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PubMed1996

Efficacy of ampicillin-sulbactam is not dependent upon maintenance of a critical ratio between components: sulbactam pharmacokinetics in pharmacodynamic interactions.

An in vitro pharmacokinetic model (IVPM) and a mouse model of lethal bacteremia were used to compare the pharmacodynamics of ampicillin-sulbactam when the two components were dosed simultaneously and in sequence against TEM-1-producing Escherichia coli. The challenge isolates included three strains of E. coli producing various levels of beta-lactamase. Human pharmacokinetics of ampicillin-sulbactam (1.5- and 3.0-g intravenous doses) were simulated in each model, and pharmacodynamic interactions were evaluated over one 6-h dosing interval. Against all three strains, the sequential dosing of sulbactam prior to ampicillin did not alter the pharmacodynamics of these combinations from comparison with results obtained with the simultaneous administration of the two components. Similar pharmacodynamics were observed for the two dosing regimens regardless of the ampicillin-sulbactam dose used or whether the bacteria were treated in an immunocompetent mouse or in the absence of immune defenses in the IVPM. When antibacterial activity was lost and regrowth of the inoculum was observed, viable bacterial counts increased in both the simultaneous and sequential regimens at a point when sulbactam levels fell below a critical concentration. These data suggest that the efficacy of ampicillin-sulbactam is not dependent upon the maintenance of a constant 2:1 ratio for the two components. Rather, the efficacy of ampicillin-sulbactam appears to be dependent upon the maintenance of one or both components above a critical concentration. Furthermore, the pharmacokinetics of sulbactam, specifically, how long sulbactam levels remain above a minimum critical concentration, appears to dictate how long antibacterial activity is maintained with the combination.

Ampicillin↗

PubMed1991

In vitro inactivation of aminoglycosides by sulbactam, other beta-lactams, and sulbactam-beta-lactam combinations.

At clinically achievable levels (e.g., 25 micrograms/ml), sulbactam exerted no effect on aminoglycoside concentrations when incubated together in pooled serum at 37 degrees C for up to 24 h. Sulbactam alone and in combination with ampicillin or cefoperazone inactivated tobramycin, gentamicin, netilmicin, and amikacin in vitro when the sulbactam concentration was 200 to 225 micrograms/ml. At 75 micrograms/ml, sulbactam inactivated only tobramycin. Inactivation of tobramycin by high concentrations of sulbactam occurred even at -20 degrees C, but not at -70 degrees C, and was influenced by the serum matrix.

Amikacin↗

PubMed1997

Tazobactam-piperacillin compared with sulbactam-ampicillin, clavulanic acid-ticarcillin, sulbactam-cefoperazone, and piperacillin for activity against beta-lactamase-producing bacteria isolated from patients with complicated urinary tract infections.

The antibacterial activity of tazobactam-piperacillin was compared with that of sulbactam-ampicillin, clavulanic acid-ticarcillin, sulbactam-cefoperazone and piperacillin against beta-lactamase-producing bacteria isolated from patients with complicated urinary tract infections. Tazobactam-piperacillin showed a broad antibacterial spectrum against gram-negative and gram-positive bacteria. The minimum inhibitory concentrations (MIC90) of tazobactam-piperacillin were 6.25 micrograms/ml against Escherichia coli, 1.56 micrograms/ml against Proteus mirabilis, 3.13 micrograms/ml against Proteus vulgaris, 6.25 micrograms/ml against methicillin-susceptible Staphylococcus aureus, and 6.25 micrograms/ml coagulase-negative methicillin-susceptible staphylococci. Against all beta-lactamase-producing bacteria tested the antibacterial activity of tazobactam-piperacillin was at least 4- to 64-fold stronger than that of piperacillin, clavulanic acid-ticarcillin, and sulbactam-ampicillin, and similar to or greater than that of sulbactam-cefoperazone except for E. coli.

Ampicillin↗

PubMed1989

Inactivation of beta-lactamases by sulbactam and enhanced clinical activity due to target-site binding of the combination of sulbactam and ampicillin.

