Search

Daishi Shimada,1 Masafumi Seki1,2 1Division of Infectious Diseases, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Japan; 2Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Hidaka City, JapanCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Yamane 1397-1, Hidaka City, Saitama, 350-1298, Japan, Tel +81-42-984-4392, Fax +81-42-984-0280, Email sekimm@saitama-med.ac.jpBackground: Respiratory syncytial virus (RSV) is a pathogenic respiratory virus that is considered to affect not only children but also adults, especially elderly persons aged ≥ 65 years. However, in Japan, the annual epidemic situation and severity of RSV infections in these adults have not yet been clarified, especially during the COVID-19 pandemic.Methods: The epidemic of RSV, especially the number of adults with RSV infection during the COVID-19 period, was retrospectively analyzed. In addition, the clinical features of patients aged ≥ 65 years (older group) and those aged ≤ 64 years (younger group) were compared.Results: A total of 58 patients were found to have RSV infections from April to August 2021. Ten were adults, and five each were detected in June and July, respectively. Of the 10 adult patients, three were in the older group and were more often infected by their grandchildren, and seven were in the younger group. All older patients had underlying diseases, including diabetes mellitus. In addition, the older group showed more severe inflammation, such as increased white blood cell counts and C-reactive protein levels, and received antibiotic therapy, whereas no antibiotics were used for the younger group. Two of the three older patients were admitted to our hospital, but survived.Conclusion: These data suggest that RSV infection in adult patients was related to the increase in pediatric RSV patients and that the infection season had shifted to summer, similar to other countries. Among the adult RSV patients, those aged ≥ 65 years were more often infected by their grandchildren and received antibiotics because of their more severe inflammatory status than patients aged ≤ 64 years during the COVID-19 pandemic in Japan.Keywords: antibiotic therapy, C-reactive protein, pediatric, underlying disease, viral pneumonia

Masafumi Seki Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Hidaka City, Saitama, JapanCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Yamane 1397-1, Hidaka City, Saitama, 350-1298, Japan, Tel +81-22-983-1221, Fax +81-22-983-1232, Email sekimm@saitama-med.ac.jpAbstract: Both nirmatrelvir/ritonavir (NMV-r) and ensitrelvir (ESV) are similar protease inhibitors that act against 3C-like protease (3CL protease) which is related the viral replication of SARS-CoV-2, and are recommended as oral treatment for COVID-19 patients in the guidance. However, NMV-r was approved in 2022 for the treatment of patients who are at high risk of progressing to severe COVID-19 based on the clinical trial data during severe original strain period, whereas ESV was approved in 2023 for the treatment of non-risk patients based on the clinical trial data during mild Omicron strain period in Japan. In this study, we investigated the differences in treatment patterns and patient characteristics between COVID-19 patients treated with NMV-r and ESV. NMV-r has usually been used for elderly patients with malignant tumors in the hospital, whereas ESV has been used for younger patients in the outpatient clinic as the common practice. It has been suggested that NMV-r and ESV have been used differently in Japan because there might be gaps in the implementation periods and the evidence from clinical trials. We should use each oral agent appropriately and make different recommendations in the guidance in the near future.Keywords: SARS-CoV-2, 3C-like protease, cytochrome P450, guidance

Daishi Shimada,1 Masafumi Seki1,2 1Division of Infectious Diseases, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Japan; 2Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Hidaka City, JapanCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Yamane 1397-1, Hidaka City, Saitama, 350-1298, Japan, Tel +81-42-984-4392, Fax +81-42-984-0280, Email sekimm@saitama-med.ac.jpBackground: Lascufloxacin (LSFX), a novel fluoroquinolone antibacterial agent, has recently been used as a drip infusion for treating pneumonia, apparently with good effectiveness against various bacteria, including anaerobes, and good intrapulmonary penetration.Methods: The clinical effectiveness of LSFX was retrospectively investigated for the 55 patients admitted to our hospital with pneumonia, including chronic lung disease exacerbations and lung abscesses, from May 2021 to July 2023.Results: The median age of the 55 patients was 76.1 (34.1– 93.1) years, 45 (81.8%) were male, and 48 (87.5%) patients had underlying disease. Community-acquired pneumonia was seen in 47 (85.5%) patients, including 9 (16.4%) with lung abscess, and the other 8 (14.5%) had nursing and healthcare-associated pneumonia/hospital-acquired pneumonia. Moderate pneumonia was present in 33 (61.8%) of 55 patients, and LSFX was used as a second-line treatment for 28 (50.9%) patients in whom first-line antibiotics were ineffective. The median duration of intravenous LSFX administration was 9 (2.0– 49) days. Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus were isolated from 3 (7.1%) and 2 (4.8%) patients, respectively. Of the 55 patients, 45 (81.5%) improved clinically with intravenous LSFX administration; 20 (95.2%) of 21 community-acquired pneumonia cases, including 9 (100.0%) of 9 bacterial pneumonia cases, were improved by LSFX as first-line treatment, and 8 (88.9%) of 9 lung abscess patients also showed clinical improvement with LSFX as a second-line treatment. There were no severe adverse effects in any of the 55 patients.Conclusion: Based on these data, intravenous administration of LSFX seems effective for bacterial pneumonia, including chronic lung disease exacerbations and lung abscesses, and it appears to have broad antimicrobial activity and good tissue penetration into the lung.Keywords: aspiration pneumonia, empyema, fluoroquinolone, lascufloxacin, lung abscess

