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Arbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). The population pharmacokinetics of arbekacin was investigated in the Japanese, using 353 patients infected with MRSA and 50 healthy or renally impaired volunteers. The age of the study population ranged from 8 to 95 years, and weight ranged from 10.8 to 107 kg. In total, 1,581 serum arbekacin concentrations were measured (primarily from routine patient care) and used to perform the present pharmacokinetic analysis. Drug concentration-time data were well described by a two-compartment open model. Factors influencing arbekacin pharmacokinetics were investigated using a nonlinear mixed-effect model analysis. The best-developed model showed that drug clearance (CL) was related to creatinine clearance (CL CR ), age, and body weight (WT), as expressed by CL (liter/h) = 0.0319CL CR + (26.5/age) (CL CR < 80 ml/min) and CL (liter/h) = 0.0130 CL CR + 0.0342WT + (26.5/age) (CL CR ≥ 80 ml/min). The volume of distribution for the central and peripheral compartments was different in healthy subjects and infected patients, and this difference was more pronounced among disease types. The elderly subjects (aged 80 years or over) exhibited, on average, a 19% greater volume for the central compartment. The volumes for the peripheral compartment were 50.6 liters in patients with pneumonia and 24.3 liters in patients with sepsis. The population pharmacokinetic parameters of arbekacin obtained here are useful for optimal use of this aminoglycoside in the treatment of MRSA-infected patients.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteria have acquired stable resistance against most clinically available antibiotics. At present, MRSA infection is treated mainly with vancomycin. However, clinical isolates of S. aureus with reduced susceptibility to vancomycin, known as glycopeptide-intermediate S. aureus or vancomycin-intermediate S. aureus have recently been reported in Japan, the United States, and Europe (5, 16, 20). On the other hand, in Japan, arbekacin has been successfully used to treat MRSA infections for more than 10 years. Arbekacin, a derivative of dibekacin, is active against MRSA and both gram-positive and gram-negative bacteria (8). Moreover, arbekacin is not affected by the inactivating enzymes produced by MRSA (9). A killing curve study demonstrated that the bactericidal activity of arbekacin depended critically on its concentration (1). As with other aminoglycosides, arbekacin is eliminated exclusively into the urine as the unchanged form via glomerular filtration and tubular reabsorption. There is a linear relationship between arbekacin pharmacokinetics and the glomerular filtration rate (4). Although therapeutic drug monitoring (TDM) of arbekacin has become a common practice to maintain drug concentrations within a therapeutic range, the target concentrations of arbekacin used to monitor efficacy and toxicity are determined simply on the basis of knowledge of other aminoglycosides, such as gentamicin, amikacin, and tobramycin (12, 15, 22). To date, the exposure-response relationship for arbekacin in patients infected with MRSA has not been established. For aminoglycosides, there is evidence that the efficacy in patients with gram-negative bacterial infections is influenced by the early onset of a high peak concentration/MIC ratio (3, 6, 7, 11). In these studies, to estimate the correlation of pharmacokinetic-pharmacodynamic indices with therapeutic outcomes in patients receiving aminoglycosides, the peak concentration was obtained from measurements 1 h after infusion (11) or extrapolated from the actual concentration obtained approximately 30 min after the end of a 30-minute infusion (3, 6, 7). In the companion article (21), we reported the population pharmacokinetic parameters of arbekacin for patients infected with MRSA. Once population pharmacokinetic parameters have been obtained, the Bayesian forecasting method is applicable for predicting the serum drug concentration-time curve in each patient on the basis of a limited number of drug concentration measurements. These predicted serum drug concentration profiles are useful to estimate individual exposure parameters to arbekacin and to analyze the relationship between exposure and response. In the present study, we analyzed the pharmacokinetic-pharmacodynamic relationship of arbekacin to determine the drug exposure parameters that correlate with the efficacy and safety of this drug and to obtain the optimal target values of these parameters. (This work was presented in part at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, 14 to 17 September 2003.)