In addition to the beta-lactamase-inactivation activity of sulbactam, a stronger bactericidal activity has been confirmed with sulbactam/ampicillin than with either antibiotic alone. To clarify this latter mechanism, binding affinities of the combination drug were compared with those of ampicillin and sulbactam alone against the PBPs of E. coli, S. aureus, P. vulgaris and H. influenzae. Ampicillin showed the highest binding activity to the PBP fraction essential for septum formation such as PBP3 of E. coli, whereas sulbactam manifested the strongest affinity for the PBP fraction necessary for cell elongation such as PBP1a of E. coli. Sulbactam/ampicillin bound strongly to both PBP fractions. Light microscopy and scanning electronmicroscopy of these bacteria grown in the presence of the antibiotics revealed that more rapid formation of bulge or spheroplast forms of the cells are seen in the presence of small amounts of sulbactam/ampicillin compared to larger amounts of each drug alone. It is concluded that sulbactam/ampicillin, by synergistic inhibition of PBP fractions essential for bacterial cell division, can manifest a stronger bactericidal effect on Gram-positive and Gram-negative bacteria than each drug alone, not only in beta-lactamase-producing strains but also in ampicillin-sensitive strains.

Ampicillin↗

PubMed1990

In vitro activities of ampicillin-sulbactam and cefoperazone-sulbactam against oxacillin-susceptible and oxacillin-resistant staphylococci.

Ampicillin-sulbactam and cefoperazone-sulbactam were tested against staphylococci that were collected from 40 different medical centers throughout the United States. Oxacillin-resistant strains were resistant to both drug combinations, but oxacillin-susceptible strains were uniformly susceptible. The latter included strains with borderline susceptibility to oxacillin and methicillin.

Ampicillin↗

PubMed1991

[Physiological model of sulbactam pharmacokinetics in rats and humans. Distribution of sulbactam in the tissues after intravenous and intramuscular administration].

A 10-compartment physiological model of sulbactam pharmacokinetics is described. The model provides simulation of the pharmacokinetic profiles of the drug observed after its intra-muscular and intravenous administration in rats and humans. The adequate description of the drug distribution in human blood suggested that the model was applicable in designing rational schemes of sulbactam use.

Animals↗

PubMed1985

The cefoperazone-sulbactam combination. In vitro qualities including beta-lactamase stability, antimicrobial activity, and interpretive criteria for disk diffusion tests.

Three concentrations of the penicillanic acid sulfone, sulbactam were tested in combination with cefoperazone against 632 recent clinical bacterial isolates. Cefoperazone was effective alone (less than or equal to 16 micrograms/mL) against 95% of Enterobacteriaceae and combined with 4 micrograms/mL sulbactam inhibited 99.5% of strains. This coverage of enteric bacilli was superior to timentin (99.1%), ceftazidime (98.2%), and tobramycin (90.9%). The minimum inhibitory concentrations (MICs) of cefoperazone-susceptible strains also were markedly decreased by sulbactam (overall MIC90s, 8.0 micrograms/mL for cefoperazone and 1.0 microgram/mL for cefoperazone and 4.0 micrograms/mL for sulbactam). Sulbactam also expanded the spectrum of cefoperazone against Acinetobacter species, some rare Pseudomonas species, and Bacteroides fragilis group species. Sulbactam had direct antimicrobial activity against the acinetobacters and Pseudomonas acidovorans, but the increased activity of cefoperazone-sulbactam against some other Pseudomonas species and anaerobes was attributed to beta-lactamase inhibition. The cefoperazone MICs against beta-lactamase producing Staphylococcus species also were lowered to the level of enzyme-deficient strains. Cefoperazone bactericidal activity was improved by 4.0 micrograms/mL sulbactam, and no antagonism was observed. beta-lactamase hydrolysis studies confirmed a slow hydrolysis of cefoperazone only by TEM beta-lactamases and a high-grade resistance to enzyme breakdown by sulbactam. Differential beta-lactamase affinity studies for cefoperazone and sulbactam showed potential efficacy and applications to plasmid-mediated TEM and OXA enzymes and only marginal effective sulbactam inhibition of Pseudomonas and Klebsiella species enzymes. Disk diffusion studies on 556 strains confirmed the applicability of the cefoperazone 75-micrograms disk to testing routine isolates other than enterococci and methicillin-resistant Staphylococcus aureus. The addition of 4.0 micrograms sulbactam/mL in a fixed concentration to dilution test systems and 15 micrograms sulbactam to the 75 micrograms cefoperazone disk were recommended for in vitro tests. Susceptibility and resistant interpretive criteria for the disk and dilution tests can be applied with confidence. Only 0.4% false-susceptibility errors and a 97.5% absolute interpretive agreement were achieved using the 75 micrograms cefoperazone/15 micrograms sulbactam disk.

