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Chronic obstructive pulmonary disease (COPD) is a respiratory and systemic disease affecting more than 300 million people globally every year, and it also becomes a substantial economic burden. COPD is commonly comorbid with various underlying diseases such as cancer, cardiovascular diseases, cerebrovascular diseases, diabetes mellitus, osteoporosis, etc. It has been shown that statins can improve a significant decline in pulmonary function among COPD patients due to their pleiomorphic effect. Some systematic reviews also reported that statins reduced the risk of COPD-related events such as cancer and cardiovascular events, eventually resulting in more favorable outcomes than for non-statin user COPD patients. However, the physiological mechanism is still elucidated. Recently, it has been reported that statins influence the gut microbial composition with increased relative abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii and act with pleiomorphic effects such as anti-inflammatory and anti-cancer effects through modulating gut dysbiosis. We described this review to focus on whether statins can be a useful preventive option for COPD.

Abstract Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson’s disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587–42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421–7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach.

Objectives: We performed a comprehensive systematic review and meta-analysis to evaluate the clinical or microbiological outcomes and safety of a combination of daptomycin (DAP) and β-lactams compared to DAP monotherapy in patients with blood stream infection (BSI) due to gram-positive cocci (GPC). Methods: We searched Scopus, PubMed, EMBASE, CINAHL, and Ityuushi databases up to January 30, 2023. Outcomes included all-cause mortality, clinical failure, and creatine phosphokinase (CPK) elevation. Results: Six cohorts or case-control studies fulfilled the inclusion criteria and were included in the final meta-analysis. Combination therapy of DAP and β-lactams significantly reduced the mortality and clinical failure rate for all BSI due to GPC compared with the DAP monotherapy (mortality, odds ratio [OR] = 0.63, 95 % confidence interval [CI] = 0.41–0.98; clinical failure, OR = 0.42, 95 % CI = 0.22–0.81). In contrast, no significant difference was noted in the incidence of CPK elevation between the two groups (OR = 0.85, 95 % CI = 0.39–1.84). Conclusion: Altogether, combination therapy of DAP and β-lactams can improve the prognosis for patients with BSI due to GPC compared with DAP alone. Therefore, it should be considered as an option for the empirical treatment of BSI caused by GPC.

The present study aimed to evaluate the impact of prospective audit and feedback (PAF) on the use of inpatient broad-spectrum antibiotics for more than 10 days using days of therapy (DOT) and a novel metric called days of antibiotic spectrum coverage (DASC) to assess whether the antimicrobial spectrum was narrowed. Conducted at Aichi Medical University Hospital in Japan, the study compared a six-month baseline period (April to September 2022) with a six-month intervention period (April to September 2023). The primary outcome measures were changes in DOT/patient and DASC/patient for broad-spectrum antibiotics. Propensity score matching was performed between two periods and a total of 172 patients were included in the study (pre-intervention, n = 86; intervention, n = 86). The DASC/patient of broad-spectrum antibiotics was statistically decreased in the intervention period compared to that in the baseline period (153.3 vs. 122.7, p < 0.05). Additionally, our PAF intervention led to a switch to narrow-spectrum antimicrobial therapy without increasing all-cause 30-day mortality (5.8% vs. 5.8%, p = 1.0). However, the DOT/patient, DASC/patient, and DASC/DOT of all antimicrobials were not significantly changed. Our study concluded that we should reconsider the timing of PAF intervention by evaluating the effort of PAF by using DOT and DASC.

Abstract Background Accurate diagnosis of prosthetic joint infection (PJI) enables early and effective treatment. However, there is currently no gold standard test for microbial detection of PJI and traditional synovial fluid culture is relatively insensitive. Recently, it has been reported that sonicating fluid culture and next-generation sequencing (NGS) improve microbial detection rates. Hence, we performed a systematic review and meta-analysis to compare microbial detection rates in microbial culture methods with and without sonication versus NGS. Methods We systematically searched EMBASE, PubMed, Scopus, CINAHL, and Ichushi databases and other sources (previous reviews) until August 2022. We evaluated the detection rates of pathogens in NGS and microbial cultures using samples of synovial or sonicated fluid. Results Of the 170 citations identified for screening, nine studies were included. Pooled analysis indicated that NGS had the highest detection rate among the microbial detection methods (NGS vs. sonicated, odds ratios [OR] 5.09, 95% confidential interval [CI] 1.67–15.50; NGS vs. synovial, OR 4.52, 95% CI 2.86–7.16). Sonicated fluid culture showed a higher detection rate than synovial fluid culture (OR 2.11, 95% CI 1.23–3.62). Conclusion NGS might be useful as a screening tool for culture-negative patients. In clinical settings, sonicated fluid culture is a practical method for diagnosing PJI.

Endometritis occurs frequently in humans and animals, which can negatively affect fertility and cause preterm parturition syndrome. Orally administered Clostridium butyricum, a butyrate-producing gram-positive anaerobe, exhibits anti-inflammatory effects. However, the precise mechanism by which Clostridium butyricum attenuates endometritis remains unclear. This in vivo study evaluated the anti-inflammatory effects of orally administered Clostridium butyricum on uterine tissues. In addition, we conducted uterine microbiome and lipid metabolome analyses to determine the underlying mechanisms. Female Balb/c mice were divided into the following four groups (n = 5–20): (1) mock group, (2) only operation group (mice only underwent operation to exposed uterine horns from the side), (3) control group (mice underwent the same operation with the operation group + perfusion of lipopolysaccharide solution from uterine horns), and (4) Clostridium butyricum administration group (mice underwent the same operation with the control group + oral Clostridium butyricum administration from days 0 to 9). Clostridium butyricum was administered via oral gavage. On day 10, we investigated protein expression, uterine microbiome, and lipid metabolism in uterine tissues. Consequently, orally administered Clostridium butyricum altered the uterine microbiome and induced proliferation of Lactobacillus and Limosilactobacillus species. The effects can contribute to show the anti-inflammatory effect through the interferon-β upregulation in uterine tissues. Additionally, oral Clostridium butyricum administration resulted in the upregulations of some lipid metabolites, such as ω-3 polyunsaturated fatty acid resolvin D5, in uterine tissues, and resolvin D5 showed anti-inflammatory effects. However, the orally administered Clostridium butyricum induced anti-inflammatory effect was attenuated with the deletion of G protein-coupled receptor 120 and 15-lipooxgenase inhibition. In conclusion, Clostridium butyricum in the gut has anti-inflammatory effects on uterine tissues through alterations in the uterine microbiome and lipid metabolism. This study revealed a gut-uterus axis mechanism and provided insights into the treatment and prophylaxis of endometritis.

