In vitro activities of quinolones against enterococci resistant to penicillin-aminoglycoside synergy.

The MICs and MBCs of CI-934, ciprofloxacin, difloxacin (A-56619), A-56620, norfloxacin, enoxacin, amifloxacin, and coumermycin were determined for 43 clinical isolates of Enterococcus faecalis known to be resistant to penicillin-aminoglycoside synergy. Results were compared with those obtained for 37 synergy-susceptible E. faecalis and 22 Enterococcus faecium strains. Although no substantial differences in quinolone activities were observed between synergy-resistant and -susceptible E. faecalis strains, CI-934 and ciprofloxacin were the drugs that demonstrated the greatest bactericidal activity against both types of E. faecalis. The MBCs of the other quinolones were generally within a single twofold dilution of the MICs, but their antienterococcal activity did not approach that of CI-934 or ciprofloxacin. The MBCs for 90% of the isolates of CI-934 for synergy-resistant and -susceptible E. faecalis strains were 1 and less than or equal to 0.5 microgram/ml, respectively. The ciprofloxacin MBC for 90% of the E. faecalis strains tested was 1 microgram/ml. For E. faecium isolates the CI-934 and ciprofloxacin MBCs for 90% of the isolates were 8 and 4 micrograms/ml, respectively. Time-kill assays performed with synergy-susceptible enterococcal strains showed that the bactericidal activities of both CI-934 and ciprofloxacin were less than those of the penicillin-aminoglycoside combinations tested. However, against synergy-resistant isolates the activities of these two quinolones were comparable with and sometimes greater than those of penicillin-aminoglycoside combinations.     

Rate of bactericidal activity for Branhamella catarrhalis of a new macrolide, CP-62,993, compared with that of amoxicillin-clavulanic acid

The rate of bactericidal activity of a new macrolide, CP-62,993, was compared with that of the combination of amoxicillin and clavulanic acid (in the proportion of 4 to 1) on strains of Branhamella catarrhalis beta-lactamase producers. The antibacterial activity of CP-62,993 was bacterostatic at 0.01 micrograms/ml. After a 6-hour period of bacteriostasis a bactericidal activity (3 log10 CFU/ml) was observed for all concentrations from 0.1 to 10 micrograms/ml after 24 h. The bactericidal rate of amoxicillin-clavulanic acid combination was more rapid during the first 6 h at 1 and 10 micrograms/ml. However, the concentration required to kill 99.9% of bacteria within 24 h was 1 microgram/ml. In conclusion, CP-62,993 was a bactericidal antibiotic for B. catarrhalis at a lower concentration. This in vitro study suggests that this macrolide may be of great interest in infections due to the B. catarrhalis beta-lactamase producer.     

In vitro activity of CI-934 compared with ciprofloxacin, enoxacin, norfloxacin, and vancomycin

The in vitro activity of the quinolone CI-934 was compared with ciprofloxacin, norfloxacin, enoxacin, and vancomycin against 607 Gram-positive and -negative isolates. CI-934 inhibited 90% of the Enterobacteriaceae, Aeromonas hydrophila, and Acinetobacter spp. at 1 microgram/ml. Decreased activity was observed against Pseudomonas aeruginosa. Pseudomonas maltophilia, and other Pseudomonas spp. with CI-934 MIC90 greater than or equal to 8 micrograms/ml. CI-934 activity against Gram-positive organisms exceeded vancomycin and the other quinolones. MIC90 for Streptococcus faecalis, Listeria monocytogenes, and Corynebacterium spp. were less than or equal to 2 micrograms/ml. CI-934 was equally effective against oxacillin-susceptible and -resistant staphylococci with MIC90 of 0.5 micrograms/ml.     

Discrepancies between MBC and actual killing of viridans group streptococci by cell-wall-active antibiotics.