Masafumi Seki,1,* Haruka Karaushi,1,* Noriko Arai,2 Takeshi Hayashi,2 Kotaro Mitsutake1 1Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Hidaka City, Saitama, Japan; 2Division of Neurology, Saitama Medical University International Medical Center, Hidaka City, Saitama, Japan*These authors contributed equally to this workCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Yamane 1397-1, Hidaka City, Saitama, 350-1298, Japan, Tel +81-42-984-4392, Fax +81-42-984-0280, Email sekimm@saitama-med.ac.jpBackground: Secondary bacterial infection was initially rare in SARS-CoV-2 infectious disease (COVID-19) patients, but COVID-19-associated bacterial infectious diseases have recently been increasing. Furthermore, it might be difficult to distinguish COVID-19 from bacterial meningitis by the symptoms, and one might be uncertain about antibiotic therapy for Listeria meningitis infection—typically caused by eating contaminated food—in elderly persons and pregnant women.Case Report: A 96-year-old woman who had been living alone was found to have SARS-CoV-2 infection in February 2023. She was admitted to our hospital with high fever and disturbance of consciousness and was started on treatment with remdesivir. Two days later, her consciousness was still disturbed, and she was found to have a stiff neck. In addition, increased white blood cell counts and C-reactive protein suggested bacterial infection. Therefore, a lumbar puncture was done, and Listeria monocytogenes was ultimately isolated from blood cultures and its genetic material was detected in cerebrospinal fluid. She had previously eaten refrigerated food and cheese products. Intravenous ampicillin 1.0 g 6×/day was started, but one week later, loss of consciousness continued, and the cerebrospinal findings were not improved, although nasal swab became negative for SARS-CoV-2. Intravenous sulfamethoxazole/trimethoprim (ST) 80/400 mg 3×/day was added, and her consciousness and fever improved by one week later. A drug rash appeared after ST was started, and she was switched to meropenem. Her condition finally improved.Conclusion: COVID-19-associated secondary listeria infection was found in an elderly woman. She was treated with not only ampicillin, but also ST and meropenem. Meningitis caused by Listeria monocytogenes should be considered as a secondary complication and carefully treated with antibiotics during the period of the COVID-19 pandemic.Keywords: penicillin, carbapenem, antibiotics, drug rash, SARS-CoV-2

Daishi Shimada,1 Motoyasu Sagawa,2 Masafumi Seki1,3 1Division of Infectious Diseases, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Japan; 2Division of Endoscopy, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Japan; 3Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Hidaka City, JapanCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Yamane 1397-1, Hidaka City, Saitama, Japan, Tel +81-42-984-4392, Fax +81-42-984-0280, Email sekimm@saitama-med.ac.jpBackground: Higher rates of diagnosis of pulmonary Mycobacterium avium-intracellulare complex (MAC) disease by bronchoscopy (BS) in patients who could not diagnose by sputum cultures have been suggested, but the detailed utility of BS, especially in combination with anti-glycopeptidolipid-core IgA antibodies (anti-MAC Ab), is still unclear.Methods: A total of 111 patients at our hospital with suspected MAC who underwent BS because they were sputum-negative from April 2018 to March 2022 were analyzed prospectively. These patients were also divided into two groups, anti-MAC Ab-positive and anti-MAC Ab-negative, and compared.Results: A total of 111 patients underwent BS, though 95 (38.0%) of 250 enrolled patients were sputum smear/culture-positive. The age of the 111 patients was 69.14 (31.0– 89.0) years, and 90 (81.0%) were female; 69 (62.2%) of 111 patients were either smear-positive (n = 42, 37.8%) or culture-positive (n = 27, 24.3%) by BS. Of the total 111 patients, 69 (62.2%) were anti-MAC Ab-positive and 57 (82.6%) of 69 patients were also positive by BS. In contrast, only 12 (28.6%) of the 42 anti-MAC Ab-negative patients were positive by BS. The sensitivity and specificity of anti-MAC Ab for positive by BS were 82.6% and 71.4%, respectively, and the area under the curve (AUC) on receiver-operating characteristic (ROC) curve analysis was 0.807.Conclusion: BS and anti-MAC Ab showed similar usefulness to confirm the diagnosis in patients who could not be diagnosed by sputum examination, but pulmonary MAC disease was strongly suspected based on chest radiography/CT findings. These two examinations were correlated, and their combination appeared to provide more accurate diagnosis and earlier therapy.Keywords: anti-MAC antibody, bronchiectasis, bronchoscopy, nontuberculous mycobacteria, sputum

Masafumi Seki,1,2 Kosuke Hashimoto,2 Nami Kondo,2 Yoshitaka Ohya,2 Futoshi Kotajima,2 Kotaro Mitsutake1,2 1Division of Infectious Diseases and Infection Control, International Medical Center, Saitama Medical University, Hidaka City, Saitama, Japan; 2COVID-19 Management Team, International Medical Center, Saitama Medical University, Hidaka City, Saitama, JapanCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, International Medical Center, Saitama Medical University, Yamane 1397-1, Hidaka City, Saitama, 350-1298, Japan, Tel +81-42-984-4392, Fax +81-42-984-0280, Email sekimm@saitama-med.ac.jpBackground: The detailed treatment regimen of COVID-19 patients with hematological malignancies has been unclear, and some fatalities have occurred, although combination therapy with antiviral agents and corticosteroids has been established for moderate to severe COVID-19 patients.Case Series: Case 1 was a 57-year-old woman who had malignant lymphoma and received CHOP therapy with obinutuzumab, and case 2 was a 70-year-old-man who had myeloma and received molecular targeted therapy with weekly corticosteroid. In both cases, SARS-CoV-2 genes and antigens were detected from their nasal swabs, and treatment was started for moderate to severe COVID-19. Case 1 received antiviral agents with high doses of corticosteroids for a long term simultaneously, but the high titer of viral antigens in her nasal swabs persisted. Ground-glass opacities and interstitial shadows also worsened in both lungs, and she finally died on day 60. In contrast, in case 2, antiviral agents were started first, and restarted the immunosuppressive agents, such as gamma globulin and corticosteroids after no titer of SARS-CoV-2 antigens was confirmed. The patient survived, and his abnormal chest shadows showed gradual improvement. Both of the patients received two vaccinations, but showed the low antibody titers for SARS-CoV-2.Conclusion: Administration of both antiviral agents and corticosteroids has been recommended for moderate to severe COVID-19 patients, but in patients with hematological malignancies, it might be better to use antiviral agents first to reduce the viral titers, and then add steroid and related immunosuppressive agents later appropriately to inhibit the excessive inflammatory state. The dose, timing, and order of the antivirals and immunosuppressive agents for COVID-19 should be considered carefully in the patients with hematological malignancies who showed low vaccine effectiveness.Keywords: SARS-CoV-2, B cell depleting agents, corticosteroid, obinutuzumab, rituximab

