In order to investigate the roles of quality requirements for antibiotics products in Japan, from historical and hygienic aspects, we examined how technology and knowledge in the production and quality control of streptomycin were introduced from the United States of America. In this study, through detailed investigations and analyses, it was confirmed that the introduction of technology and knowledge on streptomycin was strongly supported by Brigadier General CRAWFORD SAms, the chief of the Public Health and Welfare Section (PHW) of the Supreme Commander for Allied Powers/General Headquarters, via the Ministry of Welfare in Japan. Dr. SELMAN WAKSMAN, the discoverer of streptomycin, along with scientists of Merck & Co., also helped Japanese industries extensively, via PHW, by providing the original streptomycin-producing strains and transferring expertise in streptomycin production. With the technology and knowledge being introduced from the USA, domestic production of streptomycin preparations increased very rapidly. As noted in our previous report, domestic production reached amounts enough to satisfy national demand within three years. Japanese people have a racial tendency to be highly susceptible to tuberculosis known as an incurable national disease. Thanks to streptomycin therapy, the tuberculosis mortality rate (per 100,000 population) had fallen dramatically within only five years from 187.2 in 1947 to 82.2 in 1952.
A study was conducted of the 1,225 Pseudomonas aeruginosa strains that were isolated at 20 medical institutions in the Kinki district between 2011 and 2013 to determine their antimicrobial susceptibility and to characterize the strains of multidrug-resistant Pseudomonas aeruginosa (MDRP) and the metallo-β-lactamase (MBL) -producing strains. The MIC50/MIC90 values (μg/mL) of the various antimicrobial agents were as follows: imipenem, 2/>8; meropenem, 1/>8; doripenem, 0.5/8; biapenem, 1/>8; tazobactam/piperacillin, 8/>64; piperacillin, 8/>64; sulbactam/cefoperazone, 8/64; cefepime, 4/16; cefozopran, 2/>16; aztreonam, 8/>16; amikacin, 4/16; levofloxacin, 1/>4; and ciprofloxacin, 0.25/>2. From the viewpoint of the annual changes in the susceptibility rates (according to the CLSI guidelines [M100-S22]), the susceptibility to tazobactam/piperacillin, piperacillin, cefepime, cefozopran and aztreonam decreased in 2013. On the other hand, two antimicrobial agents showed high susceptibility rates each year; amikacin (94.0-95.6%) showed the highest rate, followed by doripenem (80.3-82.6%). With the exception of amikacin, there were substantial inter-institutional differences in antimicrobial susceptibility. In comparison to the previous CLSI guidelines (M100-S21), the new CLSI guidelines (M100-S22) on the use of carbapenems and penicillins show that the MIC80 has been affected. The MDRP detection rates in 2011, 2012 and 2013 were 1.8% (8 strains), 1.8% (8 strains), and 2.8% (10 strains), respectively. The MBL detection rates were as follows: bla(VIM-2), 0.2% (1 strain) in 2011; bla(IMP-1), 0.9% (4 strains) in 2012, and 1.7% (6 strains, including bla(IMP-1) [3 strains], bla(IMP-2) [2 strains] and bla(VIM-2) [1 strain]) in 2013.
We herein discovered a highly resistant clinical isolate of Pseudomonas aeruginosa with MICs to amikacin, gentamicin, and arbekacin of 128 μg/mL or higher in a drug sensitivity survey of 92 strains isolated from the specimens of Yoka hospital patients between January 2009 and October 2010, and Achromobacter xylosoxidans was separated from this P. aeruginosa isolate. The sensitivity of this bacterium to 29 antibiotics was investigated. The MICs of this A. xylosoxidans strain to 9 aminoglycoside antibiotics were: amikacin, gentamicin, arbekacin, streptomycin, kanamycin, neomycin, and spectinomycin, 1,024 μg/mL or ≥ 1,024 μg/mL; netilmicin, 512 μg/mL; and tobramycin, 256 μg/mL. This strain was also resistant to dibekacin. This aminoglycoside antibiotic resistant phenotype is very rare, and we are the first report the emergence of A. xylosoxidans with this characteristic.
