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Over the last decade, many public institutions have emphasized the importance of antimicrobial stewardship (AS) in reducing the spread of antimicrobial resistance. In our facility, we have tackled AS that has adapted to clinical practices since 2015. In many facilities, especially university hospitals, multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus and extended-spectrum β-lactamase-producing bacteria, may cause infections. Considering this, we recommend prompt treatment with suitable antibiotics and dosage. In AS teams, pharmacists are responsible for administering pharmacotherapy, including optimal dosage for each patient. Therefore, they should assess their patients carefully, implement thorough therapeutic drug monitoring, and utilize the information obtained from these assessments to administer optimal pharmacotherapy. However, optimal pharmacotherapy also requires a correct diagnosis. Although diagnostic stewardship is not a pharmacist's work, it is a great opportunity for pharmacists to learn how expert physicians think. Based on the type of situation above, we train younger pharmacists on the job.

In medical care, qualified physicians, nurses, and pharmacists have come to be recognized as a team integral to a patient's success, and this team approach to medical care has become popular. In the infectious disease field, more hospitals are practicing antimicrobial stewardship as a team, in addition to the conventional infection control team (ICT). As a result, infectious disease chemotherapy pharmacists are in demand. However, this specific qualification is hard to acquire for pharmacists working in a primary care pharmacy. The problem of multidrug-resistant bacteria is of vital interest today. The National Action Plan on Antimicrobial Resistance 2016-2020, published in Japan, includes an aim to largely reduce the consumption of each oral antimicrobial agent, in order to control the emergence of resistant bacteria. Hospitals and primary care pharmacies will achieve this aim differently. For infection control by primary care pharmacies, the emergence control of a resistant bacteria is important, as is the control of outbreak in a region.

The increasing prevalence of antimicrobial resistance (AMR) has caused intractable infections worldwide. Nearly 50% of the healthy population of Southeast Asia carries extended-spectrum β-lactamase (ESBL)-producing Escherichia coli. The overuse of antimicrobial agents in the agriculture, aquaculture, and medical care sectors causes environmental pollution, facilitating the spread of AMR. However, there is a lack of data pertaining to antimicrobial residues in environmental water in such regions. We investigated a total of 49 chemicals, including β-lactams, sulfonamides, quinolones, and tetracyclines. Water samples were collected from rivers in city centers, and ponds in livestock and aquaculture farms, in Ha Noi, Thai Binh, and Can Tho in Vietnam. We detected antimicrobial agents at 87 of 111 sampling sites (78.4%). Among the target analytes, sulfamethoxazole, sulfamethazine, trimethoprim, cephalexin, and ofloxacin were detected frequently. The residual levels of each antimicrobial agent ranged from 0.1 to 10000 ng/L. Moreover, we detected multi-drug resistant E. coli in fishes sampled from these rivers, suggesting unwanted effects of antimicrobial residues in the environment.

Recently, human serum albumin (HSA) has emerged as a versatile carrier for therapeutic agents against diabetes, cancer, and infectious diseases. Market-approved products include fatty acid derivatives of human insulin for diabetes and the paclitaxel-HSA nanoparticle for various cancers such as metastatic breast cancer and advanced pancreatic cancer. In this review, we focus on the next-generation approach including HSA-binding bioactive gas such as nitric oxide (NO) for treating ischemic/reperfusion injury, cancer, and bacterial infection. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated HSA (SNO-HSA), which is why we are investigating whether this albumin form can be therapeutically useful. Recently, we have developed SNO-HSA analogues such as SNO-HSA with many conjugated SNO groups (poly-SNO-HSA) prepared using chemical modification. Unexpectedly, we found striking inverse effects between poly-SNO-HSA and SNO-HSA. Despite the fact that SNO-HSA inhibits apoptosis, poly-SNO-HSA possesses very strong pro-apoptotic effects against tumor cells. Furthermore, poly-SNO-HSA can reduce or even completely eliminate the multidrug resistance often developed by cancer cells. In this review, we put forward the possibility that poly-SNO-HSA can be used as a safe, effective multifunctional antitumor agent.

To investigate the current status of drug-resistant bacteria (except MRSA) in Kumamoto prefecture, a study was conducted to determine the isolation numbers and ratios of extended-spectrum beta-lactamase (ESBL)-Escherichia coli, ESBL-Klebsiella species, ESBL-Proteus mirabilis, two-drug resistant Pseudomonas aeruginosa, (resistant to two drugs either carbapenems, quinolones and aminoglycosides) multi-drug-resistant Pseudomonas aeruginosa, multi-drug-resistant Acinetobacter baumannii, and vancomyacin-resistant Enterococcii in eight general hospitals from May in 2009 to April in 2010. ESBL-E. coli was mostly isolated, and two-drug resistant P. aeruginosa came second. The isolation ratio of overall drug-resistant bacteria did not increase, while the isolation ratio of two-drugs resistant P. aeruginosa declined, suggesting that infection control was successfully conducted in these hospitals. However, the isolation numbers of ESBL-Klebsiella spp. and two-drug resistant P. aeruginosa were variable in each hospital. Furthermore, drug-resistant bacteria were occasionally spread into another medical facilities by patients transferred from these hospitals, indicating that sharing information on drug-resistant bacteria between medical facilities is required.

