the catalytic reactions are proposed. Drastic substituent effects on the catalytic properties of this catalyst may lead to the development of new chiral surfactants.

Occlusal guidance of two Kabuki make-up syndrome patients: case reports.

Kabuki make-up syndrome (KMS) has been reported since 1981 by Niikawa et al. Complications of KMS were moderate mental retardation, skeletal and dermatoglyphic abnormalities. A 7 year-old boy, who had severe permanent tooth deficiency, anterior open bite, tongue thrust and mild mental retardation, was referred to our clinic. Oral characters of another patient were an anterior open bite, transposition of maxillary central and lateral incisor. Orthodontic treatment in two patients is reported and suggested future treatment plans in these patients is given.

Calcitonin in human odontoclasts regulates root resorption activity via protein kinase A.

Calcitonin is a known inhibitor of osteoclastic bone resorption, but it remains uncertain whether calcitonin also regulates human odontoclastic activity, particularly during the physiological process of root resorption. In this study, we examined the expression of calcitonin receptors in human odontoclasts and the effect of calcitonin on root resorption, using immunocytochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Actin-ring formation was used to assess cytostructural changes during resorption activity. Our results show that calcitonin receptors are expressed in human odontoclasts freshly isolated from deciduous teeth of the periodontal region. Calcitonin inhibited actin-ring formation and resorption activity. This calcitonin-induced inhibition was mimicked by forskolin and dibutyryl-adenosine 3',5'-cyclic monophosphate (db-cAMP), which are protein kinase A (PKA) activators, but not by phorbol 12-myristate 13-acetate, a protein kinase C activator. Pretreatment with adenosine 3',5'-cyclic monophosphothioate Rp diastereomer (Rp-cAMPS), a PKA inhibitor, suppressed the calcitonin-induced inhibition of actin-ring formation. These results indicate that calcitonin receptor activation suppresses odontoclastic root resorption via PKA, a signaling pathway different from that in human osteoclasts.

Expression and role of RANKL in periodontal ligament cells during physiological root-resorption in human deciduous teeth.

Although important roles of receptor activator of NF-kappaB ligand (RANKL) and its receptor (RANK) have been established for osteoclastogenesis and bone resorption, their expression and roles during physiological root resorption remain uncertain. Physiological root resorption for shedding of human deciduous teeth is mediated by osteoclast-like cells (odontoclasts). In this study, we examined the expression of RANKL and osteoprotegerin (OPG), a decoy receptor that prevents RANKL from binding to RANK in human periodontal ligament (PDL) cells during physiological root resorption using immunocytochemistry and reverse transcriptase polymerase chain reaction. The effect of RANKL on root resorbing activity of odontoclasts was evaluated by measuring the size of dissolved area on calcium phosphate-coated coverslips. The PDL cells isolated from either non-resorbing deciduous teeth or permanent teeth abundantly expressed OPG, but not RANKL. In contrast, PDL cells derived from resorbing deciduous teeth dominantly expressed RANKL. Human odontoclasts derived from resorbing deciduous teeth expressed both RANKL and RANK. It was observed that RANKL increased odontoclast actin ring formation and resorbing activity in a dose-dependent manner. These results indicate that PDL cells during the root-resorbing state express RANKL but decrease OPG expression. Expression of RANKL likely participates in odontoclastogenesis and activates physiological root resorption.

Mechanism and role of high-potassium-induced reduction of intracellular Ca2+ concentration in rat osteoclasts.

Osteoclasts are multinucleated, bone-resorbing cells that show structural and functional differences between the resorbing and nonresorbing (motile) states during the bone resorption cycle. In the present study, we measured intracellular Ca2+ concentration ([Ca2+]i) in nonresorbing vs. resorbing rat osteoclasts. Basal [Ca2+]i in osteoclasts possessing pseudopodia (nonresorbing/motile state) was around 110 nM and significantly higher than that in actin ring-forming osteoclasts (resorbing state, around 50 nM). In nonresorbing/motile osteoclasts, exposure to high K+ reduced [Ca2+]i, whereas high K+ increased [Ca2+]i in resorbing state osteoclasts. In nonresorbing/motile cells, membrane depolarization and hyperpolarization applied by the patch-clamp technique decreased and increased [Ca2+]i, respectively. Removal of extracellular Ca2+ or application of 300 microM La3+ reduced [Ca2+]i to approximately 50 nM in nonresorbing/motile osteoclasts, and high-K+-induced reduction of [Ca2+]i could not be observed under these conditions. Neither inhibition of intracellular Ca2+ stores or plasma membrane Ca2+ pumps nor blocking of L- and N-type Ca2+ channels significantly reduced [Ca2+]i. Exposure to high K+ inhibited the motility of nonresorbing osteoclasts and reduced the number of actin rings and pit formation in resorbing osteoclasts. These results indicate that in nonresorbing/motile osteoclasts, a La3+-sensitive Ca2+ entry pathway is continuously active under resting conditions, keeping [Ca2+]i high. Changes in membrane potential regulate osteoclastic motility by controlling the net amount of Ca2+ entry in a "reversed" voltage-dependent manner, i.e., depolarization decreases and hyperpolarization increases [Ca2+]i.