We determined the MBC of amoxicillin and vancomycin, two antibiotics advocated for treatment and prophylaxis of bacterial endocarditis, for 24 strains of viridans group streptococci isolated from patients with endocarditis. We found that the MIC of amoxicillin for all strains was less than or equal to 0.25 micrograms/ml and the MBC was either low (less than 0.5 micrograms/ml) in 6 nontolerant strains or high (greater than 128 micrograms/ml) in 18 tolerant strains. The MIC of vancomycin for the 24 strains was less than or equal to 1 microgram/ml, and the MBC was either low (less than 1 microgram/ml) for 3 nontolerant strains or high (greater than 128 micrograms/ml) for 21 tolerant strains. In addition to the MBC, we determined the actual reduction of the viable bacterial counts in each tube dilution after 24 h of incubation. This determination was made by subtracting the number of colonies observed on the subculture plate from the number of bacteria contained in the initial inoculum. For both antibiotics we found that the maximal reduction in viable counts was achieved at or very close to the MIC and did not increase with increasing antibiotic concentrations (up to 128 micrograms/ml). As expected, the six strains for which the amoxicillin MBC was less than 0.5 micrograms/ml and the three strains for which the vancomycin MBC was less than 1 microgram/ml had a reduction of viable counts of more than 3 log10 (greater than 99.9% killing). In contrast, among the strains defined as tolerant to amoxicillin and vancomycin, there were wide variations in the actual reduction of bacterial counts, ranging from 3 log10 to less than 1 log10. Therefore our observations suggest that the reduction of viable streptococcal counts reflects more accurately the bactericidal effect of amoxicillin and vancomycin than does the MBC, which artificially divides the strains into sensitive or tolerant strains.     

Effects of combinations of beta-lactams, daptomycin, gentamicin, and glycopeptides against glycopeptide-resistant enterococci.

Activities of combinations of beta-lactams, daptomycin, gentamicin, teicoplanin, and vancomycin against 11 clinical isolates of Enterococcus faecium highly resistant to glycopeptides, three plasmid-cured derivatives, eight E. faecalis and E. faecium transconjugants, and two susceptible recipient strains were tested. A marked synergy between penicillins or imipenem and glycopeptides against the glycopeptide-resistant strains but not against the glycopeptide-susceptible strains was observed by the double-disk agar diffusion assay. The synergy of combinations of amoxicillin, imipenem, penicillin G, or piperacillin with vancomycin or teicoplanin against resistant strains was confirmed by the checkerboard technique. The fractional inhibitory concentration indexes were generally below 0.25, except for one strain of E. faecium resistant to high levels of penicillin G. However, the combinations were not bactericidal as tested by time-killing experiments, and high concentrations (64 micrograms/ml) of amoxicillin, penicillin G, or piperacillin combined with 8 micrograms of vancomycin or teicoplanin per ml tended to be antagonistic. Addition of 4 micrograms of gentamicin per ml to these combinations enhanced their bactericidal effect, but they occasionally remained slightly less effective than beta-lactams associated with gentamicin. The combination of 10 micrograms of daptomycin per ml with gentamicin was bactericidal after 6 h against 11 glycopeptide-resistant strains.     

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.     

Bactericidal effect and regrowth of Streptococcus faecalis exposed to amoxicillin following beta-lactamase

Streptococcus faecalis usually requires high concentrations of penicillin or ampicillin to achieve killing (i.e. a high MBC/MIC ratio). However, most strains show the Eagle or paradoxical effect. We subjected 12 strains of S. faecalis to 0.1, 1, 10 and 100 micrograms/ml of amoxicillin. Turbidometry studies have shown that 3 h after the inactivation of amoxicillin by penicillinase, there was a longer effect for 1 micrograms/ml following beta-lactamase (12 h 31 min +/- 2 h 09 min) than for 10 micrograms/ml (7 h 0 min +/- 1 h 12 min) or 100 micrograms/ml (5 h 22 min +/- 0 h 52 min). After 3 h, the reduction of CFU/ml (inoculum 10(6) CFU/ml) was -1.8 +/- 0.6 for 1 micrograms/ml, -0.56 +/- 0.56 for 10 micrograms/ml and -0.21 +/- 0.20 for 100 micrograms/ml. The more rapid killing at 3 h was not the only reason for the longer effect following beta-lactamase observed with 1 micrograms/ml. Indeed, the growth curve obtained with an inoculum of 10(3) CFU/ml was 2 h delayed from the control curve (10(6) CFU/ml). In conclusion, a paradoxical effect (killing curves and effect following beta-lactamase) was observed for all S. faecalis strains included in this series.     

In vitro evaluation of BRL 42715, a novel beta-lactamase inhibitor.

