Shunji Takakura

Practice guidelines for therapeutic drug monitoring of voriconazole: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring

Arbekacin (ABK) was approved and widely used in Japan for treatment of patients infected with MRSA, and TDM was introduced in clinical practice. The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring decided to develop a clinical practice guidelines for TDM of ABK for the following reasons. First, although the daily dose of 150e200 mg was approved in Japan, recent PK- PD studies revealed that higher serum concentration is required to achieve better clinical efficacy and several findings concerning the usefulness of higher dosage regimen have obtained recently. Second, although maximal concentrations that obtained immediately after the end of administration (Cmax )w as generally adopted, the serum concentration at 1 h after initiation of administration (peak serum con- centration (Cpeak)) proved to be more suitable as an efficacy indicator of aminoglycosides. Lastly, as ABK is approved only in Japan, no international practice guideline for TDM has not been available in ABK to date. This guideline evaluated the scientific data associated with serum ABK monitoring and provided rec- ommendations based on the available evidence. Potential limitations of this guideline, however, include the findings that few prospective clinical trials of TDM of ABK are available in the treatment of MRSA infections and that most of the published literature describes observational studies.

Emergence and spread of B2-ST131-O25b, B2-ST131-O16 and D-ST405 clonal groups among extended-spectrum-β-lactamase-producing Escherichia coli in Japan

OBJECTIVES The increasing prevalence of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli has been associated with the emergence of the CTX-M-producing sequence type 131 (ST131) pandemic clonal group, a member of the O25b serogroup and the B2 phylogenetic group. To assess the clonal spread of ESBL-producing E. coli in Japan, a regional surveillance programme was conducted. METHODS A total of 581 ESBL-producing clinical specimen E. coli isolates were collected between 2001 and 2010. Clonal groups, including ST131, D-ST405, D-ST393 and D-ST69, were determined using the PCR O type, phylogenetic grouping by triplex PCR, allele-specific PCR and multilocus sequence typing (MLST). A subset of clonal groups underwent PFGE. RESULTS Among clonal strains, 215 isolates (37%) were identified as belonging to the ST131 group, 185 as B2-ST131-O25b (32%), 26 as B2-ST131-O16 (4%), 3 as B1-ST131-O25b (0.5%) and 1 as B2-ST131-O-non-typeable (0.1%). Forty-one isolates (7%) were identified as belonging to the D-ST405 clonal group, seven (1%) as D-ST69 and two (0.3%) as D-ST393. The B2-ST131-O16 clonal group was characterized by CTX-M-14 and a significantly lower ciprofloxacin resistance rate than the B2-ST131-O25b clonal group. The B2-ST131-O16 and B2-ST131-O25b clonal groups each made up a single PFGE cluster, with 65% similarity. The rate of ESBL-producing E. coli increased over the years (0.2% in 2001 to 9.7% in 2010) and corresponded to increases in the numbers of the B2-ST131-O25b, B2-ST131-O16 and D-ST405 clonal groups. CONCLUSIONS The B2-ST131-O25b, B2-ST131-O16 and D-ST405 clonal groups have contributed to the spread of ESBL-producing E. coli in Japan.

Identifying Pathogenic Genetic Background of Simplex or Multiplex Retinitis Pigmentosa Patients: A Large-Scale Mutation Screening Study

Background and purpose: More than half of the retinitis pigmentosa (RP) cases are genetically simplex or multiplex. To date, 37 causative genes of RP have been identified; however, the elucidation of gene defects in simplex or multiplex RP patients/families remains problematic. The aim of our study was to identify the genetic causes of RP in patients with unknown or non-Mendelian inheritance. Methods and results: Since 2003, 52 simplex RP patients, 151 patients from 141 multiplex RP families, and six sporadic patients with retinal degeneration were studied. A total of 108 exons of 30 RP-causing genes that harboured the reported mutations were screened by an efficient denaturing high performance liquid chromatography (dHPLC) based assay. Aberrant fragments were subsequently analysed by automatic sequencing. Twenty-six mutations, including two frameshift mutations, one single amino acid deletion, and 23 missense mutations, were identified in 28 probands (14.07%). Eighteen mutations have not been reported to date. Three pairs of combined mutations in different genes were identified in two sporadic cases and one multiplex family, indicating the possibility of novel digenic patterns. Of the 23 missense mutations, 21 were predicted as deleterious mutations by computational methods using PolyPhen, SIFT, PANTHER, and PMut programs. Conclusion: We elucidated the mutation spectrum in Japanese RP patients and demonstrated the validity of the mutation detection system using dHPLC sequencing for genetic diagnosis in RP patients independent of familial incidence, which may provide a model strategy for identifying genetic causes in other diseases linked to a wide range of genes.

