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PubMed1986

Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate and sulbactam combined with extended-spectrum penicillins against ticarcillin-resistant Enterobacteriaceae and pseudomonads.

The in-vitro synergistic activity of YTR 830, a new beta-lactamase inhibitor, combined with four extended-spectrum penicillins (ticarcillin, piperacillin, mezlocillin and apalcillin) against ticarcillin-resistant clinical isolates of Gram-negative enteric bacilli was compared with that of clavulanate and sulbactam. Synergy testing was performed with fixed concentrations of beta-lactamase inhibitors (8 mg/l) combined with doubling dilutions of beta-lactams in microdilution trays. Synergy was defined as a four-fold or greater decrease of beta-lactam MIC in the combination compared with the beta-lactam alone. For 79 ticarcillin-resistant Enterobacteriaceae, ticarcillin-YTR 830 and ticarcillin-clavulanate were synergistic against 90% of strains; for ticarcillin-sulbactam, 70% showed synergy. The synergistic activity of all three inhibitors was similar against strains resistant only to ticarcillin; for strains resistant to all four extended-spectrum penicillins, the activity of ticarcillin with YTR 830 and clavulanate was similar (synergy against 79% of strains) and superior to ticarcillin-sulbactam (synergy against 39% of strains). YTR 830 was more active than clavulanate against Serratia, Citrobacter, Proteus and Providencia spp. Piperacillin, mezlocillin and apalcillin susceptible strains, with MICs of 8-16 mg/l, showed synergy with inhibitors against 37-87% of strains. Amongst pseudomonads, no synergy was demonstrated against Pseudomonas aeruginosa; ticarcillin produced synergy with the inhibitors against Ps. maltophilia, while piperacillin-YTR 830 and apalcillin-YTR 830 were synergistic against Ps. cepacia. YTR 830 appears to have comparable in-vitro activity to that of clavulanate, and further development of this compound is warranted.

Ampicillin↗
PubMed1986

In-vitro activity of cefoperazone-sulbactam against Bacteroides species.

The in-vitro activity of two combinations of sulbactam and cefoperazone against 187 strains of Bacteroides fragilis were evaluated; their activity was compared with that of the drugs alone, and correlated with the production of beta-lactamase by the bacterial strains. The results indicated that both combinations had a synergistic effect: the addition of 8 mg/l of sulbactam to the MIC of cefoperazone reduced the percentage of resistant strains from 58% to 0.5%; while the combination of two parts of cefoperazone to one pact of sulbactam lowered the resistance rate to 1%. Synergy was observed most frequently with beta-lactamase positive strains, but it also occurred among beta-lactamase negative strains.

Bacteria, Anaerobic↗
PubMed1988

The effects of clavulanic acid and sulbactam on beta-lactamase biosynthesis.

Clavulanic acid and sulbactam were tested as inducers of beta-lactamase in 21 strains of Gram-negative bacteria. beta-Lactamase synthesis was inducible in all these strains, as demonstrated by the increased enzyme activities obtained when cells were grown in the presence of 10 mg/l of cefoxitin, the increase varying from 11- to 734-fold However, at the same concentration, neither inhibitor induced significant amounts of beta-lactamase, except in one strain of Providencia rettgeri, where both were potent inducers. When steps were taken to overcome the inhibitory effects of clavulanic acid and sulbactam, they were still found to be ineffective inducers. We conclude that, at therapeutic concentrations, clavulanic acid and sulbactam are generally poor inducers of beta-lactamase. Amoxycillin and ampicillin induced more beta-lactamase than the inhibitors, but were much less effective than cefoxitin, except for the strain of Prov. rettgeri.

Clavulanic Acids↗
PubMed1990

In-vitro and in-vivo activities of sulbactam and YTR830H against Acinetobacter calcoaceticus.