The effect of pretreatment with ranitidine, an antacid, on the absorption of AS-924, a novel prodrug-type cephem antibiotic derived from ceftizoxime (CTIZ), was examined in eight healthy adult male volunteers by the cross-over method, using cefteram-pivoxil (CTER-PI) as the control drug. The C(max) and area under the concentration (AUC) values and cumulative urinary excretion rate (0-24 h) of cefteram (CTER) after administration of CTER-PI decreased by 32, 38 and 37%, respectively, in the ranitidine pretreatment group whereas those of AS-924 were not affected by the antacid. The urinary levels of pivaloyl-carnitine determined to evaluate the solubility of these antibiotics in the gastrointestinal tract suggested that this was not affected by ranitidine. These results indicate that the absorption of CTER-PI was affected by pretreatment with ranitidine largely due to inactivation of this antibiotic in the gastrointestinal tract at high pH rather than to a decrease in solubility. In contrast, isomerization of AS-924 was hardly induced by the elevation of pH, thus demonstrating that AS-924 was less likely to be affected by pretreatment with antacids.

Background. Two triple therapies with lansoprazole (LPZ)/amoxicillin (AMPC)/clarithromycin (CAM) for eradication of Helicobacter pylori were studied in multicenter, double-blind fashion to evaluate the eradication rate of H. pylori and safety of eradiation treatment in Japanese patients with H. pylori-positive active gastric ulcers or duodenal ulcers. Methods. Patients were randomly chosen for the control treatment of LPZ 30 mg twice a day (b.i.d.; Group A-LPZ-only) or the test treatments of LPZ 30 mg plus AMPC 750 mg and CAM 200 mg b.i.d. (Group B-LAC200) and LPZ 30 mg, AMPC 750 mg and CAM 400 mg b.i.d. (Group C-LAC400). All eradication treatments lasted for a period of 7 days. Successful eradication was assessed by culture and gastric histology 1 month after completion of the ulcer treatment. Results. The eradication rates of H. pylori in the full analysis set were 0% in Group A-LPZ-only, 87.5% in Group B-LAC200 and 89.2% in Group C-LAC400 for gastric ulcer and, 4.4% in Group A-LPZ-only, 91.1% in Group B-LAC200 and 83.7% in Group C-LAC400 for duodenal ulcer. The eradication rates of Group B-LAC200 and Group C-LAC400 were 89.2% (95% CI: 84.8–93.7%) and 86.4% (95%CI: 81.5–91.3%) in total in the full analysis set, 89% (95% CI: 84.3–93.7%) and 85.3% (95%CI: 80.1–90.5%) in the per protocol set. The eradication rates in Groups B-LAC200 and group C-LAC400 were statistically significantly higher than the rate in Group A-LPZ-only for both gastric ulcer and duodenal ulcer patients (p

We evaluated the combined effects of fosfomycin (FOM) with β-lactam antibiotics, including cefepime (CFPM), cefotaxime (CTX), cefminox (CMNX), cefotiam (CTM), cefazolin (CEZ), imipenem (IPM) and benzylpenicillin (PCG), against clinically-isolated penicillin-resistantStreptococcus pneumoniae (PRSP) based on fractional inhibitory concentration (FIC) indices. The combination of FOM and the β-lactam antibiotics showed synergy and partial synergy against 70% to 90% of the 56 PRSP strains tested. Moreover, FOM combined with CTM, CMNX and PCG showed synergy against 35.7%, 58.9%, and 30.4% of strains, respectively. MIC80s of the β-lactam antibiotics in combination with FOM, using the lowest concentrations clinically achievable in cerebrospinal fluid, were several times lower than those of each β-lactam antibiotic alone. The bactericidal activities of FOM and the β-lactam antibiotics against PRSP were greater when the 2 agents were added simultaneously than when added sequentially. The PBP profiles of PRSP exposed to a low concentration of FOM combined with CFPM, CTX, IPM or PCG were evaluated. In combination with FOM and any one of these β-lactam antibiotics, the binding of [14C]-PCG on all PBPs of a given PRSP strain was reduced in comparison with that in the presence of FOM or a β-lactam antibiotic alone.

The antimicrobial activities of vancomycin (VCM) or cefpirome (CPR) at sub- and above-MICs against clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) during the postantibiotic phase (PAE-phase) induced by CPR or VCM were examined. Antimicrobial activities were determined growth suppression (post antibiotic sub-MIC effect: PA SME) at sub-MICs, and bactericidal activity at sub- and above-MICs. During the PAE-phase induced by VCM, growth suppression and bactericidal activity of CPR were enhanced at sub-MICs, compared with the non PAE-phase. On the other hand, during the PAE-phase induced by CPR, not only were growth suppression and bactericidal activity of VCM enhanced at sub-MICs, but bactericidal activity were enhanced at above-MICs compared with non PAE-phase. These suggest that enhancement of growth suppression and bactericidal activity during PAE-phase was a factor of combination effect of VCM and CPR against MRSA.

