RU 29 246, the active compound of the cephalosporin prodrug-ester HR 916. III. Pharmacokinetic properties and antibacterial activity in vivo.

The pharmacokinetics of the broad spectrum cephem RU 29 246 and its prodrug-ester HR 916 B were investigated in mice, rats and dogs and compared to those of cefpodoxime proxetil, cefuroxime axetil and cefixime. HR 916 B is well absorbed following oral administration and efficiently converted to the antibacterially active form. In mice, mean peak blood levels of 31.1 micrograms/ml of the parent compound were recorded within 20 minutes after oral administration of a single dose equivalent to 40 mg/kg RU 29 246. The bioavailability calculated on the basis of the areas under the concentration-time curves (AUC) and the urinary recoveries was about 90%. In rats, peak blood levels of 14.5 micrograms/ml were obtained 1 hour after an oral 20 mg/kg dose. The bioavailability was calculated as 70%. In dogs, 40% of an oral 10 mg/kg dose was recovered in the urine within 24 hours. Cmax was 15.9 micrograms/ml at 4.6 hours. Mean elimination half-lives of RU 29 246 were 0.35, 0.5 and 2.1 hours in mice, rats and dogs, respectively. After an oral HR 916 B dose equivalent to 50 mg/kg of RU 29 246, tissue concentrations at 0.5 hour ranged between 0.8 micrograms/g in brain and 95.7 micrograms/g in murine kidneys. These values of HR 916 B are similar to, or distinctly higher than, those of the reference compounds. Of the oral cephalosporins tested, HR 916 B had the most balanced antibacterial spectrum. With ED50s of between 0.9 and 11.5 mg/kg against staphylococci, its activity was similar to that of the additional reference compound cefaclor and higher than that of cefuroxime. Cefixime and cefpodoxime proxetil displayed low antistaphylococcal activity or were inactive. In septicemias with Enterobacteriaceae, cefixime and cefpodoxime proxetil were more potent than HR 916 B and cefaclor. Cefuroxime axetil was inactive against most of these infections. HR 916 B was also highly effective against murine lung infections caused by Klebsiella pneumoniae DT-S or Streptococcus pneumoniae 1147.     

In vitro studies with Bay V 3522, a new oral cephalosporin

The in vitro activities of Bay v 3522, cefaclor, cephalexin, cefuroxime, cefixime, amoxicillin/clavulanate (2:1) and reference penicillins were compared against 314 clinical isolates of Gram-positive and Gram-negative bacteria and nine strains of Escherichia coli that differed in their outer membrane proteins in agar dilution tests with an inoculum of 10(4) cfu/spot. The beta-lactamase stabilities of the cephalosporins were also evaluated by spectrophotometric assay using 21 different beta-lactamases. Bay v 3522 was the most potent cephalosporin overall against Gram-positive pathogens, but slightly less active than amoxicillin/clavulanate. In addition to being highly active against streptococci (MIC90 = 0.25 micrograms/ml) and methicillin-susceptible staphylococci (MIC90 = 1.0 micrograms/ml), Bay v 3522 was markedly more active than the other cephalosporins against Enterococcus faecalis (MIC90 = 4 micrograms/ml). Bay v 3522 was less potent against Gram-negative pathogens, especially nosocomial isolates of Escherichia coli and Klebsiella pneumoniae (MIC90 greater than 64 micrograms/ml), but was active against Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and beta-lactamase-negative Neisseria gonorrhoeae (MIC90 = 1.0 micrograms/ml0. Hydrolysis of Bay v 3522 by most beta-lactamases examined was significantly less than that observed for cephalothin and cefaclor; similar to that observed with cephalexin; and less than that observed with cefixime and cefuroxime. None of the beta-lactamases examined hydrolysed Bay v 3522 at a rate greater than 20 nmol/min/mg. The in vitro potency of Bay v 3522 against Gram-positive and fastidious Gram-negative pathogens and its resistance to hydrolysis by beta-lactamases produced by them support further investigation of this cephalosporin as a new oral therapeutic agent.     

常用口服头孢菌素的药动学及临床应用评价

该文综述了近年来口服的8种头孢菌素,如头孢妥仑匹酯、头孢地尼、头孢他美酯、头孢泊肟酯、头孢克肟、头孢布烯、头孢丙烯、头孢呋辛酯的PK特点并进行了PK/PD值比较,利用MIC90(tmax·MIC90/Cmax+t>MIC-tmax)≤0.5Cmax·t1/2公式计算出该药物的临床抗菌阈浓度(mg/L)。并应用8种头孢菌素临床抗菌阈浓度(mg/L),分析了对临床病原菌的抗菌疗效。     