Mitsuru Seki, Takaomi Minami Department of Pediatrics, Jichi Medical University, Tochigi, JapanCorrespondence: Mitsuru Seki, Department of Pediatrics, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan, Tel +81-285-58-7366, Fax +81-285-44-6123, Email m-seki@jichi.ac.jpAbstract: Kawasaki disease (KD), first reported as an acute febrile mucocutaneous lymph node syndrome, is a self-limiting vasculitis of unknown etiology. The most important aspect of KD is the prevention of coronary artery lesion (CAL) because myocardial ischemia or infarction due to CAL might be lethal. In addition to the CAL, patients with KD develop systemic vasculitis, which indicates the presence of vascular endothelial damage. Studies assessing pulse wave velocity or percentage change in flow-mediated dilatation have shown that aortic stiffness is increased in patients with KD history. In contrast, the cardio-ankle vascular index, a novel parameter not affected by blood pressure, has not demonstrated increased aortic stiffness in patients with KD. Although many studies using various parameters have suggested a risk of atherosclerosis in patients with a history of KD, a few others have reported no significant differences between KD patients and controls. Therefore, it will be necessary to thoroughly understand the characteristics of each parameter, before evaluating the results of those studies, to understand systemic vascular dysfunction in these populations, and to manage their vascular health. Although it is controversial whether the risk of atherosclerosis in patients with KD is higher, those with CAL are thought to be at a high risk of atherosclerosis. Therefore, appropriate treatment to prevent CAL in the acute phase and subsequent regular follow-up is important. Here, we review the pathology, risk, and management of vascular disorders, especially systemic vascular disorders, in patients with KD history.Keywords: vasculitis, aortic stiffness, atherosclerosis, vascular health

Daisuke Fukushi,1 Keigo Murakami,2 Yuji Watanabe,3 Norihiko Sugimoto,4 Hirotsugu Uehara,4 Masafumi Seki5 1Division of Gastroenterology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 2Division of Pathology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 3Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 4Fuso Pharmaceutical Industry, Osaka City, Osaka, Japan; 5Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, JapanCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-ku, Sendai City, Miyagi, 983-8536, Japan, Tel +81-22-983-1221, Fax +81-22-290-8959, Email m-seki@tohoku-mpu.ac.jp; seki@hosp.tohoku-mpu.ac.jpBackground: Detection of Mycobacterium avium complex (MAC) in tissue is essential for the diagnosis of MAC infections when the Mycobacterium is not isolated from sputum. However, detection of MAC in paraffin-embedded sections has not been established.Methods: We encountered two patients with suspected MAC infections after surgery: patient 1 had a pulmonary nodule that was initially suspected to be lung cancer and was excised under video-assisted thoracoscopic surgery (VATS). Patient 2, who was under treatment with steroids and anti-IL-6 inhibitors for rheumatoid arthritis, was suspected to have disseminated ileocecal cancer with metastasis to the lung and skin. In both cases, we postoperatively detected MAC genes in paraffin-embedded tissue sections using the novel mycobacterial nucleic acid identification test, ie tissue-direct polymerase chain reaction (tdPCR)-based nucleic acid lateral flow immunoassay (NALFIA). Both patients showed granulomatous lesions with hematoxylin-eosin staining, and mycobacteria by Ziehl–Neelsen staining in tissue sections from the lung and skin, respectively, although MAC were not isolated from the sections. MAC genes were finally detected by tdPCR-NALFIA in both cases.Conclusion: Although Ziehl–Neelsen staining and culture tests are the gold standard in identifying causative mycobacteria, the rapid results of tdPCR-NALFIA performed simultaneously with sputum and/or tissue culture may make it an important auxiliary diagnostic tool for identifying mycobacterial infection, leading to improvement in the management of MAC patients.Keywords: Mycobacterium avium complex, MAC, Ziehl–Neelsen staining, rapid diagnosis

Yuji Watanabe,1,2 Hirohito Sano,3 Shuichi Konno,3 Yasuhiro Kamioka,1,4 Maya Hariu,1,2 Kazuki Takano,1,2 Mitsuhiro Yamada,3 Masafumi Seki1 1Division of Infectious Diseases and Infection Control, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai City, Miyagi, Japan; 2Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 3Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai City, Miyagi, Japan; 4Division of Pharmacy, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, JapanCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-ku, Sendai City, Miyagi, 983-8612, Japan, Tel +81-22-259-1221, Fax +81-22-290-8956, Email m-seki@tohoku-mpu.ac.jp; seki@hosp.tohoku-mpu.ac.jpBackground: Exophiala dermatitidis is an environmental black fungus that rarely causes respiratory infections, yet its pathophysiological features and treatment regimens have not been established.Case Series: Two cases of exacerbations of chronic bronchitis and sinusitis due to E. dermatitidis infection in Japan are presented. Both patients were women, and non-tuberculous Mycobacterium (NTM) infection was suspected based on chest radiological findings, but E. dermatitidis was detected from bronchial lavage fluid and nasal mucus, respectively. Both cases were successfully treated by antifungal agents such as liposomal amphotericin B, voriconazole, and itraconazole, but clarithromycin, rifampicin, ethambutol, and sitafloxacin for NTM were not effective.Conclusion: E. dermatitidis can become a respiratory pathogen, especially in patients with chronic sinobronchial syndrome.Keywords: black fungus, bronchiectasis, rheumatoid arthritis, bronchoscope

