In vitro activity of the new fluoroquinolone CP-99,219

The in vitro activity of the new fluoroquinolone CP-99,219 [7-(3-azabicyclo[3.1.0]hexyl)naphthyridone] was compared with those of four other quinolones against 541 gram-negative, 283 gram-positive, and 70 anaerobic bacterial isolates. CP-99,219 inhibited 90% of many isolates in the family Enterobacteriaceae at a concentration of < or = 0.25 micrograms/ml (range, < 0.008 to 1 microgram/ml), an activity comparable to those of tosufloxacin and sparfloxacin and two times greater than that of temafloxacin. Ninety percent of the Proteus vulgaris, Providencia rettgeri, Providencia stuartii, and Serratia marcescens isolates were inhibited by 0.5 to 2 micrograms of CP-99,219 per ml. CP-99,219 inhibited 90% of the Pseudomonas aeruginosa and Haemophilus influenzae isolates at 1 and 0.015 micrograms/ml, respectively. The compound inhibited methicillin-susceptible Staphylococcus aureus at 0.06 micrograms/ml, whereas a ciprofloxacin concentration of 1 microgram/ml was required to inhibit these organisms. CP-99,219 inhibited 90% of methicillin-resistant S. aureus isolates at a concentration of < or = 4 micrograms/ml, while ciprofloxacin and temafloxacin had MICs against these isolates of > 16 micrograms/ml. Streptococci were inhibited by < or = 0.25 micrograms/ml, an activity comparable to that of tosufloxacin. CP-99,219 was eight times more active than ciprofloxacin against Streptococcus pneumoniae. Bacteroides species were inhibited by CP-99,219 at a concentration of 2 micrograms/ml, whereas inhibition of these species required 4- and 16-microgram/ml concentrations of tosufloxacin and ciprofloxacin, respectively. The MBCs of CP-99,219 ranged from two to four times the MICs, and inoculum size had a minimal effect on MIC. CP-99,219 was active against P. aeruginosa at pH 5.5, with only a fourfold increase in MIC compared with values obtained at pH 7.5. The addition of up to 9 mM Mg(2+) increased the MIC range from 0.03 to 0.06 microgram/ml to 0.12 to 0.5 microgram/ml. In view of its excellent in vitro activity against both gram-positive and gram-negative bacteria, CP-99,219 merits further study to determine it's clinical pharmacologic properties and potential for therapeutic use.     

In vitro activity of biapenem against beta-lactamase producing Enterobacteriaceae

The activity of biapenem was compared with that of imipenem and cefotaxime against 108 strains of beta-lactamase producing Enterobacteriaceae. Biapenem and imipenem were very active, inhibiting 90% of the strains at a concentration of 0.5 microgram/ml. Both carbapenems were very active against plasmidic beta-lactamase producers, with MIC90s below 1 microgram/ml. However, the MIC90 of biapenem for cephalosporinase producers was 1 microgram/ml. Against strains producing extended-spectrum beta-lactamases, biapenem exhibited better activity against TEM-type producers (MIC90 0.25 microgram/ml) than against SHV-type producers (MIC90 0.5 microgram/ml). Overall, the in vitro antibacterial activity of biapenem is similar to that of imipenem.     

In vitro activity of voriconazole against yeasts, moulds and dermatophytes in comparison with fluconazole, amphotericin B and griseofulvin

Voriconazole (CAS 137234-62-9, UK-109,496), a new antifungal triazole derivative, was studied in vitro against 650 clinical isolates, representing yeasts, moulds and dermatophytes, and was compared with fluconazole (CAS 86386-73-4), amphotericin B (CAS 1397-89-3), and griseofulvin (CAS 126-07-8). The mean minimum inhibitory concentrations (MICs) of voriconazole were 0.06 microgram/ml against yeasts (n = 187), 0.74 microgram/ml against moulds (n = 260) and 0.10 microgram/ml against dermatophytes (n = 203). Data from these in vitro studies showed that voriconazole was more potent than fluconazole against most species studied, but particularly against the isolates of moulds and dermatophytes. Overall, voriconazole and amphotericin B indicated comparably good activity against yeasts and moulds. Voriconazole was highly potent against 13 Aspergillus species studied (mean MIC 0.35 microgram/ml) and also showed noteworthy activity (mean MICs 0.08-0.78 microgram/ml) against emerging and less common clinical isolates of opportunistic moulds such as of Alternaria spp., Cladosporium spp., Acremonium spp., Chrysosporium spp., and Fusarium spp. In addition, voriconazole was more active in vitro than griseofulvin against most dermatophytes tested. The in vitro results confirmed that voriconazole has indeed a broad antifungal spectrum and could also be effective against a wide range of fungal infections in patients.     

