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In Japan, patients with coronavirus disease 2019 (COVID-19) who do not require medical intervention are provided care in recovery accommodation facilities (RAFs). However, some patients may require hospitalization if their symptoms become more severe during their stay. We conducted an observational study using epidemiological data of patients with COVID-19 admitted to RAFs in Tokyo.This was an observational cohort study using data from COVID-19 patients admitted to one of the RAFs in Tokyo from December 2020 to November 2021. Admissions to the facilities were limited to patients with asymptomatic or mild COVID-19 with no underlying disease or at least stable underlying disease at the time of admission. Patients were hospitalized when they required oxygen administration or when they had, or persistent fever, or severe respiratory symptoms. We evaluated the association between hospitalization and the risk factors for hospitalization using a Cox regression model.The number of patients with COVID-19 admitted to the RAF was 6176. The number of hospitalized patients was 393 (6.4%), and the median length of stay was 5.50 days (IQR: 4.50, 6.50). In the Cox regression analysis, the hazard ratio increased with age and was significantly higher among patients aged60 years (HR = 10.23, 95% CI: 6.72-15.57) than those in other age groups. This trend is similar to that observed in the sensitivity analysis.Patients with diabetes, the elderly, obesity, and medications for gout and psychiatric diseases may be at a high risk of hospitalization. In particular, an age over 60 years was strongly associated with hospitalization.

Staphylococcus aureus causes various infections, including skin and soft tissue infections and pneumonia via both, community-associated and nosocomial infection. These infectious diseases can lead to bacteremia, and may subsequently result in metastatic infections in several cases. Metastatic infections are critical complications in patients with S. aureus bacteremia, since the optimal duration of the antimicrobial treatment differs in patients with and without metastatic infection. Notably, two weeks of antimicrobial treatment is recommended in case of uncomplicated S. aureus bacteremia, whereas in patients with S. aureus bacteremia-associated endocarditis or vertebral osteomyelitis, six weeks of antimicrobial administration is vital. In addition, misdiagnosis or insufficient treatment in metastatic infection is associated with poor prognosis, functional disability, and relapse. Although echocardiography is recommended to examine endocarditis in the patients with S. aureus bacteremia, it remains unclear which patients should undergo additional examinations, such as CT and MRI, to detect the presence of other metastatic infections. Clinical studies have revealed that permanent foreign body and persistent bacteremia are predictive factors for metastatic infections, and experimental studies have demonstrated that the virulence factors of S. aureus, such as fnbA and clfA, are associated with endocarditis; however, these factors are not proven to increase the risk of metastatic infections. In this review, we assessed the incidence, predictive factors, diagnosis, and treatment for metastatic infections during S. aureus bacteremia.

The pharmacokinetics of vancomycin (VAN) was retrospectively examined based on trough concentrations at large scale to identify pharmacokinetic differences between Japanese hematologic malignancy and non-malignancy patients. Data from 261 hematologic malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN estimated by an empirical Bayesian method, were collected and analyzed. Our results showed significantly higher values for VAN clearance and shorter elimination half-lives in patients with hematologic malignancies than non-malignancy patients. In addition, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to hematologic malignancies. In conclusion, since in hematologic cancer patients VAN clearance is increased, the blood concentration of VAN becomes lower than expected and this may contribute to the survival of resistant bacteria when VAN is administered at low doses. These results suggest that early monitoring of VAN levels in hematologic cancer patients might be recommended to maintain desired effects without side-effects.

The clinical manifestations of COVID‐19 vary broadly, ranging from asymptomatic infection to acute respiratory failure and death. But the predictive biomarkers for characterizing the variability are still lacking. Since emerging evidence indicates that extracellular vesicles (EVs) and extracellular RNAs (exRNAs) are functionally involved in a number of pathological processes, we hypothesize that these extracellular components may be key determinants and/or predictors of COVID‐19 severity. To test our hypothesis, we collected serum samples from 31 patients with mild COVID‐19 symptoms at the time of their admission for discovery cohort. After symptomatic treatment without corticosteroids, 9 of the 31 patients developed severe/critical COVID‐19 symptoms. We analyzed EV protein and exRNA profiles to look for correlations between these profiles and COVID‐19 severity. Strikingly, we identified three distinct groups of markers (antiviral response‐related EV proteins, coagulation‐related markers, and liver damage‐related exRNAs) with the potential to serve as early predictive biomarkers for COVID‐19 severity. As the best predictive marker, EV COPB2 protein, a subunit of the Golgi coatomer complex, exhibited significantly higher abundance in patients remained mild than developed severe/critical COVID‐19 and healthy controls in discovery cohort (AUC 1.00 (95% CI: 1.00‐1.00)). The validation set included 40 COVID‐19 patients and 39 healthy controls, and showed exactly the same trend between the three groups with excellent predictive value (AUC 0.85 (95% CI: 0.73‐0.97)). These findings highlight the potential of EV COPB2 expression for patient stratification and for making early clinical decisions about strategies for COVID‐19 therapy.

