Keiichi Mikasa

Nationwide surveillance of bacterial respiratory pathogens conducted by the Japanese Society of Chemotherapy in 2007: general view of the pathogens' antibacterial susceptibility.

For the purpose of nationwide surveillance of the antimicrobial susceptibility of bacterial respiratory pathogens collected from patients in Japan, the Japanese Society of Chemotherapy conducted a third year of nationwide surveillance during the period from January to April 2008. A total of 1,097 strains were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections. Susceptibility testing was evaluable with 987 strains (189 Staphylococcus aureus, 211 Streptococcus pneumoniae, 6 Streptococcus pyogenes, 187 Haemophilus influenzae, 106 Moraxella catarrhalis, 126 Klebsiella pneumoniae, and 162 Pseudomonas aeruginosa). A total of 44 antibacterial agents, including 26 β-lactams (four penicillins, three penicillins in combination with β-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), three aminoglycosides, four macrolides (including a ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standard Institute (CLSI). The incidence of methicillin-resistant S. aureus (MRSA) was as high as 59.8%, and those of penicillin-intermediate and penicillin-resistant S. pneumoniae (PISP and PRSP) were 35.5 and 11.8%, respectively. Among H. influenzae, 13.9% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant (BLNAI), 26.7% to be β-lactamase-non-producing ABPC-resistant (BLNAR), and 5.3% to be β-lactamase-producing ABPC-resistant (BLPAR) strains. A high frequency (76.5%) of β-lactamase-producing strains was suspected in Moraxella catarrhalis isolates. Four (3.2%) extended-spectrum β-lactamase-producing K. pneumoniae were found among 126 strains. Four isolates (2.5%) of P.aeruginosa were found to be metallo β-lactamase-producing strains, including three (1.9%) suspected multidrug-resistant strains showing resistance to imipenem, amikacin, and ciprofloxacin. Continual national surveillance of the antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis.

Enhanced Interleukin Production after Long-Term Administration of Erythromycin Stearate

The effects of erythromycin stearate (10 mg/kg/day) were studied on productions of interleukin (IL)-1 and -2 in mice after a long-term treatment. A 28-day treatment resulted in higher levels of IL-1 production by macrophages and of IL-2 production by splenocytes, while a 7-day treatment did not increase them. T-cell growth factor activity of IL-2 preparation prepared on day 28 of treatment as determined by HT-2 cell proliferation was reduced by about 40% in the presence of anti-murine IL-4 monoclonal antibodies, while control IL-2 activity was not reduced. Furthermore, a 28-day treatment with erythromycin stearate increased concanavalin A-induced blastogenesis of splenocytes significantly. These results suggest that long-term treatment with erythromycin stearate can stimulate host defense by increasing interleukin production.

Adjuvant effect of clarithromycin on chemotherapy for murine lung cancer.

Clarithromycin (CAM) increased the median survival of patients with unresectable non-small-cell lung cancer who had received chemotherapy and/or radiotherapy [Chemotherapy 1997;43:288–296]. The present study was performed to ascertain whether CAM alone exhibits an antitumor effect against Lewis lung carcinoma (LLC) and to analyze the nature of its adjuvant effect on LLC-inoculated C57BL/6 mice. CAM at 10 mg/kg/day retarded the growth of subcutaneously inoculated LLC cells; consequently, the mean survival time of mice with LLC increased. This treatment was also effective in reducing the number of tumor nodules in the lung after intravenous inoculation with LLC cells. When tumor-bearing mice received an intravenous injection of vindesine sulfate (7 mg/kg) and cisplatin (6 mg/kg) 7 days after tumor inoculation, the chemotherapeutic effect was significantly enhanced by CAM treatment when it started 7 days after chemotherapy, but not when it started the day after chemotherapy. The delayed initiation of CAM treatment resulted in the enhancement of natural killer cell activity and CD8+ T cell cytotoxicity and increased the number of interferon-γ-producing T cells and interleukin-4-producing T cells. These findings indicate that CAM can exhibit an antitumor effect by itself and also induce the well-balanced expansion of helper T cell subsets in tumor-bearing mice recovering from the immunosuppression caused by chemotherapy. CAM may therefore be a promising adjuvant drug in anticancer chemotherapy, and treatment with this macrolide should be initiated at some interval after basic cancer therapy.