Expression patterns of proliferating cell nuclear antigen in the small intestine of mice infected with Metagonimus yokogawai and Metagonimus Miyata type

The in vitro antimicrobial activities of AM-1155, a new fluoroquinolone, tosufloxacin and fleroxacin were tested against 55 clinical isolates of Neisseria gonorrhoeae using the agar dilution method. In our previous study, all the strains had been examined for mutations in the region corresponding to the quinolone-resistance determining region of the Escherichia coli gyrA gene and the analogous region of the parC gene, and tested for susceptibility to ciprofloxacin. In this study, the 55 isolates of N. gonorrhoeae were assigned to one of three categories based on the presence or absence of alterations in GyrA and ParC. In each category, the antimicrobial activity of AM-1155 against the isolates was compared with those of tosufloxacin and fleroxacin. The MICs of AM-1155 for 11 highly fluoroquinolone-resistant isolates with alterations in both GyrA and ParC ranged from 0.06 to 1.0 microgram/ml. The MICs inhibiting 50% (MIC50) and 90% (MIC90) of these isolates were 0.125 and 1.0 microgram/ml, respectively. The MICs of AM-1155 for 20 moderately fluoroquinolone-resistant isolates with alterations only in GyrA ranged from 0.03 to 0.25 microgram/ml (MIC50, 0.06 microgram/ml; MIC90m, 0.125 microgram/ml). The MICs of AM-1155 for 24 of the quinolone-susceptible isolates without alterations in either GyrA or ParC ranged from 0.004 to 0.03 microgram/ml (MIC50, 0.008 microgram/ml. MIC90, 0.015 microgram/ml). There were significant differences between the MIC distribution of AM-1155 and each corresponding MIC distribution of tosufloxacin and fleroxacin in these three categories to which the 55 isolates were assigned (p < 0.05). Based on the MIC90S of the tested fluoroquinolones, AM-1155 was two- and eightfold more active against the highly fluoroquinolone-resistant isolates than tosufloxacin and fleroxacin, respectively. Against the moderately fluoroquinolone-resistant isolates, AM-1155 was four- and sixteenfold more active than tosufloxacin and fleroxacin, respectively. Against the quinolone-susceptible strains, AM-1155 was also two- to fourfold more active than the other fluoroquinolones. Overall, AM-1155 exhibited more potent in vitro activity against both quinolone-resistant and quinolone-susceptible isolates of N. gonorrhoeae than tosufloxacin and fleroxacin. In ciprofloxacin treatment failures of gonorrhea at single doses of 500 mg. MICs for the causative organisms have ranged from 1.0 to 16.0 micrograms/ml. The MICs of AM-1155 for the isolates harboring quinolone resistance-associated genetic alterations, including strains exhibiting ciprofloxacin MICs of 2.0 and 8.0 micrograms/ml, still ranged from 0.03 to 1.0 microgram/mL A single-dose study in humans has demonstrated higher peak serum concentrations and longer half-lives of AM-1155, resulting in the AUC0-00 values of AM-1155, which are threefold greater than those of ciprofloxacin at the single doses of 400 and 600 mg. Because of its potent in vitro antimicrobial activity and advantageous pharmacokinetic behavior, AM-1155 may be a clinically useful agent for treating gonorrhea including that caused by quinolone-resistant strains.     

Susceptibilities of bacteria isolated from patients with lower respiratory infectious diseases to antibiotics (1996)

The bacteria isolated from the patients with lower respiratory tract infections were collected by institutions located throughout Japan, since 1981. Ikemoto et al. have been investigating susceptibilities of these isolates to various antibacterial agents and antibiotics, and characteristics of the patients and isolates from them each year. Results obtained from these investigations are discussed. In 16 institutions around the entire Japan, 557 strains of presumably etiological bacteria were isolated mainly from the sputa of 449 patients with lower respiratory tract infections during the period from October 1996 to September 1997. MICs of various antibacterial agents and antibiotics were determined against 98 strains of Staphylococcus aureus, 93 strains of Streptococcus pneumoniae, 84 strains of Haemophilus influenzae, 84 strains of Pseudomonas aeruginosa (non-mucoid strains), 17 strains of Pseudomonas aeruginosa (mucoid strains), 31 strains of Moraxella subgenus Branhamella catarrhalis, 21 strains of Klebsiella pneumoniae etc., and the drug susceptibilities of these strains were assessed except for those strains that died during transportation. 1) S. aureus S. aureus strains for which MICs of oxacillin (MPIPC) were higher than 4 micrograms/ml (methicillin-resistant S. aureus) accounted for 67.3%. The frequency of the drug resistant bacteria increased comparing to the previous year's 52.7%. Arbekacin (ABK) and vancomycin (VCM) showed the highest activities against both S. aureus and MRSA with MIC80s of 1 microgram/ml. 2) S. pneumoniae Imipenem (IPM) and panipenem (PAPM) of carbapenems showed the most potent activities with MIC80s of 0.063 microgram/ml. Faropenem (FRPM) showed the next potent activity with MIC80 of 0.125 microgram/ml. The other drugs except erythromycin (EM), clindamycin (CLDM) and tetracycline (TC) were active against S. pneumoniae tested with MIC80s of 8 micrograms/ml or below. 3) H. influenzae The activities of all drugs were potent against H. influenzae tested with MIC80s of 4 micrograms/ml or below. Cefotiam (CTM), cefmenoxime (CMX), cefditoren (CDTR) and ofloxacin (OFLX) showed the most potent activities with MIC80s of 0.063 microgram/ml. 4) P. aeruginosa (mucoid strains) Tobramycin (TOB) showed the most potent activity against P. aeruginosa (mucoid strains) with MIC80 of 1 microgram/ml. Ceftazidime (CAZ), cefsulodin (CFS), IPM, gentamicin (GM), ABK and ciprofloxacin (CPFX) showed the next potent activities, with MIC80s of 2 micrograms/ml. The MIC80s of the other drugs ranged from 4 micrograms/ml to 16 micrograms/ml. 5) P. aeruginosa (non-mucoid strains) TOB and CPFX showed the most potent activities against P. aeruginosa (non-mucoid strains) with MIC80s of 1 microgram/ml. The MIC80s of piperacillin (PIPC) and cefoperazone (CPZ) were 16 micrograms/ml in 1995, and they were 64 micrograms/ml in 1996. 6) K. pneumoniae All drugs except ampicillin (ABPC) were active against K. pneumoniae. CMX, cefpirome (CPR), cefozopran (CZOP) and carumonam (CRMN) showed the most potent activities against K. pneumoniae with MIC80s of 0.125 microgram/ml. The MIC80s of the other drugs ranged from 0.25 microgram/ml to 2 micrograms/ml. 7) M.(B) catarrhalis Against M.(B.) catarrhalis, all drugs showed good activities with MICs of 4 micrograms/ml or below. IPM and minocycline (MINO) showed the most potent activities with MICs of 0.063 microgram/ml. Also, we investigated year to year changes in the characteristics of patients, their respiratory infectious diseases, and the etiology. Patients' backgrounds were examined for 557 isolates from 449 cases. The examination of age distribution indicated that the proportion of patients with ages over 60 years was 71.0% of all the patients showing a slight increase over that in 1994. Proportions of diagnosed diseases were as follows: Bacterial pneumonia and chronic bronchitis were the most frequent with 35.9% and 30.3% respectively. They were followed by bronchiectasis with a proportion of 10.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (1996). I. Susceptibility distribution