Anti-Bacterial Agents↗

PubMed1989

Single-dose pharmacokinetics of intravenous ampicillin plus sulbactam in healthy elderly and young adult subjects.

The pharmacokinetics of intravenous ampicillin and sulbactam, a beta-lactamase inhibitor, were evaluated in two different age groups. Twelve healthy elderly subjects (age 65-93 years) and 12 healthy young adult subjects (age 20-35 years) received both a dose of ampicillin 1 g plus sulbactam 0.5 g and a higher dose of ampicillin 2 g plus sulbactam 1 g after a one-week period between doses. A reverse-phase high-pressure liquid chromatography method was used for the quantitation of ampicillin and sulbactam in serum and urine. The pharmacokinetic parameters for both ampicillin and sulbactam were calculated by computer-based two-compartment nonlinear model. After a 30-min infusion, serum concentrations of both drugs declined in a biexponential manner for both doses. Elderly subjects demonstrated significantly lower total clearances (Clt) than young adult subjects of ampicillin 1 g (220.0 +/- 104.2 vs 360.0 +/- 95.8 ml/min/1.73 m2), ampicillin 2 g (72.6 +/- 36.6 vs 306.8 +/- 109.77 ml/min/1.73 m2), sulbactam 0.5 g (122.3 +/- 47.8 vs 263.9 +/- 93.7 ml/min/1.73 m2), and sulbactam 1 g (171.2 +/- 85.8 vs 391.7 +/- 70.8 ml/min/1.73 m2), respectively. Significance was defined as P less than 0.05. Renal clearance was also significantly reduced in the elderly subjects. Area under the curve was found to be significantly increased in the elderly subjects compared to the young subjects for both ampicillin and sulbactam as were the beta elimination half-lives. No significant difference in the apparent volume of distribution, when adjusted for body weight, was found for either sulbactam (P greater than 0.95) or ampicillin (P greater than 0.95) between the two groups. Linear regression analysis revealed that age was significantly correlated with the Clt of ampicillin 1 g (r = 0.85, P less than 0.001), ampicillin 2 g (r = 0.90, P less than 0.001), sulbactam 0.5 g (r = 0.80, P less than 0.001), and sulbactam 1 g (r = 0.93, P less than 0.001). A multivariate analysis showed a slight improvement in correlation when creatinine clearance was added to age and compared with Clt. Urinary recovery of both ampicillin and sulbactam was approximately 60% after 14 h.

Adult↗

PubMed1998

Comparison of concentrations of sulbactam-ampicillin administered by bolus injections or bolus plus continuous infusion in tissues of patients undergoing colorectal surgery.

The concentrations of sulbactam and ampicillin were determined in sera and different abdominal tissues of 16 patients who underwent elective colorectal surgery. Patients were randomly allocated to two groups. At the time of induction of anesthesia, patients in group 1 (eight patients) were given 1,000 mg of sulbactam with 2,000 mg of ampicillin by intravenous bolus injection (3 min). This dose was administered again after 2 h by bolus injection by the same route. Patients in group 2 (eight patients) were given the same initial dose of sulbactam-ampicillin by bolus injection (3 min). Then, a continuous infusion of 1,000 mg of sulbactam with 2,000 mg of ampicillin in normal saline was immediately started and was administered over a 4-h period. Blood samples were collected to determine peak (10 min) and trough (end of surgery) antibiotic levels. Serial blood samples were also collected at predetermined periods (at the time of opening and closing of the abdominal cavity and at the time of surgical anastomosis). Abdominal wall fat, epiploic fat, and colonic wall tissue samples were collected simultaneously. Antibiotic concentrations were determined by high-performance liquid chromatography. Similar levels of the drugs in serum were observed for the two regimens of administration, with trough sulbactam levels of 33 +/- 16 and 37 +/- 22 microg/ml in groups 1 and 2, respectively, and trough ampicillin levels of 72 +/- 55 and 79 +/- 47 microg/ml in groups 1 and 2, respectively. Similar sulbactam concentrations were observed in abdominal tissues whichever regimen of administration was used; in fatty tissues the sulbactam concentrations ranged from 2.7 to 3.8 microg/g for group 1 and from 1.7 to 4.0 microg/g for group 2, and sulbactam concentrations in the colonic wall were 5.6 +/- 7.7 and 6.8 +/- 3.2 microg/g in groups 1 and 2, respectively (not significant). Again, no influence of the regimen of administration was observed on tissue ampicillin concentrations; in fatty tissues ampicillin concentrations ranged from 4.1 to 5.4 microg/g for group 1 and from 3.2 to 5.8 microg/g for group 2, and sulbactam concentrations in the colonic wall were 7.0 +/- 2.8 and 11.0 +/- 4.7 microg/g for groups 1 and 2, respectively (not significant). In most patients, the concentrations of ampicillin-sulbactam were greater than the MIC at which 50% of isolates are inhibited (MIC50) for Bacteroides fragilis in the fatty tissues. In the colonic wall, for most patients the concentrations of ampicillin-sulbactam were greater than the MIC90 for B. fragilis. No influence of the regimen of administration was observed on the ratio of the two components in the tissues investigated and in sera. In conclusion, a second intraoperative bolus injection or a continuous infusion were equally effective in maintaining sulbactam-ampicillin concentrations in abdominal tissues. The first method of administration can be recommended since it is easier to handle.