The clinical manifestations of COVID-19 vary broadly, ranging from asymptomatic infection to acute respiratory failure and death. But the predictive biomarkers for characterizing the variability are still lacking. Since emerging evidence indicates that extracellular vesicles (EVs) and extracellular RNAs (exRNAs) are functionally involved in a number of pathological processes, we hypothesize that these extracellular components may be key determinants and/or predictors of COVID-19 severity. To test our hypothesis, we collected serum samples from 31 patients with mild COVID-19 symptoms at the time of their admission. After standard therapy without corticosteroids, 9 of the 31 patients developed severe COVID-19 symptoms. We analyzed EV protein and exRNA profiles to look for correlations between these profiles and COVID-19 severity. Strikingly, we identified three distinct groups of markers (antiviral response-related EV proteins, coagulation-related markers, and liver damage-related exRNAs) with the potential to serve as early predictive biomarkers for COVID-19 severity. Among these markers, EV COPB2 has the best predictive value for severe deterioration of COVID-19 patients in this cohort. This type of information concerning functional extracellular component profiles could have great value for patient stratification and for making early clinical decisions about strategies for COVID-19 therapy.

Vancomycin (VAN) is an anti-microbial agent used to treat a number of bacterial infections, which has a high incidence of nephrotoxicity. We examined the pharmacokinetics of VAN retrospectively based on trough concentrations at large scale and identified pharmacokinetic differences between Japanese patients having solid malignancy and non-malignancy patients. Data were analyzed from 162 solid malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN. We failed to detect differences in values for VAN clearance or shorter elimination half-lives between these two groups. In contrast, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to solid malignancies in each stage. We conclude that VAN clearance in solid malignancy patients is increased and that the blood concentration of VAN becomes lower than expected. These results suggest that early monitoring of VAN levels in solid malignancy patients might be essential for maintaining desired effects without side-effects.

A 56-year-old Japanese man diagnosed with acquired immunodeficiency syndrome, Pneumocystis jirovecii pneumonia and cytomegalovirus infection presented with thrombocytopenia after starting antiretroviral therapy, which included dolutegravir (DTG). Although good control of the human immunodeficiency virus and cytomegalovirus infections was achieved, the patient's thrombocytopenia persisted. The patient's platelet count decreased to ≤50,000 /μL even after the cessation of valganciclovir, which can cause bone marrow suppression. At five months after starting antiretroviral therapy, DTG was replaced by ritonavir-boosted darunavir. Soon after, his platelet count improved and was maintained at a level of >100,000 /μL. This is the first reported case of severe thrombocytopenia during DTG-containing antiretroviral therapy.

HIV infection, in particular in patients with developing AIDS, carries a risk of causing toxoplasmosis with encephalitis, which is mostly caused by a form (bradyzoite) of the protozoan parasite Toxoplasma gondii. HIV/AIDS in Japan has been recognized as a serious health issue in recent years. In this study, to elucidate T. gondii seroprevalence in HIV-positive patients in Japan and associated characteristics with Toxoplasma parasite infection, the titer of T. gondii IgG (Tg-IgG) was measured in 399 HIV-positive patients who visited a hospital in Tokyo, Japan, between 2015 and 2017. A questionnaire survey was also conducted to investigate associations between lifestyle and customs. As a result, the overall prevalence of Tg-IgG-positive serum was 8.27% (33 cases of 399). All the cases positive for Tg-IgG were confirmed using the Sabin-Feldman dye test; the titers between each examination correlated robustly (p 0.001, r = 0.6). A correlation between Toxoplasma infection rate and age was determined (p 0.001), whereas there was no significant correlation with lifestyle customs such as consuming undercooked meat or owning a cat. An association between Toxoplasma infection and experience of dwelling in the Hokkaido area, the northern part of Japan, was observed (p = 0.001). These results suggested that the proportion of those who were previously exposed to Toxoplasma parasites in the HIV-positive population has been maintained at a similar level as that of the HIV-negative population in Japan, providing clear information about the potential risk of toxoplasmic encephalitis.