A total of 473 strains of Enterobacteriaceae, including Escherichia coli, Klebsiella spp., Proteus spp., Citrobacter spp., Enterobacter spp., Serratia spp. and Providencia spp., were isolated from patients admitted to intensive care units and surgical units in Russia. About 90% of the isolates carried factors resistant to beta-lactams. The isolation rates of the extended-spectrum beta-lactamase (ESBL) producer defined in this study among E. coli, Klebsiella spp. and Proteus spp. were 45%, 48% and 17%, respectively. In the settings with high prevalence of the ESBL producer, flomoxef, which belongs to the oxacephem subgroup, and carbapenems retain their activity. The MIC₅₀ of flomoxef, meropenem and imipenem against total isolates were 1 µg/mL, ≤ 0.063 µg/mL and 0.25 µg/mL, respectively. Fifty-five carbapenem-resistant strains were isolated in this study. The carbapenem resistant rates of E. coli, Klebsiella spp. and Proteus spp. were 3%, 16% and 29%, respectively
Antimicrobial susceptibility testing has been conducted continuously as postmarketing surveillance of levofloxacin (LVFX) since 1994. The present survey was undertaken to investigate in vitro susceptibilities of bacteria to 33 selected antibacterial agents, focusing on fluoroquinolones (FQs), using 11,762 clinical isolates for 19 species collected from 69 centers during 2013 in Japan. The common respiratory pathogens Streptococcus pyogenes, Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae continue to show a high susceptibility to FQs, while the percentage of macrolide-resistant S. pneumoniae was markedly increased to around 80%. With H. influenzae, the percentage of β-lactamase-negative ampicillin-resistant isolates had been increasing continuously from 2002, but no increase was observed from 2010 to 2013 (25.8% in 2002, 40.0% in 2004, 50.1% in 2007, 57.9% in 2010, and 57.1% in 2013). Most strains of Enterobacteriaceae showed a high susceptibility to FQs, but the isolation frequency of levofloxacin-resistant Escherichia coli including intermediate resistance was 34.4%, showing a continuous increase. Another Enterobacteriaceae member, Klebsiella pneumoniae, showed low resistance to FQs in contrast with E. coli. Regarding methicillin-resistant Staphylococcus aureus (MRSA), the percentage of FQ-susceptible isolates was low at 15.8-18.0%, with the exception of 55.3% susceptibility to sitafloxacin. On the other hand, methicillin-susceptible S. aureus (MSSA) isolates showed high susceptibility to FQs, at 87.0-99.3%. With Enterococcusfaecium, the percentage of FQ-susceptible isolates was 6.8-24.7%. The percentage of FQ-susceptible Pseudomonas aeruginosa was 83.4-89.3% among isolates derived from urinary tract infections (UTIs), while that from respiratory tract infections (RTIs) was 88.1-93.7%. This was summarized as susceptibility to FQs over 80% in both infections. A continuous decrease in FQ-resistant P. aeruginosa was noted, especially among isolates from UTIs. Regarding multidrug-resistant P aeruginosa, the percentage has been decreasing continuously since 2007 and was 1.6% from UTIs and 0% from RTI in this survey. Acinetobacter spp. showed high susceptibility to FQs. The percentage of imipenem-resistant Acinetobacter spp. was 2.7% (14 isolates) and that of multidrug-resistant was 0.2% (1 isolate). In Neisseria gonorrhoeae, ceftriaxone (CTRX) had been showing 100% susceptibility until 2007, but CTRX-resistant strains have been detected in both 2010 and this survey. In conclusion, the resistance of methicillin-resistant staphylococci, E. faecium, N. gonorrhoeae, and E. coli to the FQs, which have been used clinically for over 20 years, was shown to be 30% or more (31.7-87.1%) in the present surveillance regarding susceptibility. These results were similar to those from previous surveillance, and no species that started to show significant resistance to FQs were identified in the present surveillance. Regarding other bacterial species, susceptibility to ciprofloxacin less than 80% was observed in some, while susceptibility to other FQs was maintained at a high level, at 80% or more.