Ampicillin↗

PubMed1988

Sulbactam: a beta-lactamase inhibitor.

The chemistry, pharmacology, microbiology, pharmacokinetics, clinical efficacy, and adverse effects of sulbactam are reviewed. Sulbactam is a competitive, irreversible beta-lactamase inhibitor. Its binding to penicillin-binding proteins imparts weak intrinsic antibacterial activity. Synergy of sulbactam with beta-lactam antibiotics is most marked in bacterial species in which beta lactamase is a major mechanism of resistance. Sulbactam sodium is available in combination with ampicillin sodium for injection in a 1:2 ratio of sulbactam to ampicillin. Sultamicillin, an oral prodrug that is hydrolyzed to equimolar amounts of ampicillin and sulbactam, is in clinical trials. Ampicillin and sulbactam have similar pharmacokinetic properties. Sulbactam-ampicillin appears to be most useful for the treatment of polymicrobial aerobic or anaerobic infections and uncomplicated gonorrhea. Persistence, relapse, and superinfections have been reported after sulbactam-ampicillin treatment of urinary-tract and respiratory-tract infections. The combination is not effective against pseudomonal infections. Sulbactam-ampicillin is generally well tolerated. By restoring or expanding the activity of older, well-established beta-lactam antibiotics, sulbactam offers a new approach to the management of bacterial infections; the minimal toxicity of sulbactam-ampicillin makes the combination appealing for the treatment of gram-negative nonpseudomonal and anaerobic infections.

Chemical Phenomena↗

PubMed1989

Pharmacokinetics of ampicillin (2.0 grams) and sulbactam (1.0 gram) coadministered to subjects with normal and abnormal renal function and with end-stage renal disease on hemodialysis.

The single-dose pharmacokinetics of intravenously administered ampicillin (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of creatinine clearance (CLCR). Six normal subjects (CLCR, greater than 60 ml/min), six patients with mild renal failure (CLCR, 31 to 60 ml/min), four patients with severe renal failure (CLCR, 7 to 30 ml/min), and four patients requiring maintenance hemodialysis (CLCR, less than 7 ml/min) were studied. The terminal half-lives for ampicillin and sulbactam more than doubled in patients with severe renal failure compared with subjects with normal renal function and mild renal insufficiency. CLCR significantly correlated with ampicillin (r = 0.88) and sulbactam (r = 0.54) total body clearance. Mean steady-state volume of distribution and nonrenal clearance for ampicillin and sulbactam were not affected by renal function. Hemodialysis approximately doubled the ampicillin and sulbactam total body clearance. Mean totals of 34.8 +/- 4.0% of the ampicillin dose and 44.7 +/- 3.2% of the sulbactam dose were removed during a 4-h hemodialysis treatment. A slight rebound in concentrations in serum after hemodialysis was observed for both drugs in all four subjects. In hemodialysis patients, the ampicillin half-life was 17.4 +/- 8.0 h and the sulbactam half-life was 13.4 +/- 7.4 h. The ampicillin and sulbactam half-lives were appreciably altered during the hemodialysis period (means of 2.2 and 2.3 h, respectively). The nearly parallel decrease in total body clearance, with volume of distribution and nonrenal clearance remaining relatively constant, suggests that the same ratio of ampicillin to sulbactam is appropriate regardless of renal function. An adjustment of the ampicillin (2.0 g) and sulbactam (1.0 g) dose to twice daily would be appropriate in patients with a CLCR between 7 and 30 ml/min. Doses should be given every 24 h for those undergoing maintenance hemodialysis. On hemodialysis days, doses should be given after hemodialysis.