We report two cases of Paragonimus westermani infection in a Chinese family in Japan. A 41-year-old husband and his 40-year-old wife were infected with P. westermani after consuming a homemade Chinese traditional "Drunken Crab." They were a family with two children who had lived in Japan for 19 years. The crabs were Eriocheir japonica sent from the Kyusyu area that they had pickled at home with soy sauce and Chinese liquor for 5 days. Their children did not eat any of the crabs. One month after consuming the crabs, the husband came to our outpatient clinic with fever and chest pain and his wife also presented with a persistent cough. Both patients had a high peripheral blood eosinophil count (husband:18,900/μL, wife:10,600/μL) with pulmonary effusion, nodular shadow, and pneumothorax in chest X-ray findings. Paragonimiasis was suspected from the episode of consuming the crabs. No parasite eggs were seen in their sputum and stool samples. A multiple-dot ELISA was performed with the sera to screen for parasitic infections, but the result was only weakly positive for P. westermani antigen in the husband and a slightly positive reaction in the wife. The diagnosis of P. westermani was achieved with the double diffusion Ouchterlony method using P. westermani antigen and P. miyazakii antigen. Praziquantel administration for three days improved the symptoms in both patients. The Ouchterlony method proved useful in diagnosing paragonimiasis in these cases.

The pharmacokinetics of meropenem have not yet been examined in Japanese patients receiving Continuous venovenous hemodialysis (CVVHD). The aim of this clinical investigation was to determine the pharmacokinetic parameters of meropenem in critically ill patients receiving CVVHD in order to estimate dosing regimens for the patient population in Japan. The values of pharmacokinetic parameters were 17.5 ± 5.6 l for V1, 1.27 ± 0.38 h(-1) for K12, 0.71 ± 0.40 h(-1) for K21 and 0.17 ± 0.02 h(-1) for K10. Based on these mean parameters (V1, K12, K21 and K10), time above MIC (T > MIC) values were estimated at different MICs using various meropenem regimens. For bacteria with a meropenem MIC of ≤ 2 μg/ml, a dosing regimen of 0.25 g every 24 h achieved more than 40% T > MIC. For a MIC of 4 μg/ml, all the regimens tested, except for 0.25 g every 24 h, achieved more than 40% T > MIC. For a MIC of 16 μg/ml, dosing regimens of 0.5 g every 8 h, 1 g every 12 h, and 1 g every 8 h achieved 40% T > MIC, reaching the pharmacokinetic-pharmacodynamic target range. This is the first study to examine the pharmacokinetics of meropenem under a CVVHD setting in Japan. The pharmacokinetic-pharmacodynamic profile of dosing regimens tested in this study will assist in selecting the appropriate meropenem regimens for patients receiving CVVHD.

We gathered data regarding age, sex, and positivity rates for human immunodeficiency virus (HIV), syphilis, gonococcus, and chlamydia from individuals who underwent free and anonymous sexually transmitted infection (STI) testing conducted at the Jikei University School of Medicine Hospital (our hospital). These data were compared to results of subjects who underwent similar testing at the Minato Health Center and several private facilities of urologists and gynecologists belonging to the Minato Ward Medical Association. The positivity rate of chlamydia was found to be high in female subjects, particularly at the Minato Health Center, with 15 of 194 subjects (7.73 %) testing positive. In our hospital, we only detected 3 of 133 subjects (2.26 %) who were gonococcus positive. On the other hand, at the doctor's facilities, 10 of 188 male subjects (5.32 %) were syphilis positive, and 8 of 185 male subjects (4.32 %) were chlamydia positive, thus showing high positivity rates for both infections. At our hospital, 1 of 231 subjects was positive for gonococcus and 4 of 230 subjects (1.74 %) were positive for chlamydia, thus showing lower positivity rates for both infections. HIV-positive subjects were, however, only confirmed at our hospital, with 2 of 243 subjects (0.82 %) being positive. We were able to diagnose infected patients using free and anonymous STI testing at hospitals, and the same as at doctors' facilities. This result suggests that the hospitals that have many opportunities to diagnose HIV patients may become potential candidates for the development of new consultation facilities, establishment of testing facilities, and enhancement of consultation processes that include STI prevention.