The antibacterial activities of sulbactam and YTR830H, both beta-lactamase inhibitors, were studied against Acinetobacter calcoaceticus, in vitro and in vivo. In-vitro susceptibility tests showed both to be very active against 80 clinical isolates of A. calcoaceticus. Against an intraperitioneal infection in mice, caused by A. calcoaceticus Ac54, the 50% effective doses of sulbactam and YTR830H were 1.62 and 16.7 mg/kg, respectively. Against A. calcoaceticus S31, a strain resistant to gentamicin, sulbactam and YTR830H were active both in vitro and in vivo.

Acinetobacter↗
PubMed1992

Effect of clavulanic acid, sulbactam and tazobactam on three different beta-lactamases from Bacteroides uniformis, Clostridium butyricum and Fusobacterium nucleatum.

The effect of three beta-lactamase inhibitors, clavulanic acid, sulbactam and tazobactam used in clinical practice were compared for their activity against purified beta-lactamases from Bacteroides uniformis, Clostridium butyricum and Fusobacterium nucleatum. The enzymes from B. uniformis and C. butyricum were produced in fermenters under controlled growth conditions and the enzyme from F. nucleatum was produced in batch cultures. Purification of the beta-lactamases was achieved by anion-exchange chromatography, gel filtration and FPLC-technique. The degree of inactivation of beta-lactamase activity was determined spectrophotometrically with nitrocefin as the substrate. The inhibitors in various concentrations were preincubated at 30 degrees C together with the enzyme for different time periods (0.5-120 min) before determination of the remaining beta-lactamase activity. The inhibitors all decreased the activity of the beta-lactamases investigated. Clavulanic acid and sulbactam were capable of reducing the enzyme activity of the B. uniformis beta-lactamase more effectively than the C. butyricum and F. nucleatum beta-lactamases. All beta-lactamases tested were more susceptible to tazobactam than to clavulanic acid and sulbactam.

Bacteroides↗
PubMed1993

Efficacy of cefoperazone in combination with sulbactam in experimental Staphylococcus aureus endocarditis in rabbits.

The activity of cefoperazone with and without sulbactam was studied in vitro and in vivo against strains of methicillin-resistant and methicillin-susceptible Staphylococcus aureus. Cefoperazone with or without sulbactam was inactive in vitro against the methicillin-resistant strain and was bound by penicillin-binding protein 2a with an IC50 of 190 mg/L (the concentration that reduced radio-labelling with 3H-penicillin by 50%). Cefoperazone was hydrolysed by beta-lactamase in vitro but sulbactam improved cefoperazone activity in a rabbit model of aortic valve endocarditis caused by a beta-lactamase producing methicillin-susceptible strain.

Animals↗
PubMed1994

Comparison of cefoxitin, cefotetan and the combination of ampicillin with sulbactam in the therapy of polymicrobial infection in mice.

The comparative efficacies of cefoxitin, cefotetan and the combination of ampicillin with sulbactam were investigated in mixed aerobic and anaerobic infections of mice. Treatment was administered by intramuscular injection for 10 days and was started 1 h before infection. After intraperitoneal infection with Escherichia coli, Bacteroides fragilis, and one other member of the B. fragilis group (either Bacteroides thetaiotaomicron, Bacteroides ovatus or Bacteroides distasonis), 41 of 90 (46%) control mice died and all survivors developed polymicrobial abscesses. Cephalosporin therapy reduced mortaligy 13% with cefoxitin, 3% with cefotetan, and 23% with ampicillin plus sulbactam; 14%, 10% and 14% of surviving animals, respectively developed abscesses. Each of the treatment regimens significantly reduced the number of all organisms in abscesses, independent of their activity in vitro. However, the reduction in the number of E. coli by ampicillin plus sulbactam was less marked (P < 0.001) than that achieved by cefoxitin (P < 0.05) or cefotetan. These data show that in vivo efficiencies of cefoxitin and cefotetan, are independent of their in vitro potencies in the early management of polymicrobial infections in mice.

Ampicillin↗
PubMed2004

Synergic in-vitro activity of imipenem and sulbactam against Acinetobacter baumannii.