Adult↗

PubMed1990

Activity of sulbactam in combination with ceftriaxone in vitro and in experimental endocarditis caused by Escherichia coli producing SHV-2-like beta-lactamase.

We studied the efficacy of sulbactam, a beta-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum beta-lactamase most similar to SHV-2, a new mechanism of resistance to broad-spectrum cephalosporins among members of the family Enterobacteriaceae. In vitro, ceftriaxone demonstrated an important inoculum effect (MICs were 2 and 256 micrograms/ml with 5 X 10(5) and 5 X 10(7) CFU of inoculum per ml, respectively). Sulbactam inhibited the beta-lactamase degradation of ceftriaxone and enhanced the killing by ceftriaxone with both inocula tested. In vivo, sulbactam (100 mg/kg every 8 h) or ceftriaxone (15 or 30 mg/kg every 24 h) alone were ineffective after a 4-day therapy. The addition of sulbactam to ceftriaxone (15 mg/kg) or to the ceftriaxone (15 mg/kg)-netilmicin (6 mg/kg every 24 h) combination produced a reduction of 2 log10 CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactam-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 log10 CFU/g of vegetation greater than that produced by single-drug therapy (P less than 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P less than 0.05), and was as effective as the ceftriaxone (15 mg/kg)-sulbactam-netilmicin combination. We concluded that (i) SHV-2 production was responsible for ceftriaxone failure in vivo, probably because of the high inoculum present in vegetations; (ii) sulbactam used in a regimen which provided levels in serum constantly above 4 micrograms/ml and a vegetation/serum peak ratio of approximately 1:3 enhanced the activity of a broad-spectrum cephalosporin in a severe experimental infection; and (iii) the highest dose of ceftriaxone in combination with sulbactam was as effective as the lowest dose of ceftriaxone plus sulbactam plus an aminoglycoside.

Animals↗

PubMed1994

Randomized comparison of ampicillin-sulbactam to cefoxitin and doxycycline or clindamycin and gentamicin in the treatment of pelvic inflammatory disease or endometritis.

OBJECTIVE: To evaluate the efficacy and safety of ampicillin-sulbactam (3 g every 6 hours) in patients with pelvic inflammatory disease or postpartum endometritis using a randomized, comparative, multicenter study of parallel design. METHODS: Eligible patients with pelvic inflammatory disease were randomized to receive either ampicillin-sulbactam or cefoxitin (2 g every 6 hours) plus doxycycline (100 mg every 12 hours). Those with endometritis were randomized to ampicillin-sulbactam or clindamycin (900 mg every 8 hours) plus gentamicin (1.5 mg/kg every 8 hours). In the ampicillin-sulbactam group, chlamydia-positive patients also received oral doxycycline. RESULTS: For pelvic inflammatory disease, the clinical response rates (cure or improvement) were 85.5% (47 of 55) and 89.6% (43 of 48) in the ampicillin-sulbactam and cefoxitin and doxycycline groups, respectively (chi 2 = 0.10, P = .76). For endometritis, the clinical response rates were 88.7% (141 of 159) and 90.8% (139 of 153) in the ampicillin-sulbactam and clindamycin and gentamicin groups, respectively (chi 2 = 0.15, P = .70). The percentages of patients with pelvic inflammatory disease who had adverse experiences were not significantly different in the cefoxitin and doxycycline group (47% [29 of 62]) than in those receiving ampicillin-sulbactam (33% [22 of 66]) (P = .12). These adverse effects were mostly mild or moderate. In the endometritis subjects, the incidence of adverse experiences in the ampicillin-sulbactam group (11% [20 of 179]) was comparable to that during treatment with clindamycin and gentamicin (12% [22 of 180]). These adverse experiences were also mostly mild to moderate. CONCLUSION: Ampicillin-sulbactam is as effective and well tolerated as combination regimens using cefoxitin plus doxycycline and clindamycin plus-gentamicin for the treatment of pelvic inflammatory disease or endometritis, respectively.

Adult↗

PubMed1996

Ampicillin-sulbactam is effective in prevention and therapy of experimental endocarditis caused by beta-lactamase-producing coagulase-negative staphylococci.