We conducted a postmarketing surveillance of tebipenem pivoxil granules (Orapenem® fine granules 10% for pediatric), an oral carbapenem antibacterial agent, between April 2010 and March 2013 to evaluate the safety and efficacy in patients with pneumonia or otitis media, or sinusitis Of 3,547 patients enrolled, 3,540 from whom survey forms were collected were analyzed. Of these 3,540 patients, there were a total of 3,331 patients included in the safety analysis, 2,844 in the efficacy analysis, 2,769 in the clinical efficacy analysis, and 461 in the bacteriological efficacy analysis. The incidence of adverse drug reactions (ADRs) was 9.97% (332/3,331 patients), and the major ADRs were gastrointestinal disorders including diarrhoea in 317 patients (9.52%). Diarrhoea was reported in 313 patients (316 events), which were not clinically significant and 94.9% (297/313 patients) were recovery and/or remission. The overall clinical efficacy rate was 94.0% (2,604/2,769 patients). The clinical efficacy rate by the type of infection was 95.6% (415/434 patients) for pneumonia, 93.7% (1,389/1,482 patients) for otitis media and 93.6% (659/704 patients) for sinusitis. The eradication rate of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella (Branhamella) catarrhalis which are major causative organisms in pediatric infection of pneumonia, otitis media and sinusitis were 94.4% (134/142 strains), 92.2% (130/141 strains) and 97.8% (45/46 strains), respectively. The compliance was good in 83.1% of the patients (2,767/3,331 patients). Overall, Orapenem® fine granules 10% for pediatric showed good safety, efficacy, and compliance. These results indicate that Orapenem® fine granules 10% for pediatric is a useful agent in pediatrics with pneumonia or otitis media, or sinusitis.
Respiratory quinolones (RQs) are broad-spectrum antimicrobial agents used for the treatment of a wide variety of community-acquired and nosocomial infections. However, bacterial resistance to quinolones has been on the increase. In this study, we investigated the predicted efficacy of RQs for various strains of 9 bacterial species clinically isolated at our university hospital using the Monte Carlo simulation (MCS) method based on pharmacokinetics/pharmacodynamics modeling. In addition, the influence of the patients' renal function on the efficacy of RQs was evaluated. We surveyed antimicrobial susceptibility testing of 9 bacterial species (n = number of strains) [Streptococcus pneumoniae (n = 15), Streptococcus pyogenes (n = 14), Streptococcus agalactiae (n = 19), methicillin-susceptible Staphylococcus aureus (MSSA) (n = 24), Escherichia coli (n = 35), Haemophilus influenzae (n = 17), Klebsiella pneumoniae (n = 14), Pseudomonas aeruginosa (n = 31), and Moraxella catarrhalis (n = 11)] to 4 RQs [garenoxacin (GRNX), levofloxacin (LVFX), sitafloxacin (STFX), and moxifloxacin (MFLX)]. We found that compared with the other RQs, Gram-positive cocci was most resistant to LVFX, and that the minimum inhibitory concentration (MIC₉₀) values for S. pneumoniae, S. pyogenes, S. agalactiae, and MSSA were high (2, 16, > 16, and 8 µg/mL, respectively). In regard to Gram-negative rods, the susceptibility of E. coli to RQs was found to be decreased, with the MIC₉₀ values of GRNX, LVFX, STFX, and MFLX being > 16, 16, 1, and 16 µg/mL, respectively. MCS revealed that the target attainment rate of the area under the unbound concentration-time curve divided by the MIC₉₀ (ƒ · AUC/MIC ratio), against S. pneumoniae was 86.9-100%, but against E. coli was low (52.1-66.2%). The ƒ · AUC/MIC target attainment rate of LVFX against S. pneumoniae, S. pyogenes, and S. agalactiae tended to decrease due to increased creatinine clearance, and that of LVFX and STFX against MSSA also tended to decrease. The findings of this study suggest that the drug susceptibility distribution of each RQ varies, even within the same bacterial species, and that the expected efficacy also varies between the drugs. Moreover, the influence of the patient's renal function on the efficacy differed among the 3 renal excretory drugs (GRNX, LVFX, and STFX), thus suggesting that the efficacy also differs. In conclusion, the findings of this study show that for the administration of RQs, it is desirable to select agents in consideration of surveyed sensitivity within the population and the pharmacokinetic characteristics.
