Search

Antimicrobial stewardship (AS) intervention strategy is a critical process in promoting appropriate antibiotic use, thus preventing unnecessarily prolonged therapy and reducing antimicrobial resistance (AMR). Although limiting unnecessary carbapenem use by AS intervention is speculated to reduce AMR, there is a lack of specific data on the efficacy of AS team (AST) intervention regarding carbapenem-resistant Pseudomonas aeruginosa (CRPA). Consequently, this study aimed to evaluate the impact of our AS strategy on carbapenem use and CRPA. The AS intervention strategy was launched in July 2017 and consisted of daily audits and feedback on carbapenem use. We evaluated the 4-year prescription trend, including the rate of switching to other antimicrobials, and the rate of CRPA and the days of therapy required prior to and after the beginning of the AST intervention. The rate of switching to narrow-spectrum antibiotics and the discontinuation of carbapenem treatment were significantly higher in the pre-intervention period compared with the post-intervention period. (7.0% vs. 14.5%; p0.001; 54.1% vs. 50.9%; p=0.027). However, there were no significant differences in the rate of CRPA prior to and after the beginning of the AST intervention. Furthermore, there was no correlation found between consumption and resistance rate (Pearson's r=0.123). Our results suggest that it is extremely important for AST to promote de-escalation and reduce unnecessary use, while the combination of process and outcome indicators other than antimicrobial consumption and resistance rate are required for the evaluation of the AS programs.

Purpose: This study aimed to evaluate the efficacy of an educational intervention on reducing the inappropriate use of oral third-generation cephalosporins, the prevalence of resistant bacteria, and clinical outcomes. Methods: A before-after study was conducted to compare the data for 1 year before and after intervention at a Japanese university hospital. Educational intervention included lectures for all medical staff on oral antibiotics and educational meetings with each medical department. The primary outcome was the use of oral third-generation cephalosporins in inpatients as measured by the monthly median days of therapy (DOTs) per 1000 patient days. Secondary outcomes included the use of each oral antibiotic in inpatients and outpatients, proportion of β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (BLNAR), penicillin-resistant Streptococcus pneumoniae (PRSP) and extended-spectrum β-lactamase producing Escherichia coli (ESBLEC), the incidence of hospital-acquired Clostridioides difficile infection (HA-CDI), and hospital mortality. Results: The use of oral third-generation cephalosporins in inpatients was significantly decreased after intervention [DOTs (interquartile range): 24.2 (23.5–25.1) vs. 3.7 (0.0–7.1), P

Structured summary Background A characteristic feature of SARS-CoV-2 is its ability to transmit from pre- or asymptomatic patients, complicating the tracing of infection pathways and causing outbreaks. Despite several reports that whole genome sequencing (WGS) and haplotype networks are useful for epidemiologic analysis, little is known about their use in nosocomial infections. Aim We aimed to demonstrate the advantages of genetic epidemiology in identifying the link in nosocomial infection by comparing single nucleotide variations (SNVs) of isolates from patients associated with an outbreak in Showa University Hospital. Methods We used specimens from 32 patients in whom COVID-19 had been diagnosed using clinical reverse transcription-polymerase chain reaction tests. RNA of SARS-CoV-2 from specimens was reverse-transcribed and analysed using WGS. SNVs were extracted and used for lineage determination, phylogenetic tree analysis, and median-joining analysis. Findings The lineage of SARS-CoV-2 that was associated with outbreak in Showa University Hospital was B.1.1.214, which was consistent with that found in the Kanto metropolitan area during the same period. Consistent with canonical epidemiological observations, haplotype network analysis was successful for the classification of patients. Additionally, phylogenetic tree analysis revealed three independent introductions of the virus into the hospital during the outbreak. Further, median-joining analysis indicated that four patients were directly infected by any of the others in the same cluster. Conclusion Genetic epidemiology with WGS and haplotype networks is useful for tracing transmission and optimizing prevention strategies in nosocomial outbreaks.

Invasive trichosporonosis is a rare and lethal fungal infection that occurs in immunocompromised patients. Breakthrough trichosporonosis can occur in patients treated with echinocandins since Trichosporon spp. are resistant to these antifungal agents. We report a case of breakthrough Trichosporon asahii fungemia. A 62-year-old Japanese woman with relapsed follicular lymphoma was treated empirically with broad-spectrum antibiotics and micafungin due to an intermittent fever during reinduction chemotherapy. After four cycles of anti-cancer chemotherapy, she experienced a high neutropenic fever and T. asahii was subsequently detected from a blood culture. The patient was not given voriconazole due to the contraindication for use with carbamazepine, and she was successfully treated with fluconazole plus liposomal amphotericin B without any serious complications. The combined therapy of fluconazole and liposomal amphotericin B may therefore be useful in treating T. asahii fungemia, especially in patients receiving antiepileptic agents.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2016. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between February 2016 and August 2016 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 1062 strains (143 Staphylococcus aureus, 210 Streptococcus pneumoniae, 17 Streptococcus pyogenes, 248 Haemophilus influenzae, 151 Moraxella catarrhalis, 134 Klebsiella pneumoniae, and 159 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 48.3%, and those of penicillin-susceptible S. pneumoniae was 99.5%. Among H. influenzae, 14.1% of them were found to be β-lactamase-producing ampicillin-resistant strains, and 41.1% to be β-lactamase-non-producing ampicillin-resistant strains. Extended spectrum β-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo β-lactamase were 4.5% and 0.6%, respectively.