The frequencies of isolation and susceptibilities to antimicrobial agents were investigated on 680 bacterial strains isolated from patients with urinary tract infections (UTIs) in 10 hospitals during the period of June 1996 to May 1997. Of the above bacterial isolates, Gram-positive bacteria accounted for 30.4% and a majority of them were Enterococcus faecalis. Gram-negative bacteria accounted for 69.6% and most of them were Escherichia coli. Susceptabilities 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 Arbekacin (ABK) and VCM showed the highest activities against both S. aureus and MRSA isolated from patients with UTIs. The MIC90S of them were 1 or 2 micrograms/ml. The others except minocycline (MINO) had low activities with the MIC90S of 32 micrograms/ml or above. 3. Staphylococcus epidermidis ABK and VCM showed the strongest activities against S. epidermis isolated from patients with UTIs. The MICs for all strains were equal to or lower than 2 micrograms/ml. Cefazolin (CEZ), cefotiam (CTM) and cefozopran (CZOP) were also active with the MIC90S of 4 micrograms/ml. Compared with antimicrobial activities of cephems is 1995, the MIC90S of them had changed into a better state. They ranged from 4 micrograms/ml 16 micrograms/ml in 1996. 4. Streptococcus agalactiae All drugs except MINO were active against S. agalactiae. ABPC, CZOP, IPM, and clarithromycin (CAM) showed the highest activities. The MICs for all strains were equal to or lower than 0.125 micromilligrams. Tosufloxacin (TFLX) and VCM were also active with the MIC90S of 0.5 micromilligrams. 5. Citrobacter freundii Gentamicin (GM) showed the highest activity against C. freundii isolated from patients with UTIs. Its MIC90 was 0.5 micrograms/ml. IPM and amikacin (AMK) were also active with the MIC90S of 1 microgram/ml and 2 micrograms/ml, respectively. Cefpirome (CPR) and CZOP were also active with the MIC90S of 8 micrograms/ml. The MIC90S of the others were 16 micrograms/ml or above. 6. Enterobacter cloacae IPM showed the highest activity against E. cloacae. The MICs for all strains were equal to or lower than 0.5 microgram/ml. The MIC90S of ciprofloxacin (CPFX) and TFLX were 1 microgram/ml, the MIC90 of AMK was 2 micrograms/ml, the MIC90S of CZOP, GM and ofloxacin (OFLX) were 4 micrograms/ml. The MIC50S of cephems except CEZ, cefmetazole (CMZ) and cefaclor (CCL) had changed into a better state in 1996, compared with those in 1995. 7. Escherichia coli All drugs except penicillins and MINO were active against E. coli. Particularly CPR, CZOP and IPM showed the highest activities against E. coli. The MIC90S of them were 0.125 microgram/ml or below. Among E. coli strains, those with low susceptibilities to cephems except CEZ, cefoperazone (CPZ), latamoxef (LMOX) and CCL have increased in 1996, compared with those in 1995. 8. Klebsiella pneumoniae K. pneumoniae was susceptible to all drugs except penicillins, with the MIC90S of 2 micrograms/ml or below. CPR had the strongest activity, the MICs for all strains were equal to or lower than 0.25 microgram/ml. Flomoxef (FMOX), cefixime (CFIX), CZOP and carumonam (CRMN) were also active with the MIC90S of 0.125 microgram/ml or below. 9. Pseudomonas aeruginosa All drugs except quinolones were not so active against P. aeruginosa with the MIC90S were 32 micrograms/ml or above. Quinolones were more active in 1996 than 1995. The MIC90S of them were between 4 micrograms/ml and 8 micrograms/ml, and the MIC50S of them were between 1 microgram/ml and 2 micrograms/ml. 10. Serratia marcescens GM showed the highest activity against S. marcescens. Its MIC90 was 1 micro     

Antipneumococcal activities of RP 59500 (quinupristin-dalfopristin), penicillin G, erythromycin, and sparfloxacin determined by MIC and rapid time-kill methodologies

