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Penetration of sulbactam and ampicillin into peritoneal fluid.

Twenty-five patients undergoing elective intraabdominal surgery received either 1 or 2 g of ampicillin together with 1 g of sulbactam intravenously before surgery. The peritoneal levels of the agent were measured. Both compounds penetrated peritoneal fluid readily; the mean percentage of penetration by ampicillin was 92%; that of sulbactam was 96%. After 1 g of each agent, the peritoneal levels of sulbactam were 47% greater than those of ampicillin. Our results suggest that 2 g of ampicillin plus 1 g of sulbactam should provide peritoneal levels that would inhibit most susceptible beta-lactamase-producing pathogens encountered in intraabdominal sepsis.

Aged↗

Susceptibility of Haemophilus influenzae type b to ampicillin-sulbactam.

Seventy-five strains of Haemophilus influenzae type b, including 45 beta-lactamase-positive strains, were tested by MIC and time kill studies for susceptibility to ampicillin-sulbactam at various ratios. beta-Lactamase-negative strains were inhibited by lower concentrations of ampicillin-sulbactam than beta-lactamase-positive organisms. beta-Lactamase-negative strains showed a decrease in CFU per milliliter by a factor of 10(4) after a 24-h incubation with ampicillin-sulbactam. beta-Lactamase-positive isolates showed an initial decrease by a factor of up to 10(2) CFU per milliliter, but by the end of incubation these isolates grew to approximately the same cell density as the antibiotic-free control regardless of ampicillin-sulbactam ratios. Caution should be exercised in the use of this combination in treatment of meningitis, in which a high bacterial density is commonly encountered.

Ampicillin↗

Use of a predictor panel for development of a new disk for diffusion tests with cefoperazone-sulbactam.

The proper disk mass for diffusion susceptibility tests with cefoperazone-sulbactam was determined by using a predictor panel of clinical isolates that included staphylococci and gram-negative bacteria intrinsically susceptible, intrinsically resistant, and of various susceptibilities because of the production of different types and amounts of beta-lactamase. A primary panel of 24 isolates was used to screen various disk masses of cefoperazone and sulbactam in disk diffusion susceptibility tests. Regression analyses were performed for each combination by comparing MICs to zone diameters. Analysis of each component demonstrated that decreasing the disk mass of cefoperazone shifted the regression line to the left while decreasing the disk mass of sulbactam diminished the slope of the line. Ten candidate disks that adequately separated susceptible and resistant strains among the primary panel were identified, and these 10 disks, along with the previously proposed 75/30-micrograms disk, were then tested against an expanded panel of 265 isolates. Results indicated that a 30/20-micrograms cefoperazone-sulbactam disk provided the best separation between susceptible and resistant strains when interpretive criteria of less than or equal to 15 mm for resistance, 16 to 19 mm for moderate susceptibility, and greater than or equal to 20 mm for susceptibility were used. They also identified discrepancies between agar and broth microdilution MICs of sufficient size to warrant separate interpretive criteria for the two methods. Overall, the use of a predictor panel to develop interpretive criteria for susceptibility tests appeared to be a very useful approach, especially when antibiotics designed to be used against drug-resistant organisms are involved.

Bacteria↗

Efficacy of ampicillin-sulbactam versus that of cefoxitin for treatment of Escherichia coli infections in a rat intra-abdominal abscess model.

We examined the efficacy of ampicillin-sulbactam (2:1) and cefoxitin in the treatment of infections caused by Escherichia coli strains exhibiting increasing levels of beta-lactamase-mediated resistance to ampicillin-sulbactam in the rat intra-abdominal abscess model. Cefoxitin was superior to ampicillin-sulbactam in the treatment of infections caused by all strains. Treatment with ampicillin-sulbactam resulted in a statistically significant decrease in CFU per gram of abscess in comparison with treatment with ampicillin alone for both the moderately resistant and the resistant strains, with an inverse correlation between the MIC and the absolute decrease in CFU per gram of abscess.

Abdomen↗

Therapy with cefoperazone plus sulbactam against disseminated infection due to cefoperazone-resistant Pseudomonas aeruginosa and Escherichia coli in granulocytopenic mice.