Use of systemic corticosteroids for the treatment for coronavirus disease 2019 (COVID-19) among chronic obstructive pulmonary disease (COPD) patients is not well described. A 58-year-old man with fever and progressive dyspnea was admitted to the Showa University Hospital, and showed severe respiratory failure which needed mechanical ventilation. His chest computed tomography scanning showed emphysema and bilateral ground-glass opacity caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. He received 30 mg prednisolone for five days with antiviral drug of favipiravir, and was successfully extubated on day five. A SARS-CoV-2 polymerase chain reaction (PCR) test became negative on day 15. He was discharged on day 21. Serum IgM and IgG antibodies against SARS-CoV-2 converted to positive on day 7 and they kept positive on day 54 for both IgM and IgG. Combination treatment of short-course systemic corticosteroid and favipiravir might improve the prognosis for critically ill COVID-19 pneumonia with COPD without negative influence on viral clearance or antibody production.

Scopulariopsis alboflavescens is a soil saprophyte that is widely distributed in nature. Recently, there have been increasing number of reports of invasive infections with Scopulariopsis species in immunocompromised patients. In this report, we described an adult woman with acute myeloid leukemia and who developed S. alboflavescens pneumonia. Liposomal amphotericin B and voriconazole combination therapy was unsuccessful and the patient died because of pneumonia. Scopulariopsis is highly resistant to available antifungal agents and almost invariably fatal. This case report should alert clinicians to the importance of listing Scopulariopsis as a pathogenic fungus in immunocompromised patients.

Pseudomonas aeruginosa, responsible for serious nosocomial-acquired infections, possesses intrinsic antibiotic resistance mechanisms and commonly exhibits multidrug resistance. Here, we report the evolving resistance profiles of strains isolated from the sputum of a patient being treated for repeated P. aeruginosa infections following cancer resection. Whole genome sequencing of six isolates obtained over a 2-month period revealed two key single nucleotide polymorphisms in the mexR and gyrB genes that affected efflux pump expression and antimicrobial resistance.

The mechanisms of azole resistance in Trichosporon asahii have not yet been fully clarified. We previously showed that T. asahii has the ERG11 gene, coding lanosterol 14-α-demethylase (Erg11 protein; Erg11p), which is the primary target of azoles. A single amino acid substitution at G453R in Erg11p was found to induce changes in the affinity of this enzyme for azoles, especially fluconazole, in vitro. In the present study, we investigated the DNA sequences of the ERG11 gene using six different strains of clinically isolated T. asahii that were highly resistant to multi-azoles, including fluconazole, itraconazole, and voriconazole. All of the T. asahii strains had a point mutation (G448A) that caused a single amino acid substitution at G150S in Erg11p. This amino acid is highly conserved among major fungal pathogens. We identified a new point mutation in the ERG11 gene that is common to clinically isolated azole-resistant T. asahii strains, suggesting that this mutation is associated with the multi-azole resistance of T. asahii.

Introduction: This study examined the risk factors for initial treatment failure in renal or retroperitoneal abscess as a multicenter study. Materials and Methods: This retrospective analysis investigated consecutive patients with renal or retroperitoneal abscess who were hospitalized in Japan. The outcomes of these patients were classified into “cured” and “failure or recurrence.” The potential clinical risk factors examined were abscess size, diabetes mellitus, major organ failure, laboratory data, fever, drainage, and causative organisms, for instance. Results: Of the 74 patients, 40 (54.1%) were diagnosed with renal abscess and 34 (45.9%) with retroperitoneal abscess, 51 (68.9%) were cured by initial treatments, and 23 (31.1%) underwent failure or relapse; 33 (44.6%) were men and 41 (55.4%) were women. In detail, 36 patients were cured by conservative therapy only. Our multivariate analysis data showed that renal failure was the only significant factor for initial treatment failure (p = 0.0281). Conclusions: Our multivariate analysis showed that renal failure was a significant risk factor for initial treatment failure or recurrence.

Objectives To investigate the efficacy of oral moxifloxacin (MFLX) as a treatment for pneumonia in hemodialysis (HD) patients and the pharmacokinetic (PK) profile of MFLX after oral administration. Methods Thirteen adult patients who required HD due to chronic renal failure were enrolled in the present study, which was performed to investigate the treatment of community-acquired pneumonia in HD patients. A standard dose of MFLX (400 mg, once daily) was administered. The therapy was continued, discontinued, or switched to another antibiotic depending on the response of the pneumonia to MFLX. A population PK model was developed using the post-hoc method. Results In total, 13 HD patients with pneumonia (male, n=7; female, n=6) were enrolled in the present study. The evaluation on the 3rd day showed that treatment was successful in 11 patients (84.6%) and that 10 patients were cured (76.9%). In the one case in which MFLX treatment failed, the patient was cured by switching to ceftriaxone (CTRX) (2 g, intravenously) plus levofloxacin (LVFX) (250 mg, orally). The causative bacterium in this male patient was P. aeruginosa. It did not display resistance to fluoroquinolones. One patient had liver dysfunction due to MFLX. The estimated PK parameters of MFLX were as follows: AUC0→24, 61.04±17.74 μg h/mL; Cmax, 5.25±1.12 μg/mL; and Ctrough, 1.15±0.45 μg/mL. The PK parameters of MFLX among the patients in whom adverse events occurred or in whom a cure was not achieved did not differ from those of the other patients to a statistically significant extent. Conclusion MFLX showed good efficacy and safety in HD patients with community-acquired pneumonia and the results of the PK analysis were favorable. Further prospective studies with larger numbers of patients will be needed to draw definitive conclusions.