Despite advances in medical technology, lung cancer still has one of the highest mortality rates among all malignancies. Therefore, efforts must be made to understand the precise mechanisms underlying lung cancer development. In this study, we conducted lung and gut microbiome analyses and a comprehensive lipid metabolome analysis of host tissues to assess their correlation. Alternations in the lung microbiome due to lung cancer, such as a significantly decreased abundance of Firmicutes and Deferribacterota, were observed compared to a mock group. However, mice with lung cancer had significantly lower relative abundances of Actinobacteria and Proteobacteria and higher relative abundances of Cyanobacteria and Patescibacteria in the gut microbiome. The activations of retinol, fatty acid metabolism, and linoleic acid metabolism metabolic pathways in the lung and gut microbiomes was inversely correlated. Additionally, changes occurred in lipid metabolites not only in the lungs but also in the blood, small intestine, and colon. Compared to the mock group, mice with lung cancer showed that the levels of adrenic, palmitic, stearic, and oleic (a ω-9 polyunsaturated fatty acid) acids increased in the lungs. Conversely, these metabolites consistently decreased in the blood (serum) and colon. Leukotriene B4 and prostaglandin E2 exacerbate lung cancer, and were upregulated in the lungs of the mice with lung cancer. However, isohumulone, a peroxisome proliferator-activated receptor gamma activator, and resolvin (an ω-3 polyunsaturated fatty acid) both have anti-cancer effects, and were upregulated in the small intestine and colon. Our multi-omics data revealed that shifts in the microbiome and metabolome occur during the development of lung cancer and are of possible clinical importance. These results reveal one of the gut-lung axis mechanisms related to lung cancer and provide insights into potential new targets for lung cancer treatment and prophylaxis.

In 2016, Tosei General Hospital, a tertiary emergency medical facility with 633 beds in Japan, experienced a large nosocomial outbreak of carbapenemase-producing Enterobacterales (CPE) that had spread to numerous sink outlets. Based on our experience with using steam cleaners to suppress CPE on environmental surfaces, we report the efficacy of steam cleaners in the disinfection of sink outlets. Steam cleaners were used to disinfect 22 target areas. CPE disappeared in 90.9% of the sink outlets within the first two months after disinfection, and, after 12 months, 54.5% of the sink outlets remained negative throughout the remainder of the study period. This study demonstrates the effectiveness of using steam cleaners to disinfect sink outlets contaminated with CPE.

Introduction: Evidenced based medicine (EBM) is necessary to standardize or treatment for infection since EBM is established based on the results of clinical trials. Entry criteria for clinical trials are very strict, and many patients have difficulties in being enrolled in any clinical trials regarding candidemia. It is questionable if the results of clinical trials reflect the real world of general medicine in this case. Patients and methods: For the purpose of examining how many patients could join any randomized clinical trials for the treatment of candidemia, we reviewed all the candidemia patients in our institute during 2014–2018. The patients were divided into two groups: patients who were eligible for clinical trials (participation possible group), and those who were not (participation impossible group). Exclusion criteria for clinical trials were set based on previous clinical trials. Results: A total of 70 patients was enrolled in this study. The median age was 73 years (range 36–93 years). Of these, 41 patients (59%) were male. As for site of infections, catheter related blood stream infection was most frequently seen in 37 (53%). Seventeen patients (24%) were classified as participation possible group and 53 patients (76%) were participation impossible group. Comparing the two groups, participation possible group patients have much better performance status, have less comorbidities and have longer overall survival times than participation impossible group patients. Conclusion: Only 24% of candidemia patients were eligible for the clinical trials. Thus, we can see that clinical trials might not correctly reflect the real world among candidemia patients.

Objectives: Procalcitonin (PCT) is an early diagnosis marker of sepsis/bacteremia. However, some reports refer to its lower responsiveness to gram-positive bacteremia. We retrospectively evaluated the PCT values at the onset of bacteremia in relation to severity index. Methods: Patients with bacteremia caused by two gram-negative bacteria (46 E. coli and 50 Klebsiella pneumoniae) and three gram-positive bacteria (45 S. aureus, 56 S. epidermidis, and 10 S. mitis) were studied. The plasma PCT and C-reactive protein (CRP) levels were compared between species and different Sequential Organ Failure Assessment (SOFA) score groups. Results: The median PCT level was higher in gram-negative than in gram-positive bacteremia in overall (13.09 vs. 0.50 ng/mL, p

The coronavirus disease (COVID-19) pandemic continues to threaten global public health. Remdesivir and monoclonal antibodies have shown promise for COVID-19 treatment of patients who are immunocompromised, including those with cancer, transplant recipients, and those with autoimmune disorder. However, the effectiveness and safety of this combination therapy for patients who are immunosuppressed remain unclear. We compared the efficacy and safety of combination therapy and remdesivir monotherapy for patients with mild-to-moderate COVID-19 who were immunosuppressed. Eighty-six patients treated in July 2021–March 2023 were analyzed. The combination therapy group (CTG) showed a statistically significant reduction in viral load compared with the monotherapy group (MTG) (p < 0.01). Patients in the CTG also experienced earlier resolution of fever than those in the MTG (p = 0.02), although this difference was not significant in the multivariate analysis (p = 0.21). Additionally, the CTG had significantly higher discharge rates on days 7, 14, and 28 than the MTG (p < 0.01, p < 0.01, and p = 0.04, respectively). No serious adverse events were observed with combination therapy. These findings suggest that combination therapy may improve the clinical outcomes of immunosuppressed COVID-19 patients by reducing the viral load and hastening recovery. Further studies are required to fully understand the benefits of this combination therapy for immunocompromised COVID-19 patients.

