Nobuyuki Shimono

Changing Trends in Antimicrobial Resistance and Serotypes of Streptococcus pneumoniae Isolates in Asian Countries: an Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study

ABSTRACT Antimicrobial resistance in Streptococcus pneumoniae remains a serious concern worldwide, particularly in Asian countries, despite the introduction of heptavalent pneumococcal conjugate vaccine (PCV7). The Asian Network for Surveillance of Resistant Pathogens (ANSORP) performed a prospective surveillance study of 2,184 S. pneumoniae isolates collected from patients with pneumococcal infections from 60 hospitals in 11 Asian countries from 2008 to 2009. Among nonmeningeal isolates, the prevalence rate of penicillin-nonsusceptible pneumococci (MIC, ≥4 μg/ml) was 4.6% and penicillin resistance (MIC, ≥8 μg/ml) was extremely rare (0.7%). Resistance to erythromycin was very prevalent in the region (72.7%); the highest rates were in China (96.4%), Taiwan (84.9%), and Vietnam (80.7%). Multidrug resistance (MDR) was observed in 59.3% of isolates from Asian countries. Major serotypes were 19F (23.5%), 23F (10.0%), 19A (8.2%), 14 (7.3%), and 6B (7.3%). Overall, 52.5% of isolates showed PCV7 serotypes, ranging from 16.1% in Philippines to 75.1% in Vietnam. Serotypes 19A (8.2%), 3 (6.2%), and 6A (4.2%) were the most prominent non-PCV7 serotypes in the Asian region. Among isolates with serotype 19A, 86.0% and 79.8% showed erythromycin resistance and MDR, respectively. The most remarkable findings about the epidemiology of S. pneumoniae in Asian countries after the introduction of PCV7 were the high prevalence of macrolide resistance and MDR and distinctive increases in serotype 19A.

Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins

Allogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for various hematologic disorders. Graft-versus-host disease (GVHD) and infections are the major complications of SCT, and their close relationship has been suggested. In this study, we evaluated a link between 2 complications in mouse models. The intestinal microbial communities are actively regulated by Paneth cells through their secretion of antimicrobial peptides, α-defensins. We discovered that Paneth cells are targeted by GVHD, resulting in marked reduction in the expression of α-defensins, which selectively kill noncommensals, while preserving commensals. Molecular profiling of intestinal microbial communities showed loss of physiologic diversity among the microflora and the overwhelming expansion of otherwise rare bacteria Escherichia coli, which caused septicemia. These changes occurred only in mice with GVHD, independently on conditioning-induced intestinal injury, and there was a significant correlation between alteration in the intestinal microbiota and GVHD severity. Oral administration of polymyxin B inhibited outgrowth of E coli and ameliorated GVHD. These results reveal the novel mechanism responsible for shift in the gut flora from commensals toward the widespread prevalence of pathogens and the previously unrecognized association between GVHD and infection after allogeneic SCT.

Community spread of extended-spectrum β-lactamase-producing Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis: a long-term study in Japan

Community-acquired infections caused by extended-spectrum β-lactamase (ESBL)-producing bacteria, particularly CTX-M-producing Escherichia coli, are a rising concern worldwide. There are few data from Japan on the acquisition of ESBLs in the community or the influx of these bacteria into hospitals. Therefore, we examined the prevalence of ESBL carriage in outpatients, in order to estimate the spread of ESBLs in community settings. We analysed bacterial isolates from outpatient samples at our institution over a 9-year period from 2003 to 2011, with respect to epidemiological data on ESBL-producing bacteria and their genotypic features. Out of 5137 isolates, 321 (6.3 %) were ESBL producers, including E. coli, Klebsiella pneumoniae and Proteus mirabilis. The detection rates of the ESBL-producing isolates gradually increased and reached 14.3, 8.7 and 19.6 % for E. coli, K. pneumoniae and P. mirabilis strains, respectively, in 2011. Genotyping analysis showed that many of the strains produced multiple β-lactamases, including TEM, SHV and CTX-M, rather than just CTX-M. The CTX-M-9 group was dominant among the CTX-M genotypes; further, the CTX-M-1 and M-2 groups were also detected (~30 %). This is believed to be the first report from Japan showing a definite increase in ESBL detection in outpatients. In addition, our findings suggest the simultaneous community spread of diverse ESBL genotypes, not an expansion of particular ESBL genes.