Among drug-resistant bacteria of recent concern, we determined minimum inhibitory concentrations (MICs) of six different quinolone antibacterial agents in Haemophilus influenzae and performed molecular genetic analysis in addition to the exploration for β-lactamase-producing and β-lactamase negative ampicillin-resistant H. influenzae (BLNAR). A total of 144 clinical H. influenzae strains isolated at the Showa University Hospital between 2012 and 2017 were subjected to MIC determination for penicillin/quinolone antibacterial agents using the nitrocefin method and the Clinical and Laboratory Standards Institute broth microdilution method. Moreover, amino acid mutations in the quinolone resistance-determining regions (QRDRs) were analyzed in the isolates showing MIC value of ≥ 0.25 µg/ml of quinolone antibacterial agents. Increasing proportions of BLNAR were noted, with 15% in 2015 to 43.5% in 2016 and 63.6% in 2017. Among quinolone antibacterial agents, all isolates remained susceptible to sitafloxacin (STFX), and STFX showed strong inhibitory potencies against both DNA gyrase and topoisomerase IV. For moxifloxacin (MXF), however, strains with MIC value of 0.5 µg/ml were detected every year since 2013 except 2015. Amino acid mutations were investigated in 17 isolates (11.8%) with MXF MIC value of ≥0.25 µg/ml, and confirmed in 11 isolates (7.6%), of which mutations of GyrA were found in 9 isolates. Future antibacterial drug regimens may need to address the emergence of quinolone-resistant H. influenzae.

Background There are limited data for direct comparisons of the efficacy of oral itraconazole (ITCZ) and oral voriconazole (VRCZ) therapy in the treatment of chronic pulmonary aspergillosis (CPA). Methods We conducted a retrospective, follow-up, observational study of CPA patients enrolled in 2 previous multicenter trials. Results Of the 273 CPA patients, 59 and 101 patients started maintenance therapy with oral ITCZ and oral VRCZ, respectively, just after the end of acute intravenous therapy in each trial. At the end of the observation period in this follow-up study (median observation period, 731 days), the percentage of patients who showed improvement was lower in the ITCZ group than in the VRCZ group (18.2% vs 40.0%). However, after including stable patients, the percentages were 50.9% and 52.6%, respectively, in the ITCZ and VRCZ groups, which were not significantly different (P = .652). Multivariable Cox regression analysis showed no significant influence of the choice of initial maintenance treatment (ITCZ or VRCZ) on overall mortality as well as CPA-associated mortality. Multivariable logistic regression showed that oral ITCZ selection for initial maintenance therapy was an independent risk factor for hospital readmission and switching to other antifungal agents (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3–7.5 and OR, 5.7; 95% CI, 2.0–15.7, respectively). Conclusions Oral VRCZ for initial maintenance therapy showed better effectiveness than oral ITCZ for clinical improvement in CPA patients. There was no difference in crude mortality between initial maintenance therapy with VRCZ and ITCZ, especially in elderly CPA patients.

Background De-escalation therapy is recommended as an effective antibiotic treatment strategy for several infectious diseases. While there is limited evidence supporting its clinical and cost-effective outcomes in patients with community-acquired bacteremic pneumonia, there is no evidence in patients with nonbacteremic pneumonia. Objective This study aimed to evaluate the antibiotic costs in patients who did and did not receive de-escalation therapy, based on the 2017 Japanese guidelines for the management of community-acquired nonbacteremic pneumococcal pneumonia of the Japanese Respiratory Society (JRS). Setting Kobe university hospital, Japan. Methods A retrospective case series review including antibiotic use and length of hospital stay was conducted using the medical records from April 2008 to May 2019 at a university hospital in Japan. Main outcome measure Impact of antibiotic de-escalation therapy on the antibiotic costs. Results Among 55 patients who were eligible, the treating physicians de-escalated antibiotics in 28 (51%). The differences in the median length of hospital stay and the incidence of adverse drug reactions between the two groups were not statistically significant (p = 0.67 and 1.0, respectively). However, the median total antibiotic cost per infected patient in the de-escalated group was significantly lower than that in the non-de-escalated group [$269.8 ($195-$389) vs. $420.5 ($221-$799), p = 0.048]. Conclusion Antibiotic de-escalation based on the 2017 JRS guidelines leads to a reduction in total antibiotic costs for the management of community-acquired nonbacteremic pneumococcal pneumonia.

Background The incidence of ocular candidiasis (OC) in patients with candidemia varies across different reports, and the issue of whether routine ophthalmoscopy improves outcomes has been raised. This study investigated the incidence of OC and evaluate whether the extent of OC impacts the clinical outcomes. Methods This retrospective study included non-neutropenic patients with candidemia who underwent treatment at one of 15 medical centers between 2010 and 2016. Chorioretinitis without other possible causes for the ocular lesions and endophthalmitis was classified as a probable OC. If signs of chorioretinitis were observed in patients with a systemic disease that causes similar ocular lesions, they were classified as a possible OC. Results In total, 781 of 1089 patients with candidemia underwent an ophthalmic examination. The prevalence of OC was 19.5%. The time from the collection of a positive blood culture to the initial ophthalmic examination was 5.0 ± 3.9 days in patients with OC. The leading isolate was Candida albicans (77.9%). Possible OC was associated with unsuccessful treatments (resolution of ocular findings) (odds ratio: 0.354, 95% confidence interval: 0.141-0.887), indicating an overdiagnosis in patients with a possible OC. If these patients were excluded, the incidence fell to 12.8%. Endophthalmitis and/or macular involvement, both of which require aggressive therapy, were detected in 43.1% of patients; a significantly higher incidence of visual symptoms was observed in these patients. Conclusion Even when early routine ophthalmic examinations were performed, a high incidence of advanced ocular lesions was observed. These results suggest that routine ophthalmic examinations are still warranted in patients with candidemia.