The penem BRL 42715, C6-(N1-methyl-1,2,3-triazolylmethylene)penem, is a potent inhibitor of a broad range of bacterial beta-lactamases, including the plasmid-mediated TEM, SHV, OXA, and staphylococcal enzymes, as well as the chromosomally mediated enzymes of Bacteroides, Enterobacter, Citrobacter, Serratia, Morganella, Escherichia, Klebsiella, and Proteus species. The concentration of BRL 42715 needed to reduce the initial rate of hydrolysis of most beta-lactamase enzymes by 50% was less than 0.01 micrograms/ml, which was 10- to 100-fold lower than for other beta-lactamase inhibitors. These potent inhibitory activities were reflected in the low concentrations of BRL 42715 needed to potentiate the antibacterial activity of beta-lactamase-susceptible beta-lactams. Concentrations of 0.25 micrograms/ml or less considerably enhanced the activity of amoxicillin against many beta-lactamase-producing strains. The MIC50 (MIC for 50% of strains tested) of amoxicillin for 412 beta-lactamase-producing members of the family Enterobacteriaceae fell from greater than 128 to 2 micrograms/ml in the presence of 1 microgram of BRL 42715 per ml, whereas 5 micrograms of clavulanic acid per ml brought the MIC50 down to 8 micrograms/ml. Among these 412 strains were 73 Citrobacter and Enterobacter strains, and 1 microgram of BRL 42715 per ml reduced the MIC50 of amoxicillin from greater than 128 to 2 micrograms/ml for the 48 cefotaxime-susceptible strains and from greater than 128 to 8 micrograms/ml for the 25 cefotaxime-resistant strains.     

In vitro activity of CI-934, a new quinolone, compared with that of other quinolones and other antimicrobial agents.

The in vitro activity of CI-934, a new 4-quinolone, was determined against gram-positive and gram-negative bacteria. The MICs for 90% of the isolates tested were 0.25 microgram/ml for Streptococcus pneumoniae, 0.5 microgram/ml for Streptococcus faecalis, 0.25 microgram/ml for staphylococci, including methicillin-resistant strains, and less than or equal to 1.0 microgram/ml for Escherichia coli, Salmonella and Shigella spp., Klebsiella spp., Proteus spp., and Citrobacter spp. CI-934 had activity superior to that of other quinolones against streptococci by four- to eightfold. Against members of the family Enterobacteriaceae, ciprofloxacin was 2- to 18-fold more active; ofloxacin and norfloxacin were twofold more active or similar to CI-934. CI-934 inhibited ampicillin-cephalothin-resistant urinary isolates of E. coli, Klebsiella pneumoniae, and Proteus mirabilis and cefoxatime-resistant Acinetobacter spp., Citrobacter freundii, Enterobacter cloacae, Proteus vulgaris, and Morganella morganii. The medium, inoculum size, and oxygen concentration, as well as the addition of serum, had not major effect on the activity of CI-934. Magnesium at a concentration of 9 mM increased MICs and MBCs four- to eightfold, and testing at pH 6 increased MICs as much as 32- to 64-fold for some organisms in comparison with MICs at pH 7. The frequency of spontaneous mutation to resistance was comparable to that for other new quinolones, but resistant isolates could be selected by repeated subculture.     

Activities of newer fluoroquinolones against Shigella sonnei.

The activities of six fluoroquinolones were determined for 117 separate strains of Shigella sonnei. The order of increasing activity (MICs for 90% of strains tested) was enoxacin (0.25 micrograms/ml), temafloxacin (0.032 micrograms/ml), sparfloxacin (0.016 micrograms/ml), CI-960 (0.008 micrograms/ml), ciprofloxacin (0.008 micrograms/ml), and PD-131628-2 (0.008 micrograms/ml). These data, along with results of killing and mutational rate studies, showed that all six fluoroquinolones were highly inhibitory against S. sonnei and five fluoroquinolones were rapidly and persistently bactericidal.     

Study of comparative antipneumococcal activities of penicillin G, RP 59500, erythromycin, sparfloxacin, ciprofloxacin, and vancomycin by using time-kill methodology.