In order to investigate penicillin resistance (Pcr) in Streptococcus pneumoniae from clinical sources in Japan, a total 1,127 strains of S. pneumoniae was collected at random from 36 institutions participating to "Working group for Pcr S. pneumoniae" around the country in 1993-1994. These strains were isolated more frequently from sputum (38.2%), throat (31.4%), nasal discharge (16.4%), and otorrhea (5.7%). A small number of isolates from blood (19 strains; 1.8%), cerebrospinal fluid (11 strains; 1.0%), and pleural fluid (2 strains; 0.2%) were included respectively. Patients from whom S. pneumoniae was isolated have mostly been associated with children or = 0.125 micrograms/ml for penicillin G were defined as a Pc resistance. Of the 1,127 strains, 471 strains (41.8%) were identified as a Pc resistance. Pcr S. pneumoniae were almost resistant to other beta-lactams, including ampicillin, oxacillin, ceftizoxime, cefixime, cefdinir. Although, the MICs of imipenem and panipenem ragned from 0.004-2.0 micrograms/ml with 2 peaks distributions, these antibiotics inhibited the growth of most of Pcr S. pneumoniae at the lowest concentrations of < or = 0.5 microgram/ml. Only vancomycin resistant strain was not detected in these isolates. Most of the Pcr strains were simultaneously resistant to macrolides and minocycline. Further more, isolation frequencies of Pcr S. pneumoniae in west Japan, were relatively high compared with those of east Japan.

The effects of food intake and age on intestinal absorption of AS-924, a novel prodrug-type cephem antibiotic, were examined in 16 healthy adult volunteers (eight young volunteers and eight elderly volunteers) by the cross-over method, using cefpodoxime proxetil (CPOD-PR) as the control drug. The gastrointestinal absorption of AS-924 and CPOD-PR was increased slightly by food intake and the extent of increase was slightly greater after administration of CPOD-PR. The absorption of AS-924 was not affected by age, whereas intestinal absorption of CPOD-PR increased with age. In conclusion, these results confirmed that AS-924 has the unique characteristics as a novel prodrug and that its absorption is less likely to be affected by food intake and age.

A total of 34 patients with intractable chronic respiratory tract infections were treated with isepamicin and/or piperacillin in different dosage regimens. A comparison of the bacteriological effect using a cross over method showed a reduction in the count of Pseudomonas aeruginosa in sputum in the group receiving once-a-day isepamicin combined with piperacillin, compared with the twice-a-day combined administration. A comparison of the clinical and bacteriological efficacy between the different regimen groups revealed no noticeable difference. The clinical effect of this regimen is comparable to the conventional regimen, but has the advantages of a safer dosage and ease of administration.

The in vitro activity of benzylpenicillin in combination with fosfomycin against 51 clinical isolates of penicillin-resistant Streptococcus pneumoniae [minimal inhibitory concentrations (MICs) of benzylpenicillin ≥0.5 mg/liter] was investigated. The fractional inhibitory concentration (FIC) index using the checkerboard method ranged from 0.38 to 0.75 (mean: 0.63). A synergy was also demonstrated in the killing curve on S. pneumoniae TW-1303 (MIC of benzylpenicillin, 2 mg/liter; MIC of fosfomycin, 32 mg/liter: FIC index, 0.38). Fosfomycin inhibited the production of all penicillin-binding proteins (PBP) except PBP 2B of S. pneumoniae TW-1303 and it decreased that of PBP 2B when it was combined with benzylpenicillin. These results suggest that the combination of benzylpenicillin and fosfomycin could be considered as the alternative treatment of penicillin-resistant pneumococcal infections.

We described three septicemia cases in which blood cultures yielded gram-positive cocci identified as Leuconostoc spp. and Pediococcus spp. Patients were three male adults aged 63 to 71 years with severe underlying diseases, pancreatic cancer, esophageal cancer and diabetes mellitus with chronic renal failure. They had fever and chills at the onsets of septicemia with acute obstructive suppurative cholangitis, acute pneumonia, and infection complicated with invasion sites of esophageal cancer contagious to bronchus and subcutaneous tissue. Blood cultures yielded catalase and oxidase negative highly vancomycin-resistant (MIC: 1024 micrograms/ml

The drug-protein interactions between cefoperazone (CPZ) and apalcillin (APPC), and between cefazolin (CEZ) and APPC were investigated in in vitro and in vivo experiments. Through the binding rates of CPZ or CEZ to rabbit serum and human serum albumin subsided remarkably with increased drug concentrations, APPC was not greatly affected, even at high concentrations. It appeared that APPC had a higher binding capacity to protein than CPZ or CEZ. From the results of competitive study, it became clear that APPC partially shared the binding sites on protein with CPZ or CEZ. The CPZ or CEZ serum levels in rabbits administered together with APPC were not different from those for the single administration, but APPC levels for the simultaneous administration were slightly lower.