Clinical characteristics of Pneumocystis pneumonia in non-HIV patients and prognostic factors including microbiological genotypes

BackgroundThe number of patients with non-HIV Pneumocystis pneumonia (PCP) is increasing with widespread immunosuppressive treatment. We investigated the clinical characteristics of non-HIV PCP and its association with microbiological genotypes.MethodsBetween January 2005 and March 2010, all patients in 2 university hospitals who had been diagnosed with PCP by PCR were enrolled in this study. Retrospective chart review of patients, microbiological genotypes, and association with 30-day mortality were examined.ResultsOf the 82 adult patients investigated, 50 patients (61%) had inflammatory diseases, 17 (21%) had solid malignancies, 12 (15%) had hematological malignancies, and 6 (7%) had received transplantations. All patients received immunosuppressive agents or antitumor chemotherapeutic drugs. Plasma (1→3) β-D-glucan levels were elevated in 80% of patients, and were significantly reduced after treatment in both survivors and non-survivors. However, β-D-glucan increased in 18% of survivors and was normal in only 33% after treatment. Concomitant invasive pulmonary aspergillosis was detected in 5 patients. Fifty-six respiratory samples were stored for genotyping. A dihydropteroate synthase mutation associated with trimethoprim-sulfamethoxazole resistance was found in only 1 of the 53 patients. The most prevalent genotype of mitochondrial large-subunit rRNA was genotype 1, followed by genotype 4. The most prevalent genotype of internal transcribed spacers of the nuclear rRNA operon was Eb, followed by Eg and Bi. Thirty-day mortality was 24%, in which logistic regression analysis revealed association with serum albumin and mechanical ventilation, but no association with genotypes.ConclusionsIn non-HIV PCP, poorer general and respiratory conditions at diagnosis were independent predictors of mortality. β-D-glucan may not be useful for monitoring the response to treatment, and genotypes were not associated with mortality.

CTX-M-27- and CTX-M-14-producing, ciprofloxacin-resistant Escherichia coli of the H30 subclonal group within ST131 drive a Japanese regional ESBL epidemic

OBJECTIVES The global increase in ESBL-producing Escherichia coli is associated with the ST131 clonal group, especially its CTX-M-15-producing H30Rx subset. To understand the rapid spread of ESBL-producing E. coli in Japan, we investigated the molecular epidemiology and ESBL-associated genetic environments of Japanese ST131 isolates. METHODS Between 2001 and 2012, 1079 ESBL-producing E. coli isolates were collected at 10 Japanese acute-care hospitals. ESBL types, ST131 status, fimH allele, H30Rx-defining sequences and ESBL-associated genetic environments were defined using PCR and sequencing. Subclonal groups were defined based on fimH allele and H30Rx status. RESULTS Overall, 461 (43%) of the 1079 ESBL-producing E. coli isolates represented ST131. According to fimH-based subclonal typing, the ST131 isolates included 398 fimH allele 30 (H30) isolates, 49 H41 isolates, 10 H22 isolates and 4 other fimH-type isolates. The 398 H30 isolates included 396 ciprofloxacin-resistant H30R isolates, of which 64 (16%) represented the H30Rx subset. Between 2001 and 2007, the CTX-M-14-producing H30R subgroup predominated, accounting for 46% of ST131 isolates, whereas the CTX-M-27-producing H30R and CTX-M-15-producing H30Rx subgroups were rarely detected. In contrast, from 2008 onward the latter two subgroups rose to dominance, accounting for 45% and 24% of ST131 isolates, respectively, versus only 15% for the (formerly dominant) CTX-M-14-producing H30R subgroup. The emergent CTX-M-27-H30R subgroup frequently had an IS26-ΔISEcp1-blaCTX-M-27-ΔIS903D-IS26-like structure, whereas the older CTX-M-14-H30R subgroup frequently had an ISEcp1-blaCTX-M-14-IS903D-like structure. CONCLUSIONS This Japanese regional ESBL-producing E. coli epidemic is closely associated with newly identified CTX-M-27- and CTX-M-14-producing ST131 H30R subclonal groups and with mobile elements IS26, ISEcp1 and IS903D.