Significant Survival Benefit to Patients with Advanced Non-Small-Cell Lung Cancer from Treatment with Clarithromycin

We carried out a randomized study of 49 consecutive patients with unresectable primary lung cancer to determine whether clarithromycin (CAM), a 14-membered ring macrolide, can improve outcome. A total of 49 patients (42 patients with non-small-cell lung cancer and 7 patients with small-cell lung cancer) had received prior chemotherapy, radiotherapy or both during their hospital stay. They were randomly allocated into two study groups on the first visit after discharge: 25 patients (22 patients with non-small-cell lung cancer, 3 patients with small-cell lung cancer) were assigned to receive CAM (400 mg/day, orally), and 24 patients (20 patients with non-small-cell lung cancer, 4 patients with small-cell lung cancer) did not receive CAM. CAM treatment after randomization was open and the treatment was to be continued as long as the patients could tolerate CAM. There was no significant difference in the median survival time for small-cell lung cancer between the CAM group and the non-CAM group. However, CAM treatment significantly increased the median survival time for non-small-cell lung cancer patients, the median survival for the CAM group was 535 days and that for the non-CAM group was 277 days. Analyses of prognostic factors showed that only treatment with CAM was predictive of longer survival for non-small-cell lung cancer, and other tested covariates had no effects on the prognosis. There were no remarkable side effects observed in the CAM group throughout treatment. We conclude that long-term treatment using CAM is beneficial for unresectable non-small-cell lung cancer patients and that it can increase the median survival of patients with advanced disease.

Pathogenic mechanism of mouse brain damage caused by oral infection with Shiga toxin-producing Escherichia coli O157:H7.

ABSTRACT In a previous study, we showed that infection with Shiga toxin (Stx)-producing Escherichia coli O157:H7 (strain SmrN-9) caused neurologic symptoms in malnourished mice with positive immunoreactions of Stx2 in brain tissues. The present study explores the mechanism of how Stx injures the vascular endothelium to enter the central nervous system in mice. Oral infection with strain SmrN-9 elicited a tumor necrosis factor alpha (TNF-α) response in the blood as early as 2 days after infection, while Stx was first detected at 3 days postinfection. In the brain, TNF-α was detected at day 3, and its quantity was increased over the next 3 days. Frozen sections of the brains from moribound mice contained high numbers of apoptotic cells. Glycolipids recognized by an anti-Gb3 monoclonal antibody were extracted from the brain, and purified Stx2 was able to bind to the glycolipids. In human umbilical vascular endothelial cells (HUVEC) cultured with fluorescein-labeled Stx2 (100 ng/ml), TNF-α (20 U/ml) significantly facilitated the intracellular compartmentalization of fluorescence during 24 h of incubation, suggesting the enhanced intracellular processing of Stx2. Consequently, higher levels of apoptosis in HUVEC were found at 48 h. Short-term exposure of HUVEC to Stx2 abrogated their apoptotic response to subsequent incubation with TNF-α alone or TNF-α and Stx2. In contrast, primary exposure of HUVEC to TNF-α followed by exposure to Stx2 alone or TNF-α and Stx2 induced apoptosis at the same level as obtained after 48-h incubation with these two agents. These results suggest that the rapid production of circulating TNF-α after infection induces a state of competence in vascular endothelial cells to undergo apoptosis, which would be finally achieved by subsequent elevation of Stx in the blood. In this synergistic action, target cells must be first exposed to TNF-α. Such cell injury may be a prerequisite to brain damage after infection with Stx-producing E. coliO157:H7.

A familial case of visceral toxocariasis due to consumption of raw bovine liver

We present 3 adult cases of visceral toxocariasis from the same family, who each consumed thin slices of raw bovine liver weekly, and developed eosinophilia and multiple small lesions in their livers and lungs. Serological examinations using the larval excretory-secretory product of Toxocara canis strongly indicated infection with Toxocara species larvae. The patients responded well to treatment with albendazole. Ingestion of raw liver from paratenic animals is considered to be a common transmission route of human toxocariasis, especially in adults.

Antitumor Effect of Erythromycin in Mice

Oral administration of erythromycin in the dose range of 1-10 mg/kg increased the survival times of tumor-bearing mice in both allogeneic and syngeneic mouse systems by two- to three-fold as compared with those of vehicle control mice, with the maximum effect at a dose of 5 mg/kg/day. During the early phase of tumor transplantation, tumoricidal macrophages and natural killer cells were active in the antitumor resistance of erythromycin-treated mice. Thereafter, the tumoricidal activity of macrophages became stronger as serum levels of interleukin-4 (IL-4) rose. Furthermore, treatment of mice with anti-IL-4 monoclonal antibody abolished the antitumor resistance conferred by erythromycin. These results indicate that erythromycin exhibits an indirect antineoplastic activity by enhancing the production of IL-4 which augments the tumoricidal activity of macrophages.