Reactivation of latent infection is considered to be the main mechanism underlying the development of Pneumocystis pneumonia in immunosuppressed patients. We retrospectively assessed the effects of prophylactic administration of sulfamethoxazole-trimethoprim on the development of P. pneumonia and airway colonization with P. jirovecii in patients undergoing examinations to diagnose or rule out P. pneumonia. Polymerase chain reaction was performed to detect P. jirovecii in bronchoalveolar lavage fluid or sputum of 60 consecutive patients between 2004 and 2012. No patients who received the prophylactic administration of sulfamethoxazole-trimethoprim (n = 10) developed P. pneumonia or demonstrated airway colonization with P. jirovecii, and none of the patients who developed P. pneumonia (n = 11) or showed colonization (n = 9) had received prophylactic treatment. Furthermore, 20 (40%) of 50 patients without prophylactic treatment showed positive results on the P. jirovecii DNA polymerase chain reaction, but all 10 patients who had prophylactic treatment showed negative results (Fisher's exact test, P = 0.02). Therefore, the prophylactic administration of sulfamethoxazole-trimethoprim has potential to be effective in preventing P. pneumonia as well as eliminating airway colonization with P. jirovecii. Further studies targeting large cohorts of patients with a variety of underlying diseases are required to develop recommendations regarding the prophylactic administration of sulfamethoxazole-trimethoprim.

Carbapenem-resistant Enterobacteriaceae (CRE) are increasing globally. Particularly, carbapenemase-producing Enterobacteriaceae (CPE) are of concern. Rapid and accurate detection of these strains is critical for appropriate antimicrobial use and hospital infection control. In the present study, criteria for CPE screening were examined using a carbapenem susceptibility disk. Carbapenemase producers showed minimal inhibition zones for faropenem (5 μg): 6-12 mm (mean: 6.9 mm). Some strains with the IMP-6 genotype showed inhibition zones of >30 mm for imipenem (10 μg) and biapenem (10 μg). All strains that formed inhibition zones for FRPM had the IMP-6 genotype. The cut off values of carbapenemase-producers, determined by ROC analysis, were 12 mm for FRPM, 24 mm for meropenem (10 μg), 29 mm for BIPM, 25 mm for doripenem (10 μg), 26 mm for IPM, and 24 mm for panipenem (10 μg). Thus, the sensitivity was the highest (100%) for FRPM. Specificities were 93.44% for MEPM and DRPM and 85.25% for FRPM. Consequently, a drug sensitivity test using FRPM (5 μg) disks facilitates simple and accurate CPE screening.

Diffuse panbronchiolitis (DPB) is a progressive inflammatory airway disease characterized by a chronic cough, copious sputum expectation, dyspnea, and chronic sinusitis. Owing to the long-term treatment of low-dose macrolides, the prognosis has been remarkably improved. However, in some cases, patients are refractory to macrolides, and the subsequent treatment strategies are controversial. We herein present a patient with the onset of DPB during treatment with long-term, low-dose clarithromycin (CAM) for chronic sinusitis who was successfully treated by switching to long-term treatment with normal-dose CAM. We should recognize that DPB may develop in patients with chronic sinusitis despite treatment with a long-term, low-dose macrolide. We also propose that increasing the dose of macrolide may be a useful strategy for treating refractory patients.

We conducted a nationwide molecular epidemiological study of Clostridium difficile infection (CDI) in Japan investigated the correlation between the presence of binary toxin genes and CDI severity. This is the first report on molecular epidemiological analyses for CDI in multiple university hospitals in Japan, to our knowledge. We examined 124,484 hospitalized patients in 25 national and public university hospitals in Japan between December 2013 and March 2014, investigating antimicrobial susceptibilities and toxin-related genes for C. difficile isolates from stools. Epidemiological genetic typing was performed by PCR-ribotyping and repetitive sequence-based (rep)-PCR to examine the genetic similarities. The results detected toxin A-positive, toxin B-positive, binary toxin-negative (A+B+CDT−) detected from 135 isolates (80.8%) and toxin A-negative, toxin B-positive, binary toxin-negative (A− B+CDT−) in 23 (13.8%). Toxin A-positive, toxin B-positive, and binary toxin-positive (A+B+CDT+) were seen in 9 isolates (5.4%). Vancomycin (n = 81, 37.7%) or metronidazole (n = 88, 40.9%) therapies were undertaken in analyzed cases. Ribotypes detected from isolates were 017/subgroup 1, 070, 078, 126, 176, 449, 475/subgroup 1, 499, 451, 566 and newtypes. Rep-PCR classified 167 isolates into 28 cluster groups including 2–15 isolates. In addition, 2 pairs of strains isolated from different institutions belonged to the same clusters. Seven out of 9 (77.8%) of the patients with binary toxin producing strains had “mild to moderate” outcome in evaluated symptoms. In conclusion, we found that binary toxin did not show regional specificity and had no relevance to severity of CDI.