The interaction between sulbactam and imipenem was evaluated with four clinical isolates of Acinetobacter baumannii, including two isolates resistant to imipenem, one of which produced IMP-1 metallo-beta-lactamase. Two isolates (one of which was imipenem-resistant) were sulbactam-resistant by undefined mechanisms. MICs were determined by standard broth microdilution methods. Time-kill assays with imipenem and sulbactam, alone or in combination at 0.5 x MIC and 1 x MIC, showed a synergic effect in all four isolates of A. baumannii after incubation for 0, 4, 8 and > 24 h at 35 degrees C.

Acinetobacter baumannii↗
PubMed1982

Effects of azlocillin in combination with clavulanic acid, sulbactam, and N-formimidoyl thienamycin against beta-lactamase-producing, carbenicillin-resistant Pseudomonas aeruginosa.

We investigated the effects of the combination of azlocillin with the beta-lactamase inhibitors clavulanic acid and sulbactam and with N-formimidoyl thienamycin against strains of Pseudomonas aeruginosa with R-factor-mediated carbenicillin resistance. The 10 strains tested (1 R-, 9 R+) were isogenic, except for the presence of individual plasmids determining each of nine plasmid-mediated beta-lactamases found in P. aeruginosa. We utilized a checkerboard technique for testing antibiotic combinations. Low concentrations of clavulanic acid produced synergy with azlocillin against the strains producing the TEM-1, TEM-2, PSE-1, PSE-3, and PSE-4 beta-lactamases; for the strains producing the OXA-1, OXA-2, OXA-3, and PSE-2 beta-lactamases, such synergy was not found. With sulbactam, synergy was demonstrated in all strains except that producing PSE-2 beta-lactamase; for several strains, however, the concentration of sulbactam required to produce synergy was substantially higher than that for clavulanic acid. N-Formimidoyl thienamycin was highly active as a single agent against all of the strains, regardless of beta-lactamase production. The combination of N-formimidoyl thienamycin and azlocillin produced synergy against only two of the strains tested.

Azlocillin↗
PubMed1982

Activity of cefoperazone and two beta-lactamase inhibitors, sulbactam and clavulanic acid, against Bacteroides spp. correlated with beta-lactamase production.

A total of 102 isolates of Bacteroides spp. were studied for beta-lactamase production and susceptibility to cefoperazone alone or in combination with either of the beta-lactamase inhibitors sulbactam and clavulanic acid. The geometric mean minimal inhibitory concentration of cefoperazone alone was 31.5 micrograms/ml and when combined with 10 micrograms of sulbactam per ml or 2 micrograms of clavulanic acid per ml was reduced to 5.4 and 9.2 micrograms/ml, respectively. When bacterial suspensions were tested for beta-lactamase production with nitrocefin, 91 (89.2%) of these isolates produced the enzyme. The geometric mean minimal inhibitory concentrations of cefoperazone rose only slightly for isolates with low or intermediate enzyme activity but rose significantly for those with high activity. The addition of EDTA to cefoperazone significantly more frequently enhanced the activity of cefoperazone against beta-lactamase-negative as opposed to beta-lactamase-positive isolates. Furthermore, EDTA resulted in synergistic activity of the cefoperazone-sulbactam combination on beta-lactamase-positive isolates for which the combination had previously not shown a synergistic effect. This study demonstrates the relationship between beta-lactamase production and the resistance of Bacteroides spp. to cefoperazone and shows that inhibition of these enzymes can reverse this resistance.

Anti-Bacterial Agents↗
PubMed1983

Pharmacokinetics of sulbactam in humans.

Sulbactam, a new beta-lactamase inhibitor, has pharmacokinetic characteristics in humans similar to those of ampicillin and amoxicillin. Its half-life in humans is approximately 1 h. In a two-compartment pharmacokinetic model, the apparent volume of distribution for the central compartment is approximately 12 liters, and half of the dose is found in the central compartment in the postdistributive phase. Approximately 75% of a parenteral dose is excreted unchanged in urine. The coadministration of sulbactam with ampicillin, penicillin G, or cefoperazone has essentially no effect upon the kinetics of either the beta-lactam antibiotic or sulbactam.