Background: The pulmonary disease caused by Mycobacterium avium shows diverse clinical manifestations. Little is known about the potential association between the genetic characteristics of M. avium strains and disease progression., Subjects and Methods: We enrolled 89 patients with disease caused by M. avium, from 12 hospitals in Japan and collected the corresponding M. avium isolates and clinical data. We divided the 89 patients into 2 groups: one group comprising 43 patients with progressive disease despite chemotherapy ("progressive"), and the other group comprising 46 patients with untreated disease ("untreated"). We compared clinical and bacteriological characteristics between these groups. The bacteriological characteristics that we examined were drug susceptibility, variable-number tandem-repeat (VNTR) typing, and presence of the insertion sequence ISMav6. Seventeen patients in the "untreated" group were started on chemotherapy because their condition had clinically deteriorated during follow-up., Results: The result of VNTR typing showed that there was no specific clustering according to geographical region or clinical group in the "untreated" or "progressive" groups. Six out of eight cases those of polyclonal infection, and 11 of 12 isolates that were highly resistant to clarithromycin were isolated from patients with progressive disease. The frequency of isolates with ISMav6 inserted into upstream region of the cfp29 gene, which is involved in the induction of interferon-gamma production, was significantly higher in patients with deteriorating disease than in stable patients in the "untreated" group (p = 0.002)., Conclusion: Polyclonal infection and clarithromycin resistance may be involved in disease progression. ISMav6 inserted into the cfp29 gene is also suggested to be a factor related to the deterioration of pulmonary Mycobacterium avium complex disease.

Recently, there have been reports concerning an increased frequency of isolation of multi-drug resistant Pseudomonas aeruginosa (MDRP) strains in hospitals and other clinical settings as well as the associated risk of their hospital-acquired infections; in such a situation, it has been a major challenge to establish methods of managing and treating the infections. In order to investigate the trend of P. aeruginosa, the Infection Forum in the Chugoku Region has conducted to a multi-center collaborative study to isolate P. aeruginosa strains from sputum and urine samples collected between October 2006 and September 2008, analyzed the drug susceptibility and the pulsed-field gel electrophoresis (PFGE) patterns of each strain, and assessed epidemiologic characteristics. Of the 738 P. aeruginosa strains collected in this study, 152 (20.6%), 179 (24.3%), 47 (6.4%), and 39 (5.3%) were found to be ciprofloxacin-resistant, imipenem-resistant, amikacin-resistant, and MDRP, respectively. Among the various antimicrobial agents tested, arbekacin (ABK) revealed the strongest inhibitory effects on each drug-resistant and MDRP strain; therefore, ABK was considered as a potential candidate for future treatment of diseases caused by P. aeruginosa. The study also showed that the detection rates of MDRP varied a lot from hospital to hospital. In addition, PFGE-based cluster analyses revealed several strains isolated in the same hospital exhibited a similar PFGE pattern and the same drug susceptibility, suggesting the presence of "unique" hospital-specific strains.

We report a case of multi-drug-resistant breast cancer with liver metastases which completely responded and improved the quality of life (QOL)by S-1 monotherapy. The patient was a 53-year-old woman, who was diagnosed as breast cancer with invasive chest wall, cervical lymph node metastases, multiple bone metastases and bilateral pleural effusion[invasive ductal carcinoma, scirrhous type, ER(-), PgR(+), HER2(1+)]. After six courses of cyclophosphamide+epirubicin(CE)and weekly paclitaxel for 3 months, cervical lymph node metastasis was judged as a partial response(PR)and the bilateral pleural effusion disappeared. After chemotherapy, aromatase inhibitor (AI) was used. However, primary lesion and multiple bone metastases no change(NC). Following pass through AI+ oral anticancer drug combination chemotherapy and oral anticancer drug monotherapy, the therapy was changed to palliative, and she was referred to our hospital in January 2007. On arrival at the hospital, respiratory distress and bilateral pleural effusion had appeared, so it was an emergency admission. After removing the pleural effusion, pleurodesis was done and the symptoms disappeared. Although AI plus bisphosphonate therapy were started at hospital discharge, disease progression and fatigue appeared. In December 2007, we started S-1 monotherapy. S-1 was given orally at 80 mg/m2 for day 1-28 followed by a 2-week rest period, within a 6-week courses. Six months after treatment was started, multiple liver metastases disappeared and peritoneal effusion decreased. During the period of S-1 treatment, there were no serious adverse events, and treatment was possible without compromising QOL. This result suggested that S-1 treatment was a reasonable option for multi-drug-resistant breast cancer.

Various elements, such as a quick response, effectiveness, economy, mobility (inside and outside the hospital) are needed for today's in-hospital infection control. An infection control group was established, consisting of a doctor, dentist, pharmacist, nurse, medical technologist, and an administer for the purpose of and swiftness was mobile, and being active about the establishment of investigation/a study of the prevention of in-hospital infection and measures in March, 2001. As duties to play a key role of the infection control that a pharmacist made use of professional ability in, the making of enlightenment, Therapeutic Drug Monitoring, for use situation grasp and the proper use of antimicrobial/the disinfectant and the medication guideline by the participation in planning, PK/PD characteristic to the administration plan is given. There are a lot of cases to become the fatal injury not only in-hospital infection by resistant bacteria becomes the obstruction of the treatment including MRSA, multidrug resistance Pseudomonas aeruginosa in the House. It is to support treatment by reasonable medication to be born to we pharmacist and keeps it in mind therefore to load the study of the specialty domain as a member of the team medical care.