Introduction: Staphylococci is the most commonly isolated bacteria in blood cultures (BC), and is mostly regarded as contamination. However, the clinical relevance and characteristics of CNS other than Staphylococcus epidermidis (Non-SE-CNS) is still unknown. Methods: For the purpose of clarifying the epidemiology and clinical significance of Non-Se-CNS infections, we retrospectively evaluated BC isolates of Non-Se-CNS at our institute from May 2013 to March 2017.Infections were defined as true bacteremia if (1) two or more positive BCs of the same species were present (or detection of the same species in another clinically relevant sample), (2) the patient had clinical symptoms as outlined in the Centers for Disease Control and Prevention's definition of primary blood stream infection8 and the symptoms or markers of inflammation (e.g., fever, symptoms, white cell counts, C-reactive protein, or procalcitonin) were improved after pathogen-directed therapy (e.g. either antibiotic therapy and/or removal of the foreign body in the case of catheter-related blood stream infections suspected) and (3) without any other infection. Results: During the period, 279 patients with BC positive for Non Se–CNS were identified. 44 patients were excluded, either due to missing data or multiple pathogens in the same BC. Among the remaining 235 patients, 67 (29%) were categorized as true bacteremia (n = 43) or possible infections (n = 24). Resistance rate to methicillin among Non-SE-CNS is about 60%, which is lower than those among S. epidermidis of 78%. Conclusion: About 30% of Non-Se-CNS isolates were clinically relevant in our study. Antibiotic susceptibility of Non-SE-CNS is quite different than those of S. epidermidis.

Introduction: The novel coronavirus disease (COVID-19) could cause a severe acute respiratory infectious disease, showing a high mortality rate of 12–45% among cases who required intensive care unit admission. COVID-19 pneumonia Patients and methods: For the purpose of identifying clinical manifestations and radiological findings of COVID-19 pneumonia, we reviewed all cases of COVID-19 pneumonia which were published by the homepage of the Japanese Association for Infectious Diseases from Feb 5 2020 until April 30 2020, including our cases. All patients were diagnosed based on positive results of the novel coronavirus-real-time RT-PCR with chest computed tomography (CT) findings. Results: A total of 92 patients were enrolled in this study. The median age was 66 years (range 16–92 years). For all, 50 (54%) were males. The most common underlying disease was hypertension in 32 (36%). Any comorbidity was seen in 60 (67%). The mortality rate was 4 (6%). In terms of clinical symptoms on an initial visit, fever and cough were confirmed in 66 (72%) and 37 (40%). Forty-three (47%) had no respiratory symptoms. As for radiological findings by chest CT scan, ground-glass opacities (GGO)s, peripheral distribution, bilateral lung involvements were seen in 88 (96%), 76 (83%) and 78 (85%), respectively. Conclusion: It is difficult to diagnose as COVID-19 pneumonia due to poor respiratory symptoms. Chest CT findings typically show GGO, peripheral and bilateral shadows. Patients should have chest CT performed if suspected for early diagnosis and therapeutic intervention, resulting in a favorable outcome and prevention of secondary nosocomial transmitted infection.

Abstract Clostridioides difficile infection (CDI) represents the leading cause of nosocomial diarrhea worldwide and is associated with gut dysbiosis and intestinal damage. Clostridium butyricum MIYAIRI 588 (CBM 588) contributes significantly to reduce epithelial damage. However, the impacts of CBM 588 on antibacterial therapy for CDI are not clear. Here we show that CBM 588 enhanced the antibacterial activity of fidaxomicin against C. difficile and negatively modulated gut succinate levels to prevent C. difficile proliferation and downregulate tumor necrosis factor-α (TNF-α) producing macrophages in the colon lumina propria (cLP), resulting in a significant decrease in colon epithelial damage. Additionally, CBM 588 upregulated T cell-dependent pathogen specific immunoglobulin A (IgA) via interleukin (IL)-17A producing CD4+ cells and plasma B cells in the cLP, and Th17 cells in the cLP enhanced the gut epithelial barrier function. IL-17A and succinic acid modulations with CBM 588 enhance gut colonization resistance to C. difficile and protect the colon tissue from CDI.

Fungemia is a fatal systemic infection that can occur in immunocompromised patients. Despite that, antifungal stewardship is spreading widely, but the mortality rate is extremely high, showing 40–60%. Loderomyces elongiporus is a newly morphologically detected pathogen, first described in 1994, followed by isolation in humans in 2008. It has been misrecognized as Candida parapsilosis. Recently, fever attributable to L. elongisporus fungemia cases has been reported, and the etiology and clinical features are still unknown. Here, we present three successfully treated L. elongisporus fungemia cases by echinocandin. In total, 11 cases were reviewed, including ours. Six of the eleven cases (55%) had external devices. All cases had some immunocompromised conditions or underlying diseases, such as diabetes mellitus, lung cancer, etc. Six patients survived, and the remaining five died. Seven patients who had received echinocandin initially survived. Risk factors for L. elongiporus fungemia overlap with those of candidemia. Even though there is no breakpoint for L. elongiporus, echinocandin can be a helpful treatment regimen for L. elongiporus fungemia.

Objective: American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines suggest that linezolid (LZD) is preferred over vancomycin (VCM) for treating methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. We conducted a systematic review and comparative meta-analysis to compare VCM and LZD efficacy against proven MRSA pneumonia. Methods: We searched EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed up to November 2019. The outcomes of the meta-analysis were mortality, clinical cure, microbiological evaluation, and adverse events. Results: Seven randomized controlled trials (RCTs) with a total of 1239 patients and eight retrospective cohort or case–control studies (CSs) with a total 6125 patients were identified. Clinical cure and microbiological eradication rates were significantly increased in patients treated with LZD in RCTs (clinical cure: risk ratio (RR) = 0.81, 95% confidential interval (CI) = 0.71–0.92; microbiological eradication: RR = 0.71, 95% CI = 0.62–0.81) and CSs (clinical cure: odds ratio (OR) = 0.35, 95% CI = 0.18–0.69). However, mortality was comparable between patients treated with VCM and LZD in RCTs (RR = 1.08, 95% CI = 0.88–1.32) and CSs (OR = 1.20, 95% CI = 0.94–1.53). Likewise, there was no significant difference in adverse events between VCM and LZD in CSs (thrombocytopenia: OR = 0.95, 95% CI = 0.50–1.82; nephrotoxicity: OR = 1.72, 95% CI = 0.85–3.45). Conclusions: According to our meta-analysis of RCTs and CSs conducted worldwide, we found robust evidence to corroborate the IDSA guidelines for the treatment of proven MRSA pneumonia.