To characterize the effect of the binding of antibiotics to tissue protein on urinary excretion, we examined the extent of the binding of 9 penicillins and 9 cephems to 100,000 X g supernatant fluid of human liver homogenates. The correlation analysis revealed a significant simple correlation between the binding to 100,000 X g supernatant fluid of liver homogenates and urinary excretion. Drugs with lesser binding were mainly excreted in the urine, conversely, urinary excretion of highly bound drugs exhibited lower values. The prediction with regard to urinary excretion of healthy subjects was done by multiple regression analysis using the binding to 100,000 X g supernatant fluid and other physicochemical factors. The values predicted for urinary excretion coincided well with the observed values.

We have reported on the clinical courses of 4 cases of adult Listeria monocytogenes (Lm) infection, and the autopsy findings of 2 cases, those we have observed over the past 5 years. They were 2 cases of meningitis, 1 case of meningitis and sepsis and 1 case of sepsis. These 4 cases had CML, neoplastic angioendotheliosis, SLE and post-renal transplant condition, as their underlying diseases, and all were receiving immunosuppressive therapy. One meningitis patient who recovered showed mild liver dysfunction during her clinical course. The other 3 patients who died had jaundice at the time of onset and severe liver dysfunction. The 2 cases those were autopsied were the sepsis cases. The one with an acute course and hepatic failure showed multiple miliary necrotic foci in the liver, where the presence of Lm in the cells could be verified. The other autopsy case, which had received adequate antibiotic therapy and the Lm infection had been cured, showed no necrotic foci in the liver. The case that had necrotic foci in the liver was the first such adult case in Japan. We have discussed the hepatic Lm infection in adult compromised hosts, which conventionally has not been considered a serious problem.

Disagreements in serum and urine cephaloglycin determinations by Sarcina lutea with those by Bacillus subtilis or Streptococcus hemolyticus after oral administration of the antibiotic have been clarified by the present studies, attention being focussed on the formation of an active metabolite, desacetylcephaloglycin. The formation of desacetylcephaloglycin was detected by paper and thin-layer chromatography. Desacetylcephaloglycin was 0.1 to 0.5 as active as cephaloglycin against B. subtilis and S. hemolyticus but of comparable activity- against S. lutea PCI-1001.

The effect of cefazolin (CEZ) on the protein binding and the pharmacokinetics of cefoperazone (T-1551) was investigated. For the simultaneous determination of T-1551 and CEZ, high pressure liquid chromatography (HPLC) was used. The extent of protein binding, the number of binding sites and the association constant to human serum albumin were 90.4%, 0.87 and 2.16 X 10(4) in T-1551, and 89.2%, 0.78 and 2.46 X 10(4) in CEZ, respectively. T-1551 and CEZ appeared to bind to the same site on the protein, since each drug competitively inhibited the binding of the other to serum protein. The mode of the binding of T-1551 to serum protein was similar to that of CEZ. When T-1551 and CEZ were co-administered, the serum level of T-1551 was lower than that with the single administration, while, urinary excretion was higher. These results suggested that the concomitantly administered drugs influenced one another's binding to serum protein in vivo and subsequently an increase in the concentration of the unbound drug in the serum made the drug available for glomerular filtration. It seemed that the high protein binding of T-1551 to serum was an important factor affecting its pharmacokinetics.