Haruka Imai,1 Yuji Watanabe,2 Daishi Shimada,1 Jun Suzuki,1 Shiro Endo,1 Mitsuo Kaku,1 Masafumi Seki1 1Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 2Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, JapanCorrespondence: Masafumi SekiDivision of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-ku, Sendai City, Miyagi, 983-8536, JapanTel +81-22-983-1221Fax +81-22-290-8959Email m-seki@tohoku-mpu.ac.jp; seki@hosp.tohoku-mpu.ac.jpBackground: The detection of the pathogens in the blood is essential for the management of septic patients; however, conventional blood culture takes 2– 3 days. Therefore, rapid and convenient methods may be useful to aid clinical decision-making.Methods: Blood samples with sepsis clinically diagnosed in cases that fulfilled the diagnostic criteria were used and analyzed the utility of a novel bacterial nucleic acid identification test using a cell-direct polymerase chain reaction (cdPCR)-based nucleic acid lateral flow immunoassay (NALFIA) which were named as “DiagnoSep” to detect representative bacteria in peripheral blood leukocytes in patients admitted to our hospital and compared the conventional blood culture results simultaneously taken from the patients.Results: We analyzed the total 42 samples in the terms of this study and found 18 (42.8%) were positive on cdPCR-NALFIA, and 24 (57.1%) were positive on blood cultures. Although the positive rate was higher with blood cultures, 15 samples showed positive results from both blood cultures and cdPCR-NALFIA, and the identified bacteria agreed for 10 samples. Of the 18 cdPCR-NALFIA-positive cases, the results for 8 samples differed from the results of blood cultures; four of them had an implanted pacemaker or prosthetic joint and were positive for Staphylococcus aureus or Staphylococcus epidermidis on cdPCR-NALFIA.Conclusion: Blood culture tests are probably the gold standard in identifying causative organisms in sepsis, but the rapid results from cdPCR-NALFIA simultaneously used with blood culture may make it an important auxiliary diagnostic tool for identifying infecting organisms and lead to the improvement of mortality of the septic patients, because these combined results provide the wide information on the possible pathogens in early phase.Keywords: bacteremia, blood culture, rapid diagnosis

Shota Kashiwagura,1 Yasuhiro Kamioka,1 Masafumi Seki,2 Satoshi Koshika,1 Kouji Okada1,3 1Department of Pharmacy, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 2Division of Infectious Diseases and Infection Control, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai City, Miyagi, Japan; 3Division of Clinical Pharmaceutics and Pharmacy Practice, Faculty of Pharmaceutics, Tohoku Medical and Pharmaceutical University, Sendai City, Miyagi, JapanCorrespondence: Masafumi SekiDivision of Infectious Diseases and Infection Control, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-ku, Sendai City, Miyagi, 983-8536, JapanTel +81-22-983-1221Fax +81-22-290-8959Email m-seki@tohoku-mpu.ac.jp; seki@hosp.tohoku-mpu.ac.jpBackground: Low trough concentrations of vancomycin (VCM) are common in patients receiving the drug, because patients are often administered relatively low doses of VCM due to its high potential for renal toxicity. However, the clinical risk factors associated with low VCM trough concentration in relation to renal function are unclear.Methods: Patients at our hospital who received VCM intravenously from January 2018 to December 2020 were analyzed. The patients were divided into two groups based on their renal function: normal and lower renal function, such as estimated glomerular filtration rate (eGFR) ≧60 and < 60 mL/min/1.73 m2, respectively. In each renal function group, patients’ background characteristics, laboratory data and treatments were compared between lower VCM concentration (< 10 mg/L) and appropriate VCM concentration (10– 20 mg/L) subgroups.Results: Among 101 patients with normal renal function, 47 and 54 patients, respectively, showed lower and appropriate VCM trough concentrations. Elderly age, short stature, and higher C-reactive protein (CRP) level were significantly more common in the lower VCM concentration group compared with appropriate VCM concentration group. Among the 45 patients with renal dysfunction, 20 and 25 patients, respectively, showed lower and appropriate VCM trough concentrations. CRP levels were significantly higher in lower VCM concentration than appropriate VCM concentration subgroups. Multivariate analysis showed that insufficient total VCM doses and higher CRP might have affected the lower VCM trough concentration in patients with normal renal function.Conclusion: The results of this study suggest that higher CRP might be one of the risk factors associated with lower VCM concentration in both normal and low renal function patients. Severely ill and emergency patients might receive a lower VCM dose due to underestimation of the acceptable VCM dose.Keywords: therapeutic drug monitoring, vancomycin, estimated glomerular filtration rate, C-reactive protein

Kazuki Takano,1,2 Daishi Shimada,1 Shota Kashiwagura,1,3 Yasuhiro Kamioka,1,3 Maya Hariu,1,2 Yuji Watanabe,1,2 Masafumi Seki1 1Division of Infectious Diseases and Infection Control, Faculty of Medicine; 2Laboratory for Clinical Microbiology; 3Division of Pharmacy, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, JapanCorrespondence: Masafumi SekiDivision of Infectious Diseases and Infection Control, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-ku, Sendai City, Miyagi, 983-8612, JapanTel +81-22-259-1221Fax +81-22-290-8956Email m-seki@tohoku-mpu.ac.jpBackground: Mycobacterium abscessus frequently causes severe infections, yet its pathophysiological features and treatment regimens have not been established.Case Report: We present five cases of severe pneumonia due to Mycobacterium abscessus infection in Japan. All cases were diabetic patients, with possible acceleration to pneumonia due to co-infection with other microorganisms. However, following a short period of hospitalization and combination therapy with intravenous imipenem/cilastatin and amikacin, all the cases were successfully treated as outpatients with oral clarithromycin and sitafloxacin.Conclusion: M. abscessus infections can become severe in the presence of diabetes mellitus and co-infection with other chronic infectious organisms. Sitafloxacin might be a key drug in the treatment of M. abscessus infection in future.Keywords: non-tuberculosis mycobacterium, macrolides, clarithromycin, fluoroquinolone, sitafloxacin