The susceptibility of 1578 Streptococcus pneumoniae strains isolated from pediatric patients at Asahikawa Kosei Hospital between 2011 and 2015 was tested to penicillin G (PCG), cefotaxime (CTX), ceftriaxone (CTRX), cefditoren (CDTR), meropenem (MEPM), erythromycin (EM) and levofloxacin (LVFX). Although no significant differences were observed, the percentage of strains with a minimal inhibitory concentration (MIC) of PCG of <0.1pg/mL increased from 55.5% (2011) to 64.0% (2015), whereas that of strains with MIC of ≥2μg/mL decreased from 14.8% to 9.5%. From 2011 to 2015, the percentage of strains with MIC ≤0.12ug/mL increased from 18.9% to 28.9% for CTX, from 20.5% to 30.2% for CTRX, from 29.2% to 40.9% for CDTR, and from 69.6% to 80.6% for MEPM. EM-resistant strains with MIC ≥22μg/mL accounted for as much as approximately 90% each year. One LVFX-resistant strain with MIC 8pg/mL has been detected each year since 2013.
A 4mg/kg dose of tebipenem pivoxil (TBPM-PI) was administered twice daily for 3 days to 34 pediatric patients with pneumonia who had chest X-ray findings indicative of pneumonia and CRP values of at least 3.0 mg/dL. The clinical effects of this regimen were evaluated by retrospectively examining medical charts for the period from April 2012 to March 2015. The patients were 6 months to 8 years old, with serum CRP values ranging from 3.06 to 14.25 mg/dL. Fever resolved within 24 hours and respiratory symptoms improved within 3 to 5 days after the start of treatment in all 34 patients. Although CRP was positive in 28 of 30 patients at the end of the treatment period, none of these children showed worsening of pneumonia. Eight patients (23.5%) experienced adverse drug reactions including diarrhea. These results indicate that a 3-day course of TBPM-PI is useful for treating pediatric pneumonia.
Supplies of high quality antibiotic products to clinics contributed greatly to the health maintenance of the citizens of Japan. In this report, we describe the results of our investigation and analyses on the establishment and amendments of 'he quality standards for individual antibiotic products, which were regarded as the guidelines for quality control in the production processes. "The minimum requirements of penicillin" enacted in May of 1947 was at a relatively moderate standard level, due to considerations for domestic technical levels. However, after several amendments, in response to the rapid development of manufacturing technologies and new penicillin preparations, standards became increasingly stricter. "The minimum requirements of streptomycin" enacted in December of 1949 was prepared by the use of streptomycin preparations imported from the USA. The 3rd and 4th standards, "the minimum requirements of dihydrostreptomycin" and "the minimum requirements of chloramphenicol", were prepared by applying provisions described in the rules for certification of the U.S. Food and Drug Administration. In accordance with an increase in the varieties of antibiotic products, "the minimum requirements of antibacterial products" was enacted by the integration of previously existing standards and newly enacted ones. Thereafter, in response to the innovation of scientific technologies and the globalization of antibiotic products, "the minimum requirements for antibiotic products in Japan" was further developed and became the basis for supplying high quality antibiotic preparations.
In vitro activities of sitafloxacin (STFX) along with fluoroquinolones (levofloxacin (LVFX), moxifloxacin (MFLX), garenoxacin (GRNX)) and macrolides (azithromycin, clarithromycin) against atypical bacteria (Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia trachomatis, Chlamydophila pneumoniae) recovered from clinical specimens from 2009 to 2014 at different healthcare facilities in Japan were investigated. The minimum inhibitory concentration of STFX at which 90% of isolates (MIC₉₀) against M pneumoniae (n= 14) was 0.03μg/mL which was comparable to GRNX, 4- and 16-fold more active than MFLX and LVFX, respectively. Reduced susceptibilities of M pneumoniae (9/14 isolates) to macrolides were observed. MIC₉₀ of STFX against L. pneumophila (n =15) was 0.004μg/mL which was 2- and 4-fold more active than GRNX/LVFX and MFLX, respectively. The minimum inhibitory concentration range of STFX against C. trachomatis (n=5) and C. pneumoniae (n=5) were from 0.015 to 0.03 and from 0.03 to 0.06μg/mL, respectively. Furthermore, differences between the activities of STFX against various clinical isolates in 2009 and those in 2012, which were already published in two articles (Jpn. J. Antibiotics 63:411- 430, 2010, 66:311-330, 2013), were also evaluated. The MIC90s of STFX against methicillin- susceptible Staphylococcus aureus (MSSA), Streptococcus spp. and Enterococcus faecalis isolated in 2012 were 4 or 8 times higher than those in 2009, however there was no difference between STFX activities against other species in 2009 and those in 2012. In conclusion, STFX showed potent activity against atypical bacteria (M pneumoniae, L. pneumophila, C. trachomatis, C. pneumoniae) and no tendency for emergence resistance to Gram- positive cocci, Gram-negative bacteria and anaerobes except MSSA, Streptococcus spp. andt. faecalis.
