In-vitro antimicrobial activity of enoxacin in combination with eight other antibiotics against Pseudomonas aeruginosa, Enterobacteriaceae and Staphylococcus aureus

Susceptibilities of 28 strains of Pseudomonas aeruginosa, 32 strains of Enterobacteriaceae and 24 strains of Staphylococcus aureus were tested against combinations of enoxacin with either cefsulodin, piperacillin, or amikacin, enoxacin with either aztreonam, latamoxef or amikacin, and enoxacin with either oxacillin, clindamycin or vancomycin, respectively. Synergy was detected by the agar dilution technique and was defined as a four-fold decrease in the inhibitory concentration of both drugs (sigma FIC less than or equal to 0.5). Against Ps. aeruginosa, synergy occurred in 28.5% of the strains for enoxacin plus cefsulodin, 17.6% for enoxacin plus piperacillin, and 3.7% for enoxacin plus amikacin. Against the Enterobacteriaceae, synergy was detected with enoxacin plus aztreonam, latamoxef or amikacin in 9.3%, 3.1% and 0% of strains, respectively. Against Staph. aureus, no synergy was demonstrable with enoxacin plus oxacillin, clindamycin or vancomycin. No antagonism was detected for any combination tested. Selected strains demonstrating synergy by the agar dilution method for enoxacin plus cefsulodin or piperacillin failed to show synergy in kinetic studies.     

Activity of cefsulodin, other beta-lactams, and aminoglycosides against Pseudomonas aeruginosa

Cefsulodin was the most active of the cephalosporins and exhibited 4-16 times more activity than carbenicillin or ticarcillin against 50 clinical isolates of Pseudomonas aeruginosa. Azlocillin and piperacillin showed good activity, while tobramycin was the most effective aminoglycoside. The activity of cefsulodin was unaltered by increases in inocula, but resistance was induced easily. When combined with gentamicin, no synergistic or antagonistic activity was observed against multiply resistant isolates.     

In vitro activity of aztreonam in combination with newer beta-lactams and amikacin against multiply resistant gram-negative bacilli

The in vitro synergistic activity of aztreonam in combination with piperacillin, moxalactam, cefotaxime, cefoperazone, and amikacin was examined against multiply resistant isolates of the family Enterobacteriaceae and Pseudomonas aeruginosa. Aztreonam in combination with amikacin demonstrated synergy against 71% of the isolates, whereas combinations of aztreonam plus a second beta-lactam demonstrated synergy against 42% of the isolates.     

Comparative in vitro activities of enoxacin (CI-919, AT-2266) and eleven antipseudomonal agents against aminoglycoside-susceptible and -resistant Pseudomonas aeruginosa strains.

The in vitro activity of enoxacin (CI 919, AT 2266), a new oral quinolone carboxylic acid compound, was compared with those of gentamicin, tobramycin, amikacin, azlocillin, piperacillin, aztreonam, moxalactam, imipenem, cefsulodin, ceftazidime, and cefoperazone against 101 aminoglycoside-susceptible and 105 aminoglycoside-resistant Pseudomonas aeruginosa strains. Among these 206 P. aeruginosa isolates were 25 strains with known mechanisms of resistance to amikacin. The activity of enoxacin was similar to that of tobramycin against aminoglycoside-susceptible strains, with MICs of 1.0 to 2.0 micrograms/ml and 0.5 to 1.0 microgram/ml, respectively, for 90% of the strains. Enoxacin was the most active agent in this in vitro study against aminoglycoside-resistant P. aeruginosa strains, with MICs of 2.0 to 4.0 micrograms/ml for 90% of the strains. Strains with enzymatic resistance to amikacin were more resistant to beta-lactams (except enoxacin and imipenem) than were strains with decreased permeability.     

Comparative in vitro synergistic activity of new beta-lactam antimicrobial agents and amikacin against Pseudomonas aeruginosa and Serratia marcescens.

The in vitro synergistic activities of moxalactam, cefoperazone, or cefotaxime in combination with amikacin or piperacillin were compared against aminoglycoside-susceptible and aminoglycoside-resistant isolates of Pseudomonas aeruginosa and Serratia marcescens by the checkerboard agar dilution method. All antimicrobial combinations demonstrated some synergy, and no antagonism was observed. Moxalactam plus amikacin and piperacillin plus amikacin were most frequently synergistic (two-thirds of the isolates inhibited synergistically by each combination), whereas combinations of moxalactam, cefotaxime, or cefoperazone with piperacillin were synergistic against only 18 to 25% of the isolates. Moxalactam plus amikacin was the combination most often synergistic for amikacin-susceptible P. aeruginosa, and piperacillin plus amikacin was the combination most frequently synergistic for amikacin-resistant P. aeruginosa and amikacin-susceptible S. marcescens. These results demonstrate frequent in vitro synergistic activity between the new beta-lactam agents and amikacin (especially moxalactam or piperacillin with amikacin), but comparative clinical trials are needed to establish the relative efficacy and toxicity of these combinations.     

