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1.  Antipneumococcal activity of BAY 12-8039, a new quinolone, compared with activities of three other quinolones and four oral beta-lactams. 
Antimicrobial Agents and Chemotherapy  1997;41(12):2786-2789.
Activities of BAY 12-8039 against 205 pneumococci were tested by agar dilution. MICs (in micrograms per milliliter) at which 50 and 90% of the isolates are inhibited (MIC50s and MIC90s, respectively) were 0.125 and 0.25 (BAY 12-8039), 2.0 and 4.0 (ciprofloxacin and ofloxacin), and 0.25 and 0.5 (sparfloxacin). Beta-lactam MIC50s and MIC90s for penicillin-susceptible, -intermediate, and -resistant strains, in that order, were 0.016 and 0.03, 0.25 and 2.0, and 2.0 and 4.0 (amoxicillin); 0.03 and 0.06, 0.25 and 4.0, and 4.0 and 8.0 (ampicillin); 0.03 and 0.06, 0.5 and 4.0, and 4.0 and 8.0 (cefuroxime); and 0.03 and 0.125, 0.25 and 2.0, and 4.0 and 8.0 (cefpodoxime). At two times their MICs after 24 h, BAY 12-8039, ciprofloxacin, ampicillin, and cefuroxime were uniformly bactericidal (99.9% killing) against 12 strains; other compounds were bactericidal at four times their MICs.
PMCID: PMC164211  PMID: 9420061
2.  Postantibiotic effect of sanfetrinem compared with those of six other agents against 12 penicillin-susceptible and -resistant pneumococci. 
Antimicrobial Agents and Chemotherapy  1997;41(10):2173-2176.
The postantibiotic effect (PAE) and postantibiotic sub-MIC effect (PAE-SME) of sanfetrinem were compared to those of penicillin G, amoxicillin, cefpodoxime, ceftriaxone, imipenem, and clarithromycin against four penicillin-susceptible, four intermediately susceptible, and four resistant pneumococci. The MICs of imipenem were the lowest against all of the strains (0.03 to 0.5 microg/ml), followed by those of sanfetrinem (0.016 to 1.0 microg/ml), amoxicillin and ceftriaxone (0.016 to 2.0 microg/ml), and cefpodoxime (0.03 to 8.0 microg/ml). High-level resistance to clarithromycin (MIC, >64.0 microg/ml) was seen in three selected strains. The PAEs of all of the oral beta-lactams tested were similar for all of the strains, ranging from 1 to 6.5 h. The PAEs of ceftriaxone and imipenem ranged from 1 to 8 h, and those of clarithromycin ranged from 1 to 7 h. The mean PAEs of all of the beta-lactams and clarithromycin were 2.8 to 4.3 and 2.5 h, respectively. PAE-SMEs could not be determined for all of the strains due to complete killing, especially at high subinhibitory concentrations. However, the overall pattern with all of the compounds tested was that PAE-SMEs were longer than PAEs. Measurable PAE-SMEs of sanfetrinem at the three subinhibitory concentrations (0.125, 0.25, and 0.5 times the MIC) were 2 to 7, 2 to 7, and 3 to 6 h, while those of amoxicillin and cefpodoxime were 1 to 7.5, 2 to 4, and 4 to 9 and 2 to 7, 4 to 7, and 4 to 6 h, respectively. Measurable PAE-SMEs of ceftriaxone and imipenem were 1 to 6.5, 2 to 9, and 2 to 9 and 1.5 to 6, 2 to 5.8, and 4 to 7.7 h, respectively. Measurable clarithromycin PAE-SMEs were 1 to 5, 1 to 5, and 1 to 6 h at the three concentrations.
PMCID: PMC164088  PMID: 9333043
3.  Comparative antianaerobic activities of the ketolides HMR 3647 (RU 66647) and HMR 3004 (RU 64004). 
HMR 3647 (RU 66647) and HMR 3004 (RU 64004), two ketolides, had MICs at which 50% of the strains are inhibited (MIC50s) of 0.06 to 0.125 microg/ml and MIC90s of 16.0 microg/ml against 352 anaerobes. MIC50s and MIC90s of erythromycin, azithromycin, clarithromycin, and roxithromycin were 0.5 to 2.0 microg/ml and 32.0 to >64.0 microg/ml, respectively. HMR 3647 and HMR 3004 were more active against non-Bacteroides fragilis-group anaerobes (other than Fusobacterium mortiferum, Fusobacterium varium, and Clostridium difficile).
PMCID: PMC164057  PMID: 9303406
4.  Susceptibility of penicillin-susceptible and -resistant pneumococci to dirithromycin compared with susceptibilities to erythromycin, azithromycin, clarithromycin, roxithromycin, and clindamycin. 
