The antimicrobial resistance of pathogens in otolaryngological infections such as acute otitis media, acute rhinosinusitis has been big problems in Japan and Asian countries. Such prevalence of drug-resistant microbes has been compelling force to reconsider the treatment guideline of infectious diseases. Rapid increase of intractable otitis media in children, however, might have been caused by several factors, i. e., immaturity of host immunity, drastic changes of life environment in children such as day-care attendance, short feeding with breast milk, and antimicrobial resistant pathogens. To cope with such intractable otitis media, we should select appropriate antimicrobial agents based on the treatment guideline using the scoring and severity system and employ approaches based on the PK/PD theory.

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We studied the prevalence, antimicrobial susceptibility, and performance in the screening of metallo-β-lactamase (MBL)-producing gram-negative bacilli from clinical specimens at Juntendo University Hospital from 2001 to 2005. A total of 352 nonduplicate strains were screened for MBL production by the routine antimicrobial susceptibility test and disk approximation test using the sodium mercaptoacetic acid (SMA) test. Of these, 247 MBL-positive strains were detected in genes for the IMP-1 group (blaI_MP-1) by PCR in 79 (32.0%) for Pseudomonas aeruginosa, 38 (15.4%) for Pseudomonas putida/fluorescens, 37 (15.0%) for Acinetobacter spp., 11 (4.5%) for Achromobacter spp., 6 (2.4%) for Alcaligenes spp., 50 (20.2%) for Enterobacter cloacae, 12 (4.9%) for Citrobacter freundii, 7 (2.8%) for Providencia rettgeri, 3 (1.2%) for Serratia marcescens, 3 (1.2%) for Klebsiella spp., and 1 (0.4%) for Escherichia coli. No strains were detected in genes for the IMP-2 group (bla_IMP-2) or VIM-2 group (bla_VIM-2). There was no significant increase in number of IMP-1 group positive strains in the last 5 years except P. aeruginosa and E. cloacae. IMP-1 group positive P. aeruginosa and E. cloacae represented slightly increase in 2005 and 2003 to 2005, respectively. Susceptibility to the 10 antimicrobial agents of IMP-1 group-positive strains was species-dependent. Most strains of Pseudomonas spp., Acinetobacter baumannii, Achromobacter spp., and S. marcescens were highly and multiresistant to antimicrobials, including carbapenems and broadspectrum β-lactams, aminoglycosides, and fluoroquinolones. Among the family Enterobacteriaceae other than S. marcescens, Acinetobacter lwoffii and Alcaligenes spp. were frequently susceptible to carbapenems. IMP-1group-positive strains have been detected most frequently in P. aeruginosa and disseminated to other glucosenonfermenters and Enterobacteriaceae at our hospital and nationwide. The incidence of MBL-producing P. aeruginosa was ranged from 0.3 to 1.5% in the last 5 years. In contrast, the incidence of multidrug-resistant P. aeruginosa characterizing as following two combinations: resistant to imipenem, gentamicin, and levofloxacin; resistant to imipenem, levofloxacin, and intermediate or resistant to amikacin have annually increased 3.7% and 3.9%, respectively in 2005. These results emphasize the need for daily surveillance of MBL-producing bacteria with both routine antimicrobial susceptibility tests and SMA tests in the microbiology laboratory.

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We analyzed 79 patients administered vancomycin hydrochloride (Vancomycin: VCM) to treat methicillinresistant Staphylococcus aureus (MRSA) from April 2003 through March 2006. In Pharmacokinetics/Pharmacodynamics (PK/PD) theory, the ratio of the area under the concentration-time curve over 24 hours to the minimum inhibitory concentration (AUC₂₄/MIC) of VCM is related to clinical outcome. According to MIC distributions for VCM against MRSA in this study, MICs in the non-treated group of patients with VCM were 1.0μg/mL, whereas nearly half of the patients treated group with VCM showed MIC of 2.0μg/mL. Among those treated with VCM, the respiratory tract, a difficult-to-reach site for VCM, accounted for 46.8% of all infection sites. In PK/PD theory, these results indicate that patients may possibly be difficult to treat. In fact, effectiveness was 51.6%(16/31) in non-TDM patients and 75.0%(36/48) in TDM patients. Despite its apparent usefulness, 35.4%(17/48) of TDM patients whose dosage was not adjusted based on PK/PD theory did not achieve sufficient blood levels, suggesting the possibility of poor therapeutic outcome. In TDM of VCM, dosage adjustment based on PK/PD theory thus appears vital to ensure safety and enhanced effectiveness. Serum albumin analyzed between successful and unsuccessful cases in patients treated with VCM therapy was significantly lower in unsuccessful than successful cases (p<0.01). To achieve better therapeutic outcome, both treatment with antimicrobial agents and nutritional support thus appear necessary.

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The development of therapy-related leukemia (TRL) and myelodysplastic syndrome (T-MDS) are the most serious complications of intensive cancer chemotherapy and radiotherapy. We report 6 cases-3 each-of TRL and T-MD after treatment for solid cancers. The primary solid cancers involved were 2 cases each of nonsmall-cell lung cancer and renal cell cancer and 1 case each of esophageal cancer, small-cell lung cancer, gastric cancer, and prostate cancer, including 2 cases of double cancer (small-cell lung cancer+prostate cancer and esophageal cancer + renal cell cancer). Post operative chemotherapy was conducted to treat solid cancers in 3 cases, combined therapy consisting of chemotherapy and radiotherapy in 2 cases, and surgical therapy alone in 1 case. The median interval from the primary solid cancer to TRL or T-MDS was 30 months (23-108). In 4 of the 6 cases, the abnormal karyotypes were observed in chromosomal analysis at bone marrow. Although 2 of 3 TRL cases were treated by combination chemotherapy, neither achieved complete remission (CR). In another case of TRL classified as M3 type based on the French-American-British classification, CR was achieved following treatment by all-trans retinoic acid. No cases of T-MDS underwent chemotherapy, but were treated with palliative care alone. Of the 6 cases reported here, 2 with T-MDS are alive and 4 have died. One died due to primary solid cancer (small-cell lung cancer), and the other 3 due to TRL or T-MDS.
An improved understanding of clinical and biological features of TRL and T-MDS is essential for successful preventing these disorders.

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A 78-year-old woman with severe stenoses in all of three branches of the coronary artery underwent coronary artery bypass grafting. Cefozopran (CZOP) was administrated because it was diagnosed a mediastinitis on day 34th after surgey and also Klebsiella pneumoniae was detected from the mediastinal fluid. On day 39th after surgey, the microbial substitution was occurred, and methicillin-resistant Staphylococcus aureus (MRSA) was detected. In consideration of renal dysfunction, arbekacin and vancomycin were not used and teicoplanin (TEIC) alone was administered. We considered that the initial dosage recommended in the package insert exhibited little effect on severe MRSA mediastinitis and maintained TEIC blood trough levels at ≥20 μg/mL (400-200mg/day) with therapeutic drug monitoring (TDM) during early administration. Clinical symptoms and test results improved to where MRSA was no longer detected. TEIC administration was halted on administration day 50.
TEIC administration at recommended doses of 5 to 10μg/mL exhibits no effect on most MRSA-infected patients, and TEIC dosage and concentration should be reviewed. A new treatment option for MRSA mediastinitis is to maintain TEIC blood trough levels at 20μg/mL or higher under positive TDM.

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