To establish the appropriate dosage of teicoplanin (TEIC), an antibiotic against methicillin-resistant Staphylococcus aureus (MRSA), we investigated covariates of the interindividual variability in pharmacokinetics using the NONMEM program. The subjects were 120 adult patients who were not on hemodialysis. These patients received TEIC upon admission to our hospital and underwent measurements of their serum TEIC concentrations. We adopted a two-compartment model and assumed an interindividual variability in TEIC clearance (CL), the central volume of distribution (V), and the transfer rate constant, k₂₁, between the two compartments. In our investigation of variation factors, we adopted single or combination models of creatinine clearance (Ccr), serum albumin (Alb), and body weight (wt), which have been found to affect the pharmacokinetics of TEIC. The best-fit model was selected by comparison of the objective functions (OBJ). This model included weight and Ccr or Ccr/Alb as variation factors of CL.
CL=0.00498 × Ccr+0.00426 × wt (L/h)
CL=0.0117 × Ccr/Alb+0.00468 × wt (L/h)
Although the OBJ in the model including Ccr/Alb was slightly better than that in the model including Ccr, there was little difference in the precision of the measurement. The interindividual variability of CL in the final models (22%) was less than half of that in base model (46.9%). Given these variation factors, more than half of the interindividual variability of CL can be accounted for. Because the final models are built on broad Ccr patient data, we expect these models to be useful for more accurate dosing programs in clinical situations.

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Population pharmacokinetic parameters of biapenem (BIPM), a carbapenem antibiotic, were generated by a nonlinear mixed effects model using the NONMEM program based on plasma concentrations in patients and healthy subjects. A total of 384 plasma samples were collected from 66 subjects, and their demographic background data were recorded. The data obtained were analyzed using the two-compartment model. The covariates (age, weight [Wt], creatinine clearance [Ccr]) and one factor (the effect of disease) were tested for an effect on the pharmacokinetics of BIPM. Population pharmacokinetic parameters were not related to the effect of disease. Total clearance (CL) was found to be associated with Ccr, and the volume of distribution of the central compartment (V1) was associated with Wt. The volume of distributionof the peripheral compartment (V2) was not associated with Wt. The final formulae for the population mean parameters were: CL=0.0720×Ccr+3.04 (L/h), V1=0.0990×Wt (L), inter-compartmental clearance (Q)=13.5 (L/h), V2=7.00 (L).The validity of the model has been evaluated by the bootstrapping method. The time above the MIC's (T>MIC) were estimated from the plasma concentration profiles calculated based on population mean parameters and MICe s in order to create tables for establishment of dosing regimens for BIPM.

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Few large-scale studies have studied the optimal administration of arbekacin (ABK), an anti-MRSA drug. In this study, we compared the efficacy between once and twice daily administrations of ABK in patients with MRSA pneumonia to determine the optimal administration method based on pharmacokinetic (PK) and pharmacodynamic (PD) parameters. The subjects were patients with MRSA pneumonia in whom ABK had been administered at a dose of 200mg per day and who had been treated between April 1998 and March 2005. All medical records were investigated retrospectively. The serum concentrations at 1 hour after ABK administration on administration days 3 to 7 were defined as the maximum serum concentrations (Cpeak), and the serum concentrations immediately before administration were regarded as the minimum blood concentrations (Ctrough). The endpoints were clinical and bacteriological efficacy and the existence/absence of renal dysfunction. One hundred eleven patients were eligible for analysis. When single and repeated administration regimens were compared using the x² test, single administration regimen produced significantly better results and clinical efficacy (p=0.048). In multiple logistic regression analyses, the significant index for clinical efficacy was Cpeak [p=0.008, Odds ratio (OR)=1.27, 95% confidential interval (95% CI)=1.06-1.57], that for bacteriological efficacy was Cpeak/MIC [p=0.016, OR=1.22, 95% CI=1.04-1.77], and those for onset of renal dysfunction were Ctrough [p=0.002, OR=2.00, 95% CI=1.32-3.34] and patient's age [p=0.046, OR=1.06, 95% CI=1.01-1.14]. A target Ctrough value according to age should be established to prevent renal dysfunction. Further studies are required to establish the upper limit of the Cpeak value.