Agar dilution with incubation in air and CO2 was used to determine the MICs of erythromycin, dirithromycin, azithromycin, clarithromycin, roxithromycin, and clindamycin for 79 penicillin-susceptible, 72 penicillin-intermediate, and 74 penicillin-resistant pneumococci (158 erythromycin-susceptible and 67 erythromycin-resistant pneumococci). MICs obtained in air were usually 1 to 3 dilutions lower than those obtained in CO2. In air, the respective MICs at which 50% (MIC50s) and 90% (MIC90s) of penicillin-susceptible, -intermediate, and -resistant strains are inhibited were as follows: erythromycin, 0.016 and 0.5, 0.03 and > 64, and 2 and > 64 microg/ml; dirithromycin, 0.03 and 0.5, 0.06 and > 64, and 8 and > 64 microg/ml; azithromycin, 0.03 and 0.5, 0.06 and > 64, and 2 and > 64 microg/ml; clarithromycin, 0.016 and 0.06, 0.03 and > 64, and 2 and > 64 microg/ml; roxithromycin, 0.06 and 2, 0.06 and > 64, and 2 and > 64 microg/ml; and clindamycin, 0.03 and 0.06, 0.06 and > 64, and 0.06 and > 64 microg/ml. The MICs of erythromycin, azithromycin, and dirithromycin were very similar; however, clarithromycin MICs were generally 1 to 2 dilutions lower and roxithromycin MICs were 1 to 2 dilutions higher than those of the other compounds tested. Strains resistant to one macrolide were resistant to all macrolides; however, not all macrolide-resistant strains were resistant to clindamycin, and 32 macrolide-resistant (MICs, > or = 28 microg/ml), clindamycin-susceptible (MICs, < or = 0.25 microg/ml) strains were encountered. Time-kill testing of six strains showed similar killing kinetics for all compounds, with 99.9% killing of all strains observed with the compounds only at or above the MIC after 24 h.
PMCID: PMC164026  PMID: 9303375
5.  Comparative activity of trovafloxacin, alone and in combination with other agents, against gram-negative nonfermentative rods. 
In the first part of this study, agar dilution MICs were used to test the activities of trovafloxacin, ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, clinafloxacin, ceftazidime, and imipenem against 458 gram-negative nonfermenters. The overall respective MICs at which 50% of isolates are inhibited (MIC50s) and MIC90s were as follows: trovafloxacin, 1.0 and 16.0 microg/ml; ciprofloxacin, 2.0 and 16.0 microg/ml; ofloxacin, 2.0 and 32.0 microg/ml; levofloxacin, 1.0 and 16.0 microg/ml; sparfloxacin, 1.0 and 16.0 microg/ml; clinafloxacin, 0.5 and 4.0 microg/ml; ceftazidime, 8.0 and 128.0 microg/ml; imipenem, 2.0 and 256.0 microg/ml. Clinafloxacin was the most active of all the quinolones tested. The MIC90s of trovafloxacin were < or = 4.0 microg/ml for Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Flavobacterium odoratum, and Chryseobacterium meningosepticum; trovafloxacin MIC90s were < or = 2.0 microg/ml for Moraxella spp., Pseudomonas stutzeri, and Chryseobacterium indologenes-C. gleum. Of the other quinolones tested, the MICs of sparfloxacin and levofloxacin were lower than those of ciprofloxacin and ofloxacin. High ceftazidime MICs (> or = 32.0 microg/ml) were observed for all nonfermentative species tested. Although for the majority of strains tested imipenem MICs were < or = 8.0 microg/ml, high imipenem MICs were observed for many species, especially S. maltophilia, Burkholderia cepacia, F. odoratum, and Chryseobacterium meningosepticum. For Alcaligenes xylosoxidans strains, the MICs of all compounds were generally a few dilutions lower than those for Alcaligenes faecalis-A. odorans. Time-kill studies with five strains revealed that trovafloxacin and all quinolones yielded more rapid time-kill kinetics than ceftazidime and imipenem. Synergy testing by checkerboard titrations of 286 strains with trovafloxacin combined with ceftazidime, amikacin, and imipenem revealed fractional inhibitory concentration (FIC) indices in the range indicating synergism (< or = 0.5) for 81, 41, and 40 strains, respectively, and FIC indices indicating additivity or indifference (> 0.5 to 4.0) for 205, 245, and 246 strains, respectively. No FIC indices indicating antagonism (> 4.0) were observed. Synergy between trovafloxacin and ceftazidime was found for 32 of 36 S. maltophilia strains. Time-kill studies with 20 strains showed that for most strains for which FIC indices were in the range indicating additivity or indifference, FIC indices indicated synergy by the time-kill method. Synergy was particularly noticeable for S. maltophilia strains with combinations of ceftazidime and trovafloxacin.
PMCID: PMC163943  PMID: 9210669
6.  Activities of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with amikacin, against acinetobacters as determined by checkerboard and time-kill studies. 
A total of 101 Acinetobacter genospecies (77 Acinetobacter baumannii strains and 24 non-A. baumannii strains) were tested for their susceptibilities to levofloxacin, ofloxacin, and ciprofloxacin and for synergy between the quinolones and amikacin by checkerboard titration and time-kill analyses. The MICs at which 50% of the isolates are inhibited (MIC50)/MIC90s for the 101 strains were as follows (in micrograms per milliliter): levofloxacin, 0.25/16.0; ofloxacin, 0.5/32.0; ciprofloxacin, 0.25/> 64.0; and amikacin, 1.0/> 32.0. At empiric breakpoints of < or = 2.0 microg/ml, 61% of the strains were susceptible to all three quinolones. At a breakpoint of < or = 16.0 microg/ml, 84% of the strains were susceptible to amikacin. Checkerboard titrations yielded synergistic fractional inhibitory concentration (FIC) indices (< or = 0.5) for one strain with levofloxacin and amikacin and for two strains with ofloxacin and amikacin. Indices of > 0.5 to 1.0 were seen for 57, 54, and 55 strains with levofloxacin plus amikacin, ofloxacin plus amikacin, and ciprofloxacin plus amikacin, respectively, and indices of > 1.0 in 43, 45, and 46 strains, respectively, were found with the above three combinations. No strains yielded antagonistic FIC indices (> 4.0). Most FIC results of > 1.0 occurred in strains for which the quinolone MICs were > 2.0 microg/ml and for which the amikacin MICs were > or = 32.0 microg/ml. By contrast, synergy (defined as > or = 2 log10 decrease compared to the more active compound alone by time-kill analysis) was found in all seven strains tested for which the quinolone MICs were < or = 2.0 microg/ml. For eight other strains for which the quinolone MICs were > 2.0 microg/ml as determined by time-kill analysis, quinolone and amikacin concentrations in combination were usually too high to permit clinical use. Time-kill analysis was found to be more sensitive in detecting synergy than was the checkerboard method.