Background Metastatic infections, such as infective endocarditis and pyogenic spondylitis, are very serious complications of Staphylococcus aureus bacteremia (SAB), because failure to identify metastatic infections may cause poor prognosis. The aim of the present study is to determine the predictive factors for metastatic infections of SAB. Methods This retrospective cohort study was conducted among patients with bacteremia due to S. aureus (including both methicillin-sensitive S. aureus and methicillin-resistant S. aureus: MSSA and MRSA) in The Jikei University Kashiwa Hospital. The study population comprised 125 adult patients with SAB between January 2014 and December 2017. Patients, that died or transferred within 3 months after the initial positive blood culture, were excluded, because metastatic infection was defined as deep-seated infection detected within 3 months after the initial positive blood culture. We analyzed several factors, including demographics, comorbidities, community acquisition, primary site of infection, persistent fever and laboratory data such as c-reactive protein (CRP) levels after treatment. Results Seventy-four patients met inclusion criteria of this study. The most common primary site of bacteremia was catheter-related [24 (32.4%) of 74]. Metastatic infection occurred in 22 (29.7%) of 74 patients, and spondylitis was most common, following psoas abscess. Of these, 11 infections (50% of 22) were community acquired. We did not find any significant differences in demographics and comorbidities, except central venous catheter-associated bloodstream infection, which was associated with low rate of metastatic infection. By multivariate analysis, the predictive factors associated with the development of metastatic infection were community onset of infection (OR 11.6; 95% CI 2.98–45.1; P < 0.001), persistent fever over 72 hours (OR 6.7; 95% CI 2.12–21.8; P = 0.001), and higher CRP levels (>3 mg/dL) lasting 2 weeks after the administration of appropriate antibiotics (OR 7.47; 95% CI 2.39–23.3; P < 0.001). Conclusion This study demonstrated that additional diagnostic tests to identify metastatic infection should be performed, especially in the patients with community-acquired SAB, persistent fever or persistently high CRP levels after the administration of appropriate antibiotics. Disclosures All authors: No reported disclosures.

MRSA causes a wide diversity of diseases, ranging from benign skin infections to life-threatening diseases, such as sepsis. However, there have been few reports of the pathophysiology and mechanisms of sepsis resulting from the gut-derived origin of MRSA. Therefore, we established a murine model of gut-derived sepsis with MRSA and factors of MRSA sepsis that cause deterioration. We separated mice into four groups according to antibiotic treatment as follows: (i) ABPC 40 mg/kg; (ii) CAZ 80 mg/kg; (iii) CAZ 80 mg/kg + endotoxin 10 microg/mouse; and (iv) saline-treated control groups. Gut-derived sepsis was induced by i.p. injection of cyclophosphamide after colonization of MRSA strain 334 in the intestine. After the induction of sepsis, significantly more CAZ-treated mice survived compared with ABPC-treated and control groups. MRSA were detected in the blood and liver among all groups. Endotoxin levels were significantly lower in the CAZ-treated group compared to other groups. Inflammatory cytokine levels in the serum were lower in the CAZ-treated group compared to other groups. Fecal culture showed a lower level of colonization of E. coli in the CAZ-treated group compared to other groups. In conclusion, we found that CAZ-treatment ameliorates infection and suppresses endotoxin level by the elimination of E. coli from the intestinal tract of mice. However, giving endotoxin in the CAZ-treated group increased mortality to almost the same level as in the ABPC-treated group. These results suggest endotoxin released from resident E. coli in the intestine is involved in clinical deterioration resulting from gut-derived MRSA sepsis.