Time-kill studies were used to examine the in vitro activities of penicillin G, RP 59500, erythromycin, ciprofloxacin, sparfloxacin, and vancomycin against 10 pneumococci expressing various degrees of susceptibility to penicillin and erythromycin. RP 59500 MICs for all strains were 0.5 to 2.0 micrograms/ml, while erythromycin MICs were 0.008 to 0.06 microgram/ml for erythromycin-susceptible strains and 32.0 to 64.0 micrograms/ml for erythromycin-resistant strains. Strains were more susceptible to sparfloxacin (0.125 to 0.5 microgram/ml) than to ciprofloxacin (0.5 to 4.0 micrograms/ml), and all were inhibited by vancomycin at MICs of 0.25 to 0.5 microgram/ml. Time-kill studies showed that antibiotic concentrations greater than the MIC were bactericidal for each strain, with the following exceptions. Erythromycin was bactericidal for one penicillin-resistant strain at 6 h, with regrowth after 12 and 24 h. Three penicillin-susceptible strains were bacteriostatically inhibited by erythromycin at concentrations greater than or equal to the MIC by 6 h. One penicillin-susceptible strain (penicillin MIC, 0.06 microgram/ml) was bacteriostatically inhibited by penicillin G at 24 h at the MIC or at one-half the MIC; a bactericidal effect was found only with penicillin G at concentrations of > or = 0.25 microgram/ml. At 10 min after inoculation a 1- to 3-log10-unit reduction (90 to 99.9%) in the original inoculum was seen for 6 of 10 strains with RP 59500 at concentrations greater than or equal to the MIC. This effect was not found with any of the other compounds tested. A bactericidal effect was found at > or = 6 h with RP 59500 at concentrations of one-half to one-quarter the MIC in 7 of 10 strains, and a bacteriostatic effect was found in 3 or 10 strains, with regrowth at 24 h. One penicillin-resistant strain was examined by the time-kill methodology at 0, 1, 2, and 3 h. RP 59500 at a concentration equal to the MIC was bactericidal within 1 h, and at a concentration of one-half the MIC it was bactericidal within 3 h. This phenomenon was not seen with the other antimicrobial agents tested. Regrowth of strains at ciprofloxacin concentrations equal to the MIC or at a one-half to one-quarter the MIC was found. For sparfloxacin, three of the four penicillin-susceptible strains and two of four penicillin-resistant strains were bacteriostatically inhibited by 6 h. Bactericidal effects were found at 6, 12, and 24 h with both intermediate-resistant, one penicillin-susceptible, and two penicillin-resistant strains. Complete killing was observed with vancomycin at concentrations greater than MIC. Of the new compounds tested, RP 59500 and sparfloxacin show promise for the treatment of infections caused by penicillin-susceptible and -resistant pneumococci. The clinical significance of rapid killing by RP 59500 remains to be determined.     

In vitro and in vivo activities of clinafloxacin, CI-990 (PD 131112), and PD 138312 versus enterococci.

Certain new fluoroquinolones have high activity against enterococci. Against Enterococcus faecalis (n = 18), MICs at which 90% of the isolates were inhibited were as follows (in micrograms per milliliter): clinafloxacin, 0.125; CI-990, 0.5; and PD 138312, 0.25 (compared with 1 microgram/ml for ciprofloxacin and 2 micrograms/ml for ofloxacin). Strains producing beta-lactamase or that were vancomycin resistant or resistant to high-level gentamicin were not quinolone cross-resistant. The drugs were bactericidal and were unaffected by 50% human serum. Oral efficacies (in milligrams per kilogram of body weight for 50% protective doses) in lethal mouse infections with quinolone-susceptible strains were 4.3 to 24 for clinafloxacin, 7.2 to 39 for CI-990, 7.2 to 76 for PD 138312, and 41 to > 100 for ciprofloxacin; when the drugs were given subcutaneously, the order was similar and values ranged from 1.1 to 12.5. Clinafloxacin, CI-990, and PD 138312 may have therapeutic potential in systemic enterococcal infections in humans.     

Comparative activity of ciprofloxacin, ofloxacin, sparfloxacin, temafloxacin, CI-960, CI-990, and WIN 57273 against anaerobic bacteria.

