Pharmacokinetic/pharmacodynamic (PK/PD) parameters are useful predictors of clinical efficacy and bacterial eradication. Aminoglycosides have concentration-dependent antibacterial activity and the Cmax/MIC ratio of aminoglycosides correlates with clinical efficacy.
We retrospectively studied 44 cases of pulmonary MRSA infection treated with axbekacin (ABK) to determine the significance of PK/PD parameters. The ABK serum concentration was determined by FPIA, PK parameters were calculated, and 1-compartment model simulation was done. Cmax/MIC of 8 or more was statistically shown to be predictive for clinical efficacy [P<0.01, odds ratio (OR)=27.1 (95% confidential interval (CI)=3.1-237)] and the correlation of Cmax/MIC with bacterial eradication [P<0.01, OR=1.68 (95%CI=1.2-2.3)] was also statistically predictive. These results suggest that the Cmax/MIC ratio correlates with clinical efficacy and bacterial eradication, and thus PK/PD parameters integrating ABK MIC as a PD parameter covariate for the PK parameter Cmax should be estimated to optimize MRSA treatment.

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Objectives: Guidelines issued by the CDC or the “Guidelines for Antibiotic Usage”(issued by the Japanese Association for Infectious Diseases and the Japanese Society of Chemotherapy) give currently recommended prophylaxis with antibiotics. We surveyed the status of their implementation.
Methods: In August and September 2003, a questionnaire was distributed to 3, 823 surgeons in 47 Japanese administrative districts (567 surgeons in Hokkaido/Tohoku, 1, 051 in Kanto, 324 in Tokai, 262 in Hokuriku/Shinetsu, 643 in Kinki, 495 in Chugoku/Shikoku, and 481 in Kyushu/Okinawa). The implementation of recommendations in guidelines was compared for geographic area, type of hospital, number of beds, and clinical experience of surgeons.
Results: Implementation of recommendations was 35% in the selection of prophylactic antibiotics (large bowel, second-generation cephamycins) and 63% for the timing of administration (just prior to surgery). For the administration period (<=4 days), implementation was 63% for gastric surgery (56% for 3 to 4days and 7% for short-term therapy) and 51% for large bowel surgery. Implementation was low for the selection of prophylactic antibiotics. The highest implementation of long-term administration was 49% in the Tokai area. Concerning the type of hospital, a difference in long-term administration was seen between general hospitals (44%) and educational hospitals (31%). Concerning the number of beds, hospitals with fewer than 100 beds showed a lower rate of adherence to recommendations than hospitals having 500 or more beds, including lower administration just prior to surgery (45% vs. 66%) and higher long-term administration (62% vs. 34%). Concerning clinical experience, more surgeons with less than 5 years of experience followed recommendations than surgeons who had 20 years or more of experience, especially for selection of antibiotics (41% vs. 34%), timing of administration (73% vs. 55%), and administration period (68% vs. 59%).
Conclusions: Implementation of recommendations was low and further education is thought to be necessary in general hospitals or hospitals with fewer than 100 beds and among surgeons with 20 years of experience or more. Concerning the administration period and the selection of antibiotics for large bowel surgery, marked differences were seen from CDC recommendations, so it may be desirable for randomized clinical trials to be conducted in Japan.

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Since Mycobacterium avium complex (MAC) infections are very refractory, the development of new drugs with strong anti-MAC activity or therapeutic regimens using ordinary antimycobacterial drugs in combination with immunomodulators is urgently desired. In this study, we studied the effects of the Chinese traditional medicines Kakkon-to, Hochu-ekki-to, and Juzen-taiho-to, which exhibit immunopotentiating activity, on the antimicrobial activity of clarithromycin (CAM) in combination with rifampicin (RFP) against MAC organisms replicating within THP-1 human macrophage (Mφ) and A-549 human type II alveolar epithelial cell lines. When MAC-infected cells were cultured for 5 days in a 5% FBS-RPMI 1640 medium in the presence or absence of CAM/RFP at Cmax doses (CAM, 2.3μg/mL; RFP, 6.2μg/mL) with or without the Chinese herbal medicines at concentrations of 1μg/mL to 100μg/mL, CAM/RFP significantly eliminated the intracellular organisms within THP-1 Mφ s and A-549 cells. The Chinese traditional medicines, however, failed to inhibit intracellular bacterial growth. Moreover, these herbal medicines did not potentiate the activity of CAM/RFP against intracellular MAC organisms.