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The frequency of the involvement of atypical microorganisms (Chlamydophila pneumoniae, Chlamydophila psittaci, Mycoplasma pneumoniae, and Legionella pneumophila) at the initial consultation for respiratory infections (pneumonia, bronchitis, pharyngolaryngitis and tonsillitis) was investigated by determining the serum antibody titers and urinary antigen levels of patients.
The subjects were the outpatients aged 20 years or over who had made an initial consultation for a respiratory infection. Five hundred thirty-two patients who visited 59 practitioner offices in 4 districts of Japan (Nagasaki, Okayama, Niigata, and Sendai) between April 2003 and June 2003 were analyzed.
Atypical microorganism were present in 99 patients (19%). The rates of positivity for each microorganism were 15% for C. pneumoniae, 4% for C. psittaci, 2% for M. pneumoniae and 0% for L. pneumophila. None of the patients tested positive for the urinary antigen of L. pneumophila. The rates of positive patients with atypical microorganisms according to disease were 19% for pneumonia, 20% for bronchitis, 19% for pharyngolaryngitis and 22% for tonsillitis; the rate was 11% for patients with two of these diseases. No tendency was observed with regard to the age distribution. The rate of C. psittaci positivity (4%) was higher than in previous reports, but no definite tendencies for age or geographic area were seen. Only two of the 21 positive patients were bird breeders.
One in five patients with respiratory infections who visited a clinical practitioner's office tested positive for atypical microorganisms. Treatment drugs with good cell penetration and that cover atypical microorganisms should be selected for the treatment of respiratory infections.

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The new quinolone antimicrobial drug gatifloxacin (GFLX) was reported to cause adverse effects in patients with abnormal blood sugar levels after it had been placed on the market (in Japan) in June 2002, and GFLX became counterindicated in diabetic patients in March 2003. Nevertheless, it is still recommended by the Japanese Respiratory Society guidelines as a “respiratory quinolone” because of its excellent antimicrobial activity and expectoration. Moreover, the AUC/MIC of GFLX for pneumococcus is 74.4 at 200mg b.i.d.(400mg/day) and 35.9 (age<65 years) and 97.2 (age>65 years) at 100 mg b.i.d.(200mg/day). Based on these results, the treatment of senior citizens at a dose of 200mg/day was thought to be feasible.
Subsequently, a clinical study was undertaken to establish the efficacy of a GFLX dose of 200mg/day for the treatment of secondary infections in senior citizens (age>65 years) chronic respiratory illnesses to determine if the effectiveness was equal to treat of 400 mg/day in non-senior citizens.
Fifty-two patients were enrolled in this study, and 32 of these patients were evaluated between November 2004 and March 2005 at our university hospital or surrounding clinics. The clinical efficacy of GFLX was 87.0%(20/23) in senior citizens and 88.9%(8/9) non-senior citizens, for an overall efficacy of 87.5%(28/32). The bacteriological clinical efficacy of GFLX was concluded to be equivalent in both groups. Moreover, only three adverse events occurred: one in the senior citizen and two in the non-senior citizen group. These adverse events were generally mild in nature. Abnormal lab results were also seen in four patients: two in the senior citizen group and two in the non-senior citizen group.
The present study suggests that GFLX at a dose of 200mg/day is equally safe and effective as a dose of 400mg/day for the treatment of secondary infections resulting from chronic respiratory disease in both senior citizens and non-senior citizens.

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Since Mycobacterium avium complex (MAC) infections are refractory, the development of new drugs with strong anti-MAC activity or therapeutic regimens using ordinary antimycobacterial drugs in combination with immunoadjuncts is urgently desired. In this study, we studied the effects of chitin, chitosan, and oligochitosan, which exhibit immunopotentiating activity, on the antimicrobial activity of clarithromycin (CAM) in combination with rifampicin (RFP) against MAC organisms replicating within murine peritoneal macrophages (MΦS). Murine peptone-induced peritoneal exudate cells were cultured for 3 days with or without chitin, chitosan, or oligochitosan at concentrations of 10 μg/mL to 100μg/mL and washed with 2% FBS-HBSS; the resulting MΦs were then infected with MAC. When MAC-infected cells were cultured in the presence or absence of CAM/RFP at Cmax doses (CAM, 2.3μg/mL; RFP, 6.2μg/mL) for 7 days, CAM/RFP significantly eliminated the intracellular organisms within MΦs. Although chitin, chitosan and oligochitosan alone did not inhibit intramacrophage bacterial growth, chitin and chitosan, but not oligochitosan, potentiated the bactericidal activity of CAM/RFP against intracellular MAC organisms. Next, chitin and chitosan were examined for their effects on the therapeutic activity of CAM/RFP against MAC infection in mice. Chitin and chitosan did not increase the anti-MAC therapeutic activity of CAM/RFP.

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