Previous time-kill studies have shown that RP 59500 is rapidly bactericidal against pneumococci. To extend these findings, the activities of RP 59500, its two components RP 57669 RP 54476, penicillin G, erythromycin and sparfloxacin against 26 penicillin-susceptible, 25 penicillin-intermediate, and 25 penicillin-intermediate, and 25 penicillin-resistant pneumococci were determined by the agar dilution MIC and the time-kill testing methodologies within 10 min (ca. 0.2 h) and at 1 and 2 h. Respective agar dilution MICs at which 90% of isolates are inhibited for penicillin-susceptible, -intermediate, and -resistant strains were as follows: penicillin G, 0.03, 1, and 4 micrograms/ml;RP 59500, 1, 1, and 1 microgram/ml; RP 57669, 8, 32, and 16 micrograms/ml; RP 54476, > 128, > 128, and > 128 micrograms/ml; erythromycin, 0.06, 2, and > 128 micrograms/ml; and sparfloxacin, 1, 0.5, and 0.5 microgram/ml. RP 59500 was equally active (MIC at which 90% of isolates are inhibited, 1.0 microgram/ml) against erythromycin-susceptible and -resistant strains. Time-kill testing results showed that only RP 59500 at one to four times the MIC killed pneumococci at 0.2 h; RP 59500 was also the most active compound at 1 and 2 h. By comparison, penicillin and sparfloxacin at one, two, and four times the MICs reduced the original inoculum by > or = 1 log at 2 h for 46, 80, and 95% and for 50, 72, and 86% of strains, respectively. The killing activity of RP 59500 was the same against erythromycin-susceptible and -resistant strains. RP 57669, RP 54479, and erythromycin were either inactive or bacteriostatic at 2 h. Of all drugs tested, RP 59500 yielded the most rapid killing.     

In vitro evaluation of voriconazole against clinical isolates of yeasts, moulds and dermatophytes in comparison with itraconazole, ketoconazole, amphotericin B and griseofulvin

The in vitro activity of voriconazole (UK-109, 496), a new antifungal triazole derivative, against 650 clinical isolates of yeasts, moulds and dermatophytes was compared with that of itraconazole, ketoconazole, amphotericin B and griseofulvin. The geometric means of the minimum inhibitory concentrations (MICs) of voriconazole were 0.05 microgram ml-1 against yeasts (n = 187), 0.58 microgram ml-1 against moulds (n = 260) and 0.08 microgram ml-1 against dermatophytes (n = 203). The overall activity of voriconazole against yeasts and moulds was good, being similar to that of itraconazole, ketoconazole and amphotericin B. Voriconazole was highly effective against Aspergillus fumigatus (mean MIC 0.23 microgram ml-1) and other Aspergillus species and showed noteworthy activity (mean MICs 0.08-0.78 microgram ml-1) against emerging and less common clinical isolates of opportunistic moulds, such as Alternaria spp., Cladosporium spp., Acremonium spp., Chrysosporium spp. and Fusarium spp. On the other hand, voriconazole was less active in vitro than the comparative agents studied against various species of zygomycetes, such as Mucor spp., Rhizopus spp. and Absidia spp. Voriconazole and the other two azoles, itraconazole and ketoconazole, were more active than griseofulvin in vitro against most dermatophytes tested.     

Pharmacodynamic analysis of the activity of quinupristin-dalfopristin against vancomycin-resistant Enterococcus faecium with differing MBCs via time-kill-curve and postantibiotic effect methods

Quinupristin-dalfopristin (Q-D) is a new water-soluble, semisynthetic antibiotic that is derived from natural streptogramins and that is combined in a 30:70 ratio. A number of studies have described the pharmacodynamic properties of this drug, but most have investigated only staphylococci or streptococci. We evaluated the relationship between Q-D, quinupristin (Q), and/or dalfopristin (D) susceptibility parameters and antibacterial activities against 22 clinical isolates of vancomycin-resistant Enterococcus faecium (VREF) by using the concentration-time-kill-curve method and by measuring postantibiotic effects. Q-D, Q, and D MICs and minimum bactericidal concentrations (MBCs) ranged from 0.125 to 1 and 0.25 to 64, 8 to 512 and >512, and 2 to 8 and 8 to 512 microgram/ml, respectively. There were no significant relationships between susceptibilities to the individual components and the susceptibilities to the Q-D combination product. In the time-kill-curves studies, Q-D at a concentration of 6 microgram/ml was at least bacteriostatic against all VREF tested. There was increased activity against more susceptible isolates when the isolates were grouped either by Q-D MBCs or by Q MICs. By multivariate regression analyses, the percent change in the inoculum from that at the baseline was significantly correlated with the Q MIC (R = 0.74; P = 0.008) and the Q-D concentration-to-MBC ratio (R = 0.58; P = 0.02) and was inversely correlated with the Q-D MBC-to-MIC ratio (R = 0.68; P = 0.003). A strong correlation existed between the killing rate and the Q-D concentration-to-MBC ratio (R = 0.99; P < 0.0001). Time to 99.9% killing was best correlated with the Q-D MBC (R = 0.96; P < 0.0001). The postantibiotic effect ranged from 0.2 to 3.2 h and was highly correlated with the Q-D concentration-to-MBC ratio (R = 0.96; P < 0.0001) and was less highly correlated with the Q MIC (R = 0.42; P = 0.04). Further study of these relationships with in vitro or in vivo infection models that simulate Q-D pharmacokinetics should further define the utility of these pharmacodynamic parameters in the prediction of Q-D activity for the treatment of VREF infections in humans.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1993). I. Susceptibility distribution