Salvage chemotherapy is necessary to maintain QOL among progressive or recurrent breast cancer patients with multiple drug resistance. We reported seven Japanese patients who received CPT-11 as salvage chemotherapy. Performance statuses of all patients were 1 or 2, and all patients were managed by ambulatory treatment. CPT-11 was administered at a dose of 80-100mg/m2 weekly on day 1 for 3 consecutive weeks, followed by a 2-week rest period. One patient had a partial response and CPT-11 was administered for 68 weeks. Two patients had grade 3 neutropenia. Grade 3 diarrhea was not observed. CPT-11 is a very useful choice as salvage chemotherapy for breast cancer patients with recurrence or local progression.

We report two cases of multidrug-resistant endometrial cancer which recurred after the initial therapy and progressed despite further anticancer chemotherapy, but could be successfully treated with medroxyprogesterone acetate (MPA). The first patient with stage IVb moderately-differentiated endometrioid adenocarcinoma of the uterine corpus underwent initial operation and postoperative chemotherapy followed by maintenance chemotherapy. Four months later, lung metastases were found. Since the hormone receptor status was positive, the patient was treated with MPA, and CR was achieved. The second patient with stage IIIc poorly-differentiated endometrioid adenocarcinoma of the uterine corpus developed lung metastases 14 months after the initial operation and postoperative chemotherapy. Subsequent chemotherapy yielded a complete response(CR). Two months later, however, a small intestinal metastasis was observed, which was treated by surgical excision and chemotherapy. The patient again remained disease-free for four months until lung metastases were observed. Since the hormone receptor status was positive, the patient was treated with MPA, and CR was achieved. No serious adverse events were observed in either patient.

Malignant transformation of an ovarian mature cystic teratoma is very rare; it arises in about 1-2% of all dermoid cysts. No standard treatment has been established for advanced and recurrent disease. In Case 1, a 78-year-old woman was diagnosed with squamous cell carcinoma arising from a mature cystic teratoma of the ovary after undergoing right salpingo-oophorectomy (RSO). She was treated with chemotherapy(TC), but the carcinoma recurred 2 months after completing first-line chemotherapy. She began second-line chemotherapy (PEC: CBDCA+PEP+etoposide), but became disoriented on the second day of treatment, and could not complete the schedule. She died 2 months after the recurrence. Case 2 was a 60-year-old woman diagnosed with stage Ic disease when she underwent a computed tomography scan during chemotherapy for breast cancer recurrence in her liver. She underwent bilateral salpingo-oophorectomy (BSO), and was treated with chemotherapy (TC+trastuzumab). She received 5 courses, but the breast cancer metastases enlarged and her chemotherapy regimen was changed. Five months later, after completing 5 courses of TC+trastuzumab, she had disseminated recurrence in the pelvis and also had a mass. She developed ileus and underwent a colostomy. She then underwent transcatheter arterial embolization via the inferior mesenteric artery and received cisplatin (100 mg/body) as second-line chemotherapy. The tumor was reduced in size about 30%, for a partial remission. However, her breast cancer recurrence was exacerbated and she died. The results of TAE, however, showed that it may be an effective second-line therapy for recurrent squamous cell carcinoma arising from a mature cystic teratoma.

Pseudomonas aeruginosa has been reported to be a leading cause of nosocomial infections. We evaluated the characteristics using 903 P. aeruginosa strains that were isolated in Fukuoka University Hospital from 2006 to 2008. Clinical specimens of P. aeruginosa were detected 47.8% from respiratory tract, 24.4% from urine, and were detected from the pus by 18.9%. Age distribution of the patients was 70 years old or older. Antimicrobial susceptibility ratio of isolates of P. aeruginosa from the outpatients against all agents tested except amikacin had more susceptible than it of isolates from the inpatients. In P. aeruginosa isolates detected from the inpatients, susceptibilities to other antibiotics were about 60% though 93.3% and 83.2% were susceptible to amikacin and piperacillin/tazobactam respectively. Isolation rate of multidrug-resistant P. aeruginosa (MDRP) in all clinical isolates was 3.3%. The report of carbapenem use was obligated in our hospital from the experience of the outbreak by MDRP in 2007, and the infection control team came to regulate the administering of antimicrobial agents more than before. Afterwards, the amounts of the antimicrobial agent use except piperacillin/tazobactam have decreased to 69% compared with the previous year. The susceptibility rates of various antimicrobial agents except amikacin have recovered by 10-17%. These results suggest that there is a necessity for attending to the drug susceptibility and the amount of the antimicrobial agent use.