Antibacterial activity of cefpodoxime against clinical isolates in 2000 and 2001

As the post-marketing surveillance of cefpodoxime proxetil (Banan), MICs of cefpodoxime (CPDX, an active form of Banan) against 1090 clinical isolates of 22 species from 15 medical institutions all over Japan from June 2000 to March 2001 were measured using the broth microdilution method approved by the Japanese Society of Chemotherapy and compared with those of oral cephem antibacterials, cefaclor, cefdinir, cefditoren, and cefcapene. In this study, remarkable change in the activity of CPDX was observed in Streptococcus pneumoniae and Haemophilus influenzae compared with the susceptibility in the studies before Banan was launched. This cause is considered to be the increase in the incidence of the following resistant strains: penicillin-intermediate S. pneumoniae (47.3%), penicillin-resistant S. pneumoniae (PRSP, 15.1%), and beta-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae (24.0%), which were scarcely isolated in 1989 when Banan was launched. Other tested drugs also exhibited low activity against these resistant strains. However, CPDX showed comparatively good activity with MIC90 of 2 micrograms/mL against PRSP. Against methicillin-susceptible Staphylococcus spp., Streptococcus pyogenes, Streptococcus agalactiae, and Moraxella catarrhalis, CPDX also showed comparatively good activity with MIC90 of < or = 4 micrograms/mL, which was almost equal to that in the studies before its marketing. Against quinolones-resistant Neisseria gonorrhoeae, CPDX showed excellent activity with MIC90 of 0.5 microgram/mL. Against members of the family Enterobacteriaceae except for Citrobacter freundii, Enterobacter spp., Proteus vulgaris, and Morganella morganii, CPDX showed good activity. However, in Escherichia coli, Klebsiella spp. Proteus spp., and Providencia spp., there are some high-resistant strains to all tested drugs including CPDX. Against Peptostreptococcus spp., MIC90 of CPDX was 8 micrograms/mL and its MIC range was widely distributed from 0.03 to 32 micrograms/mL, which were similar to those in the studies before its marketing. In this study, CPDX showed the decrease in the activity against several species as did other drugs tested, but against most of species tested, CPDX maintained good activity. Furthermore, it is necessary to pay much attention to the trend of resistant strains.     

Comparative Pharmacokinetics of Oral Ceftibuten,Cefixime, Cefaclor,and Cefuroxime Axetil in Healthy Volunteers

Study Objective . To compare the pharmacokinetics of ceftibuten, cefixime, cefuroxime axetil, and cefaclor after oral administration. Design . Randomized, four-period, crossover study. Setting . Hospital-based clinical research center. Subjects . Healthy adult men and women volunteers. Interventions . Single 400-mg doses of cefixime and ceftibuten, and 500-mg doses of cefuroxime axetil and cefaclor. Measurements and Main Results . Serum concentrations were determined by high-performance liquid chromatography methods. The mean oral clearances of cefixime, cefuroxime axetil, and cefaclor were similar, ranging from 20.4–27.0 L/hour; clearance of ceftibuten was approximately 4-fold less, 5.45 L/hour. The serum half-lives of ceftibuten (2.35 hrs) and cefixime (2.38 hrs) were prolonged compared with those of cefuroxime axetil (1.30 hrs) and cefaclor (0.693 hr). These agents also differed in terms of time to maximum concentration, time to peak plasma level, area under the curve, and apparent volume of distribution, the last reflecting differences in bioavailability. Conclusion . Ceftibuten had a relatively high time to maximum concentration and long half-life, resulting in a 3.5-fold higher area under the curve than cefixime, cefuroxime axetil, and cefaclor. These pharmacokinetic data can be used as a basis to compare the four oral cephalosporins; however, comparative susceptibility data must also be considered.     

In vitro activity of aztreonam, cefuroxime and ceftazidime against gram-negative rods isolated from hospital patients with urinary tract infection

The in vitro activity of aztreonam, cefuroxime and ceftazidime was determined against 2,372 Gram-negative rods (including Pseudomonas spp.) isolated from hospital patients with urinary tract infections during 1985. Minimum inhibitory concentrations (MICs) were determined using an agar incorporation technique in Mueller-Hinton agar. The inoculum used was approximately 10(5) colony forming units (cfu) contained in 10 microliter Mueller-Hinton broth, which was applied to the surface of the agar plates using a multipoint inoculator. Following inoculation plates were incubated aerobically at 37 degrees C for 18 h. The MIC of each antimicrobial for each organism examined was determined as the lowest concentration of the antimicrobial which completely inhibited growth of the inoculum. The minimum concentration required to inhibit the growth of 90% (MIC90) of the bacterial isolates in each genus or species examined was also determined. In general the antibacterial spectrum of aztreonam was comparable to that of ceftazidime and superior to that of cefuroxime. Against Escherichia coli, which accounted for 72% of the isolates examined, aztreonam (MIC90 less than or equal to 0.25 microgram/ml) was slightly more active than ceftazidime (MIC90 0.5 microgram/ml) and considerably more active than cefuroxime (MIC90 8 micrograms/ml). Aztreonam was active against Pseudomonas spp. (MIC90 16 micrograms/ml), although somewhat less so than ceftazidime (MIC90 4 micrograms/ml). Cefuroxime showed low activity against this genus (MIC90 greater than 128 micrograms/ml).     

The sensitivity of clinical bacteria isolated in Scotland to the oral cephalosporin, cefdinir.