An outbreak of Pseudomonas aeruginosa infections following thoracic surgeries occurring via the contamination of bronchoscopes and an automatic endoscope reprocessor

An outbreak of Pseudomonas aeruginosa infections occurred after thoracic surgeries performed between May and June 2003. Clinical data of seven patients were reviewed and the fact was revealed that bronchoscopes were used during endotracheal intubation for one-lung ventilation in most patients. P. aeruginosa was recovered from the sputum of these patients at a very early stage post-operation. Environmental samples from bronchoscopes and an automated endoscope reprocessor (AER) were cultured and P. aeruginosa strains were recovered from all of them. All of these strains were confirmed to be identical by pulsed-field gel electrophoresis (PFGE). Inspection of the sterilization cycles of bronchoscopes revealed inappropriate management of bronchoscopes and a flaw in the AER; once its detergent tank was contaminated, it was not possible to disinfect it. After all the bronchoscopes had been disinfected, and the washing machine had been remodeled, with the washing process confirmed to be appropriate, the outbreak finally ended. This outbreak had two causes, a flaw in the AER and inappropriate disinfection procedures. Outbreaks associated with bronchoscopic examinations have been reported elsewhere. Bronchoscopes are widely used to facilitate endotracheal intubation, especially for one-lung anesthesia. Although they are used for only a short time during anesthetic procedures, we should handle them more carefully.

Fulminant hepatic failure during perinatal period in a pregnant woman with Wilson's disease.

SummaryWilson’s disease associated with hepatic failure is not common and the underlying mechanism triggering the event is not known at present. We treated a 28-year-old Japanese woman with Wilson’s disease who developed hepatic failure associated with hemolytic crisis just after delivery. She was diagnosed as having Wilson’s disease at 12 years of age, at which time she started taking D-penicillamine. She had previously delivered two children without difficulty. When she found out she was pregnant this time, she stopped taking D-penicillamine in contrast to taking it faithfully during her first two pregnancies. On the day of delivery of her full-term baby, jaundice developed accompanied with severe hemolytic crisis. Plasma exchanges and blood transfusion were performed and D-penicillamine administration was started again. She gradually recovered and apparently was following a good clinical course. However, on day 30 the second hemolytic crisis occurred and subsequent liver failure led her to death on day 50. At autopsy her liver was cirrhotic and showed massive necrosis. Prophylactic oral administration of D-penicillamine and careful observation are therefore recommended to prevent hemolytic crisis during the perinatal period.

High incidence of false-positive Aspergillus galactomannan test in multiple myeloma†

Invasive aspergillosis (IA) remains one of the most significant causes of morbidity and mortality in patients with hematological malignancies undergoing chemotherapy and hematopoietic stem cell transplantation (HSCT), mainly due to the difficulty in its early diagnosis. Monitoring of galactomannan (GM) antigen, an exoantigen of Aspergillus, in the blood by sandwich ELISA is a useful and noninvasive method for early diagnosis of IA. The GM test has a sensitivity of 67-100% with a specificity of 81-99% in neutropenic patients and allogeneic transplant recipients [1-3]. Although it has been widely used as a diagnostic criterion for IA [4,5], one of the major limitations of this assay is false-positivity, particularly in pediatric patients [1], patients with graft-versus-host disease (GVHD) [6,7], and those taking dietary GM [8,9] or fungus-derived antibiotics, such as piperacillin-tazobactam (PIPC/TAZ) [10-12].