Using a granulocytopenic murine model, we evaluated the efficacy of cefoperazone plus sulbactam against disseminated infection due to isolates of beta-lactamase-producing, cefoperazone-resistant (MIC, > or = 50 micrograms/ml) Escherichia coli and Pseudomonas aeruginosa. Both isolates were susceptible in vitro to cefoperazone plus sulbactam (MIC, < or = 6.3 micrograms/ml). Mice rendered granulocytopenic with cyclophosphamide were divided into three groups: group A--infected, untreated mice (controls); group B--infected, cefoperazone-treated mice (700 mg/kg of body weight); and group C--infected, cefoperazone-plus-sulbactam-treated mice (700 mg plus 350 mg). In the E. coli experiment, survival rates in groups A, B, and C were 25, 46, and 73%, respectively. In the experiment with P. aeruginosa, survival rates in groups A, B, and C were 0, 10, and 50%, respectively (P < 0.001). Highly significant differences also were noted for colony counts in the blood, liver, and spleen of group C mice versus group A or B mice in both experiments. Thus, cefoperazone plus sulbactam appears to be a promising combination for the treatment of infections due to certain cefoperazone-resistant gram-negative bacilli, including P. aeruginosa.

Agranulocytosis↗

Bactericidal action of ofloxacin, sulbactam-ampicillin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis.

The bactericidal actions of ofloxacin and sulbactam-ampicillin, alone and in combination with rifampin and isoniazid, on exponential-phase and stationary-phase cultures of a drug-susceptible isolate of Mycobacterium tuberculosis were studied in vitro. In exponential-phase cultures, all drugs were bactericidal, with the higher concentrations of ofloxacin (5 micrograms/ml) and sulbactam-ampicillin (15 micrograms of ampicillin per ml) being as bactericidal as 1 microgram of isoniazid per ml or 1 microgram of rifampin per ml. In two-drug combinations, both drugs increased the levels of activity of isoniazid and rifampin and were almost as bactericidal as isoniazid-rifampin; they also appeared to increase the level of activity of isoniazid-rifampin in three-drug combinations. In contrast, ofloxacin and sulbactam-ampicillin had little bactericidal activity against stationary-phase cultures and were less active than isoniazid or rifampin alone. Furthermore, in two-drug or three-drug combinations, they did not increase the level of activity of isoniazid, rifampin, or isoniazid-rifampin. These findings suggest that ofloxacin and sulbactam-ampicillin are likely to be most useful in the early stages of treatment and in preventing the emergence of resistance to other drugs but are unlikely to be effective as sterilizing drugs helping to kill persisting lesional bacilli.

Ampicillin↗

In vitro antimicrobial spectrum, occurrence of synergy, and recommendations for dilution susceptibility testing concentrations of the cefoperazone-sulbactam combination.

Broth microdilution tests and an antimicrobial interaction (synergy) studies using various combinations of cefoperazone and sulbactam were performed in an effort to determine the most appropriate in vitro dilution test system. The test results with cefoperazone and sulbactam were categorized as synergistic (complete or partial) for nearly 80% of the strains isolated from clinical trial patients. The results indicate that the cefoperazone-sulbactam fixed ratio (2:1) maximized the cefoperazone spectrum of activity and best approximated the parenteral formulation of the drug. The cefoperazone-sulbactam combination had a greater antimicrobial activity than did the other comparison beta-lactams, except for imipenem, tested against strains of the family Enterobacteriaceae. To be consistent with the National Committee for Clinical Laboratory Standards interpretive breakpoints for cefoperazone alone, the following MIC breakpoints should be applied to the combination (2:1 ratio): less than or equal to 16/8 micrograms/ml, susceptible; 32/16 micrograms/ml, moderately susceptible; and greater than or equal to 64/32 micrograms/ml, resistant.

Bacteria↗

Criteria for disk susceptibility tests and quality control guidelines for the cefoperazone-sulbactam combination.

For in vitro susceptibility tests with cefoperazone and sulbactam (a beta-lactamase inhibitor), 75/30-micrograms disks may be used with the interpretive zone size breakpoints that are currently used for 75-micrograms cefoperazone disks. For dilution tests, a 2:1 ratio of cefoperazone to sulbactam is recommended. For quality control purposes, MIC limits that are used to monitor cefoperazone tests were also applied to tests with the combination of drugs. For gram-negative control strains, zone size limits were calculated to be 1 mm smaller than those used for cefoperazone disks. To monitor the sulbactam portion of the combination, Acinetobacter calcoaceticus subsp. anitratus ATCC 43498 was selected; zones with 75/30-micrograms disks were 26 to 32 mm in diameter, and broth microdilution MICs ranged from 1.0/0.5 to 8.0/4.0 micrograms/ml. With cefoperazone alone, MICs for Acinetobacter calcoaceticus subsp. anitratus were 16 to 64 micrograms/ml and zones ranged from 14 to 18 mm in diameter. For anaerobic dilution tests, only Bacteroides thetaiotaomicron ATCC 29741 is recommended for cefoperazone-sulbactam; MICs ranged from 8.0/4.0 to 32/16 micrograms/ml.

Bacteria, Anaerobic↗

Efficacy and cost of ampicillin-sulbactam and ticarcillin-clavulanate in the treatment of hospitalized patients with bacterial infections.