Abstract Background Candidemia has emerged as an important nosocomial infection, with a mortality rate of 30–50%. It is the fourth most common nosocomial bloodstream infection (BSI) in the United States and the seventh most common nosocomial BSI in Europe and Japan. The aim of this study was to assess the performance of the Sequential Organ Failure Assessment (SOFA) score for determining the severity and prognosis of candidemia. Methods We performed a retrospective study of patients admitted to hospital with candidemia between September 2014 and May 2018. The severity of candidemia was evaluated using the SOFA score and the Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score. Patients’ underlying diseases were assessed by the Charlson Comorbidity Index (CCI). Results Of 70 patients enrolled, 41 (59%) were males, and 29 (41%) were females. Their median age was 73 years (range: 36–93 years). The most common infection site was catheter-related bloodstream infection (n=36, 51%).The 30-day, and in-hospital mortality rates were 36 and 43%, respectively. Univariate analysis showed that SOFA score ≥5, APACHE II score ≥13, initial antifungal treatment with echinocandin, albumin 6, disturbance of consciousness, and CCI ≥3 were related with 30-day mortality. Of these 7, multivariate analysis showed that the combination of SOFA score ≥5 and CCI ≥3 was the best independent prognostic indicator for 30-day and in-hospital mortality. Conclusions The combined SOFA score and CCI was a better predictor of the 30-day mortality and in-hospital mortality than the APACHE II score alone.

Abstract Background Presepsin (soluble CD14 subtype) is a novel biomarker of sepsis used for early diagnosis. Originally, CD14 is known as the pattern recognition receptor for the lipopolysaccharide (LPS)/LBP complexes, and the diagnostic value of this molecule for gram-positive bacteria, which contain less amount of LPS, is uncertain. To confirm its effectiveness in the diagnosis of bacteremia caused by gram positive bacteria, and to evaluate the interspecies difference of presepsin production against various bacterial strains, we conducted an in vitro assay to evaluate presepsin levels in response to five Gram negative and four Gram positive bacteria. Results Whole blood was yielded from five healthy volunteers and co-cultured with bacterial strains at 37 °C for 4 h. Twenty seven clinical isolates of nine species (E. coli, K. pneumoniae, E. cloacae, P. aeruginosa, S. maltophilia, S. aureus, S. pyogenes, B. cereus, and C. striatum) derived from blood cultures of non-neutropenic bacteremia patients were used. Culture supernatants were harvested and presepsin levels were measured. The presepsin level in the gram-negative bacteria 273 (218–352) pg/mL was significantly higher than in the gram-positive bacteria 200 (143–275) pg/mL (p = 0.0002). The presepsin levels were significantly lower in C. striatum, in comparison to other bacteria, and S. pyogenes showed similar results. And the presepsin levels in P. aeruginosa were significantly lower compared to E. cloacae, K. pneumoniae, and S. aureus. Conclusions Presepsin production can also be evoked by gram-positive bacteria, and interspecies differences of presepsin response may exist, which should be considered in the diagnosis of sepsis, especially in certain gram-positive bacteremia such as S. pyogenes or C. striatum.

Linezolid (LZD) and Tedizolid (TZD) are oxazolidinone antibiotic for meticillin-resistant Staphylococcus aureus (MRSA). Severe hyponatremia after LZD administration have been reported. Severe hyponatremia cause seizures, unconsciousness, and even death. Therefore, we conducted a study to assess the change of serum sodium level after LZD and TZD therapy. We enrolled 67 patients treated with LZD and 28 treated with TZD. We monitored the serum sodium level from the administration to 14 days after administration of oxazolidinone drug. Hyponatremia was defined a sodiuln level ≤134 mmol/L after the initiation of oxazolidinone drug. The frequency of hyponatremia in the LZD group was significantly higher than that in the TZD group (39.7% vs. 11.1%, p < 0.05). The rate of patients administered by injection was significantly higher than in the LZD group than in the TZD group (52.9% vs. 14.8%, p < 0.01). Multiple logistic regression analyses identified the albumin level before the oxazolidinone drug therapy as the independent variables associated with the development of hyponatremia. We revealed that TZD is safer than LZD in terms of hyponatremia. Therefore, cases that LZD is administered by injection should be used more carefully with hyponatremia in patients with low albumin level.

Cefazolin (CFZ) is the first-line treatment for beta-lactamase-producing methicillin-sensitive Staphylococcus aureus (BP-MSSA) infection. In 2019, Japan experienced a CFZ shortage because of foreign object inclusion in a batch. Ampicillin/sulbactam (SAM) was preferred in many cases as definitive therapy for the treatment of BP-MSSA bacteremia to preserve broad-spectrum antibiotic stock. However, there are no previous studies reporting the clinical efficacy of SAM for BP-MSSA bacteremia. We aimed to compare the clinical efficacy and adverse effects of SAM versus CFZ in patients with BP-MSSA bacteremia. In total, 41 and 30 patients treated with SAM and CFZ, respectively, were identified. The baseline characteristics were similar in both groups. No significant differences were observed in length of hospital stay and all 30-day mortality between the two groups (p = 0.270 and 0.643, respectively). Moreover, no intergroup difference in 90-day mortality was found (hazard ratio 1.02, 95% confidential interval 0.227–4.53). Adverse effects, such as liver dysfunction, were less in the CFZ group than in the SAM group (p = 0.030). Therefore, in cases of poor CFZ supply or in patients allergic to CFZ and penicillinase-stable penicillins, SAM can be an effective therapeutic option for bacteremia due to BP-MSSA with attention of adverse effects, such as liver dysfunction.