Pretransplant serum ferritin and C-reactive protein as predictive factors for early bacterial infection after allogeneic hematopoietic cell transplantation.

Although fluoroquinolones or other antibiotics are commonly used to prevent bacterial infections after hematopoietic cell transplantation (HCT), because of the growing presence of multidrug-resistant microorganisms, it is important to identify patients who are more likely to benefit from antibacterial prophylaxis. To evaluate risk factors for early bacterial infection after allogeneic HCT, we retrospectively analyzed clinical data for 112 consecutive adult patients with hematological malignancies who received transplants without any antibacterial prophylaxis. The cumulative incidence of bacterial infection at 30 days after transplantation was 16%. Among various pre-transplant factors, only high serum ferritin (>700 ng/mL, 47 patients) and high C-reactive protein (CRP) (>0.3 mg/dL, 28 patients) levels were significantly associated with the development of bacterial infection in a multivariate analysis (hazard ratio (95% confidence interval): ferritin, 4.00 (1.32–12.17); CRP, 3.64 (1.44–9.20)). In addition, septic shock and sepsis with organ failure were exclusively observed in patients who had high ferritin and/or high CRP levels. These results suggest that pretransplant serum ferritin and CRP levels can be useful markers for predicting the risk of early bacterial infection after allogeneic HCT. It may be prudent to limit antibacterial prophylaxis to patients with predefined risk factors to ensure the safety of HCT with the use of fewer antibiotics.

Association of fluoroquinolone resistance, virulence genes, and IncF plasmids with extended-spectrum-β-lactamase-producing Escherichia coli sequence type 131 (ST131) and ST405 clonal groups.

ABSTRACT The global increase of extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli is associated with the specific clonal group sequence type 131 (ST131). In order to understand the successful spread of ESBL-producing E. coli clonal groups, we characterized fluoroquinolone resistance determinants, virulence genotypes, and plasmid replicons of ST131 and another global clonal group, ST405. We investigated 41 ST131-O25b, 26 ST131-O16, 41 ST405, and 41 other ST (OST) ESBL-producing isolates, which were collected at seven acute care hospitals in Japan. The detection of ESBL types, fluoroquinolone resistance-associated mutations (including quinolone resistance-determining regions [QRDRs]), virulence genotypes, plasmid replicon types, and IncF replicon sequence types was performed using PCR and sequencing. blaCTX-M, specifically blaCTX-M-14, was the most common ESBL gene type among the four groups. Ciprofloxacin resistance was found in 90% of ST131-O25b, 19% of ST131-O16, 100% of ST405, and 54% of OST isolates. Multidrug resistance was more common in the ST405 group than in the ST131-O25 group (56% versus 32%; P = 0.045). All ST131-O25b isolates except one had four characteristic mutations in QRDRs, but most of the isolates from the other three groups had three mutations in common. The ST131-O25b and ST405 groups had larger numbers of virulence genes than the OST group. All of the ST131-O25b and ST405 isolates and most of the ST131-O16 and OST isolates carried IncF replicons. The most prevalent IncF replicon sequence types differed between the four clonal groups. Both the ST131-O25b and ST405 clonal groups had a fluoroquinolone resistance mechanism in QRDRs, multidrug resistance, high virulence, and IncF plasmids, suggesting the potential for further global expansion and a need for measures against these clonal groups.