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Cefcapene pivoxil hydrochloride (CFPN-PI, Flomox^® Tablet 75 mg, Flomox^® Tablet 100 mg), an oral cephem antibiotic, was approved for marketing on April 22, 1997. For 2 years from approval, we studied the practical use in compliance with new Good Postmarketing Surveillance Practices (GPMSP). After 6 years of reexamination period, we applied for reevaluation on July 18, 2003.
5, 801 cases of collected from 951 medical institutes nationwide; we evaluated 5, 766 for safety, 5, 574 for clinical efficacy, and 607 for bacteriological efficacy, wiht the following results:
1) The incidence of adverse drug reactions, 2.58%(149 cases/5, 766 cases), was lower than that obtained in studies before marketing approval, 9.45%(303 cases/3, 207 cases). The most frequently observed adverse drug reaction was diarrhea, whose incidence was 0.61%(35 events/5, 766 cases).
2) Clinical efficacy by infection type was from 90.9-100.0%, and results were equivalent to those in studies before marketing approval.
3) In bacteriological evaluation, elimination was 90% or more in most strains, and results were equivalent to those in studies before marketing approval.

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Cefcapene pivoxil hydrochloride (CFPN-PI, Flomox^® Fine granules 100 mg for children), an oral cephem antibiotic, was approved for marketing on April 22, 1997. For 2 years from approval, we studied the practical use in compliance with new Good Postmarketing Surveillance Practices (GPMSP). Then, after 6 years of reexamination period, we applied for reevaluation on July 18, 2003.
3, 073 cases of collected from 566 medical institutes nationwide; we evaluated 3, 047 for safety, 2, 979 for clinical efficacy, and 326 for bacteriological efficacy, with the following results:
1) The incidence of adverse drug reactions, 4.30%(131 cases/3, 047 cases), was lower than that obtained in studies before marketing approval, 6.63%(37 cases/558 cases). The most frequently observed adverse drug reaction was diarrhea, whose incidence was 3.74%(114 events/3, 047 cases). The incidence of diarrhea tended to be higher in younger patients.
2) Clinical efficacy by infection type was 91.2-98.3%, and results were equivalent to those in studies before marketing approval.
3) In bacteriological evaluation, elimination was 90% or more in most strains, and results were equivalent to those in studies before marketing approval.
4) The drug could be taken “easily” or “without any difficulty” in 94.0% of patients.

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GATIFLO^® Tablets, containing gatifloxacin (GFLX), a synthetic fluoroquinolone antibacterial agent, were launched in Japan in June 2002.
For several months after GFLX were marketed, cases of hypoglycemia and/or hyperglycemia were reported as adverse drug reactions. Thus, Emergency Safety Information statement was issued in March 2003, stipulating the contraindication of GFLX in patients with diabetes mellitus.
Risk factors for inducing blood glucose change were estimated by analyzing data collected from 89 cases with severe blood glucose change reported by March 2003. The results were as follows:
1. Of 89 cases, hypoglycemia was noted in 75 (89%) and hyperglycemia in 14 (15.7%).
2. Patients with diabeties accounted for 58 (77.3%) of hypoglycemia and 11 (78.6%) of hyperglycemia.
3. Patients 65 years or older accounted for 68 cases (90.7%) of hypoglycemia and 10 (71.4%) of hyperglycemia.
4. Among 63 cases with records on renal function, dysfunction was found in 49 (89.1%) of 55 cases of hypoglycemia, and 7 (87.5%) out of 8 cases of hyperglycemia.
Based on the above findings, “diabetes mellitus, ” “aged person, ” and “renal dysfunction” are estimated as major risk factors for blood glucose change induced by GFLX. To prevent adverse reactions related to blood glucose change, it is essential to recognize these risk factors and to administer GFLX appropriately based on statements in labeling on the package inserts.

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