Kazuki Takano,1,2 Yuji Watanabe,1,2 Maya Hariu,1,2 Masafumi Seki1 1Division of Infectious Diseases and Infection Control; 2Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, JapanCorrespondence: Masafumi SekiDivision of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, 1-12-1 Fukumuro, Miyagino-ku, Sendai City, Miyagi, 983-8612, JapanTel +81-22-983-1221Fax +81-22-983-1232Email m-seki@tohoku-mpu.ac.jpAbstract: There is a concern that the spread of mutant strains of SARS-CoV-2 will increase the number of severe COVID-19 patients and weaken vaccine effectiveness in the world. The mutants of the spike region of SARS-CoV-2, such as N501Y, E484K, P681H, and deletion H69/V70 (del 69/70), were studied in 25 COVID-19 patients admitted from December 2020 to April 2021; there were no patients with N501Y and P681H, but nine patients had E484K alone. Their symptoms, laboratory data, and course of their disease were similar to those of the other patients with the non-mutant virus. One patient with del69/70 alone showed prolonged inflammation, viral excretion, and late exacerbation 18 days after onset. Del69/70 may be independently associated with evasion of immunity, as previously reported, and it is present in Japan.Keywords: COVID-19, N501Y, E484K, P681H, PCR, remdesivir, vaccine

Masakazu Ichinose,1 Yoshiaki Minakata,2 Takashi Motegi,3 Tsuneyuki Takahashi,4 Munehiro Seki,5 Satoko Sugaya,5 Nobuya Hayashi,6 Ichiro Kuwahira7 1Academic Center of Osaki Citizen Hospital, Osaki 989-6183, Japan; 2Respiratory Medicine, National Hospital Organization Wakayama Hospital, Wakayama 644-0044, Japan; 3Respiratory Care Clinic Tokyo, Institute of Clinical Respirology, Tokyo 104-0031, Japan; 4Department of Internal Medicine, Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Sendai 984-8560, Japan; 5Medical Department, AstraZeneca K.K., Osaka 530-0011, Japan; 6Biometrics Department, AstraZeneca K.K., Osaka 530-0011, Japan; 7Department of Pulmonary Medicine, Tokai University Tokyo Hospital, Tokyo 151-0053, JapanCorrespondence: Masakazu Ichinose Email ichinose@h-osaki.jpPurpose: Patients with chronic obstructive pulmonary disease (COPD) have decreased physical activity (PA) compared with healthy adults. As lower PA is associated with increased mortality, improving PA is an important objective for COPD management. This large-scale, multicenter, non-interventional, cross-sectional study examined the activity status of COPD patients in Japan and explored factors related to PA.Patients and Methods: Outpatients aged ≥ 40 years with confirmed COPD diagnosis and pulmonary function test data were enrolled. Primary study outcomes were measurement of daily steps (over 14 consecutive days, using an activity monitor), assessment of activity time by activity intensity (using metabolic equivalents [METs]), and evaluation of correlation between PA and patient characteristics. Secondary outcomes included further investigation of the influence of patient characteristics on PA.Results: Data from 417 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I (29.5%), II (43.9%), III (23.5%), and IV (3.1%) were evaluated. Median (Q1, Q3) daily step count was 3440.8 (1831.3, 5709.3). Median (Q1, Q3) durations of PA at ≥ 3 (moderate-to-vigorous) and ≥ 2 METs (light-to-vigorous) were 18.7 (6.5, 41.3) and 186.9 (126.9, 259.2) minutes, respectively. For > 30% of patients, time spent in ≥ 3 METs activity was ≤ 10 minutes. Unemployment was significantly correlated with reduced activity time (≥ 3 and ≥ 2 METs) and step count. Severe GOLD stage was significantly correlated with reduced activity time (≥ 3 and ≥ 2 METs). High modified Medical Research Council (mMRC) dyspnea score was significantly correlated with reduced activity time (≥ 3 METs) and step count. Patients tended to overestimate the time spent in activities requiring ≥ 2 METs in their subjective reports compared with activity monitor measurements.Conclusion: Reduced PA was observed in the Japanese COPD patients with the majority of them being GOLD stage I/II. Employment status, GOLD stage, and mMRC dyspnea score could help identify patients at risk of reduced PA.Clinical Trial Registration: NCT03642613 (ClinicalTrials.gov); UMIN000032962 (UMIN-CTR, umin.ac.jp).Keywords: COPD, physical activity, pulmonary function, activity monitor, step counts

Masafumi Seki Department of Infectious Diseases, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai City, JapanCorrespondence: Masafumi SekiDepartment of Infectious Diseases, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-Ku, Sendai City, Miyagi 983-8612, JapanTel +81-22-259-1221Fax +81-22-290-8956Email m-seki@tohoku-mpu.ac.jpAbstract: Vaccination is an important strategy to prevent influenza and its related pneumococcal pneumonia. Combined influenza and pneumococcal vaccination should be recommended because of the synergic effects of the two vaccines, compared with either influenza vaccine or pneumococcal vaccine alone.Keywords: influenza virus, Streptococcus pneumoniae, nursing and healthcare-associated pneumonia, NHCAP, mortality, cost-effectiveness

Yasuhiro Kamioka,1,2 Shota Kashiwagura,1,2 Masafumi Seki1 1Department of Infectious Diseases, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai City, Miyagi, Japan; 2Division of Pharmacy, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, JapanCorrespondence: Masafumi SekiDepartment of Infectious Diseases, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyagino-Ku, Sendai City, Miyagi 983-8612, JapanTel +81-22-259-1221Fax +81-22-290-8956Email m-seki@tohoku-mpu.ac.jpObjective: The use of baloxavir, a new anti-influenza agent, began in Japan from the 2018 to 2019 season and became the focus of attention due to its efficient viral reduction ability; therefore, we should know the prescription changes of anti-influenza agents.Methods: We analyzed the changes in the prescription of anti-influenza agents between the 2018– 19 season and the 2019– 20 season in our hospital.Results: The share of baloxavir was 15%, while the shares of oseltamivir and laninamivir were 42% and 31%, respectively in the 2018– 2019 season. However, in the 2019– 20 season, the share of baloxavir and laninamivir was reduced to 3% and 17%, respectively, in contrast to an increase in the share of oseltamivir (66%). The total prescription of anti-influenza agents for patients decreased in the 2019– 20 season (205 patients), compared with the 2018– 19 season (509 patients).Conclusion: These results suggest significant changes such as a reduction in the prescription of anti-influenza agents, especially baloxavir, likely due to the suspected prevalence of a baloxavir-resistant strain of influenza virus and the emergence of SARS-CoV-2 in Japan.Keywords: anti-influenza agents, oseltamivir, laninamivir, zanamivir, peramivir, novel coronavirus-2019, COVID-19