Adult↗
PubMed1985

In vitro efficacy of sulbactam combined with ampicillin against anaerobic bacteria.

An ampicillin-sulbactam combination was compared with ampicillin alone, chloramphenicol, clindamycin, and metronidazole against 272 strains of anaerobic bacteria. Chloramphenicol and ampicillin-sulbactam were the most effective, inhibiting 98 to 99% of strains tested at breakpoint (16 micrograms/ml). The combination of sulbactam and ampicillin was much more effective than ampicillin alone against Bacteroides fragilis strains but did not differ substantially from ampicillin alone against Fusobacterium spp., gram-positive rods, and gram-positive cocci.

Ampicillin↗
PubMed1986

Comparative activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam combined with ampicillin and broad-spectrum penicillins against defined beta-lactamase-producing aerobic gram-negative bacilli.

The in vitro synergistic activities of the beta-lactamase inhibitors YTR 830, clavulanate, and sulbactam, combined with ampicillin, ticarcillin, mezlocillin, azlocillin, piperacillin, and apalcillin, were determined against 34 strains of members of the Enterobacteriaceae family, Pseudomonas aeruginosa, Aeromonas hydrophila, and Haemophilus influenzae with characterized plasmid or chromosomal beta-lactamases or both. Strains were tested against fixed concentrations of beta-lactamase inhibitors (8 micrograms/ml) combined with doubling dilutions of beta-lactams. Synergy was defined as a fourfold or greater decrease in the MIC of the beta-lactam. Against Enterobacteriaceae producing Richmond and Sykes class III and V plasmid-mediated beta-lactamases, synergy was obtained against most strains with YTR 830- and clavulanate-beta-lactam combinations, with sulbactam being less effective. Against Enterobacteriaceae producing class I chromosomal beta-lactamases, combinations containing YTR 830 or sulbactam were more synergistic than combinations containing clavulanate. Against strains producing class V PSE enzymes, all three inhibitors were synergistic with piperacillin and apalcillin against strains producing PSE-1, -3, and -4 enzymes, while the PSE-2-producing strain was resistant to all inhibitors. YTR 830-beta-lactam combinations were also synergistic against strains producing the novel beta-lactamases OHIO-1, TLE-1, AER-1, and ROB-1. Overall, YTR 830 with piperacillin or apalcillin was the most effective combination.

Ampicillin↗
PubMed1987

Penetration of sulbactam and ampicillin into cerebrospinal fluid of infants and young children with meningitis.

Infusions of 50 mg of sulbactam per kg per day and 400 mg of ampicillin per kg per day in divided doses to infants and children with bacterial meningitis produced levels in cerebrospinal fluid approximately one-third those in serum. Concentrations in cerebrospinal fluid of 5.5 micrograms of sulbactam per ml and 16.0 micrograms of ampicillin per ml declined within a few days of therapy to 1.9 microgram of sulbactam per ml and 5.2 micrograms of ampicillin per ml.

Adolescent↗
PubMed1987

Activity of cefazolin and two beta-lactamase inhibitors, clavulanic acid and sulbactam, against Bacteroides fragilis.

One hundred clinical isolates of the Bacteroides fragilis group of bacteria were tested by agar dilution for susceptibility to cefazolin alone or in combination with clavulanic acid or sulbactam. For cefazolin, the MIC for 50% of the isolates (MIC50) was 32 micrograms/ml, the breakpoint for susceptibility. With the addition of 0.5 micrograms of clavulanic acid per ml, the MIC for 90% of the isolates (MIC90) was 8 micrograms/ml, well within the achievable range of concentrations in serum or tissue. Similarly, with the addition of 0.5 micrograms of sulbactam per ml, the MIC90 was 16 micrograms/ml. The addition of a higher concentration (4.0 micrograms/ml) of clavulanic acid or sulbactam resulted in MIC90S which were fourfold lower than those with 0.5 micrograms/ml. A fixed ratio of cefazolin-beta-lactamase inhibitor of 4:1 resulted in an MIC50 and MIC90 which were intermediate between the 0.5- and 4.0-micrograms/ml fixed concentration of beta-lactamase inhibitor.

