Both bacterial and eukaryotic cells typically contain energy-dependent efflux proteins for self-defense against penetration by toxic compounds (xenobiotics), including antimicrobial and anticancer agents, into the cells. These resistance efflux proteins have been divided into two categories, ATP-dependent and proton-dependent, based on their energy sources. In bacteria, the proton-dependent efflux proteins have been found more frequently rather than ATP-dependent efflux proteins. Comparative amino acid sequence analysis of bacterial proton-dependent efflux proteins has enabled identification of three distinct families and superfamilies: a small multidrug resistance (SMR) family, a major facilitator superfamily (MFS), and a resistance-nodulation-cell division (RND) family. Most efflux proteins typically deal with a narrow range of structurally related substrates; for example, the Escherichia coli tetracycline exporter TetA. However, efflux proteins (multidrug efflux proteins) that can clearly handle a wide range of structurally dissimilar compounds have also been identified, and they may contribute to cross resistance between a wide variety of antimicrobial agents. Investigation of the mechanisms of resistance of Pseudomonas aeruginosa to quinolones and β-lactams has demonstrated interplay between efflux proteins and other resistance factors.

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Recently, penicillin-resistant Streptococcus pneumoniae (PRSP) and βlactamase-negative ampicillinresistant Haemophilus influenzae (BLNAR) are frequently being isolated from patients with respiratory tract infections in Japan, and they are often isolated at the same time. We investigated the usefulness of cefoselis (CFSL) against mixed infection caused by PRSP and BLNAR by using in vitro and in vivo models, and compared them with other antibiotics. The following results were obtained:
1) CFSL had potent antibacterial activity against clinical isolates of S. pneumoniae and H. influenzae. The MIC₉₀ values of CFSL against PRSP and BLNAR were both 2μg/mL and 4 to 8 times lower than those of cefozopran (CZOP).
2) CFSL showed superior bactericidal activity to CZOP against mixed cultures of PRSP and BLNAR at 1μg/mL. CFSL (1g) also exhibited potent bactericidal activity against mixed cultures of PRSP and BLNAR in an in vitro pharmacokinetic model simulating human sputum concentrations. By contrast, re-growth was observed 8 hours after dosing with CZOP (1g) and imipenem/cilastatin (IPM/CS: 0.5g).
3) At a dose of 20 mg/kg CFSL had potent protective activity against mixed respiratory tract infection by PRSP and BLNAR in mice. It was more effective than CZOP, ceftazidime (CAZ), and flomoxef (FMOX), and almost as effective as IPM/CS.
4) CFSL showed a potent therapeutic effect at a dose of 0.5 g in a model simulating human serum levels in mice. It was more effective than CZOP, CAZ, FMOX and IPM/CS.
These results suggest that CFSL has potential for clinical use against mixed infections with S. pneumoniae and H. influenzae containing PRSP and BLNAR.

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A nationwide epidemiological survey of the susceptibility of clinical isolates to beta-lactam antibiotics including cefepime was performed in order to assess the emergence of resistant strains in Japan. Susceptibility to 7 beta-lactam antibiotics, cefepime, cefpirome, ceftazidime, cefoperazone/sulbactam (C/S), imipenem, and piperacillin (for gram-negatives) or oxacillin (for gram-positives), was studied in 22 medical centers, using a common protocol and method (Etest; AB BIODISK, Solna, Sweden). Inter-and intra-laboratory variations were evaluated by analysis of quality control strains, and the results demonstrated good reproducibility. No strains resistant to any of these beta-lactams except for ceftazidime were found in Oxacillin-susceptible Staphylococcus aureus or coagulase-negative staphylococci. In Escherichia coli, 14.6% of the clinical strains were resistant to piperacillin, while only 0.5% were resistant to any of the other antibiotics. All clinical strains of Klebsiella spp. and Citrobacter freundii were susceptible to cefepime and imipenem. Isolates of Enterobacter spp. were most susceptible to imipenem (0.5% resistance) and cefepime (1.0%). Isolates of Serratia spp. were more susceptible to imipenem (4.5% resistance) and cefepime (5.0%) than to the other beta-lactam antibiotics tested. Only 0.5% of indolepositive Proteus were resistant to cefepime and ceftazidime. Isolates of Pseudomonas aeruginosa were more susceptible to cefepime (9.1% resistance) than to ceftazidime (11.4%), C/S (13.7%), piperacillin (20.1%), imipenem (22.4%), or cefpirome (27.9%). These results clearly indicate that emergence of strains resistant to cefepime is less of a problem than for the other beta-lactam antibiotics tested.

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The penetration of levofloxacin (10mg/kg, p. o.) into the buccal abscess induced bycarrageenin in hypoproteinemic rats was examined at different inflammatory stages (days 1 and 5) to clarify the influence of low serum albumin levels on pharmacokinetics of the inflammatory tissue concentrations. Both in normal and hypoproteinemic rats, the concentrations of the granulation tissue were equivalent to the serum levels. The T_max of the granulation tissue and serum was faster in hypoproteinemic rats than that in normal rats. The C_max of the granulation tissue and serum concentrations was also higher in hypoproteinemic rats than that in normal rats. This tendency was found in both inflammatory stages (days 1 and 5 after injection of carrageenin). These results may have been affected by the elevation of free antibiotics which were not bound to the serum albumin in hypoproteinemic rats. However, there were no differences between T_1/2 in normal and hypoproteinemic rats.