PMCID: PMC163853  PMID: 9145872
7.  Antianaerobic activity of the ketolide RU 64004 compared to activities of four macrolides, five beta-lactams, clindamycin, and metronidazole. 
Agar dilution methodology (with added Oxyrase in the case of the macrolide group to allow incubation without added CO2) was used to compare the activity of RU 64004, a new ketolide, with the activities of erythromycin, azithromycin, clarithromycin, roxithromycin, clindamycin, amoxicillin with and without clavulanate, piperacillin with and without tazobactam, metronidazole, and imipenem against 379 anaerobes. Overall, RU 64004 yielded an MIC at which 50% of the isolates are inhibited (MIC50) of 1.0 microg/ml and an MIC90 of 16.0 microg/ml. In comparison, MIC50s and MIC90s of erythromycin, azithromycin, clarithromycin, and roxithromycin were 2.0 to 8.0 and >64.0 microg/ml, respectively. MICs of macrolides, including RU 64004, were higher for Bacteroides ovatus, Fusobacterium varium, Fusobacterium mortiferum, and Clostridium difficile than for the other species. RU 64004 was more active against gram-positive rods and cocci, Prevotella and Porphyromonas spp., and fusobacteria other than F. mortiferum and F. varium than against the Bacteroides fragilis group. Overall MIC50s and MIC90s (in micrograms per milliliter), respectively, of other compounds were as follows: clindamycin, 1.0 and 16.0; amoxicillin, 4.0 and 64.0; amoxicillin-clavulanate, 0.5 and 4.0; piperacillin, 8.0 and >64.0; piperacillin-tazobactam, 1.0 and 16.0; metronidazole, 1.0 and 4.0; and imipenem, 0.25 and 1.0.
PMCID: PMC163846  PMID: 9145865
8.  Susceptibilities of 228 penicillin- and erythromycin-susceptible and -resistant pneumococci to RU 64004, a new ketolide, compared with susceptibilities to 16 other agents. 
The susceptibilities of 228 penicillin- and erythromycin-susceptible and -resistant pneumococci to RU 64004, a new ketolide, were tested by agar dilution, and the results were compared with those for penicillin G, erythromycin, azithromycin, clarithromycin, rokitamycin, clindamycin, pristinamycin, ciprofloxacin, sparfloxacin, trimethoprim-sulfamethoxazole, doxycycline, chloramphenicol, cefuroxime, ceftriaxone, imipenem, and vancomycin. RU 64004 was very active against all strains tested, with MICs at which 90% of the isolates are inhibited (MIC90s) of 0.016 microg/ml for erythromycin-susceptible strains (MIC, < or = 0.25 microg/ml) and 0.25 microg/ml for erythromycin-resistant strains (MIC, > or = 0.5 microg/ml). All other macrolides had MIC90s of 0.03 to 0.25 and > or = 128 microg/ml for erythromycin-susceptible and -resistant strains, respectively. Among erythromycin-resistant strains, clindamycin MICs for 28 of 91 (30.7%) were < or = 0.125 microg/ml. Pristinamycin MICs for all strains were < or = 1.0 microg/ml. MIC90s of ciprofloxacin and sparfloxacin were 4.0 and 0.25 microg/ml, respectively, and were unaffected by susceptibility to penicillin or erythromycin. Vancomycin and imipenem inhibited all strains at < or = 0.5 and < or = 0.25 microg/ml, respectively. MICs of cefuroxime and cefotaxime rose with those of penicillin G. MICs of trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol were variable but were generally higher for penicillin- and erythromycin-resistant strains. RU 64004 is the first member of the macrolide group which has low MICs for erythromycin-resistant pneumococci.
PMCID: PMC163845  PMID: 9145864
9.  Bactericidal activity of DU-6859a compared to activities of three quinolones, three beta-lactams, clindamycin, and metronidazole against anaerobes as determined by time-kill methodology. 
The activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, piperacillin, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 11 anaerobes were tested by the broth microdilution and time-kill methods. DU-6859a was the most active drug tested (broth microdilution MICs, 0.06 to 0.5 microg/ml), followed by imipenem (MICs, 0.002 to 4.0 microg/ml). Broth macrodilution MICs were within 3 (but usually 1) dilutions of the broth microdilution MICs. All compounds were bactericidal at the MIC after 48 h; after 24 h, 90% killing was shown for all strains when the compounds were used at four times the MIC. DU-6859a at < or = 0.5 microg/ml was bactericidal after 48 h.
