Yoshihito Niki

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.

The first nationwide surveillance of bacterial respiratory pathogens conducted by the Japanese Society of Chemotherapy. Part 1: a general view of antibacterial susceptibility

The Japanese Society of Chemotherapy (JSC) conducted the first nationwide surveillance of bacterial respiratory pathogens during the period from January to August 2006. With the cooperation of 32 medical institutions throughout Japan, a total of 924 strains belonging to seven clinically relevant bacterial species were collected from adult patients with well-diagnosed respiratory tract infections (RTIs). Antimicrobial susceptibility testing of the 887 evaluable strains (205 Staphylococcus aureus, 200 Streptococcus pneumoniae, 9 Streptococcus pyogenes, 165 Haemophilus influenzae, 91 Moraxella catarrhalis, 74 Klebsiella pneumoniae, and 143 Pseudomonas aeruginosa) to 42 antibacterial agents was conducted at the Central Laboratory of the Research Center for Anti-infective Drugs of the Kitasato Institute, according to recommendations issued by the Clinical and Laboratory Standards Institute (CLSI). The antibacterial agents employed were 25 β-lactams, three aminoglycosides, four macrolides (including one azalide and one ketolide), one lincosamide, one tetracycline, two glycopeptides, five fluoroquinolones, and one oxazolidinone. The incidence of methicillin-resistant S. aureus (MRSA) was 63.4%, and the incidences of penicillin-intermediately resistant S. pneumoniae (PISP) and penicillin-resistant S. pneumoniae (PRSP) were 35.0% and 4.0%, respectively. Among H. influenzae, 21.2% of the strains were found to be β-lactamase-nonproducing ampicillin (ABPC)-intermediately resistant (BLNAI), 29.1% to be β-lactamase-nonproducing ABPC-resistant (BLNAR), and 4.8% to be β-lactamaseproducing ABPC-resistant (BLPAR) strains. The incidence of extended-spectrum β-lactamase-producing K. pneumoniae was 2.7% (2 of 74 strains). Three (2.1%) of the 143 P. aeruginosa strains were found to be metallo-β-lactamaseproducing, including 1 (0.7%) multidrug-resistant strain. Through the nationwide surveillance, we obtained fundamental antimicrobial susceptibility data of clinically relevant bacterial pathogens in adult RTI to various antibacterial agents. These data will be a useful reference for future periodic surveillance studies, as well as for investigations to control antimicrobial-resistant pathogens.

Linezolid-resistant methicillin-resistant Staphylococcus aureus isolated after long-term, repeated use of linezolid

We report a 54-year-old male patient with an infection caused by linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA), isolated after long-term, repeated use of linezolid. Five MRSA strains isolated from our patient were preserved and submitted to bacteriological analysis. All five of these strains were found to have identical genotypes by pulsed-field gel electrophoresis. Two strains isolated in the early hospital period were sensitive to linezolid, while three isolated in the late hospital period were resistant. These three strains that had acquired resistance to linezolid were found to have a G2576T point mutation in the 23SrRNA domain V. Linezolid-resistant MRSA is rare, but may occur with the long-term, repeated administration of linezolid.

In vitro and in vivo activities of azithromycin, a new azalide antibiotic, against Chlamydia

The in vitro and in vivo activities of azithromycin against chlamydia were investigated. The MIC of azithromycin for five standard strains of different species of chlamydia and six wild-type strains of Chlamydia pneumoniae was 0.125 microgram/ml, which was superior to that of erythromycin but inferior to those of clarithromycin and minocycline. However, the therapeutic effect of a 7-day course of azithromycin at a dose of 10 mg/kg of body weight administered orally once daily to mice with experimental Chlamydia psittaci pneumonia was excellent, with a 100% survival rate at 14 days after infection, which was the same as that for treatment with minocycline administered at 10 mg/kg twice daily; all erythromycin treated animals died within 10 days. When treatment was discontinued 3 days after the infection, the survival rate for mice treated with azithromycin was 90% and that for mice administered minocycline was 30%. These results suggest that azithromycin may be useful in the treatment of respiratory infections caused by intracellular pathogens, including chlamydia because of its excellent accumulation within host cells.

Antibiotic susceptibility survey of blood-borne MRSA isolates in Japan from 2008 through 2011

We conducted an antibiotic susceptibility survey of 830 blood-borne methicillin resistant Staphylococcus aureus collected from nationwide hospitals in Japan over a three-year period from January 2008 through May 2011. Antibiotic susceptibility was judged according to the criteria recommended by the Clinical Laboratory Standard Institute. Over 99% of the MRSA showed to be susceptible to teicoplanin, linezolid, sulfamethoxazole/trimethoprim and vancomycin, and over 97% of them were susceptible to daptomycin, arbekacin and rifampin. The majority of the MRSA strains showed resistant to minocycline, meropenem, imipenem, clindamycin, ciprofloxacin, cefoxitin, and oxacillin in the rates of 56.6, 72.9, 73.7, 78.7, 89.0, 99.5, and 99.9%, respectively. Among the MRSA strains, 72 showed reduced susceptibility to vancomycin, including 8 strains (0.96%) of vancomycin-intermediate S. aureus (VISA), 54 (6.51%) of heterogeneous vancomycin-intermediate S. aureus (hVISA), and 55 (5.63%) of β-lactam antibiotics-induced vancomycin resistant S. aureus (BIVR). Unexpectedly, among the 54 hVISA and 55 BIVR, 45 isolates (83.3% and 81.8%, respectively) showed both hVISA and BIVR phenotypes. A new trend of vancomycin resistance found in this study was that VISA strains were still prevalent among the bacteremic specimens. The high rates of the hVISA/BIVR two-phenotypic vancomycin resistance, and the prevalence of VISA in the bloodborne MRSA call attention in the MRSA epidemiology in Japan.