The minimum inhibitory concentration (MIC) of cefdinir (CI-983, FK-482), cephalexin cefuroxime, cefixime and ceftazidime were determined against clinical isolates. Cefdinir was as effective as cefixime against Haemophilus and Moraxella (Branhamella) strains and both were more effective than cefuroxime. Against streptococci, cefdinir was much more effective than cefixime and had similar efficacy to cefuroxime. Against staphylococci, cefdinir had the lowest MIC50 of all of the drugs tested. The efficacy of these antibiotics was tested against Escherichia coli K12 strains harbouring 16 of the new extended-spectrum plasmid-mediated beta-lactamases, and cefdinir was more effective than ampicillin, cephalexin, cefuroxime, ceftazidime and aztreonam.     

国内对头孢克肟的临床研究与评价

头孢克肟是第1种第3代口服头孢菌素类抗生素,由日本藤泽制药株式会社于1987年研制成功并首先在日本上市应用于临床,1989年在美国上市。1999年已在80多个国家得到广泛的临床使用。头孢克肟的制剂剂型的研究已发展有胶囊剂、颗粒剂、混悬剂、片剂(普通片剂、咀嚼片、分散片)等。笔者综述了国产头孢克肟与日本产头孢克肟在胶囊剂、颗粒剂、混悬剂、片剂(普通片剂、咀嚼片、分散片)等的药动学比较,以及头孢克肟与头孢泊肟、头孢克洛、头孢呋辛、头孢美他酯、头孢噻肟、头孢地尼、头孢特仑、头孢妥仑匹酯等体外抗菌活性及临床药效学比较。     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (1997). I. Susceptibility distribution

The frequencies of isolation and susceptibilities to antimicrobial agents were investigated on 560 bacterial strains isolated from patients with urinary tract infections (UTIs) in 9 hospitals during the period of June 1997 to May 1998. Of the above bacterial isolates, Gram-positive bacteria accounted for 29.3% and a majority of them were Enterococcus faecalis. Gram-negative bacteria accounted for 70.7% and most of them were Escherichia coli. Susceptibilities of several isolated bacteria to antimicrobial agents were as followed; 1. Enterococcus faecalis Ampicillin (ABPC) showed the highest activity against E. faecalis isolated from patients with UTIs. Its MIC90 was 1 microgram/ml. Imipenem (IPM) and vancomycin (VCM) were also active with the MIC90s of 2 micrograms/ml. The others had low activities with the MIC90s of 16 micrograms/ml or above. 2. Staphylococcus aureus including MRSA VCM and arbekacin (ABK) showed the highest activities against both S. aureus and MRSA isolated from patients with UTIs. The MIC90s of them were 1 microgram/ml. The others except minocycline (MINO) had low activities with the MIC90s of 32 micrograms/ml or above. More than a half of S. aureus strains (including MRSA) showed high susceptibilities to gentamicin (GM) and MINO, the MIC50s of 0.25 microgram/ml or 0.5 microgram/ml. 3. Enterobacter cloacae IPM showed the highest activity against E. cloacae. The MICs for all strains were equal to or lower than 1 microgram/ml. The MIC90s of ciprofloxacin (CPFX) and tosufloxacin (TFLX) were 1 microgram/ml, the MIC90s of amikacin (AMK) and ofloxacin (OFLX) were 4 micrograms/ml, the MIC90 of GM was 16 micrograms/ml. Among E. cloacae strains, those with low susceptibilities to quinolones have decreased in 1997, compared with those in 1996. But the other drugs were not so active in 1997 as 1996. 4. Escherichia coli All drugs except penicillins were active against E. coli with the MIC90s of 8 micrograms/ml or below. Particularly, flomoxef (FMOX), cefmenoxime (CMX), cefpirome (CPR), cefozopran (CZOP), IPM, CPFX and TFLX showed the highest activities against E. coli with the MIC90s of 0.125 microgram/ml or below. 5. Klebsiella pneumoniae K. pneumoniae was susceptible to almost all the drugs except penicillins. Carumonam (CRMN) had the strongest activity with the MICs for all strains equal to or lower than 0.125 microgram/ml. FMOX, CPR, CZOP, CPFX and TFLX were also active with the MIC90s of 0.125 microgram/ml or below. The MIC90s of quinolones had changed into a better state in 1997, compared with those in 1996. 6. Proteus mirabilis Almost all the drugs except ABPC and MINO showed high activities against P. mirabilis. CMX, ceftazidime (CAZ), latamoxef (LMOX), CPR, cefixime (CFIX), cefpodoxime (CPDX) and CRMN showed the highest activities against P. mirabilis. The MICs of them for all strains were equal to or lower than 0.125 microgram/ml. CPFX and TFLX were also active with the MIC90s of 0.125 microgram/ml or below. 7. Pseudomonas aeruginosa The MIC90 of GM was 8 micrograms/ml, the MIC90s of AMK, IPM and meropenem (MEPM) were 16 micrograms/ml. The others were not so active against P. aeruginosa with the MIC90s of 32 micrograms/ml or above. The MIC90s of quinolones had changed into a lower state in 1997, compared with those in 1996. 8. Serratia marcescens IPM showed the highest activity against S. marcescens. Its MIC90 was 2 micrograms/ml. GM was also active with the MIC90 of 4 micrograms/ml. The MIC90s of the others were 16 micrograms/ml or above. The MIC50s of CRMN was 0.125 microgram/ml or below, the MIC50s of CPR and CZOP were 0.25 microgram/ml.     