PMCID: PMC163808  PMID: 9087503
10.  Activities of beta-lactams against Acinetobacter genospecies as determined by agar dilution and E-test MIC methods. 
The agar dilution MIC method was used to test activities of ticarcillin, ticarcillin-clavulanate, amoxicillin, amoxicillin-clavulanate, ampicillin, ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, inhibitors alone, ceftazidime, and imipenem against 237 Acinetobacter genospecies. A total of 93.2% of strains were beta-lactamase positive by the chromogenic cephalosporin method. Overall, ampicillin-sulbactam was the most active combination against all strains (MIC at which 50% of the isolates are inhibited [MIC50] and MIC90, 4.0 and 32.0 microg/ml; 86.9% susceptible at < or = 16 microg/ml), followed by ticarcillin-clavulanate (16.0 and 128.0 microg/ml; 85.7% susceptible at < or = 64 microg/ml), piperacillin-tazobactam (16.0 and 128.0 microg/ml; 84.8% susceptible at < or = 64 microg/ml), and amoxicillin-clavulanate (16.0 and 64.0 microg/ml; 54.4% susceptible at < or =16 microg/ml). Ceftazidime and imipenem yielded MIC50s and MIC90s of 8.0 and 64.0 microg/ml (ceftazidime) and 0.5 and 1.0 microg/ml (imipenem), respectively; 71.3% of strains were susceptible to ceftazidime at < or = 16 microg/ml, and 99.2% were susceptible to imipenem at < or = 8 microg/ml. Sulbactam was the most active beta-lactamase inhibitor alone (MIC50 and MIC90, 2.0 and 16.0 microg/ml); clavulanate and tazobactam were less active (16.0 and 32.0 microg/ml for both compounds). Enhancement of beta-lactams by beta-lactamase inhibitors was not always seen in beta-lactamase-positive strains, and activity of combinations such as ampicillin-sulbactam was due to the inhibitor alone. Acinetobacter baumannii was the most resistant genospecies. By contrast, Acinetobacter haemolyticus, Acinetobacter calcoaceticus, Acinetobacter johnsonii, Acinetobacter junii, Acinetobacter radioresistens, and other non-Acinetobacter baumannii strains were more susceptible to all compounds tested. E-test MICs were within 1 dilution of agar dilution MICs in 38.4 to 89.6% of cases and within 2 dilutions in 61.6 to 98.6% of cases.
PMCID: PMC163791  PMID: 9087486
11.  Variation in erythromycin and clindamycin susceptibilities of Streptococcus pneumoniae by four test methods. 
Susceptibilities of 124 strains of Streptococcus pneumoniae to erythromycin and clindamycin were determined by the National Committee for the Clinical Laboratory Standards (NCCLS) broth microdilution method, with incubation for 20 to 24 h in ambient air and with modifications of this method by incubation for up to 48 h in air and CO2. Strains were also tested by agar dilution, E-test, and disk diffusion; good correlation was obtained with these methods, with clear separation into bimodal populations of susceptible and resistant stains. The broth microdilution method, however, using incubation in air for 24 h (NCCLS method), misclassified 4 of 92 erythromycin-resistant strains (1 as susceptible and 3 as intermediate) and 25 of 58 clindamycin-resistant strains (all as susceptible). With the exception of one strain with clindamycin, susceptible and resistant strains were correctly classified by the microdilution method with incubation in CO2 for 24 h or in ambient air for 48 h. Disk diffusion, agar dilution, and E-test methods with incubation in 5% CO2 are therefore reliable methods for susceptibility testing of pneumococci against these agents. However, the NCCLS microdilution method, which specifies incubation for 20 to 24 h in ambient air, produced significant very major errors (43%) clindamycin. Modification of the microdilution method by incubation in 5% CO2 or by extension of incubation time in ambient air to 48 h corrected these errors. Disk diffusion, however, was shown to be a simple, convenient, and reliable method for susceptibility testing of pneumococci to erythromycin and clindamycin and is suggested as the method of choice for these agents.
PMCID: PMC163673  PMID: 8980768
12.  MIC and time-kill studies of antipneumococcal activity of GV 118819X (sanfetrinem) compared with those of other agents. 
Agar dilution MIC methodology was used to test the activities of GV 118819X (sanfetrinem), ampicillin, amoxicillin, amoxicillin-clavulanate, cefpodoxime, loracarbef, levofloxacin, clarithromycin, ceftriaxone, imipenem, and vancomycin against 53 penicillin-susceptible, 84 penicillin-intermediate and 74 penicillin-resistant pneumococci isolated in the United States. GV 118819X was the most active oral beta-lactam, with MIC at which 50% of the isolates were inhibited (MIC50)/MIC90 values of 0.008/0.03, 0.06/0.5, and 0.5/1.0 micrograms/ml against penicillin-susceptible, -intermediate, and -resistant stains, respectively. Amoxicillin and amoxicillin in the presence of clavulanate (2:1) were the second most-active oral beta-lactams, followed by ampicillin and cefpodoxime; loracarbef was not active against penicillin-intermediate and -resistant strains. Clarithromycin was most active against penicillin-susceptible strains but was less active against intermediate and resistant stains. All pneumococcal stains were inhibited by ceftriaxone and imipenem at MICs of < or = 4.0 and < or = 1.0 micrograms/ml, respectively. The activities of levofloxacin and vancomycin were unaffected by penicillin susceptibility. Time-kill studies of three penicillin-susceptible, three penicillin-intermediate, and three penicillin-resistant pneumococci showed that all compounds, at the broth microdilution MIC, yielded 99.9% killing of all strains after 24 h. Kinetic patterns of all oral beta-lactams, ceftriaxone, and vancomycin were similar relative to the MIC, with 90% killing of all strains first observed after 12 h. However, killing by amoxicillin-clavulanate, imipenem, and levofloxacin was slightly faster and that by clarithromycin was slower than that by the above-described drugs. At 2 x the MIC, more strains were killed earlier than was the case at the MIC, but the pattern seen at the MIC prevailed. When MICs and kill kinetics were combined, sanfetrinem was the most active oral antipneumococcal agent in this study.