We report a case of meningococcemia without meningitis, which is a rare infectious disease in Japan. A 32-year-old woman was referred to our hospital with fever and joint pain. Her clinical presentation and the results of laboratory examination on admission suggested viral infection. However, her condition rapidly progressed to septic shock with fulminans purpura. Blood culture grew Neisseria meningitidis. She received antimicrobial therapy and underwent localized therapy for skin lesions. Meningococcal infection should be considered in patients who have fever along with skin rash or petechiae even when there are no signs of meningitis. In this report, we also review case reports of meningococcemia without meningitis in Japan.

We report two cases of Paragonimus westermani infection in a Chinese family in Japan. A 41-year-old husband and his 40-year-old wife were infected with P. westermani after consuming a homemade Chinese traditional "Drunken Crab." They were a family with two children who had lived in Japan for 19 years. The crabs were Eriocheir japonica sent from the Kyusyu area that they had pickled at home with soy sauce and Chinese liquor for 5 days. Their children did not eat any of the crabs. One month after consuming the crabs, the husband came to our outpatient clinic with fever and chest pain and his wife also presented with a persistent cough. Both patients had a high peripheral blood eosinophil count (husband:18,900/μL, wife:10,600/μL) with pulmonary effusion, nodular shadow, and pneumothorax in chest X-ray findings. Paragonimiasis was suspected from the episode of consuming the crabs. No parasite eggs were seen in their sputum and stool samples. A multiple-dot ELISA was performed with the sera to screen for parasitic infections, but the result was only weakly positive for P. westermani antigen in the husband and a slightly positive reaction in the wife. The diagnosis of P. westermani was achieved with the double diffusion Ouchterlony method using P. westermani antigen and P. miyazakii antigen. Praziquantel administration for three days improved the symptoms in both patients. The Ouchterlony method proved useful in diagnosing paragonimiasis in these cases.

Sarcoidosis is a systemic granulomatous disease of unknown etiology and is associated with a wide variety of renal disorders including nephrolithiasis, hypercalciuria, hypercalcemia, nephrocalcinosis, tubular defect, glomerulonephritis, and granulomatous interstitial nephritis. We report a case of renal sarcoidosis in which we could not detect any evidence of extrarenal involvements that was diagnosed by renal biopsy and abnormal calcium metabolism incompatible with chronic renal insufficiency. On laboratory findings, decreased creatinine clearance, proteinuria, hypercalcemia, hypercalciuria, and mildly elevated serum angiotensin-converting enzyme (ACE) were seen. Serum intact parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,alpha-25 vit D) were lower and higher than normal range, respectively, whereas the patient was already in chronic renal insufficiency. He was treated with oral corticosteroid. Serum ACE tended to fall, and 1,alpha-25 vit D level decreased with substantial fall of serum calcium and daily calcium excretion. In contrast, intact PTH increased slowly in accordance with a fall of serum calcium compatible with the level of renal impairment. Creatinine clearance and daily excretion of protein improved. The case reported here may propose that serial measurement of serum level of 1,alpha-25 vit D, calcium level, and magnitude of daily calcium excretion into urine is a simple and meaningful tool to detect the therapeutic response in sarcoidosis with abnormal calcium metabolism.

A 52-year-old male Japanese businessman with massive cerebral bleeding was transferred from India to Japan and was admitted to our hospital. Multidrug-resistant Acinetobacter baumannii was isolated from his sputum. The minimum inhibitory concentrations for this strain were as follows: imipenem, 64 μg/ml; meropenem, 32 μg/ml; ciprofloxacin, 16 μg/ml; amikacin, 16 μg/ml; aztreonam, 16 μg/ml; colistin

Objective The mortality rates for bacteremia due to Pseudomonas aeruginosa remain high. In our hospital, we performed retrospective analyses to determine risk factors for mortality among patients with bacteremia caused by P. aeruginosa. Materials and Methods This retrospective cohort study was conducted among adult patients with bacteremia due to P. aeruginosa at Jikei University Hospital. We analyzed factors, such as age, gender, underlying disease, initial antimicrobial treatment, and primary site of infection to determine which of these were predictive of mortality in patients with P. aeruginosa bacteremia. Results One hundred and thirty-four patients with P. aeruginosa bacteremia were identified between April 2003 and March 2010. The 30-day mortality rate among all patients with P. aeruginosa bacteremia was 20.9%. The most common underlying disease was leukemia (20.9%), and the most common primary site of infection was the urinary tract (24.6%). Seventy-one patients (65.7%) were treated with an appropriate initial antimicrobial regimen for P. aeruginosa bacteremia. However, these patients had similar 30-day mortality to that observed in patients not administered appropriate antibiotics. This study revealed that risk factors for the 30-day mortality were thrombocytopenia and polymicrobial P. aeruginosa bacteremia (p