Background/purpose: Acinetobacter is an aerobic, gram-negative coccobacillus, which causes nosocomial infections including bacteremia. Recent development of molecular techniques has made classification of the Acinetobacter genomospecies possible, but there are still only a few studies comparing clinical features of the subspecies. We investigated bacteremia caused by Acinetobacter, isolated subspecies, and compared clinical features for each group. Methods: A retrospective analysis of Acinetobacter bacteremia cases was made in a 900-bed hospital in Japan. In addition to conventional procedures, subspecies identification based on rpoB sequence was made, and comparison of clinical characteristics between each subspecies were analyzed. Results: We collected 35 cases (Acinetobacter baumannii 14, A. nosocomialis 12, Acinetobacter ursingii 6, and A. seifertii 3). All of the A. seifertii bacteremia cases were blood stream infection occurring in cerebrovascular disease patients, showing particularly higher incidence of shock (100%) and high Pitt bacteremia score (PBS) (6.33 ± 2.52) in comparison to A. baumannii (43% and 2.86 ± 2.25, respectively). Sequential Organ Failure Assessment (SOFA) score and the PBS were slightly higher in A. nosocomialis in comparison to A. baumannii, and the 7 day mortality rate was higher in A. nosocomialis (25%) than in A. baumannii (7%), though this difference was not found to be significant. Conclusions: A.seifertii, the recently defined novel species, showed distinctive clinical features of bacteremia. And, in contrast to previous studies, the severity of A. nosocomialis infection was not lower than that of A. baumannii, which might suggest the influence of local epidemiology. Further characterization of these subspecies should be continued. Keywords: Acinetobacter seifertii, Acinetobacter nosocomialis, Acinetobacter baumanii, Bacteremia, rpoB, Genomospecies

Background: The Japanese Respiratory Society recently updated its prognostic guidelines for pneumonia, recommending that pneumonia severity be evaluated using the sequential organ failure assessment (SOFA) and quick SOFA (qSOFA) scoring systems in a therapeutic strategy flowchart. However, the efficacy and accuracy of these tools are still unknown. Methods: All patients with community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) who were admitted to the study institution between 2014 and 2017 were enrolled in this study. Pneumonia severity on admission was evaluated by A-DROP, CURB-65, PSI, I-ROAD, qSOFA, and SOFA scoring systems. Prognostic factors for 30-day mortality were also analyzed. Results: This study included 406 patients, 257 male (63%) and 149 female (37%). The median age was 79 years (range 19–103 years). The 30-day and in-hospital mortality rates were both 5%. With respect to the diagnostic value of the predictive assessments for 30-day mortality, the area under the receiver operating characteristic curve (AUROC) value for the SOFA score was 0.769 for CAP patients and 0.774 for HCAP patients. Further, the AUROC values for the SOFA score in CAP and HCAP patients with a qSOFA score ≥2 were 0.829 and 0.784, respectively, for 30-day mortality. Conclusions: qSOFA and SOFA scores were able to correctly evaluate the severity of CAP and HCAP. Keyword: qSOFA, SOFA score, Community-acquired pneumonia, Healthcare-associated pneumonia

Abstract Background Brevibacteria are obligate aerobic gram-positive rods that are associated with milk products and are also found on human skin. Brevibacterium has been reported as a rare cause of catheter related blood steam infection mainly in immunocompromised hosts such as malignancies or AIDS patients. Case presentation A 94-year old woman, which had a past history of diabetes mellitus and chronic heart failure, presented with high fever associated with decreased oral intake and appetite loss and was admitted to our institute. A physical examination at the time of presentation was unremarkable. On day 2, both blood cultures collected on admission became positive with coryneform organism within 24 h without Staphylococci and Brevibacterium species were identified by Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Subsequently, genetic investigation by 16S ribosomal RNA analysis was performed in order to identify the organism. Finally, the result identified this pathogen as Brevibacterium paucivorans with 99.5% homology on the Ez taxon database. The patient was started empirically on meropenem and teicoplanin for broad-spectrum antibiotic coverage. The patient’s fever finally abated and labs were also improved. On day 14, the antibiotic therapy was discontinued. The site of infections was unknown. We hereby report a case of Brevibacterium paicivorans bacteremia in an immunocompetent patient and review cases of Brevibacterium specises bacteremia previously reported. This is the first case of B. paucivorans bacteremia as far as we could search. Conclusion Physicians and microbiologists should be aware that Brevibacteria are uncommon but important agents which could cause opportunistic infections in immunocompetent.

Abstract Background Pantoea is a Gram-negative, non-encapsulated, non-spore-forming, ubiquitous straight rod which can be isolated from geographical and ecological sources such as plant surfaces, buckwheat seeds, human feces, and the environment. The genus Pantoea is a rare pathogen in a clinical setting, and is divided into 20 different species such as Pantoea agglomerans, Pantoea ananatis, Pantoea deleyi, Pantoea dispersa, Pantoea septica, Pantoea stewartii or Pantoea rwandensis. Pantoea dispersa has been reported to cause other infections, including respiratory infections, neonatal sepsis, and bloodstream infections. We report a case of Pantoea dispersa bacteremia caused by acute cholangitis. This is the first case report of Pantoea dispersa bacteremia caused by acute cholangitis as far as we had searched. Case presentation A 38-year-old Japanese woman suffered from acute cholangitis; a blood culture showed that Gram-negative rod was positive. The treatment was successful with intravenously administered meropenem, and it was switched to orally administered levofloxacin according to microbiological susceptibility. The organism was identified as Pantoea dispersa by both genetic investigation by 16S ribosomal RNA and additional biochemical tests. To the best of our knowledge, this is the first case report of Pantoea dispersa bacteremia caused by acute cholangitis. Conclusion The epidemiology and clinical features of Pantoea dispersa are still unknown. More cases of infections caused by Pantoea dispersa might be revealed with advancing technical methods, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or 16S ribosomal RNA analysis. Physicians must know that a variety of infections caused by Pantoea dispersa could occur in immunocompromised as well as immunocompetent patients.