PMCID: PMC163676  PMID: 8980771
13.  Comparative activities of LY 333328, a new glycopeptide, against penicillin-susceptible and -resistant pneumococci. 
Antimicrobial Agents and Chemotherapy  1996;40(11):2661-2663.
Microdilution MIC testing was used to test the susceptibility of 202 pneumococci to LY 333328 and six other agents. LY 333328 was the most active glycopeptide (MIC at which 90% of the pneumococci were inhibited [MIC90], 0.008 microgram/ml), followed by teicoplanin (MIC90, 0.06 microgram/ml) and vancomycin (MIC90, 0.5 microgram/ml). Rifampin resistance was seen in some penicillin-resistant strains. The MICs of imipenem and ceftriaxone rose with those of penicillin. Time-kill testing confirmed the excellent antipneumococcal activity of LY 333328.
PMCID: PMC163597  PMID: 8913486
14.  Antipneumococcal activities of cefpirome and cefotaxime, alone and in combination with vancomycin and teicoplanin, determined by checkerboard and time-kill methods. 
The checkerboard titration method was used to test the synergy of cefpirome and cefotaxime with teicoplanin or vancomycin against 35 penicillin-susceptible, 34 penicillin-intermediate, and 31 penicillin-resistant pneumococci. The MICs at which 50 and 90% of isolates are inhibited (MIC50s and MIC90s, respectively) of both cefpirome and cefotaxime were 0.016 and 0.06 microgram/ml, respectively, for penicillin-susceptible strains and 0.125 and 0.5 microgram/ml, respectively, for penicillin-intermediate strains. The MIC50s and MIC90s of cefotaxime for penicillin-resistant strains were 1.0 and 2.0 micrograms/ml, respectively, and those of cefpirome were 0.5 and 1.0 microgram/ml, respectively. All pneumococci were inhibited by cefpirome at MICs of < or = 1.0 microgram/ml. The MIC50s and MIC90s of vancomycin and teicoplanin (0.25 and 0.25 microgram/ml and 0.03 and 0.03 microgram/ml, respectively) did not differ for the three groups. Checkerboard synergy studies showed that cefpirome and vancomycin showed synergy for 31 strains (fractional inhibitory concentration [FIC] indices, < or = 0.5) cefpirome and teicoplanin showed synergy for 18 strains, cefotaxime and vancomycin showed synergy for 51 strains, and cefotaxime and teicoplanin showed synergy for 27 strains. Cefpirome and vancomycin had FIC indices indicating indifference (2.0) for two strains, and cefotaxime and vancomycin had FIC indices indicating indifference for one strain. All other FIC indices indicating indifference or additivity were > 0.5 to 1.0. No FIC indices indicating antagonism (> 4.0) were found. Synergy between beta-lactams and glycopeptides for three susceptible, three intermediate, and three resistant strains were tested by the time-kill assay, and all combinations were synergistic by this method. Synergy between cephalosporins and glycopeptides can be demonstrated and may be useful for the treatment of pneumococcal infections, especially meningitis.
PMCID: PMC163457  PMID: 8878565
15.  MIC and time-kill study of antipneumococcal activities of RPR 106972 (a new oral streptogramin), RP 59500 (quinupristin-dalfopristin), pyostacine (RP 7293), penicillin G, cefotaxime, erythromycin, and clarithromycin against 10 penicillin-susceptible and -resistant pneumococci. 
Broth MICs and time-kill studies were used to test the activity of RP 59500 (quinupristin-dalfopristin), RPR 106972, pyostacine (RP 7293), erythromycin, clarithromycin, and cefotaxime for four penicillin-susceptible (MICs of 0.008 to 0.03 microgram/ml), two penicillin-intermediate (MIC of 0.25 microgram/ml), and four penicillin-resistant (MIC of 2.0 to 4.0 micrograms/ml) strains of pneumococci: 6 of 10 strains were resistant to macrolides (MICs of > or = 0.5 microgram/ml). MICs of RP 59500 (0.5 to 1.0 microgram/ml), RPR 106972 (0.125 to 0.25 microgram/ml), and pyostacine (0.125 to 0.25 microgram/ml) did not alter with the strain's penicillin or macrolide susceptibility status. Three penicillin-susceptible strains and one penicillin-intermediate strain were susceptible to macrolides (MICs of < or = 0.25 microgram/ml); the macrolide MICs for the remaining strains were > or = 4.0 micrograms/ml. Cefotaxime MICs rose with those of penicillin G, but all strains were inhibited at MICs of < or = 2.0 micrograms/ml. RP 59500 was bactericidal for all strains after 24 h at 2 x MIC and yielded 90% killing of all strains at 6 h at 2 x MIC; at 8 x MIC, RP 59500 showed 90% killing of six strains within 10 min (approximately 0.2 h). In comparison, RPR 106972 was bactericidal for 9 of 10 strains at 2 x MIC after 24 h and yielded 90% killing of all strains at 2 x MIC after 6 h; 90% killing of six strains was found at 8 x MIC at 0.2 h. Results for pyostacine were similar to those of RPR 106972. Erythromycin and clarithromycin were bactericidal for three of four macrolide-susceptible strains after 24 h at 4 x MIC. Clarithromycin yielded 90% killing of three strains at 8 x MIC after 12 h. Cefotaxime was bactericidal for all strains after 24 h at 4 x MIC, yielding 90% killing of all strains after 6 h at 4 x MIC. All three streptogramins yielded rapid killing of penicillin- and erythromycin-susceptible and -resistant pneumococci and were the only compounds which killed significant numbers of strains at 0.2 h.