There are several mechanisms for antibiotic-resistant Pseudomonas aeruginosa. The purpose of this study is to investigate the association between the expression of efflux pump-coding genes and antibiotic resistance in P. aeruginosa causing urinary tract infections (UTIs). We extracted the RNA from 105 clinical strains of P. aeruginosa isolated from UTI patients with full data on antibiotic MICs and assayed real-time quantitative reverse-transcription PCR. We investigated the gene expressions of four resistance nodulation cell division-type multi-drug efflux pump systems (MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexXY(-OprA)) and the correlation of the MICs of nine antibiotics, risk factors and antibiotic resistance-related genes with expressions of mexB, mexC, mexE and mexY. Multivariate statistical data demonstrated a significant relationship between increased expression of mexB or mexC and complicated UTI (Odds ratio=8.03, P

Most cases of deep-seated trichosporonosis develop in patients with neutropenia, but it has recently been reported that breakthrough infections with Trichosporon species can develop during the use of candin family of antifungal agents. This is due to the primary resistance of the causal fungus, Trichosporon asahii (T. asahii), to the candin agents. On the other hand, there has been a case report of infection with Trichosporon that presented high-level resistance to the azole family of antifungal agents. Therefore, the possibility that the frequent use of azole agents may lead to secondary resistance to these agents is a cause for concern. Since trichosporonosis is a relatively rare infectious disease, there has been no established breakpoint for this fungus to various antifungal agents, wherein we cannot precisely confirm its sensitivity or resistance to the agents. However, our experiment demonstrated one of the processes for acquired drug resistance, wherein the minimal inhibitory concentration of fluconazole for T. asahii was markedly elevated after its long-term in vitro exposure to the drug. Although the mechanisms for drug-resistance of Trichosporon species are unknown, it is supposed that they are the same as the mechanisms found in Candida and Aspergillus species, namely, modification of target molecules or decrease of access to the molecules. Since cases of trichosporonosis are likely to increase in the future, we believe that there is an urgent need to establish the breakpoint for T. asahii based on large-scale drug sensitivity tests, as well as to elucidate its drug-resistance mechanisms.

In this study, we compared the antibiotic use, urinary tract infection-causative bacteria and their antibiotic susceptibilities among four hospitals with different backgrounds and regions in Japan in 2014. Frequency of antibiotic use (antibiotic use density: AUD/all AUD) were: ampicillin: 0.21-20.3 (median: 1.6) and cefazolin: 0.8-34.2 (2.5), representatively. The antibiotic resistant rates of Escherichia coli were ampicillin: 1.1-52.3% (median: 51.8%), piperacillin: 47.9-49.1% (48.0%), cefazolin: 23.2-34.1% (28.9%), levofloxacin: 36.6-43.8% (40.2%).We found that there were significant correlations (1) between antibiotic resistance of E. coli and annual total amount of antibiotic use (p = 0.017), annual number of days of antibiotic use (p = 0.002) and days of therapy (DOT, p = 0.002), and (2) between antibiotic resistance of extended-spectrum β-lactamase-producing bacteria and annual number of days of antibiotic use (p = 0.004) and DOT (p = 0.004) in a rehabilitation hospital. These results suggested that more antibiotic uses could lead to antibiotic resistances. Further analyses with more number of data are being undertaken.

Objective: To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes. Design: Before-after study. Setting: National university hospital with 934 beds. Intervention: Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration. Methods: The primary outcome was the use of antipseudomonal antibiotics as measured by the monthly mean days of therapy per 1000 patient days each year. Secondary outcomes included overall antibiotic use and that of each antibiotic class, susceptibility of Pseudomonas aeruginosa, the proportion of patients isolated methicillin-resistant Staphylococcus aureus (MRSA) among all patients isolated S. aureus, the incidence of MRSA, and the 30-day mortality attributable to bacteremia. Results: The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibility to levofloxacin was significantly increased from 2009 to 2016 (P = 0.01 for trend). Its susceptibility to other antibiotics remained over 84% and did not change significantly during the study period. The proportion of patients isolated MRSA and the incidence of MRSA decreased significantly from 2009 to 2016 (P < 0.001 and = 0.02 for trend, respectively). There were no significant changes in the 30-day mortality attributable to bacteremia during the study period (P = 0.57 for trend). Conclusion The comprehensive ASPs had long-term efficacy for reducing the use of the targeted broad-spectrum antibiotics, maintaining the antibiotic susceptibility of P. aeruginosa, and decreasing the prevalence of MRSA, without adversely affecting clinical outcome.

Stenotrophomonas maltophilia has low pathogenicity potential, but if it causes bacteremia it can be fatal, because it has shown high resistance to many antibiotics and can be difficult to treat. Patient death from S. maltophilia bacteremia has increased since 2014 in our hospital. In this study, we investigated risk factors for death due to S. maltophilia bacteremia.Seventy patients from the hospital database with S. maltophilia bacteremia between January 2010 and July 2017 were investigated. We retrospectively analyzed risk factors including gender, age, wards, hospitalized duration, clinical history, devices, source of S. maltophilia identification, polymicrobial bacteremia, prior antimicrobial therapy, antimicrobial therapy after bacteremia, and resistance to antibiotics. The statistical analysis was performed to compare the period from 2010 to 2013 to from 2014 to 2017.Comparing the 2010-2013 period to the 2014-2017 period, it revealed that history of hospitalization, identification of S. maltophilia from sputum, polymicrobial bacteremia, prior carbapenem use, and mortality was significantly different in S. maltophilia bacteremia (p = 0.028, p = 0.004, p 0.001, p = 0.034, and p = 0.007, respectively). Comparison between non-survivors and survivors for 2010-2013 and 2014-2017 found ICU admission and ventilator use were seen more often in non-survivors (p = 0.030 vs p = 0.013 and p = 0.027 vs p = 0.010, respectively).Our analyses showed increase in mortality from S. maltophilia bacteremia from 2014 to 2017, and that non-survivors had a higher frequency of ICU admission and ventilator use in both the 2010-2013 and 2014-2017 periods. There were more combination antimicrobial therapy cases after bacteremia in 2014-2017. Further prospective studies with larger numbers of patients should be undertaken for definitive conclusions.