The frequencies of isolation and susceptibilities to antimicrobial agents were investigated on 657 bacterial strains isolated from patients with urinary tract infections in 10 hospitals during the period of June 1993 to May 1994. Of the above total bacterial isolates, Gram-positive bacteria accounted for 28.3% and a majority of them were Enterococcus faecalis. Gram-negative bacteria accounted for 71.7% and most of them were Escherichia coli. 1. Enterococcus faecalis Ampicillin (ABPC), imipenem (IPM) and vancomycin (VCM) showed the highest activities against E. faecalis isolated from patients with urinary tract infections. The MIC90s of them were 2 micrograms/ml. Piperacillin (PIPC) was also active with the MIC90 of 8 micrograms/ml. The others were not so active with the MIC90s of 32 micrograms/ml or above. 2. Staphylococcus aureus including MRSA VCM showed the highest activities against S. aureus isolated from patients with urinary tract infections. Its MIC90 was 1 microgram/ml. Arbekacin (ABK) was also active with the MIC90 of 2 micrograms/ml. The others were not so active with the MIC90s of 32 micrograms/ml or above. 3. Staphylococcus epidermidis VCM showed the strongest activity against S. epidermidis isolated from patients with urinary tract infections. Its MIC90 was 1 microgram/ml. ABK was also active with the MIC90 of 4 micrograms/ml. The others except ABPC were not so active with the MIC90s of 32 micrograms/ml or above. 4. Streptococcus agalactiae Most of the agents were active against S. agalactiae isolated from patients with urinary tract infections. Penicillins, cephems, erythromycin (EM), and clindamycin (CLDM) showed the highest activities. The MIC90s of them were 0.25 microgram/ml or below. Amikacin (AMK) and minocycline (MINO) showed somewhat low activities with the MIC90s of 16 micrograms/ml. 5. Citrobacter freundii IPM showed the highest activities against C. freundii isolated from patients with urinary tract infections. Its MIC90 was 2 micrograms/ml. Cefozopran (CZOP) and gentamicin (GM) were also active with the MIC90s of 8 micrograms/ml. Penicillins and cephems generally were not so active. 6. Enterobacter cloacae IPM and GM showed the highest activities against E. cloacae. The MIC90s of them were 1 microgram/ml. CZOP and tosufloxacin (TFLX) were also active with the MIC90s of 8 micrograms/ml. Penicillins and cephems except CZOP showed lower activities with the MIC90s of 64 micrograms/ml or above. 7. Escherichia coli Most of antimicrobial agents were active against E. coli. Flomoxef (FMOX), CZOP, IPM, CPFX and TFLX showed the highest activities against E. coli. The MIC90s of them were 0.125 microgram/ml or below. Cefmenoxime (CMX), ceftazidime (CAZ), cefuzonam (CZON), latamoxef (LMOX), carumonam (CRMN), norfloxacin (NFLX) and ofloxacin (OFLX) were also active with the MIC90s of 0.25 microgram/ml. Penicillins and MINO were not so active with the MIC90s of 32 micrograms/ml or above. 8. Klebsiella pneumoniae CZOP, IPM and CRMN showed the highest activities against K. pneumoniae. The MIC90s of them were 0.125 microgram/ml or below. CAZ, CZON, CFIX, CPFX and TFLX were also active the MIC90s of 0.25 microgram/ml. Penicillins were not so active with the MIC90s of 128 micrograms/ml or above. 9. Proteus mirabilis P. mirabilis was susceptible to a majority of drugs. CMX, CAZ, CZON, LMOX, CFIX, CRMN and CPFX showed the highest activities against P. mirabilis isolated from patients with urinary tract infections. The MIC90s of them were 0.125 microgram/ml or below. MINO was not so active with the MIC90 of 256 micrograms/ml or above. 10. Pseudomonas aeruginosa Most of the agents were not so active against P. aeruginosa. IPM showed MIC90 of 8 micrograms/ml.     

Antibacterial activity of teicoplanin against Clostridium difficile

The in vitro inhibitory action of teicoplanin, vancomycin, metronidazole and clindamycin against clinical isolates of Clostridium difficile was investigated. Minimum inhibitory concentrations (MICs) were determined using E test. Teicoplanin (MIC range 0.023-0.75 microgram/ml), vancomycin (MIC range 0.5-3 micrograms/ml) and metronidazole (MIC range 0.19-1 microgram/ml) were all very active against the isolates examined. No resistant strains of C. difficile to those three antimicrobial agents were observed, whereas resistance to clindamycin was found in 39.5% of the tested strains. Teicoplanin was about 4-times more potent than vancomycin. It appears to be a more promising antimicrobial for treatment of C. difficile enteric disease.     