PMCID: PMC163475  PMID: 8878583
16.  Comparative activities of clarithromycin, erythromycin, and azithromycin against penicillin-susceptible and penicillin-resistant pneumococci. 
Activities of clarithromycin, erythromycin, and azithromycin against 120 pneumococci from the United States were tested by agar dilution MIC. All three compounds yielded MICs at which 90% of the isolates were inhibited (MIC90S) of < or = 0.125 micrograms/ml against penicillin-susceptible and -intermediate strains, but MIC90S against resistant strains were > 128.0 micrograms/ml. All erythromycin-resistant strains were also resistant to clarithromycin and azithromycin. Clarithromycin yielded MICs which were generally one or two dilutions lower than those of the other two compounds for all strains. The respective bacteriostatic and bactericidal values (micrograms per milliliter) for two susceptible, two intermediate, and two resistant strains were 0.004 to 0.03 and 0.016 to 0.03 (0.004 to 0.03/0.016 to 0.03) (clarithromycin), 0.008 to 0.06/0.016/0.016 to 0.125 (erythromycin), and 0.016 to 0.06/0.03 to 0.125 (azithromycin); clarithromycin yielded the lowest values. All compounds were uniformly bactericidal after 24 h only; erythromycin was bactericidal at eight times the MIC, and azithromycin and clarithromycin were both bactericidal at two time the MIC. The relevance of these in vitro differences requires clarification by clinical trials.
PMCID: PMC163449  PMID: 8843313
17.  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.
PMCID: PMC163390  PMID: 8807057
18.  Susceptibilities of non-Pseudomonas aeruginosa gram-negative nonfermentative rods to ciprofloxacin, ofloxacin, levofloxacin, D-ofloxacin, sparfloxacin, ceftazidime, piperacillin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, and imipenem. 
Agar dilution MICs of 10 agents against 410 non-Pseudomonas aeruginosa gram-negative nonfermentative rods were determined. MICs at which 50 and 90% of the isolates were inhibited, respectively, were as follows (in micrograms per milliliter): sparfloxacin, 0.5 and 8.0; levofloxacin, 1.0 and 8.0; ciprofloxacin, 2.0 and 32.0; ofloxacin, 2.0 and 32.0; D-ofloxacin, 32.0 and > 64.0; ceftazidime, 8.0 and 64.0; piperacillin with or without tazobactam, 16.0 and > 64.0; trimethoprim-sulfamethoxazole, 0.5 and > 64.0; imipenem, 2.0 and > 64.0. With the exception of those for Stenotrophomonas maltophilia, Burkholderia cepacia, and Alcaligenes faecalis-A. odorans, agar dilution MICs for all strains tested were within 1 dilution of inhibitory (bacteriostatic) levels as determined by time-kill methodology.
PMCID: PMC163196  PMID: 8851609
19.  Activities of RPR 106972 (a new oral streptogramin), cefditoren (a new oral cephalosporin), two new oxazolidinones (U-100592 and U-100766), and other oral and parenteral agents against 203 penicillin-susceptible and -resistant pneumococci. 
Agar dilution was used to determine the MICs of RPR 106972 (a new oral streptogramin), cefditoren (a new oral cephalosporin), two new oxazolidinones (U-100592 and U-100766), and other oral and parenteral agents for 203 penicillin-susceptible and -resistant pneumococci. All pneumococci were inhibited by RPR 106972 at < or = 0.5 microgram/ml. Cefditoren was very active against all pneumococcal groups, with MICs of < or = 2.0 micrograms/ml. Amoxicillin with or without clavulanate was the next most active oral beta-lactam, followed by cefdinir, cefuroxime, cefpodoxime, and cefprozil. U-100592 and U-100766 were very active against all classes of pneumococci, with all MICs < or = 1.0 microgram/ml.
PMCID: PMC163140  PMID: 8834904
20.  MIC and time-kill study of activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem, and vancomycin against nine penicillin-susceptible and -resistant pneumococci. 
MIC and time-kill methods were used to test the activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem, and vancomycin against nine penicillin-susceptible, -intermediate, and -resistant pneumococci. The MIC of penicillin for penicillin-susceptible strains was 0.016 micrograms/ml, those for intermediate strains were 0.25 to 1.0 microgram/ml, and those for resistant strains were 2.0 to 4.0 micrograms/ml. Of the four quinolones tested, DU-6859a had the lowest MIC (0.064 micrograms/ml), followed by sparfloxacin (0.25 to 0.5 micrograms/ml) and levofloxacin and ciprofloxacin (both 1.0 to 4.0 micrograms/ml). Vancomycin inhibited all strains at MICs of 0.25 to 0.5 micrograms/ml. The MICs of imipenem and cefotaxime for penicillin-susceptible, -intermediate, and -resistant strains were 0.004 to 0.008, 0.008 to 0.032, and 0.25 micrograms/ml and 0.016, 0.125 to 0.5, and 2.0 micrograms/ml, respectively. DU-6859a was bactericidal at eight times the MICs (0.5 micrograms/ml) for seven of the nine strains after 4 h and bactericidal for all nine strains after 6 h at eight times the MICs and after 12 h at two times the MICs. By comparison, sparfloxacin, the next most active quinolone, was uniformly bactericidal at two times the MICs only after 24 h, with little activity after 2 h. Levofloxacin and ciprofloxacin were bactericidal against all strains after 12 h at eight times the MICs and against all strains at 24 h at four times the MICs. Imipenem was bactericidal against all strains, at concentrations exceeding the MICs, after 24 h. Cefotaxime was also uniformly bactericidal only after 24 h of incubation at two times the MICs. Vancomycin, despite having uniformly low MICs for all strains irrespective of their penicillin susceptibility, was uniformly bactericidal only at two times the MICs after 24 h.