Nucleic acid amplification tests (NAATs) are considered as one of critical diagnostic methods on Chlamydia trachomatis and Neisseria gonorrhoeae infections due to their high sensitivity and accuracy. However, conventional NAATs required 2-6 hours to complete the measurements including extraction, amplification, and detection of the target nucleic acids. To reduce the time, we evaluated the clinical significance of the rapid NAAT using GENECUBE (TOYOBO CO., LTD.) which can complete the measurement within 1 hour. We compared the performance of GENECUBE with those of TMA method (APTIMA" Combo2 chlamydia/ gonorrhoeae, Hologic Japan, Inc.) and lateral flow immunochromatographic assay (Clearview Chlamydia, Clearview gonorrhoeae, Alere Medical Co., Ltd.) by detecting specimens from 96 cervical swabs. The overall agreement results between GENECUBE and TMA were 95.8% and 100% for C. trachomatis and N. gonorrhoeae, respectively. The results suggested that GENECUBE showed equivalent sensitivity and specificity of TMA. Indeed, more than half of the positive samples in NAATs were measured as negative in the lateral flow. The lateral flow is known as a rapid assay, however the results revealed its poor sensitivity. We think rapid NAATs using GENECUBE on C. trachomatis and N. gonorrhoeae can be one of the methods, which realize rapid tests with high sensitivity and accuracy.
This clinical case report concerns a pediatric patient with acute enteritis caused by multi-drug resistant Salmonella enterica serovar Blockley (Salmonella Blockley). A 3-year-old boy presented to our emergency room with a 5-day history of fever, abdominal pain, and bloody diarrhea. Stool culture tested positive for a Salmonella species, while the blood culture was negative. The patient was successfully treated with an oral antibiotic regimen of fosfomycin. The stool isolate was found to be resistant to multiple drugs, including cefpodoxime, cefotaxime, ceftazidime, and aztreonam, and was confirmed to be a CTX-M-15 extended-spectrum β-lactamase (ESBL)-producing strain of Salmonella Blockley. This is the first report of a pediatric patient in Japan with acute enteritis caused by a CTX-M-15 ESBL- producing strain of Salmonella Blockley.
Influenza A and B viruses possess an enzyme "sialidase" that cleavages terminal sialic acid from glycochains. These viral sialidase proteins are highly expressed on the virus infected cells. We developed sialidase imaging probe "BTP3-Neu5Ac" that enables histochemical fluorescence staining of sialidase activity. BTP3-Neu5Ac was able to perform speedy and easy fluorescence imaging of these virus infected cells, with no needs of specific antibody and cell fixation. In addition, combination use of anti-influenza drugs (sialidase inhibitors) and BTP3-Neu5Ac resulted in selective fluorescence imaging for detection and high-efficiency isolation of drug-resistant virus. Fluorescence imaging of drug-resistant virus will be a powerful method for study of the drug-resistance mechanism, for monitoring of drug-resistant viruses. A novel tool for fluorescence imaging of viral sialidase activity is described in this review.
Nontypeable Haemophilus influenzae, one of the major causative bacteria for acute otitis media (AOM), is also considered to cause intractable otitis media including prolonged AOM and recurrent AOM in children by the mechanism of internalization of the bacteria into epithelial cells of middle ear mucosa. In this study, we visualized the dynamics of H. infiuenzae internalization in cultured human cells. We also examined the effects of antimicrobials, including a novel quinolone, tosufloxacin, and a cephem antibacterial agent, cefditoren, on H. influenzae internalized in cultured human cells. The results indicated that (1) H. infiuenzae were internalized into human cells, (2) cefditoren has no effect on internalized H. influenzae, and (3) tosufloxacin has a bactericidal action on H. infiuenzae invading human cells. These data strongly support high clinical efficacy of tosuffoxacin on intractable otitis media in children.