Detection of Extended-Spectrum-β-Lactamase-Producing Escherichia coli ST131 and ST405 Clonal Groups by Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry

ABSTRACT Escherichia coli sequence type 131 (ST131) and ST405 are important clonal groups, because they are associated with the global increase of extended-spectrum-β-lactamase (ESBL) producers. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) is emerging as a rapid, inexpensive, and accurate method for bacterial identification. We investigated the detection performance of MALDI-TOF for the ST131 and ST405 clonal groups using 41 ST131-O25b, 26 ST131-O16, and 41 ST405 ESBL-producing isolates and 41 ESBL-producing isolates frrom other STs. The main spectra representing each clonal group were used for classification with Biotyper (Bruker Daltonics GmbH, Bremen, Germany). The peak that had the highest area under the receiver-operating characteristic curve generated by ClinProTools (Bruker) was detected with FlexAnalysis (Bruker), and an optimal signal-to-noise ratio cutoff was determined. The optimal detection models were generated by ClinProTools. Classification by Biotyper could detect the ST131-whole (O25b and O16 together) group with a sensitivity of 98.5% and a specificity of 93.9%. With FlexAnalysis, a peak of 9,720 Da detected the ST131-whole group with a sensitivity of 97.0% and a specificity of 91.5% at a cutoff value of 8.0. The ClinProTools models exhibited good performance for the detection of the ST131-whole group (sensitivity and specificity, 94.0% and 92.7%, respectively), the ST131-O25b group (95.1% and 98.2%, respectively), and the ST405 group (90.2% and 96.3%, respectively). MALDI-TOF MS had high detection performance for the ST131-whole, ST131-O25b, and ST405 clonal groups. MALDI-TOF MS should be considered as an alternative method to monitor the epidemiology of the ESBL-producing E. coli ST131 and ST405 clonal groups.

Environmental Risk Factors for Pulmonary Mycobacterium avium-intracellulare Complex Disease

BACKGROUND Mycobacterium avium-intracellulare complex (MAC) is a ubiquitous pathogen found in soil and water. Environmental exposure is the primary route for MAC infection. However, specific environmental risk factors have been poorly determined in immunocompetent patients with pulmonary MAC disease. METHODS A case-control study was performed with 106 patients with pulmonary MAC disease (men [women], 23 [83]; age, 64.3 ± 9.2 years) and 53 age-matched control patients with bronchiectasis but not pulmonary MAC infection (men [women], 7[46]; age, 63.0 ± 11.0 years). All participants completed a standardized questionnaire that included questions about medical history, smoking history, alcohol usage, age at menopause, and environment exposures. Environment exposures included soil exposure from farming or gardening; water exposure from bathing, showering, hot tub use, dishwashing, swimming, and drinking water; and pet exposure. RESULTS No differences were identified in the patient characteristics and underlying diseases. More case patients experienced high soil exposure (≥ 2 per week) than control patients (23.6% vs 9.4%, P = .032); this remained significant after multivariate analysis (OR, 5.9; 95% CI, 1.4-24.7; P = .015). There were no significant differences in other environmental exposures. Case patients with high soil exposure were significantly older than those with low soil exposure (67.3 ± 7.3 years vs 64.3 ± 9.5 years, P = .037). Other characteristics, underlying diseases, and mycobacterial species did not differ between the two groups. CONCLUSIONS Patients with pulmonary MAC disease had significantly more soil exposure than noninfected control patients, which suggests that environmental soil exposure is a likely risk factor for the development of pulmonary MAC disease.

Surgical site infection due to Mycobacterium peregrinum: a case report and literature review

OBJECTIVES Mycobacterium peregrinum is a species included in the Mycobacterium fortuitum complex, a member of the group of rapidly growing non-tuberculous mycobacteria (RGM). Only a few cases of infection with M. peregrinum have been reported, and no relevant review has been published. METHODS Following the treatment of a patient with M. peregrinum infection after plastic surgery, we undertook a review of the literature of previously reported cases of M. peregrinum infection. RESULTS Ten previously reported cases were identified. Like other cases of the M. fortuitum complex infections, the majority of M. peregrinum infections were related to surgical site infections and catheter-related infections. In the literature, most of the antibiotic regimens were based on a combination of quinolones with various antibiotics, and the duration of treatment ranged from 6 weeks to 4 months. CONCLUSION The fact that the optimal treatment for M. peregrinum infection has not yet been established has resulted in the use of a diverse range of therapies. It is important that clinicians carefully review each case so that a more appropriate treatment for M. peregrinum infections can be determined.