Abstract Background Any immunological mechanisms induced by influenza virus could cause severe secondary bacterial superinfection such as those by Streptococcus pyogenes [group A streptococcus (GAS)], Streptococcus pneumoniae or Staphylococcus aureus. Over recent years, the frequency of pleural empyema has increased in children with influenza infection. We present a severe case of acute empyema caused by S.pyogenes after influenza A infection. Case presentation A previously healthy 39-year old woman was diagnosed as influenza A and received oral Oseltamivir 75 mg twice daily for 5 days. She had no vaccination of influenza A. Although her influenza A infection improved, she complained of fever and cough to our institute. Chest radiography showed encapsulated pleural effusion of the left lung and pleural effusion which was consistent with acute empyema. Then, she was diagnosed as having acute empyema and was admitted to our institute. Streptococcus pyogenes was identified by pleural fluid culture on day 4. thus, MNZ was changed to clindamycin (CLDM) 600 mg three times a day. While thoracic drainage with intrapleural urokinase and combination antibiotic therapy of ceftriaxone and CLDM were performed, her general condition and chest radiographic findings were not improved. She received video-assisted thoracic debridement on day 10. After the operation, the antibiotic therapy was changed to ABPC 6 g daily iv. Due to good clinical course, the antibiotic therapy was switched to oral amoxicillin 500 mg three times daily on day 28. Then, she was discharged. Conclusion Influenza A virus infection could lead to severe GAS infection, while the latter can occur in otherwise healthy individual as well. Physician must consider the possibility of severe GAS infection after influenza A infection.

Current guidelines recommend the use of ceftriaxone and sulbactam-ampicillin for the initial treatment of community-acquired pneumonia (CAP). However, there are no clear data on these guidelines. Therefore, this systematic review and meta-analysis aims to evaluate the effectiveness of ceftriaxone and sulbactam-ampicillin in the initial treatment of CAP. The Embase, Scopus, PubMed, Ichushi, and Cumulative Index to Nursing and Allied Health Literature databases were systematically searched from inception to July 2022. The studies included patients who received ceftriaxone or sulbactam-ampicillin as the initial antibiotic therapy for CAP. The mortality and clinical cure rates were evaluated. Of the 2152 citations identified for screening, four studies were included. Results of the pooled analysis indicated no significant differences in the mortality and clinical cure rates between patients treated with ceftriaxone and those treated with sulbactam-ampicillin (mortality, odds ratio [OR]: 1.85, 95% confidence interval [CI]: 0.57–5.96; clinical cure rate, OR: 1.08, 95% CI: 0.18–6.44). This study supports the guidelines for CAP treatment, though further studies are needed to obtain a deeper understanding.

Although a 2 g once daily administration of ceftriaxone remains the standard dosing regimen for the treatment of aspiration pneumonia, there are no studies to investigate the optimal dosing method. Hence, we retrospectively evaluated the effectiveness and safety of 1 g twice daily versus 2 g once daily administration of ceftriaxone in adult patients with aspiration pneumonia. Patients who received ceftriaxone for the treatment of aspiration pneumonia between 2015 and 2021 were included in this study. Clinical responses, inflammatory markers, and incidence of adverse events after completion of ceftriaxone therapy were investigated. In total, 33 patients received 1 g twice daily (group 1) and 28 received 2 g once daily (group 2) ceftriaxone for the treatment of mild-to-moderate aspiration pneumonia. Compared with that of group 1, group 2 demonstrated significantly improved clinical responses (group 1 vs. group 2, 84.8% vs. 100%, p = 0.0316). Although the safety profile was not significantly different between the two groups, the incidence of choleliths during ceftriaxone therapy in group 1 was higher than that in group 2 (31.3% vs. 9.1%, p = 0.174). Therefore, a 2 g once daily administration of ceftriaxone appeared to be a simple regimen adequate for the treatment of inpatients with mild-to-moderate aspiration pneumonia, which might not be heavily involved by anaerobes.

Vancomycin or daptomycin is administered to hemodialysis patients infected with methicillin-resistant Staphylococcus and Enterococcus species. Although serious concerns regarding nephrotoxicity due to vancomycin have been raised, it might not be a critical issue in hemodialysis patients. Moreover, very few studies have investigated the effectiveness of vancomycin versus daptomycin in patients undergoing hemodialysis. Hence, we retrospectively evaluated the effectiveness and safety of vancomycin and daptomycin in patients undergoing hemodialysis. We investigated the following measures: mortality, clinical and microbiological effectiveness, and incidence of adverse events in hemodialysis patients who received vancomycin or daptomycin from 2014 to 2019. Moreover, we evaluated the covariates related to 30-day mortality. We found that 73 patients received vancomycin, while 34 received daptomycin for the treatment of infections due to methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative Staphylococci, and Enterococcus faecium. Mortality after vancomycin treatment was significantly lower than daptomycin treatment (4.1% vs. 26.5%, p < 0.01). The clinical and microbiological effectiveness as well as the safety were not significantly different between the two treatments. Although daptomycin treatment with a loading dose was associated with lower mortality, the mortality of the treatment (8.3%) did not differ significantly compared to that of the vancomycin treatment (4.1%). Therefore, our findings suggest that vancomycin remains the first-line treatment for hemodialysis patients; however, a loading dose may be beneficial for patients receiving daptomycin.

Although combination therapy using trimethoprim–sulfamethoxazole (TMP–SMX) plus echinocandins has been reported to reduce the mortality of patients with pneumocystis pneumonia (PCP), it remains unclear whether it is more effective than TMP–SMX monotherapy, the current first-line treatment for this disease. Hence, we performed a systematic review and meta-analysis to compare the efficacies of these treatment options for PCP. The Scopus, EMBASE, PubMed, CINAHL, and Ichushi databases were searched for studies (up to January 2022) reporting the mortality and positive response rates (fewer clinical symptoms, improved partial pressure of arterial oxygen, and resolution of pneumonitis on chest imaging) of PCP patients receiving monotherapy or combination therapy. Four studies met the inclusion criteria. All four presented mortality data and one had positive response rates. Compared with the monotherapy, the combination therapy resulted in significantly lower mortality and higher positive response rates (mortality: odds ratio (OR) 2.20, 95% confidence interval (CI) 1.46–3.31; positive response rate: OR 2.13, 95%CI 1.41–3.23), suggesting it to be an effective and promising first-line therapy for PCP. However, further safety evaluations are needed to establish this as a fact.