In-vitro susceptibility of Pseudomonas aeruginosa to old and new beta-lactam antibiotics and aminoglycosides

In-vitro, activities of gentamicin, tobramycin, netilmicin, amikacin, cefsulodin, latamoxef (moxalactam), carbenicillin, ticarcillin and piperacillin were compared against 147 randomly selected strains of Pseudomonas aeruginosa. Tobramycin was the most active aminoglycoside (MIC 90:4 mg/l), complete cross resistance with gentamicin (MIC 90:8 mg/l) was observed. Amikacin was the best alternative aminoglycoside (MIC 90:12 mg/l) Netilmicin showed only moderate activity (MIC 90:16 mg/l). Cefsulodin was the most active beta-lactam antibiotic (MIC 90:8 mg/l) but significant cross-resistance was observed with ticarcillin (MIC 90:32 mg/l) and piperacillin (MIC 90:12 micrograms/ml). Carbenicillin was two dilutions less active than ticarcillin, latamoxef showed a good activity (MIC 90:64 mg/l). Having the highest ratio between serum achievable concentration and MIC 90, piperacillin could be the best alternative drug to the aminoglycosides, of the tested antibiotics.     

In vitro comparison of Pseudomonas aeruginosa isolates with various susceptibilities to aminoglycosides and ten beta-lactam antibiotics.

Susceptibilities of 98 clinical isolates of Pseudomonas aeruginosa, including 33 strains with known mechanisms of amikacin resistance, were tested by the agar dilution method against 10 beta-lactam drugs. Ceftazidime, imipenem, and cefsulodin had the greatest activity, regardless of the aminoglycoside susceptibilities. The strains which were highly resistant to amikacin appeared to be less susceptible to some beta-lactam drugs, especially if their resistance was related to amikacin-inactivating enzymes; statistical significance, however, was observed for aztreonam only.     

In vitro synergistic activities of aminoglycosides and new beta-lactams against multiresistant Pseudomonas aeruginosa

The in vitro interactions between amikacin, netilmicin, tobramycin, gentamicin, and various antipseudomonal beta-lactams were studied by the agar dilution checkerboard technique against 30 Pseudomonas aeruginosa strains resistant to all tested antibiotics. Amikacin produced more frequent synergy both at the total and clinically applicable level. Among the beta-lactams, clinically relevant synergistic interactions were obtained in the following order: ceftazidime and ceftriaxone greater than moxalactam greater than aztreonam greater than cefotaxime greater than azlocillin greater than cefoperazone greater than cefsulodin greater than carbenicillin.     

The effect of rifampicin on the in-vitro activity of cefpirome or ceftazidime in combination with aminoglycosides against Pseudomonas aeruginosa

The in-vitro activity of cefpirome and ceftazidime when combined with aminoglycosides (gentamicin, amikacin, and tobramycin) in the presence and in the absence of rifampicin was evaluated against 32 isolates of Pseudomonas aeruginosa by two methods. Agar dilution susceptibilities demonstrated a marked reduction in synergy (FIC less than or equal to 0.5) when rifampicin was added to the combination. Synergy rates decreased from 59.4-84.4% without to 3.1-9.4% with the addition of rifampicin. In contrast, kill curve tests performed on two P. aeruginosa strains demonstrated synergy at 24 h when rifampicin was added to cefpirome, ceftazidime, gentamicin or a beta-lactam agent plus gentamicin combination. The addition of rifampicin to the combinations of cefpirome or ceftazidime plus gentamicin achieved a 2-log10 lower bacterial count at 24 h than that of the beta-lactam and gentamicin combination alone. When rifampicin was added to the combination cefpirome or ceftazidime plus gentamicin at different times during incubation, a greater bactericidal effect was observed when rifampicin was added at 0 and 1 h of incubation than when added later. No antagonism was observed with rifampicin when used in combination with beta-lactam agents and/or aminoglycosides.     

In vitro susceptibility of cephalothin-resistant Enterobacteriaceae and Pseudomonas aeruginosa to Amikacin and selected new beta-lactam agents.