Clinical laboratory approach for estimating effective administrative dosage of cefmenoxime. Observation on the MICS and cefmenoxime disc susceptibility test

The in vitro activity of cefmenoxime (CMX) was determined using agar dilution at inoculum level of 10(6) cfu/ml against 333 clinical bacterial isolates. CMX was highly active against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter aerogenes and Haemophilus influenzae and also Streptococcus Pyogenes and Streptococcus pneumoniae with MIC values in the range of 0.024 to 3.13 micrograms/ml. Against Staphylococci and Serratia marcescens, CMX showed the antimicrobial activity with MIC90 6.25 micrograms/ml. However, CMX was not active against Pseudomonas aeruginosa and Acinetobacter anitratus and exhibited no useful activity against Streptococcus faecalis. Reliability of CMX disc diffusion susceptibility test for quantitative estimation of the antimicrobial activity was also investigated, using 8 mm diameter disc (Showa) and 6 mm diameter disc (Wako), both of them containing 30 micrograms of CMX. These disc susceptibility test results were well correlated with MICs, capable of utilizing CMX disc susceptibility test for the estimation of proper administrative dose of CMX. Using 6 mm diameter disc containing 30 micrograms CMX, FUCHS et al. have proposed the following tentative zone size break points: greater than or equal to 22 mm = MIC 8 micrograms/ml, susceptible; 15 to 21 mm = MIC 16 approximately 32 micrograms/ml, moderately susceptible (intermediate); and less than or equal to 14 mm = MIC greater than 32 micrograms/ml, resistant. In this investigation, the following zone size break points have preferred: greater than or equal to 25 mm = MIC less than or equal to 3 micrograms/ml (3+); 20 to 24 mm = MIC greater than 3 to 15 micrograms/ml (2+); 16 to 19 mm = MIC greater than 15 to 60 micrograms/ml (+) and less than or equal to 15 mm = MIC greater than or equal to 60 micrograms/ml (-). Based on CMX pharmacokinetic data currently available, MIC break points proposed, less than or equal to 3 micrograms/ml and less than or equal to 15 micrograms/ml, would be useful for estimating the administrative dose of this antibiotic to obtain the effective blood level (e.g. the bacteriostatic activity in serum 1: greater than or equal to 8 for treatment of severe infection.     

Comparative studies of antimicrobial agents against causative organisms isolated from urinary tract infections (1984). I. Susceptibility distribution

Our research group was engaged for 3 years (1979-1981) in a study on sensitivities to antibiotics of 4 bacterial groups including representative pathogenic bacteria found in cases of urinary tract infections; i.e. E. coli, Klebsiella spp., Citrobacter spp., and Proteus spp. Since 1982, all the bacterial strains isolated by our group from patients with urinary tract infections and deemed by doctors in charge as pathogens were sent to the Laboratory of Clinical Pathology of Juntendo University, where they were refixed and subjected to MIC determination. This is the third year of the new study. E. coli was detected most frequently from patients with urinary tract infections and the detection frequency was 28% (323/1,153) this year (1984), whereas it was 35.3% (304/860) last year, showing a 7% decline from last year to this year. E. faecalis was next frequent organism (12.7% or 147/1,153) followed by P. aeruginosa (10.8% or 124/1,153). This order, however, was reversed from last year. Other pathogens, in a decreasing order of isolation frequencies following the above three, were as follows: Proteus spp. (9.5% or 109/1,153), S. marcescens (6.2% or 71/1,153), S. epidermidis (5.4% or 62/1,153), K. pneumoniae (4.9% or 56/1,153), Enterobacter spp. (2.4% or 28/1,153) and Citrobacter spp. (2.3% or 27/1,153). The results of the determination of the sensitivity of bacterial strains to the antibiotics are described below. Of all the oral antibacterial and antibiotic agents used against E. coli, mecillinam (MPC), cefaclor (CCL) and pipemidic acid (PPA) proved to have high antibacterial potency, and their MIC90 (the concentration to inhibit growths of 90% of the objective bacteria) was 3.13 micrograms/ml. The MIC90's of cefotiam (CTM), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX) and latamoxef (LMOX) were less than 0.39 microgram/ml. The MIC90's of cefmetazole (CMZ) and cefoperazone (CPZ) were invariably 1.56 micrograms/ml. K. pneumoniae was not sensitive to ampicillin (ABPC) and did not show much sensitivity to other oral antibacterial and antibiotic agents also. Of all the injectable preparations of antibiotics, cephem antibiotics of the third generation showed the most potent antibacterial effects against K. pneumoniae, and their MIC90's were lower than 0.10 microgram/ml for CZX, 0.20 microgram/ml for CTX, 0.39 microgram/ml for CMX, and 0.78 microgram/ml for LMOX, while MIC90's of CPZ was 6.25 micrograms/ml, which was equal to that of CMZ. The MIC90 of CTM was 0.78 microgram/ml which was identical to that of LMOX.(ABSTRACT TRUNCATED AT 400 WORDS)     

RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. II. Stability to beta-lactamases and affinity for penicillin-binding proteins.