Objective: Infection control is essential for health care facilities. Aiming at improving the activity for infection control, increasing number of health care facilities has settled infection control team (ICT) in this decade. However, the quality of infection control activity has not been evaluated., Method: The quality of infection control was investigated in 49 hospitals and 55 welfare institutions for the aged in Akita prefecture using a questionnaire., Result: All the hospitals with more than 400 beds or more had ICT; however, less than 50% of the hospitals with 399 beds or less had ICT. The coverage of full-time specialist for infection control remained at a low level. Collection and analysis of information such as the prevalence of multi-drug resistant microorganisms and the consumption of antibiotics remained at a low level. More than 88% of the facilities hoped for a regional infection control network system to improve infection control activities. Reciprocal help in case of outbreak, education, lectures, sharing rules on infection control, making guidelines and teaching materials for infection control, analysis of infection control-related epidemiological data and getting suggestions and recommendations from authorized infection control specialists were included in the strongly required functions of the network.

Multidrug-resistant Pseudomonas aeruginosa (MDRP), defined as Pseudomonas aeruginosa resistant to aminoglycosides, carbapenems, and fluoroquinolones, has emerged as an increasingly problematic cause of hospital-acquired infection. With parenteral colistin unavailable in Japan, effective antimicrobial options are severely limited. We report a case of MDRP bacteremia successfully treated with antibiotic combination therapy screened by a 'Break-point Checkerboard Plate'. A 54-year-old man with malignant lymphoma who became febrile 9 days after a recent course of chemotherapy had a neutrophil count of 176/microL. Treatment with meropenem and vancomycin was ineffective and high fever persisted. Methicillin-resistant Staphylococcus aureus (MRSA) and MDRP were isolated from blood culture and combination therapy with aztreonam and amikacin was selected for MDRP based on 'Break-point Checkerboard Plate' results. Linezolid was used for MRSA. The patient recovered successfully from MDRP and MRSA sepsis.

A case was 38 years old male. He was pointed out abnormal shadow on chest X-ray and complained respiratory infection symptoms. He had not past history of tuberculosis. He was diagnosed as multi-drug resistant tuberculosis (MDR-TB) in a certain hospital and was referred to our hospital to undergo treatment. His drug sensitivity test by Ogawa medium was resistant to all anti-tuberculosis drugs except for kanamycin (KM) and enviomycin (EVM). His chest X-ray revealed large cavities in the right upper field and infiltrations in the right lower field and small cavitary lesions in the left lower field. The right pneumonectomy was done because he took anti-tuberculosis drugs but his sputum examinations continued to be smear and culture positive without improvement of the lesions. After the surgical treatment (right pneumonectomy), he continued anti-tuberculosis drugs therapy and the chest X-ray improved including the collapse of left lower cavitary lesions. This case was a difficult case to treat because of bilateral cavitary lesions. However he was successfully treated by the surgical treatment.

A 72-year-old man was admitted to our hospital, complaining of exertional breathlessness. Chest radiograph revealed a right pleural effusion. Cytology for pleural effusion revealed adenocarcinoma; thus, he was diagnosed with advanced lung cancer (clinical stage T 4 N 0 M 0, Stage IIIB). Since tumor recurrence occurred despite CBDCA+gemcitabine, docetaxel, gefitinib and vinorelbine administrations, he received fifth-line oral chemotherapy using TS-1 at 120 mg/day (80 mg/m(2)/day) for 28 days, followed by withdrawal for 14 days. Chest computed tomography showed a partial response. Hematologic and non-hematologic toxicities were mild with the TS-1 administration. TS-1 could be an effective agent for treatment of multidrug-resistant non-small cell lung cancer.

Use of invertebrate models of infection has given exciting insights into host-pathogen interaction for a number of bacteria. In particular, this has revealed important factors of the host response with remarkable parallels in higher organisms. Recently, emerging of multi-drug resistant bacteria raises a requirement of developing new therapies such as controlling host defense system. Finding host factors that can purge bacteria from human body could give us a new concept of pharmaceutical targets. For this purpose, fruit flies, Drosophila melanogaster, has been used as a model animal for human infectious diseases and became a tractable tool for identifying novel gene products that can activate host defense mechanisms. In this review we will discuss about recent progress of Drosophila model of pathogen infection, which could imply a useful genetically tractable model for human infectious diseases.

Although corticosteroids and immunosuppressants are widely used for the treatments of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), we often experience patients who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, plays a pivotal role in the acquisition of drug resistance. However, the relevance of MDR-1 and P-gp to resting and activated lymphocyte, major targets of the treatments in autoimmune diseases, remains unclear. We found that peripheral lymphocytes in patients with SLE and RA express P-gp on the surface and its expression is highly correlated with disease activity. P-gp on lymphocytes is induced by activation with cytokines such as IL-2, IL-4 and TNF-alpha, resulting in active efflux of corticosteroids from cytoplasm of lymphocytes, which mechanisms could lead to drug-resistance and high disease activity. However, the addition of P-gp antagonists such as ciclosporin A and inhibitors of P-gp synthesis successfully reduce efflux of corticosteroids from lymphocytes in vitro and these results imply that P-gp antagonists and P-gp synthesis inhibitors could work in order to overcome drug-resistance in vivo. Therefore, we propose that measurement of P-gp on lymphocytes is useful marker to indicate drug resistance and requirement of antagonists and/or intensive treatments to overcome drug resistance in active SLE and RA patients.