There is increasing evidence regarding the optimal therapeutic strategies for multidrug-resistant (MDR) bacteria that cause common infections and are resistant to existing antibiotics. Combination therapies, such as β-lactam combined with β-lactamase inhibitors or combination antibiotics, is a therapeutic strategy to overcome MDR bacteria. In recent years, the therapeutic options have expanded as certain combination drugs have been approved in more countries. However, only a handful of guidelines support these options, and the recommendations are based on low-quality evidence. This review describes the significance and efficacy of combination therapy as a therapeutic strategy against Gram-negative MDR pathogens based on previously reported meta-analyses.

Metabolites are thought as the end products in cellular regulatory processes and their levels show the strongest relationships with the phenotype. Previously, we showed that the administration of Clostridium butyricum MIYAIRI 588 (CBM 588) upregulated protectin D1, an anti-inflammatory lipid metabolite, in colon tissue under antibiotic therapy. However, how CBM 588 induces protectin D1 expression and whether the metabolite has anti-inflammatory effects on antibiotic-induced inflammation are unclear. Therefore, here, we evaluated the effect of CBM 588 on lipid metabolism and protectin D1 in gut protection from antibiotic-induced intestinal disorders. In the CBM 588 treatment group, expression levels of genes encoding lipid receptors related to the conversion of DHA to protectin D1, such as polyunsaturated fatty acid (PUFA) receptors, G-protein coupled receptor 120 (GPR120), and 15-lipoxygenase (LOX), were increased in colon tissue. CD4+ cells producing interleukin (IL)-4, the main component of T helper type 2 (Th2) cells that can activate 15-LOX, also increased in CBM 588-treated groups even after clindamycin co-administration. In addition, similar to CBM 588, exogenously administered protectin D1 reduced inflammatory cytokines, while IL-10 and TGF-β1, works as anti-inflammatory cytokines, were increased. Our data revealed that CBM 588 activated 15-LOX to enhance protectin D1 production by increasing IL-4-producing CD4+ cell population in the intestinal tract. Additionally, CBM 588-induced protectin D1 clearly upregulated IL-10-producing CD4+ cells to control antibiotic-induced gut inflammation. We provide new insights into CBM 588-mediated lipid metabolism induction for the treatment of gut inflammatory diseases.

Summary: Clostridium butyricum MIYAIRI 588 (CBM 588) is a probiotic bacterium that has previously been used to prevent antibiotic-associated diarrhea. However, the underlying mechanism by which CBM 588 protects the gut epithelial barrier remains unclear. Here, we show that CBM 588 increased the abundance of Bifidobacterium, Lactobacillus, and Lactococcus species in the gut microbiome and also enhanced the intestinal barrier function of mice with antibiotic-induced dysbiosis. Additionally, CBM 588 significantly promoted the expansion of IL-17A-producing γδT cells and IL-17A-producing CD4 cells in the colonic lamina propria (cLP), which was closely associated with changes in the intestinal microbial composition. Additionally, CBM 588 plays an important role in controlling antibiotic-induced gut inflammation through upregulation of anti-inflammatory lipid metabolites such as palmitoleic acid, 15d-prostaglandin J2, and protectin D1. This study reveals a previously unrecognized mechanism of CBM 588 and provides new insights into gut epithelial barrier protection with probiotics under conditions of antibiotic-induced dysbiosis. : Microbiome; Clinical Microbiology Subject Areas: Microbiome, Clinical Microbiology

Mycoplasma genitalium is recognized as a remarkable pathogen since azithromycin-resistant strains and treatment failure have been increasingly reported. Nevertheless, international guidelines still recommend azithromycin as a first-line treatment and moxifloxacin as a second-line treatment. We performed a systematic review and meta-analysis to validate the efficacy and safety of both drugs in the initial treatment of M. genitalium. We systematically searched the EMBASE, PubMed, Scopus, Ichushi, and CINAHL databases up to December 2021. We defined efficacy as clinical and microbiologic cure, and safety as persistent diarrhea. Overall, four studies met the inclusion criteria: one showed clinical cure (azithromycin treatment, n = 32; moxifloxacin treatment, n = 6), four showed microbiologic cure (n = 516; n = 99), and one showed safety (n = 63; n = 84). Moxifloxacin improved the microbiologic cure rate compared with azithromycin (odds ratio [OR] 2.79, 95% confidence interval [CI], 1.06–7.35). Clinical cure and safety did not show a significant difference between azithromycin and moxifloxacin treatments (OR 4.51, 95% CI 0.23–88.3; OR 0.63, 95% CI 0.21–1.83). Our meta-analysis showed that moxifloxacin was more effective than azithromycin at eradicating M. genitalium infections and supports its preferential use as a first-line treatment.

Clostridium butyricum is a human commensal bacterium with beneficial effects including butyrate production, spore formation, increasing levels of beneficial bacteria, and inhibition of pathogenic bacteria. Owing to its preventive and ameliorative effects on gastrointestinal infections, C. butyricum MIYAIRI 588 (CBM 588) has been used as a probiotic in clinical and veterinary medicine for decades. This review summarizes the effects of C. butyricum, including CBM 588, on bacterial gastrointestinal infections. Further, the characteristics of the causative bacteria, examples of clinical and veterinary use, and mechanisms exploited in basic research are presented. C. butyricum is widely effective against Clostoridioides difficile, the causative pathogen of nosocomial infections; Helicobacter pylori, the causative pathogen of gastric cancer; and antibiotic-resistant Escherichia coli. Accordingly, its mechanism is gradually being elucidated. As C. butyricum is effective against gastrointestinal infections caused by antibiotics-induced dysbiosis, it can inhibit the transmission of antibiotic-resistant genes and maintain homeostasis of the gut microbiome. Altogether, C. butyricum is expected to be one of the antimicrobial-resistance (AMR) countermeasures for the One-health approach.