PMCID: PMC163117  PMID: 8834881
21.  Activities of oral and parenteral agents against penicillin-susceptible and -resistant pneumococci. 
This study examined bacteriostatic and bactericidal activities of oral and parenteral antibiotics for penicillin-susceptible and intermediately and fully penicillin-resistant pneumococci. beta-Lactamase inhibitors did not affect beta-lactam results. The activities of ampicillin, amoxicillin +/- clavulanate, WY-49605, cefuroxime, cefpodoxime, cefdinir, cefixime, and cefaclor against two penicillin-susceptible, two intermediately penicillin-resistant, and two fully penicillin-resistant pneumococcal strains were tested. For all three groups, bacteriostatic values of amoxicillin and WY-49605 were lower than were those of other beta-lactams tested. Of the cephalosporins, cefdinir, cefuroxime, and cefpodoxime yielded the lowest bacteriostatic values. All beta-lactams were bactericidal (reduced original counts by > or = 3 log10 CFU/ml) at 1 dilution above bacteriostatic values, except for cefpodoxime (bactericidal at 2 dilutions above bacteriostatic values for one susceptible strain and one intermediately resistant strain), cefuroxime (bactericidal at 2 dilutions above bacteriostatic values for one intermediately resistant strain), and ampicillin (bactericidal at 2 dilutions above bacteriostatic values for one intermediately resistant strain). The activities of piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftriaxone, ceftazidime, and ciprofloxacin against four penicillin-susceptible, two intermediately penicillin-resistant, and four fully penicillin-resistant pneumococcal strains were evaluated. Bacteriostatic values of piperacillin, ampicillin, and ceftriaxone for all groups were lower than were those of ticarcillin and ceftazidime. Bacteriostatic values of ciprofloxacin were unaffected by penicillin susceptibility. All beta-lactams were bactericidal at 1 dilution above the bacteriostatic value, except for piperacillin (bactericidal at 2 dilutions above the bacteriostatic value for one intermediately resistant strain), ticarcillin (bactericidal at 2 dilutions above the bacteriostatic value for one susceptible strain and one resistant strain), ampicillin (bactericidal at 2 dilutions above the bacteriostatic value for two resistant strains), ceftriaxone (bactericidal at 2 dilutions above the bacteriostatic value for one resistant strain), and ceftazidime (bactericidal at 2 dilutions above the bacteriostatic value for one susceptible strain).
PMCID: PMC162770  PMID: 7492093
22.  Susceptibilities of 200 penicillin-susceptible and -resistant pneumococci to piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftazidime, and ceftriaxone. 
Antimicrobial Agents and Chemotherapy  1994;38(12):2905-2907.
MICs of eight beta-lactams (piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftazidime, and ceftriaxone) were determined by agar dilution against 64 penicillin-susceptible, 70 intermediately penicillin-resistant, and 66 fully penicillin-resistant pneumococci. The MICs of piperacillin with and without tazobactam for 90% of the susceptible, intermediately resistant, and resistant strains tested (MIC90s) were < or = 0.064, 2.0, and 4.0 micrograms/ml, respectively. By comparison, those of ampicillin with and without sulbactam were 0.125, 2.0, and 4.0 micrograms/ml and those of ceftriaxone were < or = 0.064, 1.0, and 2.0 micrograms/ml, respectively. Strains were less susceptible to ticarcillin with and without clavulanate (MIC90s, 2.0, 64.0, and 128.0 micrograms/ml) and ceftazidime (MIC90s, 1.0, 8.0, and 32.0 micrograms/ml).
PMCID: PMC188305  PMID: 7695281
23.  Activity of WY-49605 compared with those of amoxicillin, amoxicillin-clavulanate, imipenem, ciprofloxacin, cefaclor, cefpodoxime, cefuroxime, clindamycin, and metronidazole against 384 anaerobic bacteria. 
Antimicrobial Agents and Chemotherapy  1994;38(11):2599-2604.