A 92-year-old man with a history of bronchial asthma and allergic rhinitis received antibiotics for sepsis by methicillin-resistant Staphylococcus aureus and multidrug-resistant Enterococcus gallinarum. During the antibiotics treatment, skin eruptions, liver dysfunction, and hypereosinophilia developed, followed by dyspnea, congestive heart failure, electrocardiographic abnormalities, and diffuse mild myocardial hypokinesis. After the discontinuation of the antibiotics and the administration of steroid, skin eruptions, liver dysfunction, and hypereosinophilia improved parallel with the improvement of the congestive heart failure. Vancomycin hydrochloride and teicoplanin were suspected as the causative drugs on the basis of the treatment course. Although congestive heart failure is rare in the case of drug-induced hypereosinophilia, it is one of life-threatening complications. We describe herein a case of congestive heart failure associated with hypereosinophilia developed during antibiotics treatment, successfully treated with steroid after the discontinuation of the causative drug.

Since the introduction of rifampicin, it has been believed that pulmonary tuberculosis can be cured with medication alone. However, if tubercle bacilli are resistant to isoniazid and rifampicin, the success rate of medical treatment falls considerably. These bacilli are defined as multidrug-resistant tuberculosis (MDR-TB) and have been of great concern. To improve the outcome of chemotherapy in patients with MDR-TB, adjuvant resectional surgery has been advocated. Currently the most common indication for pulmonary resection in patients with tuberculosis is MDR-TB. Pulmonary resection for MDR-TB achieves a high cure rate with low morbidity and mortality. The majority of the MDR-TB patients in the previously reported surgical series were middle-aged, and pulmonary resection for MDR-TB has not been performed on the octogenarians. The oldest patient in our series was 65 years old. Nevertheless, pulmonary resection is worth considering for an octogenarian infected with MRD-TB because pulmonary resection achieves a high success rate with low morbidity and mortality.

We investigated the isolation circumstances of multiple-drug-resistant Pseudomonas aeruginosa (MDRP) in the UOEH hospital and the bacterial analysis of isolated MDRP. From January to October 2003, MDRP was isolated from 2 patients. During this period, the isolation frequency of MDRP was 0.57% (2/350). Case 1 had 2 MDRP isolates from catheter urine, and case 2 had 5 MDRP isolates from pus. Regarding serotype, 2 isolates from case 1 were B type and the other 16 isolates from case 2 were E type. Pyomelanin was produced by 9 isolates of 16 E type isolates. The same PFGE patterns were observed in 2 isolates from case 1; that is, 9 pyomelanin producers from case 2 and the other 7 isolates from case 2, respectively. Metallo-beta-lactamase was produced by 2 isolates from case 1. bla(IMP) was detected from the 2 isolates by PCR, and the clones from case 1 were quite different from the clones from case 2. Regarding the pyomelanin producing isolates from case 2, although the clones were the same genetically, the MICs of imipenem and meropenem increased from 8 to > 32 microg/ml with the progress of time. In the UOEH hospital, 6 patients with MDRP isolates have been isolated so far, but these 6 patients are not correlated with each other. It is important that we detect and report MDRP as early as possible to prevent nosocomial infection.

One hundred forty-seven Campylobacter were isolated using 3,204 samples taken from sporadic diarrheic patients from January 2001 to December 2003. The detection rate of Campylobacter in 16 to 30 year old patients (12.9%, 83/641) was significantly higher than that in patients less than 16 years of age, 5%, (29/1,155) (p < 0.001) and more than 30 years of age, 2.5% (35/1,408) (p < 0.001), respectively. The highest detection rate was obtained from the stool of males in the 16 to 30 year old range during the months from May to August, 26% (32/123). If the minimal inhibitory concentration (MIC) breakpoint for resistance of gentamicin (GM), erythromycin (EM), ciprofloxacin (CPFX), tetracycline (TC) were defined tentatively > or = 16 microg/ml, > or = 16 microg/ml, > or = 2 microg/ml, > or = 16 microg/ml, the resistant rate would be 0.0%, 0.0%, 22.0%, 42.8% in C. jejuni, 0.0%, 62.5%, 62.5%, 87.5% in C. coli, respectively. All the Campylobacter isolates were susceptible to GM. Three of the 8 C. coli isolates were multi-resistant in EM, CPFX, and TC. Five highly EM resistant strains with an MIC of > or = 512 microg/ml did not show any zone around the EM disk; 7 susceptible strains with an MIC of less than 16 microg/ml showed = zones of 24mm to 36mm and revealed a good correlation with the Etest method and the agar dilution method. Between the two time periods of January 2001-June 2002 and July 2002-December 2003, the resistant rate of CPFX in C. jejuni decreased from 27.5% to 15.5%, however, that was not significant decrease (p = 0.133).

ABC (ATP binding cassette) transporters consist of transmembrane domains which confer specificity, and structurally conserved nucleotide binding domains that contain highly conserved amino acid motifs. They act not only as transporters but also as receptors or channels that use energy generated by ATP hydrolysis. ABC transporters are widely dispersed in nature. They are found in cells ranging from prokaryotes (bacteria) to eukaryotes (including humans) and several are considered to play crucial roles in cellular homeostasis. Defects in ABC transporters in humans are associated with severe diseases such as type 2 diabetes and cystic fibrosis. Some ABC transporters extrude xenobiotics and confer resistance to chemotherapeutics on microbial pathogens and cancer cells. Thus ABC transporters are of considerable medical importance. Structure-function analysis of ABC transporters has begun to elucidate their mechanisms of substrate recognition, the functional regulation of ATP-binding and hydrolysis and to identify intrinsic physiological functions. In pathogenic fungi, ABC transporters contribute to the clinical problem of drug resistance. The application of new technologies to the examination of fungal ABC transporter function is providing new insights into the use of antifungal drugs in medical mycology and contributing to a better understanding of these important membrane proteins.