Yuji Watanabe,1,2 Yasuhiro Kamioka,1,3 Masafumi Seki1 1Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 2Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 3Department of Pharmacy, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, JapanCorrespondence: Masafumi SekiDivision of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, 1-12-1 Fukumuro, Miyagino-ku, Sendai City, Miyagi, 983-8612, JapanTel +81-22-983-1221Fax +81-22-983-1232Email m-seki@tohoku-mpu.ac.jpAbstract: Human rhinovirus (HRV) is known as one of the most important respiratory pathogens, and the clinical characteristics of HRV infection might be similar to those of coronavirus disease 2019 (COVID-19). We identified 11 HRV-infected patients by polymerase chain reactions of the HRV genes among 151 outpatients with fever. All nine adult patients had underlying diseases and finally improved with the appropriate treatment in this COVID-19 pandemic period. Differential diagnosis between HRV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will be needed to save lives and medical resources.Keywords: SARS-CoV-2, human rhinovirus, PCR, antimicrobial stewardship

Yuji Watanabe,1,2 Nozomi Oikawa,1,2 Maya Hariu,1,2 Masafumi Seki11Division of Infectious Diseases and Infection Control; 2Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, JapanBackground: Small-colony variants of methicillin-resistant Staphylococcus aureus (SCV-MRSA) recently were described as slow-growing, thymidine-dependent strains; typically, SCV-MRSA were isolated from patients receiving sulfamethoxazole-trimethoprim, but detection of these strains frequently was delayed because of their small colony size and slow growth. Bacteremia cases due to SCV-MRSA sometimes become lethal when the initiation of treatment with intravenous anti-methicillin-resistant Staphylococcus aureus (MRSA) drugs starts too late.Methods: Here, we evaluated the use of general MRSA-specific agar plates in Japan, including MS-CFX, X-MRSA, and CHROMagar, for the efficient detection of SCV-MRSA, including the comparative detection efficiencies of these media for stock strains and clinical isolates.Results: Among the three MRSA-specific agar plates that were tested, X-MRSA and CHROMagar showed similar detection efficiencies for both 24 and 48 hrs culturing; in contrast, MS-CFS did not permit the detection of SCV-MRSA in stock strains. For clinical isolates of SCV-MRSA, X-MRSA plates permitted detection of the smallest and slowest-growing colonies of SCV-MRSA at 48 hrs of culturing; in contrast, CHROMagar and MS-CFX sometimes did not identify SCV-MRSA at 24 and 48 hrs.Conclusion: Optimization of media and incubation times will be necessary for efficient identification for SCV-MRSA, which would prevent delays in diagnosis and treatment with anti-MRSA drugs.Keywords: SCV-MRSA, thymidine-dependent MRSA, X-MRSA, CHROMagar, MS-CFS, sheep blood agar

Maya Hariu,1,2 Yuji Watanabe,1,2 Nozomi Oikawa,1,2 Takafumi Manaka,1,2 Masafumi Seki1 1Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 2Department of Laboratory Medicine, Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan Background: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is now widely used to detect pathogens in clinical settings in Japan. Method: Here, we report the effects of adding lysis buffer in the MALDI-TOF MS method to directly detect bacteria from 3 blood culture systems and compare their detection efficiencies for each pathogen. Results: Blood culture broths from BD, bioMérieux, and Oxoid showed similar detection efficiencies without lysis buffer use and Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa were efficiently detected in all broths when lysis buffer was used. However, Streptococcus pneumoniae was not detected in BD broth when lysis buffer was added. Furthermore, Haemophilus influenzae and Bacteroides fragilis were not detected in all 3 systems when lysis buffer was used. Conclusion: Optimization of blood culture system and lysis buffer is necessary according to each pathogen for direct identification by MALDI-TOF MS methods. Keywords: blood cultures broth, lysis buffer, Escherichia coli, Haemophilus influenzae, Streptococcus pneumoniae, time-of-flight mass spectrometry

Masafumi Seki,1 Yuji Watanabe,2 Hiroki Kawabata3 1Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 2Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan; 3Department of Bacteriology-1, National Institute of Infectious Diseases, Tokyo, Japan Abstract: This report presents the case of a Japanese patient who developed Lyme disease. The patient was a 44-year-old woman who had general fatigue and the inability to open her mouth. She was initially suspected of having mild tetanus with lockjaw; however, she reported a past history of a tick bite while camping in the USA and had erythema migrans 2 months before this visit. Finally, Lyme disease was serologically confirmed. A few cases of Lyme disease are annually reported in Japan; however, this infectious disease should also be suspected. Keywords: Borrelia burgdorferi, Clostridium tetani, tetracycline, facial nerve palsy, erythema migrans

