Takaya Maruyama

Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents: double blind, randomised and placebo controlled trial

Objective To determine the efficacy of a 23-valent pneumococcal polysaccharide vaccine in people at high risk of pneumococcal pneumonia. Design Prospective, randomised, placebo controlled double blind study. Setting Nursing homes in Japan. Participants 1006 nursing home residents. Interventions Participants were randomly allocated to either 23-valent pneumococcal polysaccharide vaccine (n=502) or placebo (n=504). Main outcome measures The primary end points were the incidence of all cause pneumonia and pneumococcal pneumonia. Secondary end points were deaths from pneumococcal pneumonia, all cause pneumonia, and other causes. Results Pneumonia occurred in 63 (12.5%) participants in the vaccine group and 104 (20.6%) in the placebo group. Pneumococcal pneumonia was diagnosed in 14 (2.8%) participants in the vaccine group and 37 (7.3%) in the placebo group (P<0.001). All cause pneumonia and pneumococcal pneumonia were significantly more frequent in the placebo group than in the vaccine group: incidence per 1000 person years 55 v 91 (P<0.0006) and 12 v 32 (P<0.001), respectively. Death from pneumococcal pneumonia was significantly higher in the placebo group than in the vaccine group (35.1% (13/37) v 0% (0/14), P<0.01). The death rate from all cause pneumonia (vaccine group 20.6% (13/63) v placebo group 25.0% (26/104), P=0.5) and from other causes (vaccine group 17.7% (89/502) v placebo group (80/504) 15.9%, P=0.4) did not differ between the two study groups. Conclusion The 23-valent pneumococcal polysaccharide vaccine prevented pneumococcal pneumonia and reduced mortality from pneumococcal pneumonia in nursing home residents. Trial registration Japan Medical Association Center for Clinical Trials JMA-IIA00024.

A New Strategy for Healthcare-Associated Pneumonia: A 2-Year Prospective Multicenter Cohort Study Using Risk Factors for Multidrug-Resistant Pathogens to Select Initial Empiric Therapy

BACKGROUND Optimal empiric therapy for hospitalized patients with healthcare-associated pneumonia (HCAP) is uncertain. METHODS We prospectively applied a therapeutic algorithm, based on the presence of risk factors for multidrug-resistant (MDR) pathogens in a multicenter cohort study of 445 pneumonia patients, including both community-acquired pneumonia (CAP; n = 124) and HCAP (n = 321). RESULTS MDR pathogens were more common (15.3% vs 0.8%, P < .001) in HCAP patients than in CAP patients, including Staphylococcus aureus (11.5% vs 0.8%, P < .001); methicillin-resistant S. aureus (6.9% vs 0%, P = .003); Enterobacteriaceae (7.8% vs 2.4%, P = .037); and Pseudomonas aeruginosa (6.9% vs 0.8%, P = .01). Using the proposed algorithm, HCAP patients with ≥2 MDR risk factors, one of which was severity of illness (n = 170), vs HCAP patients with 0-1 risk factor (n = 151) had a significantly higher frequency of MDR pathogens (27.1% vs 2%, P < .001). In total, 93.1% of HCAP patients were treated according to the therapy algorithm, with only 53% receiving broad-spectrum empiric therapy, yet 92.9% received appropriate therapy for the identified pathogen. Thirty-day mortality was significantly higher for HCAP than for CAP (13.7% vs 5.6%, P = .017), but among HCAP patients with 0-1 MDR risk factor, mortality was lower than with ≥2 MDR risk factors (8.6% vs 18.2%, P = .012). In multivariate analysis, initial treatment failure, but not inappropriate empiric antibiotic therapy, was a mortality risk factor (odds ratio, 72.0). CONCLUSIONS Basing empiric HCAP therapy on its severity and the presence of risk factors for MDR pathogens is a potentially useful approach that achieves good outcomes without excessive use of broad-spectrum antibiotic therapy. CLINICAL TRIALS REGISTRATION Japan Medical Association Center for Clinical Trials, JMA-IIA00054.

A prospective comparison of nursing home-acquired pneumonia with hospital-acquired pneumonia in non-intubated elderly

There are no prospective comparison of the etiology and clinical outcome between hospital-acquired pneumonia (HAP) and nursing home-acquired pneumonia (NHAP) in non-intubated elderly. This study prospectively evaluated the etiology of HAP and NHAP in non-intubated elderly. A prospective cohort study was carried out in a rural region of Japan where the population over 65 years of age represents 30% of the population. A total of 108 patients were enrolled. There were 33 patients with HAP and 75 with NHAP. Etiologic diagnosis was established in 78.8% of HAP and in 72% of NHAP patients. The most frequent pathogens were Chlamydophila pneumoniae followed by Streptococcus pneumoniae, Staphylococcus aureus and Influenza virus. The frequency of Streptococcus pneumoniae and Influenza virus was significantly higher, whereas the frequency of Staphylococcus aureus and Enterobacteriaceae was significantly lower in NHAP compared to HAP. Performance and nutritional status were significantly worse in patients with HAP than in those with NHAP. Hospital mortality was significantly lower in patients with NHAP compared to those with HAP. This study demonstrated that C. pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus and Influenza virus are frequent causative agents of pneumonia in non-intubated elderly and that the responsible pathogens and clinical outcome differ between NHAP and HAP.

Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients

The rapid increase in the elderly population is leading to a corresponding increase in the number of people requiring medical care. To date no comparative study between community-acquired pneumonia (CAP) and nursing home-acquired pneumonia (NHAP) has been reported in the very elderly non-intubated patients. The present study was undertaken to compare the clinical characteristics and microbial etiology between CAP and NHAP in elderly patients >/=85-years old. There were 54 patients with NHAP and 47 with CAP. Performance status was significantly worse in the NHAP than in the CAP group. Among all patients, the most frequent pathogens were Chlamydophilia pneumoniae followed by Streptococcus pneumoniae, Mycoplasma pneumoniae influenza virus and Staphylococcus aureus. The frequency of S. peumoniae was significantly higher in NHAP patients than in CAP patients after adjusting for age and sex. Physical activity, nutrition status and dehydration were significant prognostic factors of pneumonia among all patients. In-hospital mortality was significantly higher in NHAP than in CAP after adjusting for age and sex. This study demonstrated that the etiology and clinical outcome differ between CAP and NHAP patients in the very elderly non-intubated population.

Role of the coagulation system in allergic inflammation in the upper airways

Thrombin has been detected and demonstrated to play a role in the airways of patients with bronchial asthma, but its role in the upper airways including during allergic rhinitis is unknown. This study was conducted to explore whether thrombin is presence in the upper airways and, if so, whether it affects mucin secretion. Fifteen patients with allergic rhinitis were enrolled in the clinical study; primary nasal septum epithelial cells and normal bronchial epithelial cells were used for in vitro evaluation, and rats as animal models. Significant concentrations of thrombin were found in nasal secretion after allergic provocation in allergic patients, and thrombin and its agonistic receptor peptide induced significant secretion of mucin in primary nasal cells and normal bronchial epithelial cells as compared to non-stimulated cells. Increased mucosubstance secretion in septum epithelial cells was also induced after nasal instillation of thrombin in rats. Further, the anticoagulant, activated protein C, significantly inhibited thrombin-induced mucin secretion from septum epithelial cells in rats. The results of this study suggest that activation of the coagulation system occurs during the allergic response and that thrombin plays a crucial role in the regulation of mucin production in the upper airways.

Community-acquired macrolide-resistant Mycoplasma pneumoniae pneumonia in patients more than 18 years of age

A macrolide-resistant Mycoplasma pneumoniae strain was isolated from two patients with community-acquired pneumonia. The pneumonia severity score of both patients was mild, and rapid clinical improvement was seen after administration of fluoroquinolone. Clinical features of macrolide-resistant M. pneumoniae pneumonia were identical to those of macrolide-sensitive M. pneumoniae pneumonia. An A-to-G transition at position 2063 and 2064, respectively, in domain V of the 23S rRNA gene was identified. The minimum inhibitory concentration of erythromycin of these isolates was greatly elevated. In Japan, macrolide-resistant M. pneumoniae infections are common in pediatric patients but not in adults. However, physicians should pay attention to macrolide-resistant M. pneumoniae not only in children but also in adults.

Different bile concentration of micafungin and itraconazole in a patient with candidal cholecystitis.