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Penetration of five parenteral antibiotics (piperacillin (PIPC: 50 mg/kg, i. v.), cefazolin (CEZ: 30mg/kg, i. v.), cefmetazole (CMZ: 16-22mg/kg, d.i.v.), cefoperazone (CPZ: 20mg/kg, d.i.v.), and latamoxef (LMOX: 15-24 mg/kg, d.i.v.)) into human mandibular bone after a single administration was determined. PIPC, CEZ, and CMZ levels in mandibular bone were higher than the respective MIC₉₀ values of these drugs against Streptococcus sp., which is frequently isolated from patients with oral infections. These antibiotics should therefore be useful in treatment of mandibular osteomyelitis and prevention of postoperative infections. CPZ and LMOX levels did not reach the comparable MIC₉₀ values against Streptococcus sp. in many patients, however, so the dosages for these antibiotics must be carefully considered.

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To evaluate the effectiveness of prophylaxis of infection after tooth extraction, antibiotic concentrations in exodontia wounds were determined after talampicillin (TAPC, 500 mg), cefaclor (CCL, 500 mg), and cefteram pivoxil (CFTM-PI, 200 mg) were given orally. The percentage of patients whose concentrations were higher than the MIC₈₀ value against Streptococcus sp., which are frequently detected in oral infections, was 83.3-100% for TAPC at 60-360 min, 33.3-64.3% for CCL at 60-180 min, and 80.0-100% for CFTM-PI at 60-480 min. These findings indicate that TAPC or CFTM-PI ismore reliable for prophylaxis. For effective prophylaxis, TAPC should be given about 60 min preoperatively and CFTM-PI about 60-120 min preoperatively.

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This study describes a pharmacokinetic approach to safe and effective treatment with vancomycin (VCM), an antibiotic used for infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Therapeutic drug monitoring was performed in 22 patients (April 1995-February 1999) with various degrees of renal functional impairment. The serum concentrations of VCM were measured at steady state, immediately before (trough), and 2 hours after (peak), intravenous infusion. The initial VCM doses for 15 non-dialysis patients were determined by using Moellering's nomogram. At these initial doses, none of the patients had VCM levels in the toxic range. Among these 15 patients, the trough levels of 12 patients and the peak levels of 2 patients were within the therapeutic range (trough: 5-15 μg/mL, peak: 20-40μg/mL). There were 5 patients whose initial VCM dosage needed to be adjusted for effective treatment. Pryka's population pharmacokinetic parameters and a simple one-compartment model were used to calculate the patients' pharmacokinetic parameters by the Bayesian method to adjust the dosage. The dosage was appropriately, adjusted 4 patients had trough levels, and 4 patients had peak levels, within the therapeutic range. The Bayesian method accurately predicted the actual VCM concentrations. At the trough level (n=9) the mean prediction error (ME) was -1.83μg/mL, the mean absolute prediction error (MAE) was 2.14μg/mL, the root mean squared prediction error (RMSE) was 2.79μg/mL, and at the peak level (n=9) the ME was 2.01μg/mL, the MAE was 3.70μg/mL, and the RMSE was 5.22μg/mL. Four patients on dialysis received an initial VCM dose of 15 mg/kg/week, and the dosage of two patients was adjusted by using the Sawchuk-Zaske method. Efficacy of VCM treatment was recognized in 83% of the patients, and there was no renal impairment caused by VCM. The results of the present study suggest that safe and effective dosage regimens can be identified by determining the initial dosage by using Moellering's nomogram followed by individual dosage adjustment by the Bayesian or the Sawchuk-Zaske method.

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We evaluated the fluid penetration of gatifloxacin, a new oral fluoroquinolone, and its clinical effectiveness in respiratory tract infections.
1. Concentrations in sputum and serum
Gatifloxacin was orally administered to a patient with chronic bronchitis at a dose of 200mg, twice a day, for 7 days. The concentrations of gatifloxacin in the sputum and serum were determined on the 1 st, 3rd and 5 th days of administration. The level of gatifloxacin in the sputum exceeded that in the serum throughout the time period beginning 6 hours after the 1 at dose on the 1 at day and ending 2 hours after the 1 st dose on the 5 th day. The maximum level of gatifloxacin in the sputum during this 5-day period was 6.94μg/g, while that in the serum was 2.91μ/mL. The sputum penetration was satisfactory, with a ratio of sputum vs serum levels ranging from 1.25 to 2.38.
2. Clinical efficacy
Twenty-seven patients (1 with acute bronchitis, 11 with chronic bronchitis, 5 with bacterial pneumonia, 1 with chlamydial pneumonia, 1 with mycoplasma pneumonia and 8 with infections secondary to chronic respiratory disease) were orally treated with gatifloxacin at doses of 100 to 200 mg, twice a day, for 7 to 14 days. The clinical response was excellent in 2 patients, good in 22 patients, fair in 1 patient, and poor in 2 patients. The clinical efficacy rate was 88.9%. Regarding side effects, mild epigastric distress was observed in 1 patient. Abnormal laboratory findings were observed in a total of 3 patients (one case each of an increased S-GPT, S-GOT and γ-GTP level).
The results suggest that gatifloxacin can penetrate into the sputum and is an effective antimicrobial agent for the treatment of respiratory tract infections.

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