The case is 47-year-old, homeless man. He was diagnosed as cavitary, sputum smear positive pan-sensitive lung tuberculosis, and admitted to TB ward of our hospital. At the age of 4-year-old he had tuberculous hilar lymphadenopathy and took medicine. He had no other associated disease, and HIV test was negative. He started standard chemotherapy and 2 months later his sputum culture was converted to negative. His adherence to medicine was thought to be good. But about 2 weeks after the sputum conversion, his sputum culture was re-converted to positive for Mycobacterium tuberculosis. Thereafter, during and after the completion of standard chemotherapy, his sputum culture had been intermittently positive. The drug sensitivity tests of the strain after re-conversion showed multi-drug resistance. RFLP analysis revealed that the strain before conversion was totally different strain from the strain after re-conversion to positive. The case was considered to be caused by the double infection of MDR strain of Mycobacterium tuberculosis during the course of treatment for tuberculosis due to a sensitive strain of Mycobacterium tuberculosis.

Remarkable advances have been made in cancer chemotherapy by developing new anticancer drugs and pharmacogenomics strategies. However, multidrug resistance in human cancers is the major obstacle to long-term, sustained patient response to chemotherapy. Several ATP-binding cassette (ABC) transporters cause multidrug resistance in cancer cells by actively extruding the clinically administered chemotherapeutic drugs. P-glycoprotein (ABCB1/MDR1/P-gp) and MRP1 (ABCC1/GS-X pump) have been well characterized in terms of their molecular structure and function. In addition, ABCG2/breast cancer resistance protein (BCRP) is the most recently identified/ABC transporter, and is also reportedly associated with cellular resistance against chemotherapeutic agents, such as DNA topoisomerase I, II inhibitor. It is important to note that these ABC transporters are expressed not only in cancer cells but also in normal tissues to play a pivotal role in the absorption, distribution, and excretion of endogenous substances as well as xenobiotics. ABC transporters are key factors that can affect the pharmacokinetic profiles of drugs. Recent studies have revealed that many single nucleotide polymorphisms (SNPs) reside in these ABC transporter genes. Functional analysis of the genetic polymorphism of ABC transporters would greatly contribute to our understanding of individual differences in the drug response and also to the development of personalized medicine in the near future.

Cyclosporin is a non-cytotoxic immunomodulating drug which inhibits NF-AT-dependent IL-2 transcription in lymphocytes. Cyclosporin is, therefore, beneficial as a monotherapy or as a combined therapy with methotrexate for refractory rheumatoid arthritis (RA). We also document that cyclosporin recovers the low concentration of intracellular multidrugs in lymphocytes by competitively binding to P-glycoprotein, a product of multidrug resistance gene-1, in vitro. Thus, cyclosporin could be used for the reversal of multidrug resistance, experienced in patients with longterm treated RA.

We present here a patient with acute myeloid leukemia (M2) who developed fatal infective endocarditis. On admission, the patient (67-year-old male) had mitral stenosis and atrial fibrillation. Complete remission was achieved after induction chemotherapy. During the course of consolidation therapy, he developed sepsis caused by coagulase-negative staphylococcus, which was successfully treated with antibiotics. Thereafter, blood culture yielded multidrug-resistant staphylococcus epidermidis. An echocardiogram revealed mitral valve regurgitation with vegetation. He was diagnosed as having infectious endocarditis. In spite of prolonged antibiotic therapy, destruction of the mitral valve progressed, and the patient underwent valve replacement therapy. He died of cardiac tamponade 5 days after the surgery.

Recently, monoclonal antibody(MoAb) therapies which direct at antigens such as CD33, CD45 and GM-CSF receptors on myeloid leukemia cells have been in progress. There are three major MoAb therapies against acute myeloid leukemia(AML), which include unconjugated MoAb, MoAb conjugated with chemotherapy or toxins, and MoAb conjugated with radioisotopes. Gemtuzumab ozogamicin is consisting of an engineered human anti-CD33 antibody linked with the potent anti-tumor antibiotic calicheamicin, which is the most effective for AML. However, recent studies suggested that calicheamicin was also pumped out by multi-drug resistance(MDR) related P-glycoprotein. The combination therapy with MDR modifiers may improve the effect of gemtuzumab ozogamicin.