Candidal cholecystitis is a rare infection that occurs in patients with disseminated candidal infections during post operative recovery or in the immunocompromised host. Micafungin or itraconazole are effective for the treatment of superficial and disseminated candidasis, however, their efficacy in candidal cholecystitis is unknown. The therapeutic efficacy of micafungin and itraconazole in treatment of candidal cholecystitis may depend on their biliary excretion rate but so far there are no reports. Here, we report a case of candidal cholecystitis in a 90year old man who was receiving systemic chemotherapy and radiation therapy for esophageal cancer. The infectious complications were treated with percutaneous drainage and systemic antifungal therapy. The patient had high fever and upper abdominal pain. Physical and laboratory examination showed findings consistent with the diagnosis of cholecystitis. Culture of two blood samples from the patient were positive for Candida albicans without other pathogens. Eye examination presented characteristic findings of candidal retinopathy. Abdominal CT showed gallbladder swelling with irregular hypertrophy of the walls and gallstones. He underwent percutaneous transhepatic gallbladder drainage. Culture of bile samples obtained from the patients were positive for C. albicans without other pathogens. A diagnosis of disseminated candidasis with candidal cholecystitis was made. He had been managed with percutaneous transhepatic gallbladder drainage and combination therapy with intravenous micafungin (150 mg every 24 h) and itraconazole (100 mg every 12 h). His condition gradually improved. However the clinical course of the patient deteriorated during monotherapy with oral itraconazole without intravenous micafungin. The clinical condition of the patient improved when both drugs were administered for 58 days. He was discharged on the 60th hospital day and the subsequent clinical course of the patient was stable. No adverse events were caused by the combination therapy. C. albicans isolated from the bile samples of the patient was susceptible to micafungin (minimal inhibitory concentrations (MIC): 0.06 mg/ml) and itraconazole (MIC: 0.06 mg/ml). Biliary excretion of micafungin and itraconazole was measured by determining the concentration of micafungin (BLM Corp, Tokyo, Japan) and itraconazole (SLR Corp, Tokyo, Japan) in both serum and bile samples using high performance liquid chromatography. The minimal concentrations of the antifungal agents in serum and bile samples were measured 24 h after infusion of 150 mg of micafungin and 12 h after ingestion of 100 mg of oral itraconazole. The minimal concentration of the antifungal agents in serum was: micafungin: 1.537 mg/ml, itraconazole: 0.1216 mg/ml and hydroxyitraconazole: 0.2485 mg/ml while in bile it was: micafungin: 1.925 mg/ml, itraconazole: <0.01 mg/ml and hydroxyitraconazole: <0.01 mg/ml. To our knowledge this is the first report of the biliary concentration of micafungin and itraconazole in a patient with systemic candidiasis with cholecystitis. The use of micafungin and itraconazole in the clinic depends on several factors, such as whether there is chronic renal insufficiency which is a contraindication for the use of amphotericin B. The clinical course of our patient improved with administration of micafungin, whereas oral itraconazole therapy alone was ineffective. In a patient with a liver transplant, candidal cholangitis was successfully treated with caspofungin as the peak level of caspofungin in serum and bile was greater than the in vitro MIC of caspofungin for C. albicans. Ketoconazole, however, was ineffective in candidal cholecystitis, probably because the drug was not significantly excreted in bile. In our patient, the minimum concentrations of both micafungin and itraconazole in serum were greater than the MIC of C. albicans isolated from the bile. However, micafungin was significantly excreted in bile and its concentration was greater than the MIC but itraconazole was not significantly secreted into the bile and did not reach the MIC. Similarly in a previous study in rats; the biliary excretion of micafungin was about 10% of the micafungin dose after intravenous administration, whereas biliary excretion of itraconazole and hydroxyitraconazole were less than 0.5% of the itraconazole dose after intravenous administration. This difference in biliary excretion rate shown in the present report supports the idea that micafungin is useful for treating candidal biliary infection and that itraconazole is not. It appears that the pharmacokinetics of other echinocandins (e.g. caspofungin) is similar to that of micafungin. However, the pharmacokinetics of itraconazole is different from other triazoles. The excretory mechanism is not clear but a previous study in rats suggested that multidrug resistance-associated protein-2 is involved in the hepatobiliary excretion of micafungin.

Original Research: Chest InfectionsOutcomes and Prognostic Features of Patients With Influenza Requiring Hospitalization and Receiving Early Antiviral Therapy: A Prospective Multicenter Cohort Study

BACKGROUND In Japan, the routine use of early antiviral therapy for patients with influenza is standard. METHODS This multicenter prospective cohort evaluation of hospitalized patients with laboratory-confirmed influenza identified prognostic factors among the patients receiving antiviral therapy. RESULTS Of 1,345 patients with influenza (766 pediatric, 579 adult), excluding those aged < 1 year (who are not approved for antiviral therapy), 97.7% (1,224 of 1,253) received antiviral therapy. Among the adult patients, 24 (4.1%) died within 30 days, whereas none of the pediatric patients died. Five hundred twenty-eight (91.2%) adult patients had influenza A, 509 (87.9%) had a chronic underlying illness, and 211 (36.4%) had radiographically confirmed pneumonia. Twenty of the 24 patients who died had pneumonia of the following etiologies: Streptococcus pneumoniae (12.3%); Staphylococcus aureus (10.9%), including methicillin-resistant S aureus (MRSA) 3.3%; Enterobacteriaceae (8.1%); and Pseudomonas aeruginosa (3.3%). Of the adult patients, 151 were classified as having community-acquired pneumonia (CAP) and 60 as having health-care-associated pneumonia (HCAP). Inappropriate therapy was more common in HCAP than in CAP (15.2% vs 2%, P = .001). Potential multidrug-resistant (MDR) pathogens were more common (21.7% vs 2.6%, P < .001) in patients with HCAP, particularly MRSA (10% vs 0.7%, P = .002) and P aeruginosa (8.3% vs 1.3%, P = .021). Using Cox proportional hazards modeling with prescribed independent variables, male sex, severity score, serum albumin levels (malnutrition), and pneumonia were associated with survival 30 days from the onset of influenza. CONCLUSIONS Among the prognostic factors, malnutrition and pneumonia are amenable to medical intervention. An opportunity exists to improve empirical therapy for patients with HCAP and influenza. TRIAL REGISTRY Japan Medical Association Center for Clinical Trials; No.: JMA-IIA00123; URL: http://www.jmacct.med.or.jp/en/.