Clonal spread in Eastern Asia of ciprofloxacin-resistant Escherichia coli serogroup O25 strains, and associated virulence factors

A significant problem in the field of infectious diseases is the increase in fluoroquinolone (FQ)-resistant Escherichia coli. Although mutation of strains and clonal dissemination are supposed to be the cause of this increase, little is known about the prevalence of this organism. We investigated 219 FQ-resistant E. coli strains in Japan and nine Asian countries by serotyping and genotyping. Seventy-one strains (32.4%) were serogroup O25, which was prevalent in South Korea, China and Japan, especially in the southwest part of Japan. Aerobactin, a virulence factor in uropathogenic and avian pathogenic E. coli, was associated with the presence of FQ-resistant O25 strains of E. coli. Seven of the seventy-one FQ-resistant E. coli O25 had extended-spectrum beta-lactamase genes (six CTX-M-14 and one SHV-12), however, we were unable to find any E. coli O25-ST131 clone that produced CTX-M-15, which was previously reported to have emerged across continents. These data demonstrate that a clonal group of FQ-resistant and virulent E. coli recently became prevalent at least in East Asia and suggest that this might become a public health problem because the strains may acquire resistance to other antimicrobial agents.

Decreased secretion of Paneth cell α-defensins in graft-versus-host disease

Intestinal microbial ecology is actively regulated by Paneth cell‐derived antimicrobial peptides, α‐defensins. Graft‐versus‐host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (SCT). We previously demonstrated that Paneth cells are targeted by GVHD, and their expression of antimicrobial peptide α‐defensins is impaired, leading to a loss of physiological diversity among the microflora and development of bloodstream infection. Herein, we evaluated whether fecal levels of α‐defensins could be surrogate marker of intestinal dysbiosis.

Geographic distribution of fluoroquinolone-resistant Escherichia coli strains in Asia.

Fluoroquinolone (FQ) resistance is usually caused by point mutations within the quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC and/or parE. However, little is known about the worldwide increase in FQ-resistant Escherichia coli or, more specifically, about the geographical distribution of QRDR mutations and the clonal spread of isolates. In this study, we analysed 68 FQ-resistant E. coli isolates from eight Asian countries using QRDR amino acid mutation patterns and examined their susceptibility to FQs. Of the isolates, 38% had mutations at S83 and D87 of GyrA and S80 of ParC (MM/-/M-/-) and 34% had mutations at S83 and D87 of GyrA, S80 of ParC and S458 of ParE (MM/-/M-/M). MIC(50) values (minimum inhibitory concentrations for 50% of the isolates) for isolates with at least mutation at S458 of ParE for ciprofloxacin and prulifloxacin were relatively higher than MIC(50) values of isolates without this mutation. Based on their geographic distribution and the QRDR mutation patterns, the isolates were divided into a common type in which the organisms were isolated from three or more countries, and a local type in which the isolates were from one or two countries. Mutation types at S83L and D87N in GyrA and S80I in ParC with no or another site in the QRDR were the most frequent among the FQ-resistant isolates, especially among the common type. Gene typing indicated that isolates in the common type were not similar between countries. These data suggest that the increase in FQ-resistant E. coli strains is mainly generated by mutations in the QRDR in each geographical area rather than through intercontinental spread.

Combination therapy with micafungin and amphotericin B for invasive pulmonary aspergillosis in an immunocompromised mouse model

OBJECTIVES Antifungal monotherapy with polyenes, azoles or echinocandins is not always effective for invasive pulmonary aspergillosis (IPA). The main purpose of this study was to evaluate the efficacy of a combination of micafungin and amphotericin B for the primary treatment of IPA in an immunocompromised mouse model. METHODS Female ICR mice were used in all experiments. An immunosuppressive state was induced in mice by an intraperitoneal injection of cyclophosphamide. Mice were intratracheally inoculated with Aspergillus fumigatus conidia, treated with micafungin, amphotericin B or both for 7 days, and were tested for their survival 20 days after the Aspergillus inoculation. Fungal burden in lungs, serum galactomannan index (GMI) and histopathology of lungs, spleen and kidneys were also evaluated. RESULTS Combination therapy with micafungin and amphotericin B gave excellent survival of infected mice compared with monotherapy with micafungin or amphotericin B alone. Combined therapy reduced the fungal burden in the lungs and the serum GM levels compared with monotherapy or untreated controls, resulting in a significant histological improvement with disappearance of fungi in the lungs. CONCLUSIONS These findings suggest that combination therapy with micafungin and amphotericin B is more effective compared with monotherapy with either of them alone for IPA treatment.