Amikacin was evaluated in vitro by agar dilution testing against 148 different clinical isolates of cephalothin-resistant Enterobacteriaceae and Pseudomonas aeruginosa in parallel with cephalothin, cefoxitin, moxalactam, N-formimidoyl thienamycin, ceftriaxone, and cefmenoxime. Cefsulodin was also evaluated against 39 isolates of P. aeruginosa. More than 80% of all isolates tested were also gentamicin resistant, as determined by disk testing. Moxalactam and amikacin had comparable high activities against Proteus species, Escherichia coli, Serratia species, and Providencia species, and both amikacin and N-formimidoyl thienamycin had comparably high activities against the Klebsiella-Enterobacter group. N-Formimidoyl thienamycin was the most active agent against P. aeruginosa, followed by cefsulodin and amikacin.     

Unpredictable interactions between cefotetan and penicillins or aminoglycosides

The bacteriostatic and bactericidal activity of gentamicin, amikacin, piperacillin, azlocillin, ampicillin, benzyl penicillin, and oxacillin against 85 selected isolates was measured alone and in the presence of subinhibitory concentrations of cefotetan. A potential for antagonistic interactions between cefotetan and acylamino penicillins (piperacillin greater than azlocillin greater than ampicillin) were observed with some strains; synergy was suggested with other isolates, however, Bacteriostatic and bactericidal activity of the two aminoglycosides was enhanced by cefotetan with most gram-negative bacilli, but bactericidal activity was significantly diminished with 4 of 65 strains. Piperacillin and cefotetan were clearly antagonistic with 11 of 44 strains and synergistic with 4 of 44 strains of gram-negative bacilli: the remaining 21 strains gave off scale end points and could not be analyzed in that way.     

Activity of levofloxacin and ciprofloxacin in combination with cefepime, ceftazidime, imipenem, piperacillin-tazobactam and amikacin against different Pseudomonas aeruginosa phenotypes and Acinetobacter spp

BACKGROUND: Combination therapy is used to widen the antimicrobial spectrum, minimize toxicity and prevent the emergence of resistant mutants. METHODS: Synergy between levofloxacin or ciprofloxacin and ceftazidime, cefepime, imipenem, piperacillin-tazobactam and amikacin was evaluated by checkerboard assay with 55 strains and by time-kill curves with 8 strains of Pseudomonas aeruginosa and Acinetobacter spp. RESULTS: In the checkerboard assay, synergy and additivity were the most frequent effects observed among all the combinations against P. aeruginosa and Acinetobacter spp., with no significant differences between the two fluoroquinolones. No antagonism was observed. In the time-kill curves, synergy was evidenced against all the tested strains, at least for one combination at one of the time points considered. Levofloxacin and ciprofloxacin combined with ceftazidime, as well as levofloxacin plus amikacin, were synergistic for all the strains tested. CONCLUSION: Combinations of fluoroquinolones with beta-lactams or amikacin show an enhanced activity against P. aeruginosa and Acinetobacter spp.     

In vitro studies of investigational beta-lactams as possible therapy for Pseudomonas aeruginosa endocarditis.

The inadequacy of the present medical therapy of Pseudomonas aeruginosa endocarditis prompted an investigation of the in vitro activities of aztreonam, cefsulodin, and imipenem compared with that of ticarcillin against 37 strains of P. aeruginosa isolated from patients with endocarditis. Inhibitory and bactericidal activities were studied for each beta-lactam alone and in combination with tobramycin. All agents showed excellent inhibitory activity. Imipenem was the most inhibitory beta-lactam yet lacked inhibitory synergy against 95% of the strains and bactericidal synergy against 62%. Tolerance to imipenem was seen in six strains. Aztreonam alone was bactericidal against 46% of the strains (at 16 micrograms/ml) and showed bactericidal synergy in 70%. Cefsulodin alone was even less active but similar to aztreonam synergistically. Ticarcillin and tobramycin inhibited all strains as single agents and showed universal bactericidal synergy in combination. None of the new beta-lactams showed consistent superiority to the presently used agent, ticarcillin.     