Clinical efficacy and safety of micafungin in Japanese patients with chronic pulmonary aspergillosis: a prospective observational study

Aspergillosis has been the prevailing deep-seated mycosis in Japan since the 1990s. Although micafungin (MCFG) has been approved in Japan for the management of patients with such infections caused by Candida and Aspergillus species, there are relatively few reports on its use in patients with chronic pulmonary aspergillosis (CPA). Therefore, we conducted a prospective observational study to evaluate the efficacy and safety of the use of MCFG in Japanese patients with CPA. The efficacy of the antifungal was assessed on the basis of improvements in clinical symptoms and radiological findings. In addition, adverse events, including abnormal laboratory findings were determined. The overall clinical efficacy rate was 68.4% (26/38 patients), which is comparable to the results obtained in clinical trials for marketing approval conducted in Japan. Although adverse drug reactions were observed in six patients (15.8%), they were not serious. The most common of these reactions was abnormal liver functions. No relationship between the incidence of adverse drug reactions and age of the patients, MCFG dose, or duration of treatment was observed. Consequently, MCFG has favorable efficacy and safety profiles in Japanese CPA patients with various backgrounds.

Clinical viability of Fungitell, a new (1→3)-β-d-glucan measurement kit, for diagnosis of invasive fungal infection, and comparison with other kits available in Japan

Fungitell, a (1→3)-β-d-glucan (β-d-glucan) measurement kit, was approved in the United States in 2004. Three other kits for measurement of β-d-glucan, Fungitec G test MK (G-MK), β-Glucan test Wako (Wako), and β-Glucan test Maruha (Maruha), are commonly used for diagnosis of invasive fungal diseases in Japan. We evaluated the clinical viability of the Fungitell kit and compared it with the 3 kits generally used in Japan. The plasma β-d-glucan values measured with each kit showed some differences, possibly because different β-d-glucan standards, blood pretreatment methods, and kinds of horseshoe crab (a raw material for the main reagent) are used in each kit. Measures of diagnostic efficiency, for example the sensitivity, specificity, and positive and negative predictive values, varied among the kits. Although the areas under the receiver operating characteristic curves of the kits were not significantly different, the sensitivity of the Fungitell kit was the highest, followed by that of the G-MK kit. The sensitivity of the Wako and Maruha kits was low, but the specificity of these tests was higher than that of the G-MK or Fungitell kits. These inconsistent β-d-glucan measurements could interfere with diagnosis of invasive fungal infection. Early establishment of an international standard method for measurement of β-d-glucan is required.

Emergence of Linezolid-Resistant Mutants in a Susceptible-Cell Population of Methicillin-Resistant Staphylococcus aureus

ABSTRACT Methicillin-resistant Staphylococcus aureus with a MIC of linezolid of 4 μg/ml, isolated from a patient who had undergone unsuccessful linezolid therapy, yielded linezolid-resistant mutants in blood agar at 48 h of incubation. The resistant clones showed a MIC of linezolid ranging from 8 to 64 μg/ml and accumulated the T2500A mutation(s) of the rRNA genes. Emergence of these resistant clones appears to be facilitated by a cryptic mutation or mutations associated with chloramphenicol resistance.

Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

ABSTRACT Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection.

Comparative Study on the Efficacy of Liposomal Amphotericin B and Voriconazole in a Murine Pulmonary Aspergillosis Model

Background:No clinical studies have compared the efficacy of liposomal formulation AMB (L-AMB) and voriconazole (VRC) in the treatment of pulmonary aspergillosis. The aim of this study was to compare the efficacy of L-AMB and VRC in murine pulmonary aspergillosis.Methods: Leucopenic mice were infected intratracheally with Aspergillus fumigatus and treated intravenously with L-AMB (once a day) or VRC (twice a day). Results: L-AMB and VRC at a dose of ≥5 and ≥20 mg/kg, respectively, significantly prolonged the survival time of infected mice and reduced the pulmonary fungal burden in comparison with the control group. At the maximum recommended dose for clinical use, 5 mg/kg of L-AMB exhibited greater efficacy than 10 mg/kg of VRC, which achieved an area under the concentration-time curve level equivalent to that of 6 mg/kg (loading dose) in humans, in terms of increasing survival and reducing the fungal burden. Conclusion: The in vivo efficacy of L-AMB was superior to that of VRC at the maximum recommended dose in a murine pulmonary aspergillosis model.