The aminothiazolyl-cephalosporin RU 29 246, the active metabolite of the prodrug-ester HR 916, is active against strains producing the widespread plasmid-encoded TEM-1, TEM-2 and SHV-1 beta-lactamases. Except for TEM-7 the activity of RU 29 246 against strains producing extended broad spectrum beta-lactamases (TEM-3, TEM-5, TEM-6, SHV-2, SHV-4, SHV-5, CMY-1, CTX-M), however, is low. Relative hydrolysis rates of RU 29 246 are comparable with those of cefpodoxime, the active metabolite of CS-807, and are extremely low for the TEM-1 and SHV-1 beta-lactamases. The compound demonstrates remarkable inhibitory activity against the chromosomal beta-lactamase of Enterobacter cloacae P99. In the presence of 1.7 microM this enzyme loses 50% of its activity. At concentrations of 0.43, 0.003 and 0.01 micrograms/ml the compound binds preferentially to the penicillin-binding protein (PBP) 3 of Escherichia coli K12, to the PBPs 2x and 3 of Streptococcus pneumoniae R6 and to PBP 1 of Staphylococcus aureus SG 511, respectively.     

Cefdinir activity against contemporary North American isolates from community-acquired urinary tract infections

Cefdinir is an oral cephalosporin approved by the US Food and Drug Administration in 1997 for the treatment of community-acquired (CA) respiratory tract and uncomplicated skin and soft tissue infections. The objective of the present study was to evaluate the in vitro activity of cefdinir against recent clinical isolates collected from CA-urinary tract infections (UTIs), a possible expanded indication. A total of 456 isolates from CA-UTI were collected from medical centres in North America (NA; United States and Canada) in 2003 and susceptibility tested by NCCLS reference broth microdilution methods. Cefdinir and cefpodoxime were the most active compounds tested against Escherichia coli (98.7% susceptibility), followed by nitrofurantoin (97.0%) and ciprofloxacin (95.0%). Cefdinir was 8- to 16-fold more potent than cefuroxime axetil and cefprozil against E. coli, Klebsiella spp. and Staphylococcus saprophyticus. The activity of cefdinir was most similar to that of cefpodoxime against E. coli and Klebsiella spp., but cefpodoxime showed inferior activity against S. saprophyticus. The cefdinir spectrum was significant superior (+3.8 to 16.5%) to that of trimethoprim/sulphamethoxazole against all pathogens evaluated. The cefdinir spectrum and potency were comparable or superior to other orally administered beta-lactams tested against recent (2003) clinical isolates from CA-UTI.     

In vitro activity of flomoxef compared to moxalactam, cefoxitin, cefotaxime, and clindamycin against anaerobes

To assess the in vitro activity of flomoxef (6315-S), moxalactam, cefoxitin, cefotaxime, and clindamycin against anaerobes 197 clinical isolates (27 Bacteroides fragilis, 42 B. thetaiotaomicron, 10 B. vulgatus, 7 B. ovatus, 6 B. uniformis, 6 B. distasonis, 7 Bacteroides melaninogenicus group, 11 Bacteroides oralis group, 21 Clostridium difficile, 7 C. perfringens, 3 C. sporogenes, 3 Clostridium spp., 33 Propionibacterium acnes, 14 Peptococcaceae) were studied by means of agar dilution tests. The MIC90 of B. fragilis was less than 2 micrograms/ml for flomoxef, less than 4 micrograms/ml for moxalactam, less than 16 micrograms/ml for cefoxitin, less than 128 micrograms/ml for cefotaxime and less than 2 micrograms/ml for clindamycin. The respective MIC90's of B. thetaiotaomicron were less than 64, less than 128, less than 32, less than 256 and 8 micrograms/ml. Strains of the other Bacteroides species and groups were more susceptible to flomoxef and the other antibiotics than B. thetaiotaomicron. Against Clostridium difficile flomoxef (MIC90 less than 4 micrograms/ml) proved to be superior to the other agents tested. Most of the Clostridium strains other than C. difficile were also susceptible to flomoxef; anaerobic grampositive cocci and Propionibacterium acnes were very sensitive (MIC90's less than 1 and less than or equal to 0.125 micrograms/ml, respectively). Its anti-anaerobic activity, together with its efficacy against aerobes, should make flomoxef a useful adjunct to the arsenal of modern antibiotic therapy.     