The mechanisms of azole resistance in Trichosporon asahii have not yet been fully clarified. We previously showed that T. asahii has the ERG11 gene, coding lanosterol 14-α-demethylase (Erg11 protein; Erg11p), which is the primary target of azoles. A single amino acid substitution at G453R in Erg11p was found to induce changes in the affinity of this enzyme for azoles, especially fluconazole, in vitro. In the present study, we investigated the DNA sequences of the ERG11 gene using six different strains of clinically isolated T. asahii that were highly resistant to multi-azoles, including fluconazole, itraconazole, and voriconazole. All of the T. asahii strains had a point mutation (G448A) that caused a single amino acid substitution at G150S in Erg11p. This amino acid is highly conserved among major fungal pathogens. We identified a new point mutation in the ERG11 gene that is common to clinically isolated azole-resistant T. asahii strains, suggesting that this mutation is associated with the multi-azole resistance of T. asahii.

The guideline for the "Clinical Evaluation Methods for New Antimicrobial Agents to Treat Respiratory Infections (Second Version)," published by the Japanese Society of Chemotherapy in January 2012, was proposed to achieve consistency with FDA guidelines based on the concept of clinical evaluation used in Japan. We assessed the clinical efficacy of levofloxacin (LVFX) in patients with bacterial pneumonia according to this new set of guidelines for the first time. The clinical efficacy of LVFX in patients with community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) at the test of cure (TOC) was 87.5% (56/64) and 85.7% (6/7), respectively, with an overall efficacy of 87.3% (62/71). The clinical efficacy of LVFX at TOC was as follows: intravenous 81.5% (22/27), oral 88.9% (24/27), switchover from intravenous to oral administration 100% (10/10), respectively. The bacterial eradication rate in the patients with CAP and HCAP and overall efficacy at the end of therapy (EOT) was 95.3% (41/43), 100.0% (4/4) and 95.7% (45/47), respectively. The frequent causative bacterial strains included Streptococcus pneumoniae (18), Haemophilus influenzae (14) and Moraxella catarrhalis (6). The incidence of adverse reactions in the patients whose safety was evaluated was 15.7% (14/89), similar to that previously reported. The clinical efficacy of LVFX at the early phase, EOT and TOC of CAP, as assessed according to the new and former guidelines, was 70.4% (38/54) and 27.8% (15/54), 87.0% (60/69) and 79.1% (53/67), 87.5% (56/64) and 88.1% (59/67), respectively, with no significant differences. Therefore, the new efficacy evaluation method can be used in exchange for the former evaluation method.

Background: Teicoplanin (TEIC) is a glycopeptide currently used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). A plasma trough concentration (Cmin) of >20 mg/l should be used for severe infections. The aim of this study was to assess the efficacy, safety and use of Cmin >20 mg/l on day 4-6 in patients with complicated MRSA infections. Methods: Blood samples were drawn from the 41 included patients just before TEIC administration between day 4 and 6. The patients were divided into three groups (group A: >20 mg/l, group B: 10-20 mg/l and group C: min on day 4-6. Results: Differences in efficacy between the groups were significant, but differences in safety were not. The patients in group A required lower cumulative doses than those in either groups B or C. Conclusions: The optimal clinical efficacy and safety might be associated with TEIC Cmin on the fourth to sixth day.

Aims Idiopathic pulmonary fibrosis continues to be a devastating clinical disorder for which there are few therapeutic options, and the pathogenesis of this disease remains largely unknown. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in cholesterol biosynthesis, and they have been reported to exert pleiotropic effects on the cellular signaling involved in tissue inflammation and in organ fibrosis/remodeling. We examined the preventive effects of statins on fibrogenic mediator expression and production in normal human lung fibroblasts (NHLF). Main methods NHLF were pretreated with 100 nM pitavastatin or medium alone (control), and were then stimulated with transforming growth factor-β1 (TGF-β1). mRNA expression and protein secretion of several mediators from cells were analyzed by real-time polymerase chain reaction, enzyme-linked immunosorbent assay or multiplex assay. Key findings TGF-β1-induced expression or production of mediators, such as collagen-1, vascular endothelial growth factor and chemokine C–X–C motif ligand 8, in NHLF pretreated with pitavastatin was significantly suppressed with inhibition of Smad-3 phosphorylation, as compared to untreated controls. In addition, the inhibitory effects of pitavastatin were negated by addition of mevalonate. Significance Pitavastatin appeared to inhibit TGF-β1-induced fibrogenic mediator production from lung fibroblasts via the mevalonic cascade. Although further evaluation of the signaling pathways for these phenomena is necessary, our results suggest the potential benefits of pitavastatin.