The in vitro activities of seven fluoroquinolones against 290 anaerobes were determined by agar dilution. CI-960 and WIN 57273 inhibited greater than 95% of the strains at less than or equal to 2 micrograms/ml. CI-990 required less than or equal to 16 micrograms/ml. Clustering around 2 to 4 micrograms/ml was noted for Bacteroides fragilis group organisms with CI-990, sparfloxacin, and temafloxacin. Temafloxacin and sparfloxacin inhibited most strains at less than or equal to 2 micrograms/ml. B. fragilis was more susceptible to all quinolones than were the other B. fragilis group strains.     

Beta-lactamase production and susceptibilities to amoxicillin, amoxicillin-clavulanate, ticarcillin, ticarcillin-clavulanate, cefoxitin, imipenem, and metronidazole of 320 non-Bacteroides fragilis Bacteroides isolates and 129 fusobacteria from 28 U.S. centers.

beta-Lactamase production (nitrocefin disk method) and agar dilution susceptibility of amoxicillin, amoxicillin-clavulanate, ticarcillin, ticarcillin-clavulanate, cefoxitin, imipenem, and metronidazole were determined for 320 Bacteroides species (not Bacteroides fragilis group) and 129 fusobacteria from 28 U.S. centers. Overall, 64.7% of Bacteroides species and 41.1% of fusobacteria were beta-lactamase positive. Among the Bacteroides species, positivity rates were highest for B. bivius (85.0%), followed by B. splanchnicus (83.3%), B. eggerthii (77.8%), and B. oralis (77.1%); 54.5% of black-pigmented Bacteroides species were beta-lactamase positive. Among the fusobacteria, Fusobacterium mortiferum showed the highest rate of beta-lactamase positivity (76.9%). MICs of amoxicillin (128 micrograms/ml) and ticarcillin (64 micrograms/ml) for 90% of all beta-lactamase-positive strains were reduced to 4 and 2 micrograms/ml, respectively, with the addition of clavulanate. MICs of amoxicillin and ticarcillin for 90% of all beta-lactamase-negative strains were 1 and 4 micrograms/ml, respectively, and greater than or equal to 98.4% of the strains were susceptible to the beta-lactams tested. Of the beta-lactamase-producing strains, 45.9% were susceptible to amoxicillin at less than or equal to 4 micrograms/ml and 93.4% were susceptible to ticarcillin at less than or equal to 64 micrograms/ml; the addition of clavulanate raised the rates to 90.4 and 100%, respectively. All strains were susceptible to cefoxitin, imipenem, and metronidazole. The activity of amoxicillin against 29 beta-lactamase-producing strains (10 Bacteroides species and 19 fusobacteria) was not enhanced by the addition of clavulanate; however, 82.7% of these strains were susceptible to amoxicillin, and all were susceptible to ticarcillin. Although beta-lactamase positivity is on the increase in non-B. fragilis group Bacteroides species and fusobacteria, amoxicillin-clavulanate, ticarcillin, cefoxitin, imipenem, and metronidazole should be suitable for the treatment of infections with these strains. The addition of clavulanate does not appreciably improve the efficacy of ticarcillin against these organisms.     

In vitro susceptibility of group G streptococci to ten antimicrobial agents with broad gram-positive spectra

Minimal inhibitory and bactericidal concentrations (MICs, MBCs) of ten antibiotics with broad spectra against grampositive cocci were determined for 25 group G streptococci (GGS). Penicillin G, cefotaxime, and ampicillin were the most active bactericidal agents, with 100% of MBCs less than or equal to 0.6 micrograms/ml. Among the nonpenicillin, noncephalosporin agents, vancomycin had the lowest MBCs, with all strains killed by less than or equal to 2.5 micrograms/ml. Despite good in vitro activity against other streptococci, erythromycin, clindamycin, and chloramphenicol had disappointing bactericidal activity against GGS. Three strains were tolerant to erythromycin, while 15 strains were tolerant to clindamycin. Chloramphenicol was the least active inhibitory agent, with an MIC90 of 13.8 micrograms/ml; this agent was also the least active bactericidal agent against GGS. with no MBCs less than 2.5 micrograms/ml and 9 strains with MBCs greater than or equal to 20 micrograms/ml. There were no GGS strains tolerant to either penicillin G or vancomycin.     

In vitro antistaphylococcal activities of two investigative fluoroquinolones, CI-960 and WIN 57273, compared with those of ciprofloxacin, mupirocin (pseudomonic acid), and peptide-class antimicrobial agents.