Forty-three patients with multidrug-resistant tuberculosis at National Chiba-Higashi Hospital were studied retrospectively. TB cases excreting tubercle bacilli which are resistant to both 0.1 microgram/ml of isoniazid and 50 micrograms/ml of rifampicin were defined as multidrug-resistant cases. From 1993 to 1997, we experienced 1627 patients with pulmonary tuberculosis, and among them 43 patients (23-79 years old, 35 males and 8 females) were proved to be multidrug-resistant. Six cases were initially treated cases and other 37 cases had been treated previously. On admission, 40 out of 43 cases (93.0%) were smear positive by sputum examination of mycobacteria and 38 out of 43 cases (88.4%) had cavitary lesions on chest X-ray. Six patients were complicated with diabetes mellitus, two with cancer, one with alcohol dependence, one with chronic hepatitis, and others did not have prominent complications. Three operated patients were cured, the fact shows that the surgical treatment is still a useful measure for cases with the indication. Sixteen patients were cured, eight were still under treatment, and thirteen were died of tuberculosis. One of reasons of poor prognosis of multidrug-resistant tuberculosis is that multidrug-resistant tubercle bacilli are usually resistant to other drugs, too. In case of multidrug-resistant tuberculosis, patients were obliged to be treated in a hospital long-term to prevent the spread of tubercle bacilli. Therefore, it is very important to find out new tuberculosis cases as an early as possible, treat them with proper regimen and prevent dropout by directly observed therapy, thus preventing the emergence of multidrug-resistant tuberculosis. Development of new antituberculous agents is strongly expected.

We used paclitaxel to successfully treat a patient with small-cell lung cancer resistant to multiple drugs. The patient was diagnosed with small-cell lung cancer (cT4N2M1, extensive disease) and initially treated with CDDP 80 mg/m2 (day 1) + etoposide 100 mg/m2 (day 1-3) from August 1996 (4 courses). A partial response (PR) was obtained, but there was a gradual regrowth in the primary site after 17 months. The next chemotherapy was weekly chemotherapy (CODE regimen) from May 1998 for 5 weeks, but the response was no change (NC). After the therapy, a regrowth of the primary site was observed, and a CT scan demonstrated multiple metastases of the lung and liver. From March 1999, he was administered the next chemotherapy regimen of carboplatin (CBDCA) 350 mg/m2 (day 1) + etoposide 100 mg/m2 (day 1-3) (2 courses). However, the response was NC again. From August 1999, we changed the chemotherapy regimen and administered CBDCA AUC 5 (day 1) + paclitaxel (TXL) 175 mg/m2, (day 1, 3-hour-infusion) (1 course). A chest radiograph showed an extreme shrinkage of the primary and metastatic sites. A PR was obtained, but Grade 4 neutropenia and thrombocytepenia were observed with this therapy. Thus, he was treated with TXL alone (100 mg/m2, day 1, 1-hour-infusion) in the next course. After this therapy, a chest radiograph showed a more extreme shrinkage of the primary and metastatic sites. It is suggested that combination chemotherapy using TXL is effective in the treatment of a patient with small-cell lung cancer resistant to multiple drugs.

The prevalence of organisms producing extended-spectrum beta-lactamases(ESBLs) has been increasing all over the world. ESBLs confer resistance to cefotaxime, ceftazidime, aztreonam, extended-spectrum penicillins, and structurally related beta-lactams in clinical isolates of K. pneumoniae and E. coli. Under the influence of antimicrobial agents, bacteria that primarily produce TEM-type or SHV-type beta-lactamases developed point mutations in structural genes which served to extend the substrate specificity of the enzymes. Infections caused by ESBLs producing isolates are difficult to detect with current susceptibility tests, and are difficult to treat. This article provides an historical overview of the emergence of ESBLs carrying gram-negative rods and consider how to treat their infections.

Although most cases of infections in humans with normal host defenses can be treated with a single antimicrobial agent today, there are several cases to whom combination chemotherapy should be adopted. Five reasons have been advanced to justify the use of antimicrobial combinations: prevention of the emergence of resistant organisms, control of polymicrobial infections, initial therapy when causative organism is unclear, appearance of synergism, and management of infections in immunocompromised host. But, a clear advantage has been difficult to demonstrate in vivo. Furthermore, inappropriate use of antimicrobial combinations may lead patients to antagonism, cost, and even adverse effects. Therefore, antimicrobial combination therapy requires careful evaluation prior to clinical use.

The development and use of antibiotics for the chemotherapy of bacterial infections was one of the most remarkable accomplishments in medicine of the 20th. However, antibiotic-resistant bacteria were found in clinical isolates soon after the introduction of the earliest antimicrobial agents into the market. Significant increases in prevalence of resistance to antimicrobial agents have been observed in common pathogens of humans in the worldwide and problems of resistance are still presently serious among the immunocompromised host. The most important of these organisms are methicillin-resistant Staphylococcus aureus penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus, and certain gram-negative bacilli due to extended-spectrum beta-lactamase production. These antibiotic resistances have made antimicrobial therapy of many infections extremely difficult or virtually impossible in some instances. In this article, we reviewed the history of antibiotic-resistance and discussed on the future.