INHIBITORY EFFECTS OF MACROLIDE ANTIBIOTICS ON EXACERBATIONS AND HOSPITALIZATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN JAPAN: A RETROSPECTIVE MULTICENTER ANALYSIS

To the Editor: We appreciate the concerns of Drs. Sutin and Rougas about applying the Assessing the Care of Vulnerable Elders (ACOVE) hypertension quality indicators (QIs) to the very old (aged 85) and those with low diastolic blood pressure (BP). Our QIs were based on a literature review and expert panel interpretation of the existing evidence. We focused on systolic hypertension (SH) in response to prevailing lack of systolic BP control in older patients and strong evidence that treatment of SH results in fewer strokes and cardiovascular events in older and very old patients. These benefits appear to be independent of lowering diastolic BP even in the very old. We agree with their concerns about overtreatment of hypertension in older patients. Our literature search targeted possible harmful outcomes of aggressive antihypertensive therapy such as greater risk of falls. We found several observational analyses of the J-shaped relationship between mortality and low diastolic BP, meta-analyses on the very old that we interpreted as inconclusive regarding all-cause mortality, and falls associated with diuretic use. Drs. Sutin and Rougas’ letter has brought to our attention that we should have more strongly emphasized several points in our article. First, ACOVE QIs measure processes of care (i.e., whether the clinician has recommended or provided particular services) rather than outcomes of care (i.e., achieving a health state such as a particular BP). Accordingly, QI 7 focuses on developing and documenting a goal BP through shared decision-making by the clinician and patient, regardless of what BP goal is elected. This focus on shared decisionmaking sets our QIs apart from other performance measures that measure achievement of BP less than 140/90 for adults aged 46 to 85. Second, acceptable care processes aimed at achieving the goal BP include recommending nonpharmacological modifications (QI 9). Third, the QIs allow 6 months to achieve the goal BP before the clinician needs to document why the goal pressure could not be achieved (QI 10). Again, neither QI 9 nor 10 requires achieving the goal BP. Finally, we intended for the documented goal systolic BP to override any of the systolic BP goals that appear in QI 9 and 10, which currently read: ‘‘ . . . diabetes mellitus or chronic renal disease, 130 mmHg; home ambulatory monitoring 135 mmHg; all other patients, 140 mmHg or any other specified goal’’ (italics added). The final phrase should have, at the least, been offset by a semicolon but would have been more clearly understood as a separate explanatory sentence. We will revise QIs 9 and 10 on RAND’s ACOVE Web site.

Anti-Cachectic Effect of Clarithromycin for Patients with Unresectable Non-Small Cell Lung Cancer

We have previously reported that long-term treatment with clarithromycin (CAM) increased the median survival of patients with non-small cell lung cancer, and improved various clinical parameters in these patients. In the present study, CAM was administered to 33 patients with unresectable primary non-small cell lung cancer, who had received chemotherapy, radiotherapy or both (basic cancer therapy). Patients with clinical backgrounds matched to the CAM group, who did not receive CAM treatment, were included into this study as a control group (non-CAM group). CAM treatment was initiated 4 weeks after the basic cancer therapy. The non-CAM group did not receive a placebo. Before and after the 3-month treatment with CAM, body weight, serum levels of interleukin-6 (IL-6, a cytokine which, together with TNF-α, plays a crucial role in the development of cancer cachexia), total protein, albumin, cholinesterase and hemoglobin were measured for the evaluation of the patients’ clinical status. There were no statistically significant differences in serum levels of IL-6 between the CAM group before the treatment and the non-CAM group. After 3 months of CAM treatment, serum levels of IL-6 significantly decreased. In contrast, body weight, cholinesterase, and hemoglobin increased to a significant extent. Among these four parameters, however, the decrease in serum IL-6 levels was only statistically correlated with the increase in body weight, but not with that in other parameters. Furthermore, CAM-treated patients whose serum IL-6 levels were decreased after 3 months of treatment survived longer: there was a statistically significant correlation between the decrease in serum IL-6 and survival time. In contrast, in the non-CAM group, these parameters did not change significantly during the study. These results suggest that CAM may reduce the progression of cancer-associated cachexia.

Revision of the severity rating and classification of hospital-acquired pneumonia in the Japanese Respiratory Society guidelines

Background and objective:  Based on the results of a multicentre collaborative survey of hospital‐acquired pneumonia (HAP) conducted in Japan, the severity rating and classification of pneumonia in the Japanese Respiratory Society guidelines for management of HAP were examined.