Therapeutic drug monitoring (TDM) of voriconazole is important to optimize efficacy and to minimize toxicity and intolerance. In this study, we evaluated the effect of sustained high plasma trough concentration of voriconazole on the incidence of hepatotoxicity in hospitalized Japanese patients.Thirty-nine patients were divided into 3 groups according to trough concentrations in two consecutive TDMs:4 μg/ml in the first TDM (group A, n=25),4 μg/ml in the first and4 μg/ml in the second TDM (group B, n=8), and4 μg/ml in both first and second TDMs (group C, n=6).Incidences of hepatotoxicity in groups A, B and C were 16.0, 25.0 and 83.3%, and significant differences were observed between groups A and C and groups B and C. Multiple logistic regression analysis identified the classification into groups A, B and C as an independent variable of hepatotoxicity.These results suggest that sustained high trough concentration of voriconazole may increase the risk of hepatotoxicity, and decreasing trough concentration to4 μg/ml by dose adjustment after the initial TDM may reduce the incidence of hepatotoxicity in patients treated with voriconazole.

The switch from intravenous to oral antibiotic therapy is recommended for treating hospitalized patients with community-acquired pneumonia (CAP). We performed a multicenter, randomized study to assess the benefit of switching from intravenous sulbactam/ampicillin (SBT/ABPC) to oral garenoxacin (GRNX) in patients with CAP. Among adult CAP patients who must be hospitalized for intravenous antibiotic treatment, those with Pneumonia Patient Outcomes Research Team (PORT) scores of II–IV (mild to moderate) were initially treated with intravenous SBT/ABPC (6 g/day) for 3 days. A total of 108 patients who fulfilled the inclusion criteria (improved respiratory symptoms, CRP < 15 mg/dl, adequately improved oral intake, fever ≤ 38 °C for ≥ 12 h), were divided into two groups based on the antibiotic administered, the GRNX (switch to GRNX 400 mg/day) and SBT/ABPC groups (continuous administration of SBT/ABPC), for 4 days. Improvement in clinical symptoms, chest radiographic findings, and clinical effectiveness were evaluated by a central review board. Improvement in clinical symptoms was 96.3 and 90.2 % in the GRNX and SBT/ABPC groups, respectively. Improvement in chest radiographic findings was 94.4 and 90.2 % and clinical effectiveness was 94.4 and 90.2 % in the GRNX and SBT/ABPC groups, respectively. Microbiological efficacy was 90.9 and 69.2 % in the GRNX and SBT/ABPC groups, respectively. There were no significant differences between the groups. Converting to GRNX was as effective as continuous SBT/ABPC treatment in mild to moderate CAP patients in whom initial intravenous antibiotic treatment was successful.

Aim Deaths from aspiration pneumonia in elderly patients are occasionally considered to be "death from age-related physical debility", because most aspiration pneumonias are a result of aging and lead to death without any definitive therapy. The aim of the present study was to assess physicians' attitudes toward the diagnosis of and actual description of "death from age-related physical debility" on death certificates for deceased patients with aspiration pneumonia. Methods This study surveyed 62 Japanese physicians including 36 pulmonologists and 26 other physicians who treat patients with pneumonia. Their attitudes regarding consideration and actually recorded "death from age-related physical debility" for deceased patients with aspiration pneumonia were assessed by using anonymous questionnaires, which included the decision-making process and the necessity of detailed diagnostic criteria. Results A total of 32 (52%) respondents had considered deceased patients with aspiration pneumonia to be "death from age-related physical debility", and 10 (16%) have actually stated this on the death certificate. Advanced age, bedridden status, inability of oral intake and disturbance of consciousness including dementia were major factors in their decision-making. A total of 34 (55%) of the respondent physicians wanted detailed criteria to be established. Conclusions Physicians' attitudes toward the definition of "death from age-related physical debility" vary a great deal depending on the respondent. The description in death certificates therefore might inaccurately reflect the results of current mortality statistics in Japan.

Summary Statins are 3-hydroxy-3-methylglutaryl-co-enzyme A reductase inhibitors of cholesterol biosynthesis, and have been reported to exert pleiotropic effects on cellular signalling and cellular functions involved in inflammation. Recent reports have demonstrated that previous statin therapy reduced the risk of pneumonia or increased survival in patients with community-acquired pneumonia. However, the precise mechanisms responsible for these effects are unclear. In the present study, we examined the effects of statins on cytokine production from lipopolysaccharide (LPS)-stimulated human bronchial epithelial cells (BEAS-2B). Interleukin (IL)-6 and IL-8 mRNA expression and protein secretion in LPS-stimulated cells were inhibited significantly by the lipophilic statin pitavastatin and the hydrophilic statin pravastatin. As these inhibitory effects of statin were negated by adding mevalonate, the anti-inflammatory effects of statins appear to be exerted via the mevalonic cascade. In addition, the activation levels of Ras homologue gene family A (RhoA) in BEAS-2B cells cultured with pitavastatin were significantly lower than those without the statin. These results suggest that statins have anti-inflammatory effects by reducing cytokine production through inhibition of the mevalonic cascade followed by RhoA activation in the lung.