We investigated the in vitro efficacy of combinations of carbapenems with clindamycin (CLDM) and minocycline (MINO) against Bacteroides fragilis and Peptostreptococcus species. We selected the carbapenems imipenem, meropenem, panipenem, doripenem, and biapenem. To evaluate the antibiotic efficacy of these combination regimens, the fractional inhibitory concentration index (FICI) was calculated against clinical isolates. Consequently, combination regimens of each carbapenem with CLDM or MINO showed synergistic or additive effects against 83.3–100.0% and no antagonistic effects against P. anaerobius isolates. However, against the B. fragilis group (B. fragilis, B. thetaiotaomicron, and Parabacteroides distasonis), although the combination with other carbapenems and CLDM or MINO did not show remarkable synergistic effects, the combination regimen of IPM with CLDM or MINO indicated mainly additive antibiotic efficacies (FICIs: >0.5 to ≤1.0) to B. fragilis groups. Then, antagonistic effects were admitted in only 5.6% of B. fragilis groups. The effectiveness of antibiotic combination therapy against pathogenic anaerobes has remained unclear. Then, our results can provide new insights to explore the effective combination regimens against multidrug-resistant anaerobic bacteria as empirical and definitive therapies, while this study used only carbapenem susceptible isolates. Hence, further studies are needed to use highly antibiotic-resistant anaerobic isolates to carbapenems.

Carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) have become global threats. CRE− and CPE− derived infections have been associated with high mortality due to limited treatment options. Nacubactam is a β-lactamase inhibitor and belongs to the new class of diazabicyclooctane. The agent has an in vitro antimicrobial activity against several classes of β-lactamase-producing Enterobacterales. This study evaluated antimicrobial activity of combination therapies including β-lactams (aztreonam, cefepime, and meropenem) and nacubactam against four Enterobacter cloacae and six Klebsiella pneumoniae isolates with murine pneumonia model. Based on changes in bacterial quantity, antimicrobial activities of some regimens were assessed. Combination therapies including β-lactams (aztreonam, cefepime, and meropenem) with nacubactam showed enhanced antimicrobial activity against CRE E. cloacae (−3.70 to −2.08 Δlog10 CFU/lungs) and K. pneumoniae (−4.24 to 1.47 Δlog10 CFU/lungs) with IMP-1, IMP-6, or KPC genes, compared with aztreonam, cefepime, meropenem, and nacubactam monotherapies. Most combination therapies showed bacteriostatic (−3.0 to 0 Δlog10 CFU/lungs) to bactericidal (10 CFU/lungs) activities against CRE isolates. This study revealed that combination regimens with β-lactams (aztreonam, cefepime, and meropenem) and nacubactam are preferable candidates to treat pneumonia due to CRE and CPE.

The gut microbiome is closely related to gut metabolic functions, and the gut microbiome and host metabolic functions affect each other. Clostridium butyricum MIYAIRI 588 (CBM 588) upregulates protectin D1 production in host colon tissue following G protein-coupled receptor (GPR) 120 activation to protect gut epithelial cells under antibiotic-induced dysbiosis. However, how CBM 588 enhances polyunsaturated fatty acid (PUFA) metabolites remains unclear. Therefore, we focused on the metabolic function alterations of the gut microbiome after CBM 588 and protectin D1 administration to reveal the interaction between the host and gut microbiome through lipid metabolism during antibiotic-induced dysbiosis. Consequently, CBM 588 modified gut microbiome and increased the butyric acid and oleic acid content. These lipid metabolic modifications induced GPR activation, which is a trigger of ERK 1/2 signaling and directed differentiation of downstream immune cells in the host colon tissue. Moreover, endogenous protectin D1 modified the gut microbiome, similar to CBM 588. This is the first study to report that CBM 588 influences the interrelationship between colon tissue and the gut microbiome through lipid metabolism. These findings provide insights into the mechanisms of prevention and recovery from inflammation and the improvement of host metabolism by CBM 588.

Abstract Background Some reported that organizing pneumonia (OP) may occur after influenza A infections including swine-origin influenza A (H1N1). However, OP associated with influenza B infection has never been reported. We report the first case of secondary OP associated with viral pneumonia caused by influenza B. Case presentation A 23-year old woman was diagnosed as viral pneumonia caused by type B influenza. Despite of antiviral therapy, abnormal chest shadows were not improved. Bronchoscopy and transbronchial lung biopsy showed organizing pneumonia due to viral pneumonia caused by influenza B. Corticosteroid therapy was started at 30 mg daily (0.5 mg/kg), and the dose was reduced to 25, 20, 15 or 10 mg per day every month with symptomatic and radiological resolution. Even after corticosteroid therapy was discontinued, we did not confirm disease recurrence. Conclusions Physicians should be aware of the possibility for SOP and severe viral pneumonia even in case of type B as well as type A influenza infections.

There are limited data of amikacin pharmacokinetics (PK) in the elderly population. Hence, we aimed to describe the population PK of amikacin in elderly patients (>70 years old) and to establish optimized initial dosing regimens. We simulated individual maximum concentrations in plasma (Cmax) and minimal concentrations (Cmin) for several dosing regimens (200–2000 mg every 24, 48, and 72 h) for patients with creatinine clearance (CCr) of 10–90 mL/min and analyzed efficacy (Cmax/minimal inhibitory concentration (MIC) ≥ 8) for MICs of 4, 8, and 16 mg/L and safety (Cmin < 4 mg/L). A one-compartment model best described the data. CCr was the only covariate associated with amikacin clearance. The population PK parameter estimates were 2.25 L/h for clearance and 18.0 L for volume of distribution. Dosing simulations recommended the dosing regimens (1800 mg) with dosing intervals ranging 48–72 h for patients with CCr of 40–90 mL/min based on achievement of both efficacy for the MIC of 8 mg/L and safety. None of the dosing regimens achieved the targets for an MIC of 16 mg/L. We recommend the initial dosing regimen using a nomogram based on CCr for an MIC of ≤8 mg/L in elderly patients with CCr of 40–90 mL/min.