Outcomes and Prognostic Features of Patients With Influenza Requiring Hospitalization and Receiving Early Antiviral Therapy: A Prospective Multicenter Cohort Study

BACKGROUND In Japan, the routine use of early antiviral therapy for patients with influenza is standard. METHODS This multicenter prospective cohort evaluation of hospitalized patients with laboratory-confirmed influenza identified prognostic factors among the patients receiving antiviral therapy. RESULTS Of 1,345 patients with influenza (766 pediatric, 579 adult), excluding those aged < 1 year (who are not approved for antiviral therapy), 97.7% (1,224 of 1,253) received antiviral therapy. Among the adult patients, 24 (4.1%) died within 30 days, whereas none of the pediatric patients died. Five hundred twenty-eight (91.2%) adult patients had influenza A, 509 (87.9%) had a chronic underlying illness, and 211 (36.4%) had radiographically confirmed pneumonia. Twenty of the 24 patients who died had pneumonia of the following etiologies: Streptococcus pneumoniae (12.3%); Staphylococcus aureus (10.9%), including methicillin-resistant S aureus (MRSA) 3.3%; Enterobacteriaceae (8.1%); and Pseudomonas aeruginosa (3.3%). Of the adult patients, 151 were classified as having community-acquired pneumonia (CAP) and 60 as having health-care-associated pneumonia (HCAP). Inappropriate therapy was more common in HCAP than in CAP (15.2% vs 2%, P = .001). Potential multidrug-resistant (MDR) pathogens were more common (21.7% vs 2.6%, P < .001) in patients with HCAP, particularly MRSA (10% vs 0.7%, P = .002) and P aeruginosa (8.3% vs 1.3%, P = .021). Using Cox proportional hazards modeling with prescribed independent variables, male sex, severity score, serum albumin levels (malnutrition), and pneumonia were associated with survival 30 days from the onset of influenza. CONCLUSIONS Among the prognostic factors, malnutrition and pneumonia are amenable to medical intervention. An opportunity exists to improve empirical therapy for patients with HCAP and influenza. TRIAL REGISTRY Japan Medical Association Center for Clinical Trials; No.: JMA-IIA00123; URL: http://www.jmacct.med.or.jp/en/.

A Therapeutic Strategy for All Pneumonia Patients: A 3-Year Prospective Multicenter- Cohort Study Using Risk Factors for Multidrug Resistant Pathogens To Select Initial Empiric Therapy

BACKGROUND Empiric therapy of pneumonia is currently based on the site of acquisition (community or hospital), but could be chosen, based on risk factors for multidrug-resistant (MDR) pathogens, independent of site of acquisition. METHODS We prospectively applied a therapeutic algorithm based on MDR risks, in a multicenter cohort study of 1089 patients with 656 community-acquired pneumonia (CAP), 238 healthcare-associated pneumonia (HCAP), 140 hospital-acquired pneumonia (HAP), or 55 ventilator-associated pneumonia (VAP). RESULTS Approximately 83% of patients were treated according to the algorithm, with 4.3% receiving inappropriate therapy. The frequency of MDR pathogens varied, respectively, with VAP (50.9%), HAP (27.9%), HCAP (10.9%), and CAP (5.2%). Those with ≥2 MDR risks had MDR pathogens more often than those with 0-1 MDR risk (25.8% vs 5.3%, P < .001). The 30-day mortality rates were as follows: VAP (18.2%), HAP (13.6%), HCAP (6.7%), and CAP (4.7%), and were lower in patients with 0-1 MDR risks than in those with ≥2 MDR risks (4.5% vs 12.5%, P < .001). In multivariate logistic regression analysis, 5 risk factors (advanced age, hematocrit <30%, malnutrition, dehydration, and chronic liver disease), as well as hypotension and inappropriate therapy were significantly correlated with 30-day mortality, whereas the classification of pneumonia type (VAP, HAP, HCAP, CAP) was not. CONCLUSIONS Individual MDR risk factors can be used in a unified algorithm to guide and simplify empiric therapy for all pneumonia patients, and were more important than the classification of site of pneumonia acquisition in determining 30-day mortality. CLINICAL TRIALS REGISTRATION JMA-IIA00146.