Clinical laboratory approach to estimate effective administrative dose of minocyclin. Reevaluation of in vitro MIC break points in disc susceptibility test

Antimicrobial activities of minocycline (MINO) against various clinical isolates, 270 strains obtained in 1988, were determined and the reliability of the MINO disc susceptibility test in estimating approximate values of MICs was studied. Clinical significance of a 4 category system for the interpretation of the disc tests, which is widely used in Japan, and that of a 3 category system used in the USA and Europe, were also evaluated to determine which system would be more suitable for the evaluation of proper dose levels of administration. In this study, MICs were determined using the agar dilution method at an inoculum level of 10(6) CFU/ml. MIC80 values of MINO against Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pneumoniae were all less than or equal to 0.78 micrograms/ml. Those against Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Proteus vulgaris were 0.39, 6.25, 3.13, 25, 50 micrograms/ml, respectively. MIC80 values against Pseudomonas aeruginosa, Serratia marcescens, Enterobacter spp., and Citrobacter spp. were 50, 100, 50 and 12.5 micrograms/ml, respectively. The inhibition zones obtained with the disc method were compared with MICs. The results of MINO disc susceptibility test either with 200 micrograms disc (Showa) or 30 micrograms disc (prepared in this laboratory) were well correlated with MICs, showing the reliability of the disc method in estimating approximate values of MICs. In the 4 category classification system currently used, break points in MIC values proposed are ( ) MIC less than or equal to 2 micrograms/ml, (++) MIC greater than 2-10 micrograms/ml, (+) greater than 10-50 micrograms/ml, (-) MIC greater than 50 micrograms/ml. The results obtained with 200 micrograms and 30 micrograms discs showed false positive in 26.6% and 20.5% of the samples, and false negative in 5.8% and 23.6% of the samples, respectively. The disc results of S. aureus, S. epidermidis, S. pneumoniae, etc. were relatively well classified, but those of E. coli, K. pneumoniae, Proteus spp. were not, showing more false positive results. Changing the lower 2 MIC break points in the 4 category system to: ( ) MIC less than or equal to 3 micrograms/ml and (++) MIC greater than 3-15 micrograms/ml, the false positive results with both 200 micrograms and 30 micrograms discs were reduced to 12% and 6.2%, respectively. The false negative results were 5.8% and 23.6%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1986). I. Susceptibility distribution

Susceptibilities to various antibacterial and antibiotic agents of bacterial strains isolated from urinary tract infections at 8 hospitals in Japan from July to October in 1986 are summarized as follows. 1. Enterococcus faecalis was susceptible to sulfamethoxazole/trimethoprim (ST) and imipenem (IPM) with MIC90s of 0.78 and 1.56 microgram/ml. Minocycline had the strongest activity against Staphylococcus aureus; the MICs for all strains tested were lower than 0.39 microgram/ml. The MIC80s of dicloxacillin, and arbekacin (HBK) were 0.20 and 0.78 microgram/ml, respectively. Among the cephems, the MIC80 of flomoxef was 25 micrograms/ml, whereas those of cefmenoxime (CMX) and cefotiam (CTM) were 50 micrograms/ml. 2. Escherichia coli was most susceptible to ofloxacin (OFLX) among the oral antibacterial and antibiotic agents tested. OFLX showed the minimum inhibitory concentration against 90% (MIC90) of the 274 strains of E. coli tested to be lower than 0.10 microgram/ml. The antibacterial activities of the third generation cephems such as CMX and latamoxef (LMOX) were the strongest among the injectable antibiotics tested. The MIC90s of CMX and LMOX were lower than 0.10 and 0.20 microgram/ml, respectively. CTM and cefmetazole, the second generation cephems, were also highly active against E. coli with MIC90s of 0.39 and 1.56 micrograms/ml, respectively. 3. Among the oral antibacterial and antibiotic agents tested, OFLX was the most active against Klebsiella pneumoniae. Its MIC90 was 0.78 microgram/ml. Among the injectable antibiotics tested, CMX was the strongest with an MIC90 of 0.20 microgram/ml; MIC90 of CTM and LMOX were 0.39 microgram/ml. 4. The tested antibacterial and antibiotic agents were generally less active against Citrobacter freundii than against other bacteria. The MIC80 of OFLX was 0.39 microgram/ml. Gentamicin (GM) and ST were slightly active against C. freundii. Among the cephems, CMX had the MIC80 of 25 micrograms/ml. 5. Enterobacter cloacae was less susceptible to the cephems tested. OFLX, GM, and mecillinam were active against this bacteria with MIC80s of 0.78, 0.78 and 1.56 micrograms/ml, respectively. 6. Among the oral antibacterial and antibiotic agents and penicillins examined, piperacillin (PIPC) was the most active against Proteus mirabilis. Its MIC90 was 0.39 microgram/ml. Those of sulbenicillin, cefaclor, ampicillin, OFLX, and ST were 0.78, 0.78, 1.56, 3.13 and 3.13 micrograms/ml, respectively. CMX was highly active against P. mirabilis with an MIC90 of less than or equal to 0.10 microgram/ml; LMOX followed with an MIC90 of 0.20 microgram/ml among the injectable antibiotics tested. CTM was also active against this bacterium; the MIC90 was 0.39 microgram/ml. 7. The antibacterial and antibiotic agents were generally only slightly active against Proteus vulgaris.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antibacterial activity of oral cephems against various clinically isolated strains and evaluation of efficacy based on the pharmacokinetics/pharmacodynamics theory