MRSA causes a wide diversity of diseases, ranging from benign skin infections to life-threatening diseases, such as sepsis. However, there have been few reports of the pathophysiology and mechanisms of sepsis resulting from the gut-derived origin of MRSA. Therefore, we established a murine model of gut-derived sepsis with MRSA and factors of MRSA sepsis that cause deterioration. We separated mice into four groups according to antibiotic treatment as follows: (i) ABPC 40 mg/kg; (ii) CAZ 80 mg/kg; (iii) CAZ 80 mg/kg + endotoxin 10 microg/mouse; and (iv) saline-treated control groups. Gut-derived sepsis was induced by i.p. injection of cyclophosphamide after colonization of MRSA strain 334 in the intestine. After the induction of sepsis, significantly more CAZ-treated mice survived compared with ABPC-treated and control groups. MRSA were detected in the blood and liver among all groups. Endotoxin levels were significantly lower in the CAZ-treated group compared to other groups. Inflammatory cytokine levels in the serum were lower in the CAZ-treated group compared to other groups. Fecal culture showed a lower level of colonization of E. coli in the CAZ-treated group compared to other groups. In conclusion, we found that CAZ-treatment ameliorates infection and suppresses endotoxin level by the elimination of E. coli from the intestinal tract of mice. However, giving endotoxin in the CAZ-treated group increased mortality to almost the same level as in the ABPC-treated group. These results suggest endotoxin released from resident E. coli in the intestine is involved in clinical deterioration resulting from gut-derived MRSA sepsis.

We evaluated the role of IL-1 during Pseudomonas aeruginosa bacteremia by intravenously injecting P. aeruginosa strain D4 into IL-1-deficient and WT mice. The two strains showed equivalent mortality rates. However, when the mice were pretreated with cyclophosphamide, bacteremia-induced mortality was significantly greater in the IL-1-deficient mice than in the WT mice (P < 0.01). We then investigated the role of neutrophils and macrophages in protecting IL-1-deficient mice from bacteremia by administering anti-Gr-1 antibody or liposomes containing dichloromethylene diphosphonate, respectively. After P. aeruginosa inoculation survival was significantly lower in the macrophage-depleted IL-1-deficient mice than in the WT mice. In contrast, neutrophil depletion did not have this effect. Compared to the macrophage-depleted WT mice, the macrophage-depleted IL-1-deficient bacteremic mice had higher bacterial counts in various organs 48 and 72 hr post-infection. They also had lower TNF-alpha, IL-6, and INF-gamma concentrations in their livers during the early phase of sepsis. Thus, IL-1 deficiency becomes disadvantageous during P. aeruginosa bacteremia when it is accompanied by immunosuppression, particularly when macrophage functions are seriously impaired.