In vitro activity of RP59500, an injectable streptogramin antibiotic, against vancomycin-resistant gram-positive organisms

The in vitro activity of RP59500, a streptogramin antibiotic, against 146 clinical isolates of vancomycin-resistant gram-positive bacteria was examined. Five strains of the species Enterococcus casseliflavus and Enterococcus gallinarum, for which the MIC of vancomycin was 8 micrograms/ml, were also studied. Twenty-eight vancomycin-susceptible strains of Enterococcus faecalis and Enterococcus faecium were included for comparison. The drug was highly active against Leuconostoc spp., Lactobacillus spp., and Pediococcus spp. (MICs, < or = 2 micrograms/ml). RP59500 was more active against vancomycin-susceptible strains of E. faecium than E. faecalis (MICs for 90% of the strains [MIC90s], 1.0 versus 32 micrograms/ml). Vancomycin-resistant strains of E. faecalis were as resistant to RP59500 as vancomycin-susceptible strains (MIC90, 32 micrograms/ml), but some vancomycin-resistant E. faecium strains were relatively more resistant to the new agent (MIC90, 16; MIC range, 0.5 to 32 micrograms/ml) than were vancomycin-susceptible organisms of this species.     

In vitro activity of a new ketolide antibiotic, HMR 3647, against Chlamydia pneumoniae

The in vitro activities of HMR 3647, roxithromycin, erythromycin, and azithromycin against 19 strains of Chlamydia pneumoniae were tested. The MIC at which 90% of the isolates are inhibited and the minimum bactericidal concentration at which 90% of the isolates are killed of HMR 3647 were 0.25 microgram/ml (range, 0.015 to 2 micrograms/ml). Nine recently obtained clinical isolates from children with pneumonia were more susceptible (MICs, 0.015 to 0.0625 microgram/ml) than older strains that had been passaged more extensively.     

In vitro and in vivo antibacterial activities of ER-35786, a new antipseudomonal carbapenem

ER-35786 is a new parenteral 1 beta-methyl carbapenem with a broad antibacterial spectrum and a potent antipseudomonal activity. It showed high in vitro activity, comparable to those of meropenem and a new carbapenem, BO-2727, against methicillin-susceptible Staphylococcus aureus and streptococci, with MICs at which 90% of strains tested are inhibited (MIC90S) of < or = 0.39 microgram/ml. Against methicillin-resistant S. aureus, ER-35786 was the most active among the compounds tested, yet its MIC90 was 12.5 micrograms/ml. Against members of the family Enterobacteriaceae, Moraxella catarrhalis, and Haemophilus influenzae, ER-35786 inhibited 90% of strains tested at a concentration of < or = 1.56 micrograms/ml. The MIC90 of ER-35786 for Pseudomonas aeruginosa was 3.13 micrograms/ml, and the compound was more active than meropenem. In addition, the activity of ER-35786 against imipenem-, meropenem-, cefclidin-, or ceftazidime-resistant P. aeruginosa was equal to or higher than that of the most active reference compound. The in vivo activity of ER-35786 was consistent with this in vitro activity. The in vivo activity of ER-35786 was highest for systemic infection models with methicillin-resistant S. aureus and beta-lactam-resistant P. aeruginosa strains. In acute pneumonia caused by P. aeruginosa, ER-35786 produced a greater reduction in the viable cell count in the lungs than did imipenem-cilastatin or meropenem.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from patients with urinary tract infections (1995). I. Susceptibility distribution]

The frequencies of isolation and susceptibilities to antimicrobial agents were investigated on 704 bacterial strains isolated from patients with urinary tract infections (UTIs) in 11 hospitals during the period of June 1995 to May 1996. Of the above bacterial isolates, Gram-positive bacteria accounted for 29.8% and a majority of them were Enterococcus faecalis. Gram-negative bacteria accounted for 70.2% and most of them were Escherichia coli. Susceptibilities of several isolated bacteria to antimicrobial agents were as followed; 1. Enterococcus faecalis Ampicillin (ABPC) and imipenem (IPM) showed the highest activities against E. faecalis isolated from patients with UTIs. The MIC90S of them were 1 microgram/ml. Vancomycin (VCM) and piperacillin (PIPC) were also active with the MIC90S of 2 micrograms/ml and 4 micrograms/ml, respectively. The others had low activities with the MIC90S of 16 micrograms/ml or above. 2. Staphylococcus aureus including MRSA VCM showed the highest activities against S. aureus isolated from patients with UTIs. Its MIC90 was 1 microgram/ml against both S. aureus and MRSA. Arbekacin (ABK) was also active with the MIC90 of 2 micrograms/ml. The other except minocycline (MINO) had very low activities with the MIC90S of 64 micrograms/ml or above. 3. Staphylococcus epidermidis ABK and MINO showed the strongest activities against S. epidermidis isolated from patients with UTIs. The MIC90S of them were 0.25 microgram/ml. VCM was also active with the MIC90 of 1 microgram/ml. The MIC90S of cephems ranged from 2 micrograms/ml to 16 micrograms/ml in 1994, but they ranged from 8 micrograms/ml to 128 micrograms/ml in 1995. These results indicated that some resistances existed among S. epidermidis to cephems. 4. Streptococcus agalactiae All drugs except gentamicin (GM) were active against S. agalactiae. ABPC, cefmenoxime (CMX), IPM, erythromycin (EM), clindamycin (CLDM) and clarithromycin (CAM) showed the highest activities. The MICs for all strains were lower than 0.125 microgram/ml. The MIC90S of the others were 2 micrograms/ml or below. 5. Citrobacter freundii IPM showed the highest activity against C. freundii isolated from patients UTIs. Its MIC90 was 1 microgram/ml. GM was also active with the MIC90 of 2 micrograms/ml. Cefpirome (CPR), cefozopran (CZOP) and amikacin (AMK) were also active with the MIC90S of 4 micrograms/ml. Penicillins and cephems except CMX, CPR and CZOP showed low activities with MIC90S of 256 micrograms/ml or above. 6. Enterobacter cloacae IPM showed the highest activity against E. cloacae. The MICs for all strains were equal to or lower than 1 microgram/ml. MINO and tosufloxacin (TFLX) were also active with the MIC90S of 8 micrograms/ml. Penicillins and cephems except CPR and CZOP showed lower activities with the MIC90S of 256 micrograms/ml or above. 7. Escherichia coli. Most of the antimicrobial agents were active against E. coli. Particularly CPR, CZOP and IPM showed the highest activities against E. coli. The MICs for all strains were equal to or lower than 0.5 microgram/ml. CMX and TFLX were also active with the MIC90S of 0.125 microgram/ml or below. Penicillins were slightly active with MIC90S of 128 micrograms/ml or above. 8. Klebsiella pneumoniae K. pneumoniae was susceptible to all drugs except penicillins, with MIC90S of 2 micrograms/ml or below. Carumonam (CRMN) had the strongest activity against K. pneumoniae, the MICs for all strains were equal to or lower than 0.125 microgram/ml. Comparing with the result of 1994, the sensitivities of K. pneumoniae against all drugs had obviously changed into a better state. For example, the MIC90S of cephems ranged from 0.25 microgram/ml to 16 micrograms/ml in 1994, but they were all lower than 2 micrograms/ml in 1995. 9. Proteus mirabilis P. mirabilis was susceptible to a majority of drugs. CMX, ceftazidime (CAZ), cefixime (CFIX), and CRMN showed the highest activities against P. mirabilis isolated from patients with UTIs. MICs of CRMN for all     