Maya Hariu,1,2 Yuji Watanabe,1,2 Nozomi Oikawa,1,2 Masafumi Seki1 1Division of Infectious Diseases and Infection Control, 2Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan Abstract: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (TOF-MS) is now widely used to detect pathogens in clinical settings in Japan. Here, we report the ability of TOF-MS to detect bacteria from blood culture (BC) broths, and compare the efficacy of TOF-MS to that of conventional culture methods. Bacteria were correctly detected from 63 monomicrobial samples within 80 minutes; results matched those obtained by conventional BC methods, although the conventional methods took 2–3 days. In addition to the 63 monomicrobial samples, another three polymicrobial samples were tested; notably, the infecting bacteria were not correctly identified in two of these three samples. To better assess the TOF-MS detection of polymicrobial samples, we tested various ratios of mixed broth samples, including combinations of the bacteria that we were unable to detect in clinical samples. Combinations of Enterobacter cloacae and Pseudomonas aeruginosa were correctly detected at a culture ratio of 2:1, but not in the 3:1 mixture. These results suggested that TOF-MS is a strong tool for the rapid and correct detection of pathogens from monomicrobial BC samples, though results need to be carefully checked when handling known or suspected polymicrobial samples. Keywords: bacteremia, polymicrobial sample, Enterobacter cloaca, Pseudomonasa aeruginosa

Yuji Watanabe,1,2 Nozomi Oikawa,1,2 Maya Hariu,1,2 Ryota Fuke,1 Masafumi Seki1 1Division of Infectious Diseases and Infection Control, 2Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai City, Miyagi, Japan Abstract: Procalcitonin (PCT) and C-reactive protein serve as biomarkers of infection in patients with sepsis/bacteremia. The present study assessed the clinical characteristics of 280 patients with suspected sepsis who were admitted to Tohoku Medical and Pharmaceutical University Hospital between January 2012 and December 2013. Among the patients, 133 and 147 were positive and negative for PCT, respectively. Patients who were PCT positive were older and more frequently male, had reduced levels of platelets and albumin, and increased levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, and C-reactive protein. Patients who were PCT positive had significantly higher blood culture positivity compared with those who were PCT negative, and the sensitivity and specificity of PCT for detecting positive blood cultures were 74.5% and 59.1%, respectively. Escherichia coli was detected in PCT-positive patients, whereas Staphylococcus epidermidis and Staphylococcus lugdunensis were frequently detected in PCT-negative patients. Levels of PCT were higher in the patients infected with gram-negative rods than those with gram-positive cocci. Furthermore, extended-spectrum β-lactamase (ESBL)-producing bacteria cases showed higher levels of PCT than those of non-ESBL cases. These results suggest that PCT may be a useful biomarker of sepsis, and it might serve as a strong tool to detect patients with severe gram-negative rod bacteremia including ESBL-producing bacteria cases early due to its relative high sensitivity. Keywords: biomarker, sepsis, Escherichia coli, gram-negative rods, ESBL

Hiroki Takahashi,1,* Masafumi Seki,2,4,* Norihisa Yamamoto,2 Shigeto Hamaguchi,2 Masahiro Ojima,1 Tomoya Hirose,1 Kazuhisa Yoshiya,1 Masahiro Toyokawa,3 Isao Nishi,3 Hiroshi Ogura,1 Takeshi Shimazu,1 Kazunori Tomono21Department of Traumatology and Acute Critical Medicine, Osaka University Hospital, Suita, Osaka, Japan; 2Division of Infection Control and Prevention, Osaka University Hospital, Suita, Osaka, Japan; 3Laboratory for Clinical Investigation, Osaka University Hospital, Suita, Osaka, Japan; 4Division of Infection Control and Prevention, Tohoku Pharmaceutical University Hospital, Sendai, Japan *These authors contributed equally to this work Abstract: Surveillance is very important to prevent the nosocomial spread of methicillin-resistant Staphylococcus aureus (MRSA), and infection sources and routes have historically been identified using molecular and epidemiological genotyping with pulsed-field gel electrophoresis. However, phage-open reading frame typing (POT) has recently been developed. Here, we investigated whether POT would be useful to survey MRSA outbreaks and transmission. We therefore applied POT to 91 MRSA isolates detected in cultures from inpatients at our hospital between May and October 2014. Among the 91 isolates, 12 POT types comprising 38 isolated MRSA strains were considered as overlapping. Five of them were detected in different wards, whereas the remaining seven were found in the same ward, including the emergency department. Three of seven POT number 93-155-111 strains were detected in the surgical ward, and all of four POT number 93-157-61 strains were detected in the cardiosurgical ward. These data suggested that transmission of the MRSA strains with the same POT-types from the same wards was nosocomial, and that POT accurately and rapidly identified MRSA strains, which allowed effective control of infection and transmission. Keywords: MRSA, active surveillance, POT, nosocomial transmission

Masafumi Seki,1,2,* Hiroki Takahashi,3,* Norihisa Yamamoto,1 Shigeto Hamaguchi,1 Masahiro Ojima,3 Tomoya Hirose,3 Kazuhisa Yoshiya,3 Hiroshi Ogura,3 Takeshi Shimazu,3 Kazunori Tomono1 1Division of Infection Control and Prevention, Osaka University Hospital, Suita, Osaka, Japan; 2Division of Infection Control and Prevention, Tohoku Pharmaceutical University Hospital, Sendai, Japan; 3Department of Traumatology and Acute Critical Medicine, Osaka University Hospital, Suita, Osaka, Japan *These authors contributed equally to this work Abstract: Conventional culture methods to detect methicillin-resistant Staphylococcus aureus (MRSA) take a few days, and their sensitivity and usefulness also need to be improved. In this study, active screening was performed using the polymerase chain reaction (PCR) for colonization with MRSA on admission and follow-up surveillance after admission to an emergency department between June 2012 and August 2012, and the backgrounds of PCR and/or culture-method-positive patients were compared. Among 95 patients, 15 (15.8%) patients were positive for MRSA on PCR and/or culture; 6.3% (6/95) of patients were positive on admission, and 9.5% (9/95) became positive during the stay after admission. The major primary diagnoses in MRSA-positive patients were trauma and cerebrovascular diseases. Nine (60%) of 15 patients were MRSA-positive on both PCR and culture, compared with three (20%) of 15 who were PCR-positive but culture-negative. The other three (20%) of 15 patients were PCR-negative but culture-positive. Furthermore, there was a tendency for younger age and shorter stay to be associated with PCR-positive but culture-negative results. These findings suggest that active surveillance with PCR may be highly sensitive and useful for the early diagnosis of MRSA colonization to prevent nosocomial transmission from the emergency department to the regular inpatient wards of the hospital. Keywords: active surveillance, length of stay, nosocomial transmission, BD GeneOhm MRSA assay, sensitivity, specificity