Kazuaki Matsumoto,1 Masashi Kitaoka,1 Yuko Kuroda,1 Kazuro Ikawa,2 Norifumi Morikawa,2 Junichi Sasaki,3 Osamu Iketani,4 Satoshi Iwata,4 Tetsuya Horino,5 Seiji Hori,5 Junko Kizu1 1Division of Practical Pharmacy, Keio University Faculty of Pharmacy, Tokyo, 2Department of Clinical Pharmacotherapy, Hiroshima University, Hiroshima, 3Department of Emergency and Critical Care Medicine, 4Center for Infectious Diseases and Infection Control, Keio University School of Medicine, 5Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Tokyo, Japan Background: Daptomycin is recommended for complicated skin and skin-structure infections. However, information on the penetration of daptomycin into skin is limited. Therefore, the aim of this in vivo investigation was to determine the pharmacokinetics and skin penetration of daptomycin in rats. Materials and methods: Concentrations of daptomycin were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis was conducted to estimate the rate and extent of daptomycin penetration from the systemic circulation into skin tissue. Since protein binding of daptomycin in rat serum was 89.3%, the free maximum concentration (Cmax) and free area under the curve from time 0 to infinity (AUC0–∞) for plasma were calculated as follows: fCmax, plasma = (1 – 0.893) × Cmax, plasma, fAUC0–∞, plasma = (1 – 0.893) × AUC0–∞, plasma. Results: The following values (mean ± standard deviation) were obtained: 0.06±0 L/h/kg for total clearance (CLtotal), 0.44±0.06 hours for elimination-rate constant, 1.58±0.23 hours for half-life, 0.14±0.02 L/kg for steady-state volume distribution, and 2.28±0.33 hours for mean residence time. Time to Cmax was 3.0 hours for plasma and skin tissue. Cmax and AUC0–∞ for plasma were 175.8±5.1 µg/mL and 811.8±31.9 µg × h/mL, respectively. Cmax and AUC0–∞ for skin tissue were 19.1±1.7 µg/mL and 113.9±21.8 µg × h/mL, respectively. Furthermore, fCmax and fAUC0–∞ for plasma were 18.8 µg/mL and 86.9 µg × h/mL, respectively. The degrees of skin-tissue penetration, defined as the Cmax, skin tissue/fCmax, plasma ratio and AUC0–∞, skin tissue/fAUC0–∞, plasma ratio, were 1.0 and 1.3, respectively. Conclusion: Daptomycin exhibited good penetration into skin tissue, supporting its use for the treatment of complicated skin and skin-structure infections. However, further studies are needed in infected patients in order to investigate the relationship between the antimicrobial efficacy of daptomycin and its drug concentrations in skin tissues. Keywords: daptomycin, pharmacokinetics, rat, skin-tissue penetration

The role of interleukin (IL)-1 in infectious diseases is controversial; some investigators indicated an enhancing effect of IL-1 on host resistance whereas others demonstrated the protective role of IL-1 receptor antagonist in infection. We evaluated the role of endogenous IL-1 in gut-derived sepsis caused by Pseudomonas aeruginosa, by comparing IL-1-deficient mice and wild-type (WT) mice.Gut-derived sepsis was induced by intraperitoneal injection of cyclophosphamide after colonization of P. aeruginosa strain D4 in the intestine.The survival rate of IL-1-deficient mice was significantly lower than that of WT mice (P0.01). Bacterial counts in the liver, mesenteric lymph node and blood were significantly higher in IL-1-deficient mice than in WT mice. Tumor necrosis factor alpha and IL-6 in the liver were significantly higher in IL-1-deficient mice than in WT mice. In vitro, phagocytosis and cytokine production by macrophages were impaired in IL-1-deficient mice compared with WT mice.Our results indicate a critical role for IL-1 during gut-derived P. aeruginosa sepsis. The results also suggest that both impairment of cytokine production and phagocytosis by macrophages are caused by IL-1 deficiency and lead to impaired host response.

Background Metastatic infections such as infective endocarditis and psoas abscess are serious complications of Staphylococcus aureus bacteremia because failure to identify these infections may result in bacteremia relapse or poor prognosis. in the present study, we determined the predictive factors for metastatic infection due to methicillin-sensitive S. aureus bacteremia. Methods A retrospective cohort study was conducted among patients with methicillin-sensitive S. aureus bacteremia at the Jikei University Hospital between January 2008 and December 2012. Factors analyzed included the underlying disease, initial antimicrobial treatment and primary site of infection. Results During the 5-year study period, 73 patients met the inclusion criteria and were assessed. The most common primary site of bacteremia was catheter-related bloodstream infection (25/73 [34.2%]). Metastatic infection occurred in 14 of 73 patients (19.2%) (infective endocarditis [3], septic pulmonary abscess [3], spondylitis [4], psoas abscess [4], epidural abscess [3] and septic arthritis [1]). six patients had multiple metastatic infections. Multivariate analysis revealed that the predictive factors associated with the development of metastatic infection were a delay in appropriate antimicrobial treatment of > 48 hours, persistent fever for > 72 hours after starting antibiotic treatment and lowest C-reactive protein levels of > 3 mg/dL during 2 weeks after the onset of bacteremia. Conclusions This study demonstrated that additional diagnostic tests should be conducted to identify metastatic infection, particularly in patients with delayed antimicrobial treatment, persistent fever and persistently high C-reactive protein levels.