In vitro antibacterial activity of a new fluoroquinolone, fleroxacin, against hospital bacteria and regression curve

Minimal inhibitory concentrations (MICs) of fleroxacin (FLE) were determined by agar dilution for 1261 bacterial strains isolated in 1992 in 4 university hospitals; in addition, antibiograms by agar diffusion were performed with 5 micrograms disks. Activity of FLE against nalidixic acid (NAL) susceptible (S) Enterobacteriaceae was close to that of other fluoroquinolones (FQ) (MIC 50 and 90: 0.12-0.25 micrograms/ml); like for other FQ, this activity was reduced against NAL intermediate and resistant (R) Enterobacteriaceae (4-32). MICs of FLE against P. aeruginosa were between 1 and 128 (8-128). FLE had also a good activity against NAL-S A. baumannii (0.12-0.5) but this activity is reduced against NAL-R Acinetobacter (64-128). FLE was highly active against Haemophilus (0.06-0.12), Gonococci (0.03-0.25), Meningococci (0.016-0.03) and B. catarrhalis (0.12-0.25). FLE showed activity close to the currently available FQ against methicillin susceptible Staphylococci (0.25-1); the resistant strains (32- > 128) are usually methicillin resistant. FLE is less effective against Enterococci (4-128), Streptococci (8-16) and Pneumococci (4-8). The coefficient correlation of the regression curve is 0.93; for MIC breakpoints of 1 and 4 micrograms/ml, zone diameter breakpoints should be 20 and 15 mm.     

Antimicrobial susceptibility testing of 59 strains of Campylobacter fetus subsp. fetus

The susceptibilities of 59 Campylobacter fetus subsp. fetus isolates to eight antibiotics were studied by the agar dilution, E-test, and disk diffusion methods. None of the isolates were beta-lactamase producers. All were susceptible to ampicillin, gentamicin, imipenem, and meropenem as determined by the three methods, with MICs at which 90% of the isolates are inhibited (MIC90s) (determined by agar dilution) of 2, 1, < or = 0.06, and 0.12 microgram/ml, respectively. Twenty-seven percent of the isolates were resistant to tetracycline, with complete agreement between the agar dilution and disk diffusion results. The MIC90s determined by agar dilution were 2 micrograms/ml for erythromycin, 1 microgram/ml for ciprofloxacin, and 8 micrograms/ml for cefotaxime.     

In vitro efficacy and fungicidal activity of voriconazole against Aspergillus and Fusarium species

Twenty-nine Aspergillus isolates and 25 Fusarium isolates underwent in vitro antifungal susceptibility testing by a broth macrodilution procedure adapted from the National Committee for Clinical Laboratory Standards guidelines. The MIC50s of both voriconazole and amphotericin B were 0.5 microg/ml and 1 microg/ml against species of Aspergillus and Fusarium, respectively, while the MIC90s of both agents were 1 and 2 microg/ml. Voriconazole was more active in vitro than amphotericin B: the geometric mean MICs of voriconazole and amphotericin B against Aspergillus spp. were 0.36 microg/ml and 0.64 microg/ml, respectively. Voriconazole also demonstrated fungicidal activity against Aspergillus spp., with 86% (24/29) of isolates exhibiting minimum lethal concentrations of < or = 4 microg/ml.     

Clinical guidelines and the law: advice, guidance or regulation?