Optimal strategies for the prophylaxis and therapy of endocarditis caused by oxacillin-resistant, coagulase-negative staphylococci in patients with native or prosthetic valvular heart disease are not well defined. We compared the in vivo efficacies of ampicillin-sulbactam-based regimens with those of vancomycin-based oxacillin-resistant, beta-lactamase-producing coagulase-negative staphylococcal isolate (Staphylococcus haemolyticus SE220). Ampicillin-sulbactam (100 and 20 mg/kg of body weight, respectively, given intramuscularly in a two-dose regimen) was equivalent to vancomycin (30 mg/kg given intravenously in a two-dose regimen) in its prophylactic efficacy against the coagulase-negative staphylococcal strain (93 and 80%, respectively). The combination of ampicillin-sulbactam plus either rifampin or vancomycin did not enhance the prophylactic efficacy compared with that of ampicillin-sulbactam or vancomycin alone. In the therapy of established aortic valve endocarditis in rabbits caused by this same coagulase-negative staphylococcal strain, animals received 7-day ampicillin-sulbactam-based or vancomycin-based regimens with or without rifampin. All treatment regimens were effective at lowering intravegetation coagulase-negative staphylococcal densities and rendering vegetations culture negative compared with the coagulase-negative staphylococcal densities and vegetations of untreated controls, with ampicillin-sulbactam in combination with rifampin or vancomycin being the most active regimen. However, only the regimen of ampicillin-sulbactam in combination with vancomycin effectively prevented relapse of endocarditis posttherapy after a 5-day antibiotic-free period. For animals receiving rifampin-containing regimens, relapses of endocarditis were associated with the in vivo development of rifampin resistance among coagulase-negative staphylococcal isolates in the vegetation. Ampicillin-sulbactam was highly effective in the prevention of experimental endocarditis caused by a beta-lactamase-producing, oxacillin-resistant coagulase-negative staphylococcal strain. Ampicillin-sulbactam was also efficacious for the therapy of coagulase-negative staphylococcal endocarditis, especially when it was combined with vancomycin to prevent posttherapeutic relapses.

Ampicillin↗

PubMed1998

Pharmacodynamics of ampicillin-sulbactam in an in vitro infection model against Escherichia coli strains with various levels of resistance.

The activity of ampicillin-sulbactam against beta-lactamase-producing Escherichia coli has been questioned. Therefore, in this study, the killing activity of ampicillin-sulbactam was investigated in an in vitro infection model which simulates human pharmacokinetics. One ampicillin-sensitive strain (E. coli ATCC 25922, ampicillin-sulbactam MIC = 4/2 microg/ml) and three ampicillin-resistant TEM-1-producing strains with various levels of ampicillin-sulbactam resistance (EC11, MIC = 4/2 microg/ml; TIM2, MIC = 12/6 microg/ml; and GB85, MIC > 128/64 microg/ml) were studied. The E. coli strains were exposed to ampicillin-sulbactam at a starting inoculum of 6 to 7 log10 CFU/ml. Ampicillin-sulbactam was infused over 30 min to simulate doses of 3 and 1.5 g every 6 h for 24 h. The 3-g ampicillin-sulbactam dose was bactericidal against E. coli ATCC 25922, EC11, and TIM2. The 1.5-g dose displayed bactericidal activity against ATCC 25922 and EC11 similar to that of the higher dose but failed to kill TIM2 due to inadequate time above the MIC and increased MICs over 24 h. GB85 was highly resistant and grew similarly to controls. Despite an MIC at 10(7) CFU/ml indicating resistance (20/10 microg/ml), TIM2 was killed by the 3-g dose of ampicillin-sulbactam. Current MIC breakpoints may not adequately portray the activity of ampicillin-sulbactam, considering both the activity in in vitro infection models and clinical data.

Ampicillin↗

PubMed1987

The efficacy of sulbactam-ampicillin in the therapy of respiratory disease associated with ampicillin resistant Pasteurella species in housed calves.