We established silkworm infection model for developing a novel antibiotic. Silkworm model has less ethical issues and is low cost compared to mammalian model, thus allow us to use a lot of individuals for screening assay. In addition, we can evaluate therapeutic activity and toxicity of candidate samples because silkworm has similar pharmacokinetics as mammals. Using this system, we identified a novel antibiotic named "Lysocin E". In this review article, we describe advantages of silkworm model for development of antimicrobial agents.
Human metapneumovirus (hMPV) is known as one of popular agents of acute respiratory infection in children. We reviewed the patients' background, result of initial blood test, bacterial culture, chest X-ray and clinical features of hospitalized children with lower respiratory tract infections caused by hMPV from March 2014 to February 2015 and compared them with the infections due to respiratory syncytial virus (RSV) and other causative agents. Of 419 patients tested by rapid virus antigen tests, 35 were positive for hMPV, 145 were positive for RSV, and 239 were negative for both viruses. Most of hMPV infections occurred between March and June, and 72% of households of hMPV-positive children got sick. hMPV-positive children did not have any specific symptoms such as wheezing in RSV- positive children. However, many of them were admitted due to prolonged high fever and/or ill appearance despite of no respiratory distress. Although it is said that hMPV-positive children admitted to hospitals tend to have pneumonia, the ratio of children'with pneumonia in this study was less than 60%.
We investigated the susceptibility to antibacterial agents of 186 clinical isolates of Pseudomonas aeruginosa isolated from medical facilities in Gifu, Aichi, Toyama, and Fukui prefectures from October 2013 to February 2014. MIC₅₀/₉₀ of piperacillin (PIPC), tazobactam/piperacillin (TAZ/PIPC), ceftazidime (CAZ), cefepime (CFPM), imipenem (IPM), meropenem (MEPM), doripenem (DRPM), aztreonam (AZT), ciprofloxacin (CPFX), levofloxacin (LVFX), amikacin (AMK) and colistin (CL) against P aeruginosa was 8/32, 4/32, 2/8, 2/16, 1/32, 0.5/8, 0.25/4, 8/32, 0.25/8, 0.5/16, 4/8 and 1/1pg/mLrespectively. Two strains of multidrug resistant P aeruginosa were isolated (1.1%). They were isolated from the respiratory tract, intra-abdominal, and urinary infection. The susceptible ratio against P aeruginosa derived from intra-abdominal infection for carbapenem was lower than those from respiratory tract and urinary infection. The susceptible ratio against P aeruginosa derived from urinary infection for penicillin, cephem, monobactam, and fluoroquinolone was lower than those from respiratory and intra-abdominal infection. It is meaningful to pay attention to the susceptibility to antibacterial agents in each clinical specimen from infected organ.
Visual disturbance or central symptom like hallucination is well known to be one of the common drug adverse events in response to voriconazole (VRCZ). We observed 123 patients treated VRCZ from April 2012 to January 2016. Two of these cases experienced visual disturbance and 4 of these cases experienced central symptom. Six patients appeared visual disturbance or central symptom within 1 week after administration of VRCZ (visual disturbance; 3 days [2-42 days], central symptom; 6 days [3-9 days]) and disappeared visual disturbance or central symptom at an early date after discontinuation of administration or decreasing dose of VRCZ. The trough concentration of VRCZ in patients who experienced central symptom was similar with that in-patients who did not experience adverse events by VRCZ (case 3; 3.79μg/ mL, case 4; 1.28μg/mL vs 3.73μg/mL [0.09-13.27 μg/mL]). On the other hand, the trough concentration of VRCZ in patients who experienced visual disturbance was higher than that in patients who did not experience adverse events by VRCZ (case 5; 7.49μg/mL, case 6; 4.45μg/ mL vs 3.73μg/mL [0.09-13.27μg/mL]). In conclusion, we thought that the risk factor of visual disturbance was the increasing concentration of VRCZ. Therefore, we should monitor the onset of visual disturbance or central symptom in patients treated with VRCZ, especially central symptom that the concentration is unconcerned.