We compared the antimicrobial activity of commercially available oral cephem agents, cefaclor (CCL), cefroxadine (CXD), cefdinir (CFDN), cefixime (CFIX), cefpodoxime (CPDX), cefteram (CFTM), cefcapene (CFPN), and cefditoren (CDTR), against Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes, and ESBL-producing bacteria isolated from clinical materials in Kansai Medical University Hospital between 2002 and 2003. Based on the Pharmacokinetics/Pharmacodynamics (PK/PD) theory, we determined the concentration of each agent at which the time above MIC (TAM) value was 40% or more, and calculated the rate of efficacy against each type of bacteria. In S. pneumoniae strains, the MIC(50,80,90) values of CDTR were 0.25, 0.5, and 0.5 microg/ml, respectively, lower than those of the other agents, demonstrating the most potent antimicrobial activity. However, the efficacy rate for CDTR calculated based on the PK/PD theory was 58.5%. CFTM showed the highest efficacy rate (66.1%). In H. influenzae strains, the antimicrobial activity of CDTR was most potent, followed by that of CFTM and that of CFPN/CFIX. The MIC90 value of CDTR was lowest (0.25 microg/ml), followed by that of CFTM (0.5 microg/ml). The efficacy rate for CDTR was 100%. This result supports that CDTR frequently eradicates H. influenzae. In E. coli strains, the MIC90 values of the above agents, excluding CCL and CXD, ranged from 0.5 to 1 microg/ml. The antimicrobial activity of CFIX against K. pneumoniae was most potent, followed by that of CFDN/CPDX and that of CFTM. In ESBL-producing bacteria, most agents showed an MIC90 value of more than 4 microg/ml. In S. agalactiae and S. pyogenes strains, all of the agents showed satisfactory MIC values. In methi- cillin-sensitive Staphylococcus aureus (MSSA) strains, CFDN and CXD showed a high efficacy rate, whereas the efficacy rates for the other agents were low. The frequent use of oral agents has increased the number of cephem-resistant bacteria. ESBL-producing bacteria become highly resistant, and the presence or absence of response can be readily evaluated. However, when a mutation of penicillin-binding protein (PBP) occurs, drug resistance is less marked. Therefore, it is difficult to evaluate the treatment response in many cases. In S. pneumoniae strains, the efficacy rates for all of the agents were low in the evaluation using the PK/PD theory, suggesting that a dose higher than the standard dose should be established. Thus, in the future, the efficacy should be evaluated based on the PK/PD theory, appropriate antimicrobial treatment should be administered, and the administration method that does not increase the number of resistant bacteria must be established.     

Bacteriological, pharmacokinetic and clinical studies of 5% and 10% granules of cefdinir in the pediatric field]

Bacteriological, pharmacokinetic and clinical studies on cefdinir (CFDN, FK482), a new oral cephalosporin, 5% and 10% granules, were performed in the field of pediatrics. The results are summarized below. 1. Antibacterial activities Antibacterial activities of CFDN against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, Escherichia coli and Klebsiella pneumoniae were studied in comparison with those of cefaclor (CCL), cefixime (CFIX) and amoxicillin (AMPC). MIC80's of CFDN against S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, B. catarrhalis, K. pneumoniae and E. coli were 0.78, 0.20, less than or equal to 0.025, 0.39, 0.10, 0.20 and 0.10 micrograms/ml, respectively. These results show that CFDN has high antibacterial activities against these organisms. MIC80's of CFDN against Gram-positive bacteria were similar to those of AMPC, and was lower than those of CCL and CFIX. As for antibacterial activities against Gram-negative bacteria (GNB), the MIC80 of CFIX against H. influenzae was 0.05 micrograms/ml, which was slightly lower than that of CFDN. THe MIC80's of CFDN against other GNB were similar to those of CFIX. 2. Absorption and excretion Blood concentrations and urinary excretion rates of CFDN 5% and 10% granules and 100 mg capsule were determined. The data on CFDN 10% granules were similar to those on CFDN 5% granules. At a dose of 3 mg/kg, peak blood concentrations (Cmax's) of CFDN ranged from 0.20 to 2.12 micrograms/ml with 5% granules and from 0.50 to 1.15 micrograms/ml with 10% granules at 2 to 3 hours after dosing. At a dose of 6 mg/kg, peak concentrations were 0.66-2.06 micrograms/ml and 0.70-1.52 micrograms/ml with 5% granules and with 10% granules, respectively. At 8 hours after dosing, blood concentrations were 0.04-0.54 micrograms/ml at 3 mg/kg and 0.06-0.27 micrograms/ml at 6 mg/kg. Blood half-lives were 1.33-4.36 hours at 3 mg/kg and 1.14-3.27 hours at 6 mg/kg. AUC's were 1.7-11.0 micrograms.hr/ml with 3 mg/kg and 2.4-8.7 micrograms.hr/ml with 6 mg/kg. With administration of single 100 mg capsule, Cmax's, blood concentrations after 8 hours, T1/2's and AUC's were 0.79-1.88 micrograms/ml, 0.20 micrograms/ml, 1.54-2.72 hours, and 5.2 micrograms.hr/ml, respectively. Urinary recovery rates in the first 8 hours ranged from 6.85 to 39.2% with 3 mg/kg and 6.08-25.5% with 6 mg/kg.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1985). I. Susceptibility distribution