Synergistic interactions of ciprofloxacin and extended spectrum beta-lactams or aminoglycosides against Acinetobacter calcoaceticus ss. anitratus

The susceptibility of 54 clinical isolates of Acinetobacter calcoaceticus ss. anitratus to 16 antimicrobial agents was determined in vitro with inoculum of 10(4) and 10(6) cfu by a standard agar dilution method. The most active agents were imipenem, SCH 34343, ciprofloxacin, difloxacin (A-56619), and A-56620. Only imipenem and Abbott quinolones (A-56619 and A-56620) remained active when tested with the heavier inoculum. Except for ticarcillin and ceftazidime, which showed only moderate activity, the extended-spectrum penicillins and cephalosporins, as well as aztreonam and aminoglycosides, were inactive against these highly resistant strains. Nine isolates were selected for combination studies of ciprofloxacin with seven beta-lactams and three aminoglycosides using a checkerboard agar dilution technique. Synergistic or additive interactions at clinically achievable concentrations were more common with amikacin (eight isolates), tobramycin (seven), ceftazidime (six), cefoperazone (six), and aztreonam (six), than with other agents, including mezlocillin (four), piperacillin (three), gentamicin (two), and cefsulodin (two). Antagonism was rare, only occurring with mezlocillin in a single strain. These data suggest that combinations of ciprofloxacin with these agents may be useful for some nosocomial multidrug resistant A. calcoaceticus ss. anitratus infections.     

Bacteriological studies with cefsulodin (CGP 7174/E), the first antipseudomonal cephalosporin.

The new cephalosporin, cefsulodin, has considerable antibacterial activity against Pseudomonas aeruginosa. When 217 strains of Ps. aeruginosa were tested against both azlocillin and cefsulodin, 26.3% were found to have the same minimal inhibitory concentration (MIC); the MIC for azlocillin was lower than that for cefsulodin in 16.6% of strains, but higher in 57.1%. 22 gentamicin-resistant strains were all susceptible to cefsulodin. Biophotometer investigations demonstrate less bactericidal effects for cefsulodin and azlocillin than for carbenicillin and ticarcillin using higher inocula than used in the agar of tube dilution test. Cefsulodin and gentamicin are synergistic against Ps. aeruginosa. Using high pressure liquid chromatography and biological techniques, cefsulodin is found to be moderately stable in solution and in standard solid laboratory media.     

Synergy studies with Pseudomonas aeruginosa resistant to gentamicin and/or carbenicillin.

The predictability of synergy with strains of Pseudomonas aeruginosa highly resistant to gentamicin in combination with carbenicillin has been controversial. 30 clinical isolates of P. aeruginosa resistant to gentamicin and/or carbenicillin were tested by checker-board technique. 14 were found to be highly resistant to gentamicin (minimal inhibitory concentration MIC greater than or equal to 128 microgram/ml) and/or carbenicillin (MIC greater than or equal to 512 microgram/ml). Of these 14, 4 isolates showed synergy. 10 of 16 isolates with moderate resistance demonstrated synergy. It is concluded that the level of resistance to gentamicin with P. aeruginosa cannot be used in predicting whether synergy will occur.     

Geographic variations in activity of broad-spectrum beta-lactams against Pseudomonas aeruginosa: summary of the worldwide SENTRY Antimicrobial Surveillance Program (1997-2000)

With reports of increasing resistance to antimicrobial agents among Pseudomonas aeruginosa clinical isolates worldwide, the activities of cefepime and eight other broad-spectrum beta-lactams against 6969 isolates collected during 1997-2000 from the four regions of the SENTRY Antimicrobial Surveillance Program. P. aeruginosa isolates were tested by the reference broth microdilution method against nine beta-lactam antimicrobial agents (aztreonam, cefepime, ceftazidime, imipenem, meropenem, piperacillin +/- tazobactam, ticarcillin +/- clavulanate), three aminoglycosides (amikacin, gentamicin, tobramycin), and two fluoroquinolones (ciprofloxacin, levofloxacin). The strains were contributed by more than 100 medical centers. National Committee for Clinical Laboratory Standards criteria were used to identify susceptible and resistant isolates. P. aeruginosa strains from Latin America were generally the most resistant to all classes of antimicrobials, compared with strains from other regions. The beta-lactams exhibited a wide range of potency, with carbapenems most active (meropenem, 80-91% susceptible; imipenem, 76-88% susceptible). Piperacillin/tazobactam was the most active penicillin (77-80% susceptible), and cefepime (67-83% susceptible) had an average 2% (range, 0.7-3.5%) greater susceptibility rate than ceftazidime (66-80% susceptible) across all regions. The rank order of beta-lactam activity according to percent resistant isolates in North American P. aeruginosa strains was: meropenem (4.8% resistant) > cefepime (6.8%) > imipenem (8.6%) > piperacillin/tazobactam (10.3%) > piperacillin (12.9%). Only 2.3% and 6.5% of isolates were resistant to amikacin or tobramycin, respectively, and nearly 16% of P. aeruginosa strains were resistant to ciprofloxacin. Compared with other geographic regions, strains of P. aeruginosa remain most susceptible in North America. In all regions, aminoglycosides in combination with carbapenems, cefepime, or piperacillin/tazobactam would provide more potential antipseudomonal activity than fluoroquinolone combinations for wide-spectrum empiric regimens.     