Bacteroides fragilis↗
PubMed1988

Comparative efficacies of amoxicillin-clavulanic acid and ampicillin-sulbactam against experimental Bacteroides fragilis-Escherichia coli mixed infections.

Amoxicillin-clavulanic acid was compared with ampicillin-sulbactam in preventing the development of mixed infections produced in mice by subcutaneous inoculation of amoxicillin-resistant strains of Bacteroides fragilis and Escherichia coli. At doses designed to produce concentrations in mouse plasma similar to those obtained in humans, both amoxicillin-clavulanic acid and ampicillin-sulbactam were effective in preventing an infection caused by B. fragilis VPI 8908 mixed with E. coli E96, both strains being susceptible in vitro to each combination. However, ampicillin-sulbactam failed to arrest the progression of infections involving a more potent beta-lactamase-producing strain, E. coli 41548, even when a comparatively low inoculum was tested. In contrast, amoxicillin-clavulanic acid therapy effectively reduced the bacterial numbers at the site of infection. These data illustrate the need to treat polymicrobial infections with agents effective against the responsible aerobic as well as anaerobic bacteria.

Amoxicillin↗
PubMed1988

In vitro activity of cefoperazone plus sulbactam compared with that of other antimicrobial agents against anaerobic bacteria.

The activity of two cefoperazone-sulbactam combinations against anaerobic bacteria was tested and compared both with that of cefoperazone alone and with that of other commonly used antimicrobial agents. Imipenem was the most active of the tested agents, followed by chloramphenicol, metronidazole, and cefoperazone-sulbactam (90 to 100% of bacterial growth inhibited). Clindamycin and cefoxitin inhibited approximately 80%, cefoperazone inhibited 63%, and penicillin G inhibited 47% of the strains tested. The agents were variable in activity against the Bacteroides fragilis group, with percents susceptible as follows: cefoperazone-sulbactam, imipenem, metronidazole, and chloramphenicol, 99 to 100%; cefoxitin and clindamycin, approximately 80%; cefoperazone, 49%; and penicillin G, 15.5%.

Anti-Bacterial Agents↗
PubMed1988

Pharmacokinetics of cefoperazone (2.0 g) and sulbactam (1.0 g) coadministered to subjects with normal renal function, patients with decreased renal function, and patients with end-stage renal disease on hemodialysis.

The single-dose pharmacokinetics of intravenously administered cefoperazone (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of renal failure. In an open, parallel experimental design, six normal subjects (creatinine clearance, greater than 90 ml/min), two patients with mild renal failure (creatinine clearance, 31 to 60 ml/min), eight patients with moderate renal failure (creatinine clearance, 7 to 30 ml/min), and four functionally anephric patients (creatinine clearance, less than 7 ml/min) were studied. The functionally anephric patients were given two test doses to allow study of drug disposition both on and off hemodialysis. Serial blood and urine samples were collected from time zero to 12 h after dosing in normal subjects and from 0 to 72 h in renal patients. Serum concentrations of both drugs declined biexponentially. For cefoperazone, the terminal elimination half-lives averaged from 1.6 to 3.0 h and were similar in subjects and patients. No cefoperazone pharmacokinetic parameters were appreciably altered by renal failure or hemodialysis, and there was no correlation between the total body clearance of cefoperazone and estimated creatinine clearance. In contrast, the sulbactam total body clearance was highly correlated with estimated creatinine clearance (r = 0.92, P less than 0.01) and was significantly higher in normal volunteers than in the renally impaired groups (P less than 0.01). The sulbactam terminal elimination half-life in functionally anephric patients (9.7 +/- 5.3 h) differed significantly from that of normal volunteers (1.0 +/- 0.2 h) and patients with mild renal failure (1.7 +/- 0.7 h, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