Kaori Yabuno,1,2,* Masafumi Seki,1,* Koji Miyawaki,1,2 Yoshihiro Miwa,2 Kazunori Tomono11Division of Infection Control and Prevention, 2Department of Pharmacy, Osaka University Hospital, Osaka, Japan *These authors contributed equally to this workBackground: The recommended daptomycin dosage is 4 or 6 mg/kg/day for the treatment of complicated skin and soft tissue infections or for Staphylococcus aureus bacteremia, endocarditis, and osteomyelitis. Every other day administration is usually recommended for patients with mild to moderate renal impairment. Higher doses (>6 mg/kg/day) have been explored as a possible alternative. Daptomycin is considered a safe anti-methicillin-resistant S. aureus (MRSA) drug, although renal dysfunction may be worsened. In this paper we report on three patients with chronic renal failure who received a higher dose of daptomycin daily for successful treatment for MRSA bacteremia, MRSA osteomyelitis, and methicillin-resistant S. epidermidis (MRSE) endocarditis.Results: Previous administration of other drugs, including vancomycin, teicoplanin, and linezolid, had failed. In spite of daily treatment with daptomycin instead of the recommended alternate day regimen, adverse effects, such as elevation of creatinine and creatine phosphokinase, did not occur.Conclusion: These experiences suggest that administration of high-dose/short-interval daptomycin can be efficient and safe even in the setting of renal dysfunction, and should be considered for the treatment of severe MRSA/MRSE infections in these patients.Keywords: daptomycin, high-dose, renal failure, methicillin-resistant Staphylococcus aureus, creatine phosphokinase

Shigeto Hamaguchi,1,* Masafumi Seki,1,* Norihisa Yamamoto,1 Tomoya Hirose,2 Naoya Matsumoto,2 Taro Irisawa,2 Ryosuke Takegawa,2 Takeshi Shimazu,2 Kazunori Tomono11Division of Infection Control and Prevention, 2Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka, Japan *These authors contributed equally to this workAbstract: Haemophilus influenzae type b was once the most common cause of invasive H. influenzae infection, but the incidence of this disease has decreased markedly with introduction of conjugate vaccines to prevent the disease. In contrast, the incidence of invasive infection caused by nontypable H. influenzae has increased in the US and in European countries. Neutrophil extracellular traps (NETs) are fibrous structures released extracellularly from activated neutrophils during inflammation, including in pneumonia, and rapidly trap and kill pathogens as a first line of immunological defense. However, their function and pathological role have not been fully investigated. Here, we report a case of fatal nontypable H. influenzae infection with severe pneumonia and bacteremia in an adult found to have a vast amount of NETs in his sputum. The patient had a two-day history of common cold-like symptoms and was taken to the emergency room as a cardiopulmonary arrest. He recovered temporarily, but died soon afterwards, although appropriate antibiotic therapy and general management had been instituted. Massive lobular pneumonia and sepsis due to nontypable H. influenzae was found, in spite of H. influenzae type b vaccine being available. His sputum showed numerous bacteria phagocytosed by neutrophils, and immunohistological staining indicated a number of NETs containing DNA, histone H3, and neutrophil elastase. This case highlights an association between formation of NETs and severe respiratory and septic infection. An increase in severe nontypable H. influenzae disease can be expected as a result of “athogen shift”due to increased use of the H. influenzae type b vaccine in Japan.Keywords: neutrophil extracellular traps, sepsis, pneumonia, Haemophilus influenzae, type b, nontypable

Masafumi Seki,1,* Kaori Yabuno,1,2,* Koji Miyawaki,1,2 Yoshihiro Miwa,2 Kazunori Tomono11Division of Infection Control and Prevention, 2Department of Pharmacy, Osaka University Hospital, Suita, Osaka, Japan*These authors contributed equally to this workBackground: A trough concentration of >20 mg/L is considered the optimal dosage of teicoplanin required to ensure early therapeutic effects against methicillin-resistant Staphylococcus aureus (MRSA) infections including those in patients who develop febrile neutropenia after chemotherapy. This study determines appropriate initial doses during the first 2 days of administration and evaluates the therapeutic target teicoplanin trough concentration.Method: A 2-day regimen was evaluated in patients treated with 600 mg and 1200 mg or 1200 mg and 600 mg (total 1800 mg, Group 1), 800 mg and 800 mg (total 1600 mg, Group 2), and 800 mg and 400 mg (total 1200 mg, Group 3) of teicoplanin on Days 1 and 2, respectively. We also compared the efficiency and adverse effects at trough concentrations of 15–20 mg/L (Group A, n = 28) with >20 mg/L (Group B, n = 27) of teicoplanin, and also compared them with those on the similar concentrations of vancomycin (Groups C and D, n = 50 and 34, respectively).Results: The mean trough concentrations of teicoplanin on Days 4 or 5 were 22.2, 17.5, and 16.2 mg/L in Groups 1, 2, and 3, respectively. The clinical efficiency was 85.7%, 81.5%, 92.0%, and 91.5%, in Groups A, B, C, and D, respectively. The rates of adverse effects were not high in teicoplanin (nephrotoxicity, 7.1% and 3.7%, and hepatotoxicity, 14.3% and 11.1% in Groups A and B, respectively). However, more adverse effects tended to arise in patients who received vancomycin in nephrotoxicity (14.0% and 11.8%, in Groups C and D, respectively).Conclusion: These results suggest that the 2-day regimens with total 1800 mg achieved the most effective therapeutic trough plasma concentration of teicoplanin (20 mg/L). However, 15–20 mg/L might also be an effective trough target for initial teicoplanin treatment. These teicoplanin regimens might be safer in terms of renal function than vancomycin.Keywords: therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, Staphylococcus aureus, MRSA, dosing regimen, adverse effect