The pharmacokinetics of each drug on the concomitant administration of piperacillin (PIPC) and cefazolin (CEZ) or cefoperazone (CPZ) were studied in rabbits. When rabbits received the consecutive drip infusion administration of CEZ (0.71 mg/kg/minute) and PIPC (1.38 mg/kg/minute) and likewise of CPZ (0.72 mg/kg/minute) and PIPC (1.54 mg/kg/minute) for 1 hour, respectively, the serum half-lives of CEZ and CPZ were respectively prolonged about 1.8 and 1.6 times during drip infusion of PIPC than administered alone. However, when the sequence of administration were reversed, the serum levels of PIPC were not affected by the consecutive drip infusion administration of CEZ and CPZ. To study these findings in detail, the single intravenous dose of 20 mg/kg of CEZ and CPZ were administered under drip infusion of PIPC (2.65-2.93 mg/kg/minute). The serum half-lives of CEZ and CPZ were also prolonged about 5.4 and 1.9 times, respectively, whereas urinary excretion of CEZ, and urinary and biliary excretion of CPZ were reduced by PIPC. Moreover, when the single intravenous dose of 20 mg/kg of PIPC were administered under drip infusion administration of CEZ (0.96-2.60 2.60 mg/kg/minute), the pharmacokinetics of PIPC was not affected by the presence of CEZ. However, under drip infusion administration of CPZ (2.60-2.70 mg/kg/minute), the PIPC serum half-life was prolonged about 1.4 times, and biliary excretion of PIPC was reduced but urinary excretion was not. From the results of renal clearance experiments, tubular secretion appeared to be the predominant mechanism of renal elimination for these three drugs. These results indicate that PIPC influences the pharmacokinetics of both drugs by the competitively inhibiting tubular secretion in CEZ, and tubular secretion and hepatic transport system in CPZ. Therefore, in this respect PIPC seems to have probenecid-like action.

The clinical efficacy and safety of Cefodizime (CDZM), a new cephem antibiotic, was objectively compared with that of Cefotaxime (CTX) in patients with respiratory infections under a well-controlled comparative study. Patients were administered CDZM or CTX by drip infusion b.i.d. for 14 days in principle at a daily dose of two grams. The parameters assessed were clinical efficacy, safety and clinical usefulness. The following results were obtained: 1. On the basis of committee judgement the clinical efficacy rate was 78.1% (125/160) for the CDZM group, 82.7% (124/150) for the CTX group, and no significant difference was observed between the two drug groups. On the other hand, on the basis of judgement by physicians in charge, the clinical efficacy rate was 83.1% (133/160) for the CDZM group, 83.9% (125/149) for the CTX group, and no significant difference was observed between the two groups. 2. The corresponding figures for patients with pneumonia and pulmonary suppuration were 82.4% (70/85) for the CDZM group, 79.7% (59/74) for the CTX group and no significant difference was observed according to the committee judgement. The judgement by physicians in charge also revealed 83.5% (71/85) for the CDZM group and 82.2% (60/73) for the CTX group. No significant difference was noted between the two groups. While, the committee judgement for the clinical efficacy in patients with chronic respiratory tract infections showed 73.3% (55/75) for the CDZM group, 85.5% (65/76) for the CTX group, and no significant difference was observed between the two drug groups. The corresponding figures were 82.7% (62/75) for the CDZM group, 85.5% (65/76) for the CTX group, and no significant difference was observed between the two drug groups on the judgement by physicians in charge. Furthermore, the clinical efficacy of both drugs on chronic respiratory tract infections was assessed according to "Criteria for Evaluation of Clinical Efficacy of Chemotherapeutics on Chronic Respiratory Tract Infection". It was 76.8% (53/69) for the CDZM group, 76.3% (58/76) for the CTX group, and no significant difference was observed between the two groups. 3. The bacteriological eradication rate of causative pathogens was 92.4% out of 66 patients treated with CDZM and 95.5% out of 67 patients treated with CTX in whom judgement was possible. No significant difference was observed between the two drug groups. 4. The adverse reactions occurred in 4 (2.2%) patients for the CDZM group and 8 (4.5%) patients for the CTX group respectively, with no significant inter-group difference in frequency of these reactions for all cases.(ABSTRACT TRUNCATED AT 400 WORDS)

This paper is based on the results of clinical use fections showed good responses less frequently of a new chemotherapeutic agent, gentamicin, than other categories of infection, in 339 patients in Japan, compiled from the reTable 4 summarizes the results of 141 patients ports of 33 investigators. Of these 339 patients, with urinary tract infections. In this table the 179 were reported at the First International cases were classified as "simple acute" and Symposium on Gentamicin in Paris, January, "chronic complicated" infections. Of the simple 1967. acute urinary tract infections, all but 2 were sueAs shown in table 1, 162 of the patients were cessfully treated with gentamicin, but 307o of males and 177 females; they ranged in age from the cases of chronic, complicated urinary tract 22 days to 81 years. infections failed to improve. Treatment of inTable 2 shows the classification according to fections caused by Pseudomonas and Proteus was site of infection and the causative microorganisms. less successful than those due to other microor