The National Committee for Clinical Laboratory Standards agar dilution method was used to compare the in vitro activity of WY-49605 (also called SUN/SY 5555 and ALP-201), a new broad-spectrum oral penem, to those of amoxicillin, amoxicillin-clavulanate, imipenem, ciprofloxacin, cefaclor, cefpodoxime, cefuroxime, clindamycin, and metronidazole against 384 clinically isolated anaerobes. These anaerobic organisms included 90 strains from the Bacteroides fragilis group, 87 Prevotella and Porphyromonas strains, non-B. fragilis group Bacteroides strains, 56 fusobacteria, 55 peptostreptococci, 49 gram-positive non-spore-forming rods, and 47 clostridia. Overall, WY-49605 had an MIC range of 0.015 to 8.0 micrograms/ml, an MIC at which 50% of the isolates are inhibited (MIC50) of 0.25 microgram/ml, and an MIC at which 90% of the isolates are inhibited (MIC90) of 2.0 micrograms/ml. Good activity against all anaerobe groups was observed, except for Clostridium difficile and lactobacilli (MIC50s of 4.0 and 2.0 micrograms/ml, respectively, and MIC90s of 8.0 and 2.0 micrograms/ml, respectively). Imipenem had an MIC50 of 0.03 microgram/ml and an MIC90 of 0.25 microgram/ml. Ciprofloxacin was much less active (MIC50 of 2.0 micrograms/ml and MIC90 of 16.0 micrograms/ml). By comparison, all oral beta-lactams were less active than WY-49605, with susceptibilities as follows: amoxicillin MIC50 of 8.0 micrograms/ml and MIC90 of > 256.0 micrograms/ml), amoxicillin-clavulanate MIC50 of 1.0 microgram/ml and MIC90 of 8.0 micrograms/ml, cefaclor MIC50 of 8.0 micrograms/ml and MIC90 of > 32.0 micrograms/ml, cefpodoxime MIC50 of 4.0 micrograms/ml and MIC90 of > 32.0 micrograms/ml, and cefuroxime MIC50 of 4.0 micrograms/ml and MIC90 of > 32.0 micrograms/ml. Clindamycin was active against all groups except some members of the B. fragilis group, Fusobacterium varium, and some clostridia ( overall MIC50 of 0.5 micrograms/ml and overall MIC90 of 8.0 micrograms/ml). Metronidazole was active (MIC of less than or equal to 4.0 micrograms/ml) against all gram-negative anaerobic rods, but most gram-positive non-spore-forming rods, some peptostreptococci, and some clostridia were less susceptible. To date, WY-49605 is the most active oral beta-lactam against anaerobes: these results suggest clinical evaluation for clinical indications suitable for oral therapy.
PMCID: PMC188248  PMID: 7872754
24.  Activity of CP 99,219 compared with those of ciprofloxacin, grepafloxacin, metronidazole, cefoxitin, piperacillin, and piperacillin-tazobactam against 489 anaerobes. 
Antimicrobial Agents and Chemotherapy  1994;38(10):2471-2476.
Agar dilution was used to compare the in vitro activity of CP 99,219 with those of ciprofloxacin, grepafloxacin, metronidazole, cefoxitin, piperacillin, and piperacillin-tazobactam against 489 anaerobes. CP 99,219 yielded a MIC for 50% of the strains tested (MIC50) of 0.25 micrograms/ml and a MIC90 of 1.0 microgram/ml, with 99.6% of the strains susceptible at a breakpoint of 2.0 micrograms/ml. Ciprofloxacin and grepafloxacin were less active (MIC50, 4.0 micrograms/ml; MIC90, 32.0 micrograms/ml and 2.0 and 16.0 micrograms/ml, respectively). Metronidazole was active against all gram-negative rods (MIC90, 4.0 micrograms/ml), but 31% of the gram-positive anaerobes were resistant at > 8.0 micrograms/ml. Cefoxitin was active against 84% of all strains at < or = 16.0 micrograms/ml, with a MIC50 of 4.0 micrograms/ml and a MIC90 of 32.0 micrograms/ml. Tazobactam enhanced the activity of piperacillin against > 95% of the beta-lactamase-producing gram-negative anaerobic rods (MIC90, 16.0 micrograms/ml).
PMCID: PMC284766  PMID: 7840591
25.  Susceptibilities of 123 strains of Xanthomonas maltophilia to eight beta-lactams (including beta-lactam-beta-lactamase inhibitor combinations) and ciprofloxacin tested by five methods. 
Antimicrobial Agents and Chemotherapy  1994;38(10):2317-2322.
This study evaluated the susceptibility of 123 Xanthomonas maltophilia strains to ticarcillin, ticarcillin-clavulanate, ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, imipenem, and ciprofloxacin by Kirby-Bauer disk, E test, and Sensititre dehydrated microdilution MIC and conventional agar dilution MIC methodology. Intermediate susceptibility breakpoints for members of the family Enterobacteriaceae were used. When results were analyzed as MICs for 50 and 90% of the strains tested and percentages of strains susceptible at the breakpoint, good correlation between the methods was observed, with ticarcillin-clavulanate clearly the most active beta-lactam by all four methods. However, when the various methods were compared with the agar dilution methodology by regression analysis, poor r2 values (0.3 to 0.7) were obtained for compounds with sufficient on-scale values to permit analysis. When the number of strains with log2 ratios of reference agar dilution MICs to test MICs of +3 to -3 were analyzed, correlation was also poor, with many major and very major discrepancies for all methods tested. Results obtained with time-kill studies of nine strains with discrepant ticarcillin-clavulanate MICs appeared to correlate best when compared at 24 h with agar dilution MICs. The concentration of ticarcillin-clavulanate required to reduce the colony count by > or = 2 log10 reduction values for eight of nine strains compared with that for growth controls was < or = 16.0/2.0 micrograms/ml at 6 h and ranged from 16.0/2.0 micrograms/ml to 128.0/2.0 micrograms/ml at 24 h. The susceptibility method of choice for X. maltophilia has not yet been standardized, but time-kill studies correlated best with agar dilution MICs.
PMCID: PMC284737  PMID: 7840563

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