A broth microdilution assay was performed to determine the minimal inhibitory concentrations (MICs) of 25 antimicrobial agents for two strains of Borrelia (B.) burgdorferi sensu lato and one strain of B. hermsii. The method comprised BSK II medium lacking gelatin and an incubation period of 72 hours. To investigate the influence of reading mode and density of inoculum on MIC values, microscopical as well as macroscopical MIC reading was performed using standardized final inocula of 10(6) and 10(7) borreliae/ml. Data were processed by two-way analysis of variance. In the microdilution assay, MIC values were significantly influenced either by the inoculum density or reading mode. However, using clearly defined criteria for macroscopical endpoint determination, MICs from macroscopical and microscopical reading were found to be in close agreement. B. burgdorferi sensu lato strains tested were highly susceptible to azithromycin, erythromycin, mezlocillin, piperacillin as well as ceftriaxone, with MICs ranging from < or = 0.016 to 0.125 microgram/ml. B. hermsii was highly susceptible to azithromycin and erythromycin. In comparison to B. hermsii, the beta-lactam antibiotics revealed a significantly higher activity and gentamicin, ofloxacin, and rifampin revealed a significantly lower activity against B. burgdorferi sensu lato strains. To further investigate interactions between BSK II medium, incubation time, and antibiotic efficacy, an agar diffusion bioassay was performed. Out of seven antibiotics tested, the activities of mezlocillin, penicillin G, and piperacillin were significantly influenced by BSK II medium and incubation period and showed a marked decrease of on average 84.0% within 72 hours of incubation.     

Basic and clinical studies on tazobactam/piperacillin in pediatric field

A drug susceptibility test of the combination drug TAZ/PIPC, which consists of a newly developed beta-lactamase inhibitor, tazobactam (TAZ), and one of penicillin antibiotics, piperacillin (PIPC), with combination ratio of 1:4 in potency, was conducted with stock strains and clinical isolates. The clinical efficacy and safety of its injection was also evaluated in children with a variety of infectious diseases. The results were as follows: 1. In susceptibility test, 114 strains from 4 species of stock strains were treated with 8 drugs, that is, TAZ/PIPC, PIPC, penicillin G (PCG), ampicillin (ABPC), cefotiam (CTM), cefotaxime (CTX), ceftazidime (CAZ), and sulbactam/cefoperazone (SBT/CPZ). Of three clinically isolated species from patients, Staphylococcus aureus (S. aureus) was treated with TAZ/PIPC, PIPC, methicillin (DMPPC), CTM, CTX, and SBT/CPZ, and the others were treated with the same drugs except for DMPPC. The MICs were measured for these bacterial strains inoculated at the concentration of 10(6) CFU/ml. The MIC90 values of TAZ/PIPC against 45 strains of Streptococcus pyogenes (S. pyogenes), one of the stock cultures of Gram-positive cocci, were 0.05 microgram/ml and similar to those of PIPC, CTM, CAZ, and SBT/CPZ. The MICs of TAZ/PIPC for 28 strains of Streptococcus agalactiae (S. agalactiae) were 0.39 microgram/ml and similar to those of PIPC, CTM, CAZ, and SBT/CPZ. As for Gram-negative bacilli, the MIC90 of TAZ/PIPC against 10 strains of Bordetella pertussis (B. pertussis) were 0.10 microgram/ml and similar to those of PIPC. The MIC90 of TAZ/PIPC against 31 strains of Haemophilus influenzae (H. influenzae) were 0.05 microgram/ml and similar to those of PIPC, CTX, and SBT/CPZ. Regarding Gram-positive cocci isolated from patients received this combination drug, the MIC90 of TAZ/PIPC against 2 strains of S. aureus, a non beta-lactamase producing strain and a low-beta-lactamase producing strain, were 0.78 microgram/ml and 3.1 micrograms/ml, respectively; the former value was similar to those of PIPC, DMPPC, CTM, and CTX, and the latter was similar to those of PIPC, DMPPC, CTX, and SBT/CPZ. Of 4 strains of Streptococcus pneumoniae, 2 strains were inhibited at 0.05 microgram/ml, and the others at 1.56 micrograms/ml; both values were similar to those of PIPC, SBT/CPZ. As for Gram-negative bacilli, 6 of 7 strains of H. influenzae did not produce beta-lactamase and 1 strain was a high producer. The MICs of TAZ/PIPC against beta-lactamase nonproducing strains were < or = 0.025 microgram/ml in 5 strains and 0.39 microgram/ml in 1 strain, and the values were similar to those of PIPC and SBT/CPZ. While the MIC of TAZ/PIPC against the high beta-lactamase producing strain was 0.78 microgram/ml; similar to that of SBT/CPZ and smaller than that of PIPC. 2. The results of clinical effects on 7 diseases in 33 cases were as follows: TAZ/PIPC was clinically judged "excellent" in 17 (51.5%); good in 14 (42.4%); fair in 2 (6.1%). No case with no response was seen in this study, and the total efficacy rate of "excellent" and "good" was 93.9%. 3. Bacteriological effects were evaluated in 17 strains of 4 species, and all of them were eradicated. 4. Adverse reactions were judged in 35, which consisted of 33 in which the clinical effects were evaluated and 2 dropped from this study. Of these cases, diarrhea was observed in 4 (11.4%). 5. Laboratory tests revealed an increase in platelets in 1 of 32 cases (3.1%), and eosinophilia in 2 of 29 cases (6.9%). Biochemical profile showed an increase in GPT alone and abnormal increases in both GOT and GPT in 1 each out of 21 cases.