By using broth microdilution, 373 clinical isolates of staphylococci were studied to determine their susceptibilities to CI-960, WIN 57273, ciprofloxacin, mupirocin, vancomycin, teicoplanin, and ramoplanin. Test strains comprised 179 strains of Staphylococcus aureus and 194 strains of coagulase-negative species. Strains of S. aureus were susceptible to CI-960, which had a mode MIC of 0.032 micrograms/ml and an MIC for 90% of the strains of 2 micrograms/ml. CI-960 was equally active against methicillin-susceptible and -resistant S. aureus strains as well as ciprofloxacin-resistant strains. Similarly, WIN 57273 was highly active, with a mode MIC of 0.008 micrograms/ml and an MIC for 90% of the strains of 1 micrograms/ml. No cross-resistance to CI-960 and WIN 57273 among ciprofloxacin-resistant strains was detected. Mupirocin was four- to eightfold more active than ramoplanin, vancomycin, and teicoplanin. With regard to coagulase-negative staphylococci, CI-960 and WIN 57273 were the most active of the test compounds, inhibiting all strains at 0.5 and 1 micrograms/ml, respectively. Against the same strains, mupirocin was fourfold more active than ramoplanin and eightfold more active than vancomycin. Five strains of S. haemolyticus were found to be resistant to ciprofloxacin, while resistance to teicoplanin was found among strains of S. epidermidis, S. haemolyticus, S. hominis, S. saprophyticus, S. simulans, S. warneri, and S. xylosus.     

Susceptibilities to ceftriaxone of streptococcal strains associated with infective endocarditis

We determined the bactericidal activity of ceftriaxone on 20 streptococci isolated from patients with infective endocarditis and that of penicillin G on 5 strains. The MICs of ceftriaxone were less than or equal to 2 micrograms/ml and the MBCs were low for 5 nontolerant strains (less than or equal to 2 micrograms/ml) and high for 15 tolerant strains (greater than or equal to 16 micrograms/ml). The maximal reduction of the viable bacterial counts after 24 h of exposure to antibiotic was achieved for a concentration of ceftriaxone of 4, 32 and 256 micrograms/ml, respectively for 5, 10 and 19 strains. The activity of penicillin G was similar.     

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.     

Comparative Study of Anti-Pseudomonas Activity of Azlocillin, Mezlocillin, and Ticarcillin

The anti-pseudomonas activities of azlocillin and mezlocillin were compared with that of ticarcillin. We measured the minimal inhibitory and minimal bactericidal concentrations of the three drugs against 20 different strains of Pseudomonas aeruginosa and found significantly lower values for azlocillin than for the other two drugs. We then infused 5 g of each drug into 10 volunteers on three consecutive days and determined the serum levels of the three antibiotics at 1-h intervals from 1 to 6 h after injection. The levels of azlocillin were significantly higher than those of mezlocillin and ticarcillin (at 1 h: 236.55 mug/ml +/- 12.9 for azlocillin, 192.45 mug/ml +/- 28.8 for mezlocillin, and 131.5 mug/ml +/- 10.9 for ticarcillin). The inhibitory and bactericidal activities of the sera obtained 1 and 6 h after the injection against the same 20 strains of P. aeruginosa demonstrated a significantly greater anti-pseudomonas activity of azlocillin when compared with mezlocillin and ticarcillin; mezlocillin and ticarcillin had approximately the same activity. The mean values for bactericidal activity against the strains tested were 1/32 for azlocillin, 1/8 for mezlocillin, and 1/8 for ticarcillin. Azlocillin thus appears to be a promising anti-pseudomonas drug and should be tested in clinical trials.     

In vitro activity of amoxicillin in combination with clavulanic acid against Mycobacterium tuberculosis.

The comparative in vitro activity of amoxicillin alone and in combination with clavulanic acid against 15 isolates of Mycobacterium tuberculosis was evaluated by broth dilution susceptibility testing. Amoxicillin inhibited 4 of 15 isolates at 8 micrograms/ml or less but was not bactericidal against any of the isolates at that concentration. Amoxicillin in combination with clavulanic acid was bactericidal for 14 of 15 isolates tested at an amoxicillin concentration of 4 micrograms/ml or less and a clavulanic acid concentration of 2 micrograms/ml or less.