This study was designed to investigate the usefulness of treatment with 5-FU preceding CDDP in combination chemotherapy with THP, 5-FU and CDDP. Using the human KB carcinoma cell line and its multidrug resistant cell line KB-C1, the difference in the antitumor effect due to the sequence of administration of CDDP and 5-FU (TCF or TFC) was examined on cultured cells and nude mouse tumor xenografts. When KB and KB-C1 were treated with THP (0.01 microgram/ml) on day 1, CDDP (0.05 microgram/ml) on day 2 or day 4 and 5-FU (0.25 microgram/ml) on day 3 and 4 or day 2 and 3, TFC suppressed the cell proliferation more strongly than TCF (p < 0.05), though there was no difference between KB and KB-C1. In nude mouse xenografts, intraperitoneal administrations of THP (0.5 mg/kg) on day 1, CDDP (2 mg/kg) on day 2 or day 5, and 5-FU (10 mg/kg) on day 3-5 or day 2-4 inhibited tumor growth more effectively in KB than in KB-C1. At three weeks postadministration, growth inhibition by TCF and TFC was 29.9% and 57.4% in KB and 25.2% and 49.8% in KB-C1, respectively. These results indicate that TFC was superior to TCF in cytocidal and antitumor effects for KB and KB-C1.

During the 20-year period between 1979-1998, a total of 4,176 strains of hemolytic streptococci have been isolated from 20,118 healthy primary school children and little children in Tokyo Metropolitan (Tokubetsuku, Tama and Tosho). Culture of throat swabs every November and the following February during the 20-year period were made and serological grouping and typing for isolates were done by T agglutination method. The results were as follows. 1) Serological group of hemolytic streptococci isolated from children were 3,188 strains (76.3%) for isolates of group A out of total strains of 4,176, 569 strains (13.6%) for isolates group B, 63 strains (1.5%) for isolates of group C and 356 strains (8.5%) for isolates of group G. 2) The most dominant was T12 during 1979-1998, and other relatively frequent serotypes were T28, T1, T4, T6 in that order. These ranks of and the main epidemic serotypes showed a similar trend in the 3 areas. 3) The isolation rates of group A streptococci were 15.9% in Tokubetsuku, 17.1% in Tama and 14.9% in Tosho. The average of 3 areas were 15.8%. 4) The epidemic cases seemed to be caused by group A streptococci were 20 cases, their isolated serotype were 7 cases by T28, 5 cases by T12, 4 cases by T6, 2 cases by T4, each 1 case by T1 and T25. 5) A total of 2,927 strains of group A streptococci were examined for drug sensitivity. All strains were sensitive to beta-lactam group of antibiotics (benzylpenicillin and cephaloridine). Resistant (MIC > or = 25 micrograms/ml) to TC, CP and EM etc. were 740 strains (25.3%) in this study. The incidence of resistant strains were to TC 493 strains (66.6%) out of 740 strains, 81 strains (10.9%) for TC.CP, 72 strains (9.7%) for EM and 66 strains (8.9%) for TC.CP.EM.OL.LCM. TC resistant strains have not varied much through the whole period, but CP and EM resistant strains were very variable by year. Many resistant strains to TC were T4, to EM and multiple drug resistant were T12. 6) The rates of isolates of the same type of group A streptococci in school child individual during for the tests taken twice a year were 12.3%, indicating group A streptococci, according to the duration of the carrier state, seems to be a short period.

Objectives: To assess patient compliance and efficacy of a combination chemotherapy consisting of weekly administration of paclitaxel and carboplatin for gynecologic malignancy in Japanese women., Methods: Fourteen ovarian and three uterine cancer patients received 80 mg/m2 of paclitaxel (paclitaxel) and AUC 1.5 to 2.0 of carboplatin weekly. The toxicity was evaluated and patients' QOL was tested., Results: Neutropenia higher than grade 3 were observed in 29.4%. Four patients received G-CSF support. Grade 1 neurotoxicity was seen in 76.5% of patients. Evaluation of QOL by EORTC-QLQC30 showed significantly better tolerance of a weekly than monthly regimen. Three out of four patients with lung metastasis showed complete disappearance of the lesions. One patient with stage IIIb cervical cancer underwent postchemotherapy-hysterectomy and a complete pathological response was confirmed. The overall response rate was 64.7% including patients previously treated with platinum based multidrug regimens., Conclusions: A weekly paclitaxel and carboplatin regimen was well tolerated by Japanese women. The regimen was active in over 60% of cases and it also appeared active in multidrug resistant cases.

We investigated the causes of nosocomial infection of P. aeruginosa in a recent outbreak of P. aeruginosa in our hospital. Multi-drug-resistant-P. aeruginosa(MDRPS) that did not produce class B beta-lactamase was isolated from 20(40.0%) patients, occurring in 50 patients hospitalized in the Internal Medicine Ward E in our hospital in 1999 was investigated. All of the patients had brain-vesicular damage as the underlying disease, and 12 patients had been fed by nasal feeding or through a gastric stoma. MDRPS was isolated from sputum(7), urine samples(8), wound discharge(4) and 1 catheter. The bacteria were resistant to piperacillin, ceftazidime, sulbactam/cefoperazone, minocycline and ofloxacin, and in 40% the MIC of the imipenem was more than 8 micrograms/ml. We did not detect MDRPS in any equipment parts or waste water, including the sink in Ward E, but it was detected in the nutrient fluid for nasal feeding and in the line of one patient. The DNA homology of MDRPS isolated from the patient and the nutritive liquid was the same as that of some strains isolated in Ward E, as shown by random amplified DNA polymorphism PCR. In conclusion, we speculated that some nosocomial infections due to MDRPS resistant to imipenem were caused by contaminated nasal feeding.