Background: We analyzed the pharmacokinetic-pharmacodynamic relationship of vancomycin to determine the drug exposure parameters that correlate with the efficacy and nephrotoxicity of vancomycin in patients with methicillin-resistant Staphylococcus aureus pneumonia and evaluated the need to use peak concentration in therapeutic drug monitoring (TDM). Methods: Serum drug concentrations of 31 hospitalized patients treated with vancomycin for methicillin-resistant S. aureus pneumonia were collected. Results: Significant differences in trough concentration (Cmin)/minimum inhibitory concentration (MIC) and area under the serum concentration-time curve (AUC0–24)/MIC were observed between the response and non-response groups. Significant differences in Cmin and AUC0–24 were observed between the nephrotoxicity and non-nephrotoxicity groups. Receiver operating characteristic curves revealed high predictive values of Cmin/MIC and AUC0–24/MIC for efficacy and of Cmin and AUC0–24 for safety of vancomycin. Conclusions: These results suggest little need to use peak concentration in vancomycin TDM because Cmin/MIC and Cmin are sufficient to predict the efficacy and safety of vancomycin.

Most cases of deep-seated trichosporonosis develop in patients with neutropenia, but it has recently been reported that breakthrough infections with Trichosporon species can develop during the use of candin family of antifungal agents. This is due to the primary resistance of the causal fungus, Trichosporon asahii (T. asahii), to the candin agents. On the other hand, there has been a case report of infection with Trichosporon that presented high-level resistance to the azole family of antifungal agents. Therefore, the possibility that the frequent use of azole agents may lead to secondary resistance to these agents is a cause for concern. Since trichosporonosis is a relatively rare infectious disease, there has been no established breakpoint for this fungus to various antifungal agents, wherein we cannot precisely confirm its sensitivity or resistance to the agents. However, our experiment demonstrated one of the processes for acquired drug resistance, wherein the minimal inhibitory concentration of fluconazole for T. asahii was markedly elevated after its long-term in vitro exposure to the drug. Although the mechanisms for drug-resistance of Trichosporon species are unknown, it is supposed that they are the same as the mechanisms found in Candida and Aspergillus species, namely, modification of target molecules or decrease of access to the molecules. Since cases of trichosporonosis are likely to increase in the future, we believe that there is an urgent need to establish the breakpoint for T. asahii based on large-scale drug sensitivity tests, as well as to elucidate its drug-resistance mechanisms.

Background and objective: More than 100 000 Japanese die of pneumonia every year. The number of people residing in nursing homes is increasing with the ageing of the population. In 2005, the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) published important guidelines for the management of healthcare-associated pneumonia (HCAP). In Japan, however, the optimum strategy for management of HCAP is still unclear. The purpose of this study was to clarify the clinical features of patients with HCAP. Methods: Patients (n = 202) who were consecutively admitted with a diagnosis of acute pneumonia between October 2007 and September 2009 were retrospectively evaluated. Using the ATS/IDSA guidelines, patients were divided into three groups: a community-acquired pneumonia (CAP) group (n = 123), a nursing home-acquired pneumonia (NHAP) group (n = 46) and a HCAP other than NHAP (O-HCAP) group (n = 33). These groups were then compared with respect to laboratory data, microbiological findings and mortality. Results: Thirty-day mortality in the NHAP group (10.9%) tended to be higher than that in the CAP group (3.3%) or the O-HCAP group (0%). The pathogens most frequently identified were Streptococcus pneumoniae and Haemophilus influenzae in the CAP group, methicillin-resistant Staphylococcus aureus and Klebsiella pneumoniae in the NHAP group, and S. pneumoniae and K. pneumoniae in the O-HCAP group. Conclusions: The NHAP group was clinically different from the O-HCAP group, based on bacteriological examination and mortality rates. In order to accurately diagnose, and formulate optimum treatment strategies for Japanese patients, the categories of HCAP, as specified in the ATS/IDSA guidelines, should not be applied directly either to patients with NHAP or those with O-HCAP.

Multidrug-resistant Pseudomonas aeruginosa, especially metallo-beta-lactamase (MBL)-producing P. aeruginosa, is an important pathogen in nosocomial infection and emergence of this pathogen has revived interest in polymyxin B (PMB) and colistin (COL). In this study, we evaluated the efficacies of PMB, COL and other antipseudomonal agents against IMP-type MBL-producing P. aeruginosa both in vitro and in vivo. A total of 75 isolates of bla(IMP)-positive P. aeruginosa obtained from clinical specimens (94.6% of isolates demonstrated resistance to beta-lactam, fluoroquinolone and aminoglycoside agents) were evaluated in the in vitro study. More than 90% of the examined isolates were susceptible to PMB (minimum inhibitory concentration for 50/90% of the isolates (MIC(50)/MIC(90)) 4/4 mg/L), although COL was less potent (MIC(50)/MIC(90) 8/16 mg/L). Cyclophosphamide-treated mice were intraperitoneally inoculated with bla(IMP)-positive P. aeruginosa. Treatment with PMB, but not COL, imipenem/cilastatin or aztreonam, significantly improved the survival rate and decreased the number of bacteria in the blood in a dose-dependent manner. Our results indicate that, among the agents studied, PMB is the most effective agent against bla(IMP)-positive P. aeruginosa.

Neutropenic mice with latent trichosporonemia were given various antifungal agents (amphotericin B, fluconazole, itraconazole) or saline to determine which antifungal agent could be useful for prophylaxis. The 3-week-survival rate was 80% in the fluconazole group, 50% in the amphotericin B group, 45% in the itraconazole group, and 30% in the saline group. Compared with the other antifungal agents, fluconazole offered superior prophylaxis against the progression of trichosporonosis fungemia to disseminated disease (P