Sulbactam-ampicillin is a combination of sulbactam, a beta-lactamase inhibitor, and ampicillin, a broad spectrum beta-lactam antibiotic. The efficacy of sulbactam-ampicillin was evaluated in the treatment of calf respiratory disease associated with ampicillin-sensitive and ampicillin-resistant strains of Pasteurella haemolytica and Pasteurella multocida. Treatment with sulbactam-ampicillin was compared with treatment with ampicillin alone in 123 Friesian calves, between three and five weeks old, exhibiting clinical signs of respiratory disease. Seven of the 59 calves treated with ampicillin died whereas only one death occurred in the 64 calves treated with sulbactam-ampicillin. In the calves which survived, treatment with sulbactam-ampicillin resulted in a significantly better clinical response, as measured by the reduction in severity of clinical signs. The results of bacteriological examinations indicated that there was a marked increase in the proportion of ampicillin-resistant isolates of P haemolytica subsequent to treatment with ampicillin, whereas the proportion of ampicillin-resistant isolates of P. haemolytica recovered from calves treated with sulbactam-ampicillin had declined. The superior efficacy of sulbactam-ampicillin observed in this study is explained by the inhibitory effect of sulbactam on beta-lactamases produced by resistant bacteria, thus rendering them susceptible to the ampicillin.

Ampicillin↗

PubMed1987

Efficacy of sulbactam-ampicillin in the treatment of neonatal calf diarrhoea.

Sulbactam-ampicillin is a combination of sulbactam, a beta-lactamase inhibitor, and ampicillin, a broad spectrum beta-lactam antibiotic. The efficacy of sulbactam-ampicillin was evaluated in the treatment of neonatal calf diarrhoea under conditions where a major proportion of the calves were excreting enterobacteria which were resistant to beta-lactam antibiotics. In a series of six studies with a common experimental design, three treatments (sulbactam-ampicillin, ampicillin alone and untreated control) were compared in over 300 Friesian and Ayrshire calves aged between three and 10 days and of known immunological status as determined by their zinc sulphate turbidity values. A mortality rate of 26.4 per cent in the negative control calves was reduced to 14.0 per cent with ampicillin alone and 9.5 per cent with sulbactam-ampicillin. The probability of diarrhoea subsequent to initiation of treatment was reduced from 0.50 in the negative control calves to 0.44 with ampicillin alone and 0.35 with sulbactam-ampicillin. The differences in mortality and diarrhoea observed between the calves treated with sulbactam-ampicillin and the calves in each of the other treatment groups were statistically significant. The superior efficacy of sulbactam-ampicillin is explained by the inhibitory effect of sulbactam on the beta-lactamases produced by resistant bacteria, thus rendering them susceptible to the ampicillin in the combination.

Ampicillin↗

PubMed1985

In vitro antimicrobial activity of cefoperazone-sulbactam combinations against 554 clinical isolates including a review and beta-lactamase studies.

Cefoperazone was tested against 554 clinical isolates alone and with sulbactam in three combinations. The addition of sulbactam in low concentrations (less than or equal to 4 micrograms/ml) improved the spectrum of cefoperazone principally against gram-negative bacilli such as Acinetobacter species, some Pseudomonas species, and beta-lactamase-positive Enterobacteriaceae. Nearly all of the spectrum increase was achieved at a sulbactam level of less than or equal to 2 micrograms/ml. Sulbactam was found to be an effective antimicrobial agent against Acinetobacter species (MIC50, 1.0 microgram/ml), Pseudomonas acidovorans (MIC50, 2.0 micrograms/ml), Neisseria gonorrhoeae (MIC50, less than or equal to 0.5 microgram/ml), and N. meningitidis (MIC50, less than or equal to 0.5 microgram/ml). Sulbactam had a higher affinity and binding constant for the plasmid-mediated beta-lactamases such as TEM-1 and TEM-2 compared to cefoperazone (greater than or equal to 10-fold difference). This finding was important as cefoperazone can be hydrolyzed at a moderate rate by the highly efficient TEM enzymes (less than 2% of clinical Escherichia coli isolates). Sulbactam increased the susceptibility (less than or equal to 16 micrograms/ml) of 220 isolates of Enterobacteriaceae to cefoperazone from 88.6 to 96.3% when 4.0 micrograms/ml of sulbactam was added. The cefoperazone antimicrobial activity was also increased against the nonenteric bacilli from a 69.5 to a 87.4% total inhibition. MICs among cefoperazone-susceptible gram-negative and gram-positive strains were routinely decreased 2- to 32-fold, as calculated from MIC90 results. Therefore, sulbactam should predictably increase the antimicrobial spectrum and clinical effectiveness of cefoperazone against nosocomial and other pathogens such as the plasmid-containing enteric bacilli, Bacteroides species and Acinetobacter species, and possibly provide the opportunity to reduce dosage schedules for infecting species already susceptible to cefoperazone alone.

Bacteria↗