The results of determinations of sensitivities of bacterial strains to various antibiotics are summarized as follows: 1. Against Escherichia coli, ofloxacin (OFLX) showed the strongest activity among oral antibacterial and antibiotic agents. Its MIC90 was below 0.10 micrograms/ml. The next strongest activity was found in mecillinam (MPC), cefaclor (CCL) and pipemidic acid (PPA); MIC90's of these agents 3.13 micrograms/ml. Cefotiam (CTM), cefotaxime (CTX), ceftizoxime (CZX), cefmenoxime (CMX) and latamoxef (LMOX) had MIC90 below 0.39 micrograms/ml. MIC90's of cefmetazole (CMZ) and cefoperazone (CPZ) were 1.56 micrograms/ml. Aztreonam (AZT) and carumonam (CRMN) in the monobactam group showed strong activities with MIC90's at 0.20 micrograms/ml. 2. Although Klebsiella pneumoniae had a strong resistance to ampicillin (ABPC) and showed relatively low sensitivities to other oral antibacterial and antibiotic agents, OFLX maintained high activity against this species and showed MIC90 of 0.39 micrograms/ml. Among injectable antibiotics, third generation cephems showed the strongest activity to this species with MIC90 of CZX below 0.10 micrograms/ml, of CTX and CMX 0.20 micrograms/ml, and of LMOX 0.78 micrograms/ml. MIC90 of CPZ was 6.25 micrograms/ml, which was the same as those of cefazolin (CEZ) and cefoxitin (CFX). CTM had similar MIC90 to LMOX, namely, 1.56 micrograms/ml. MIC90 of CMZ was 3.13 micrograms/ml. Monobactams AZT and CRMN showed strong activities to this species; their MIC90's were below 0.10 micrograms/ml and 0.20 micrograms/ml. 3. Although Citrobacter freundii generally exhibited low sensitivities to antibacterial and antibiotic agents examined, it showed high sensitivity to OFLX, at MIC80 of 0.78 micrograms/ml. This species showed low sensitivities to MPC, nalidixic acid (NA), PPA, and sulfamethoxazole-trimethoprim (ST). Among injectable antibiotics, LMOX and CMX had activities against this species; namely, MIC80's were 6.25 and 3.13 micrograms/ml, respectively. Among monobactams, AZT showed MIC80 of 12.5 micrograms/ml, and CRMN had that of 6.25 micrograms/ml. 4. Against Enterobacter cloacae, the strongest antibacterial activity was found with OFLX which had MIC90 of 0.39 micrograms/ml. A relatively strong activity was seen with MPC. MIC80 of MPC was 1.56 micrograms/ml. Except to CTM, this species had poor sensitivities to injectable first and second generation cephems, and their MIC80's were over 200 micrograms/ml. MIC80 of CTM was 25 micrograms/ml.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antimycoplasmal activities of ofloxacin and commonly used antimicrobial agents on Mycoplasma gallisepticum

In vitro activities of ofloxacin (OFLX), a new quinolone derivative, against 29 strains of Mycoplasma gallisepticum was compared with those of 4 commonly used antimicrobial agents, doxycycline (DOXY), tylosin (TS), spectinomycin (SPCM) and thiamphenicol (TP). Antimycoplasmal activities of the drugs were evaluated on the MIC (final MIC) and MPC (minimum mycoplasmacidal concentration) values which were determined by a broth dilution procedure. The following results were obtained. 1. The MIC90s of OFLX and DOXY were both 0.20 micrograms/ml. The MICs of TS were distributed through a wide range (less than or equal to 0.006 - 0.78 micrograms/ml), and its MIC90 was 0.78 micrograms/ml. Of 29 M. gallisepticum strains, 27.6% were recognized as TS-resistant. The MIC90 values of SPCM and TP were 1.56 micrograms/ml and 3.13 micrograms/ml, respectively. The MIC90 of OFLX was equal to that of DOXY and 4- to 16-fold smaller than the values of the other 3 antibiotics. 2. The MPC of OFLX was the lowest among the antibiotics tested, its MPC90 value was 0.39 micrograms/ml and was followed by DOXY (1.56 micrograms/ml). The MPCs of TS were distributed in a wide range (0.012 - 3.13 micrograms/ml), and its MPC90 was 3.13 micrograms/ml. The MPC90 values of SPCM and TP were both 6.25 micrograms/ml. Therefore, the mycoplasmacidal activity of OFLX evaluated with MPC90 values was 4- to 16-fold greater than those of the other 4 antibiotics.