Cefsulodin: antibacterial activity and tentative interpretive zone standards for the disk susceptibility test.

Cefsulodin (SCE-129) is a cephalosporin with a spectrum of antibacterial activity largely limited to Pseudomonas aeruginosa and Staphylococcus aureus. Cefsulodin was compared with carbenicillin, ticarcillin, mezlocillin, and piperacillin against 779 nonenteric gram-negative bacilli and staphylococci collected from five geographically separate institutions. Against P. aeruginosa, cefsulodin was somewhat more active than piperacillin and much more active than other penicillins. In addition, cefsulodin was active against penicillinase-producing strains of S. aureus. Collaborative efforts in three laboratories led to the following tentative zone size breakpoints for 30-micrograms cefsulodin disks: susceptible greater than or equal to 18 mm (minimal inhibitory concentration) [MIC] less than or equal to 16 micrograms/ml) and resistant less than or equal to 14 mm (MIC greater than or equal to 64 micrograms/ml). These zone standards are still tentative since the dosage schedule has not yet been defined and sufficient clinical experience has not yet been gathered to support the validity of these MIC breakpoints.     

Cefepime,piperacillin/tazobactam,gentamicin, ciprofloxacin,and levofloxacin alone and in combination against Pseudomonas aeruginosa

A beta-lactam plus an aminoglycoside is the standard for treating severe Pseudomonas aeruginosa infections. However, the fluoroquinolones are safer and have been widely used as an alternative to the aminoglycosides in this setting. In this study we compared the synergistic activities of piperacillin/tazobactam and cefepime when either drug was combined with gentamicin, ciprofloxacin, or levofloxacin against P. aeruginosa. Susceptibility testing and time-kill curves were performed against 12 clinical isolates of P. aeruginosa. All combinations were bactericidal and retained this activity over the 24 hr period except for piperacillin/tazobactam in combination with levofloxacin or ciprofloxacin against 2 isolates and cefepime in combination with levofloxacin against 1 isolate. None of the combinations were antagonistic. No statistical difference in the frequency of synergy exists between the beta-lactam plus gentamicin (79%) and the beta-lactams plus either ciprofloxacin or levofloxacin combinations (58%, 67%). Furthermore, no differences in synergistic activity were noted between ciprofloxacin combinations (58%) and levofloxacin combinations (67%). In conclusion, the degree of synergy between a beta-lactam plus aminoglycoside and a beta-lactam plus fluoroquinolone seem to be comparable. Furthermore, there is a similar rate of synergy among different fluoroquinolone-based combinations. However, faster killing, less regrowth, and decrease in the development of resistance were seen with the beta-lactam plus aminoglycoside combination.     

In vitro synergy of ciprofloxacin and gatifloxacin against ciprofloxacin-resistant Pseudomonas aeruginosa

Multidrug-resistant Pseudomonas aeruginosa with combined decreased susceptibility to ceftazidime, ciprofloxacin, imipenem, and piperacillin is increasingly being found as a cause of nosocomial infections. It is important to look for combinations of drugs that might be synergistic. Ciprofloxacin resistance by P. aeruginosa is mediated in part by an efflux pump mechanism. Gatifloxacin, an 8-methoxyfluoroquinolone, inhibits a staphylococcal efflux pump. An earlier in vitro study using an Etest synergy method and time-kill assay suggested synergy of ciprofloxacin and gatifloxacin against P. aeruginosa. Synergy testing was performed by Etest and time-kill assay for 31 clinically unique, plasmid DNA distinct, U.S. P. aeruginosa isolates. Etest MICs for ciprofloxacin were 4 to >32 microg/ml, and for gatifloxacin they were >32 microg/ml. Ciprofloxacin plus gatifloxacin showed synergy by the Etest method for 6 (19%) of the 31 P. aeruginosa isolates using a summation fractional inhibitory concentration of < or = 0.5 for synergy. Synergy was demonstrated for 13/31 (42%) of isolates by time-kill assay. No antagonism was detected. The remaining isolates were indifferent to the combination. The Etest method and time-kill assay were 65% (20/31) concordant. The mechanism of the in vitro synergy may include P. aeruginosa ciprofloxacin efflux pump inhibition by gatifloxacin.