STUDY OBJECTIVE: To evaluate the efficacy and cost of treatment with two beta-lactam/beta-lactamase-inhibitor combinations. DESIGN: Retrospective, open-label multicenter study. SETTING: Fifty-four hospitals across the United States. PATIENTS: Eight hundred ninety patients with skin and soft tissue, intraabdominal, gynecologic, respiratory, urinary tract, or other infections that required parenteral antibiotic therapy. INTERVENTION: Patients were administered either ampicillin-sulbactam 1.5 or 3.0 g every 6 hours or ticarcillin-clavulanate 3.1 g every 6 hours. MEASUREMENTS AND MAIN RESULTS: The agents did not differ significantly in efficacy for most infections; although, ampicillin-sulbactam was bacteriologically superior to ticarcillin-clavulanate in the treatment of intraabdominal infections (p=0.0011). Costs of ampicillin-sulbactam, particularly the 1.5-g dose, were lower than those of ticarcillin-clavulanate for skin and soft tissue (p<0.001), intraabdominal (p=0.005), and respiratory tract (p<0.001) infections. CONCLUSION: Ampicillin-sulbactam provides effective coverage for patients with the above infections and is as effective as the broader-spectrum agent.

Adult↗

In-vitro susceptibility of Burkholderia pseudomallei to cefoperazone-sulbactam combination.

Melioidosis is endemic in Malaysia. Emerging resistance with new and current antimicrobial agents has underscored the need to look further for new antimicrobial agents for the treatment of melioidosis. Hence, we evaluated the in-vitro susceptibility of fifty locally isolated strains of Burkholderia pseudomallei, the causative agent of melioidosis to cefoperazone-sulbactam combination using the method of NCCLS. All the fifty strains tested were susceptible in-vitro to cefoperazone-sulbactam. The MIC90 of the organism for cefoperazone-sulbactam was 4 mg/L. The results of our findings suggested that cefoperazone-sulbactam may be useful in the treatment of melioidosis.

Burkholderia pseudomallei↗

Therapeutic interchange of ampicillin-sulbactam for cefoxitin.

A therapeutic interchange program based on microbial patterns within an institution is described. A change in anaerobic susceptibility patterns, increased prevalence of enterococcal infections, and cost factors provided the rationale for the therapeutic interchange of ampicillin-sulbactam for cefoxitin. Ampicillin-sulbactam was recommended for prophylaxis in intraabdominal or gynecological surgery as well as for treatment for gynecological infections. Cefoxitin was restricted to penicillin-allergic patients and women who were pregnant or breast-feeding. The transition from cefoxitin to ampicillin-sulbactam proceeded smoothly as a result of preliminary education of pharmacists and physicians. Pharmacists participated in continuing-education programs and received concise guidelines for the interchange and follow-up instructions; physicians learned of the program from the drug newsletter published by the pharmacy department. Three months after the program began, only one physician was resistant to the interchange. After the program began, 11 antimicrobials, including cefoxitin, were used less frequently and ampicillin-sulbactam use increased. No adverse clinical consequences from the interchange were detected. A therapeutic interchange program based on institution-specific microbial patterns and educational efforts by the pharmacy department produced a change in physician prescribing.

Ampicillin↗

[Stability of beta-lactamase inhibitors and beta-lactam antibiotics in parenteral formulations as well as in body fluids and tissue homogenates. Comparison of sulbactam, clavulanic acid, ampicillin and amoxicillin].

Stability of beta-Lactamase Inhibitors and beta-Lactam Antibiotics in Parenteral Formulations as Well as in Body Fluids and Tissue Homogenates/Comparative studies with sulbactam, clavulanic acid, ampicillin and amoxicillin. The beta-lactamase inhibitors and the beta-lactam antibiotics are markedly different in chemical stability. The comparative examination of 4 different infusion solutions at 4 degrees C, 25 degrees C and 37 degrees C gives the following sequence of decreasing stability: sulbactam (CAS 68373-14-8), ampicillin (CAS 69-53-4), amoxicillin (CAS 61336-70-7) and clavulanic acid (CAS 58001-44-8). It is particularly striking that the two beta-lactamase inhibitors, sulbactam and clavulanic acid, behave very differently. Sulbactam is also much more stable than clavulanic acid to incubation at 37 degrees C in body fluids or in tissue homogenates. The differences in the stability of the individual drugs should be born in mind during clinical use of combination formulations such as sulbactam/ampicillin (Unacid) and clavulanic acid/amoxicillin.

Amoxicillin↗

Ampicillin and sulbactam pharmacokinetics and pharmacodynamics in continuous ambulatory peritoneal dialysis (CAPD).

The fixed combination antibiotic ampicillin/sulbactam may provide a new, safe, and effective method of treating dialysis-related bacterial peritonitis. The pharmacokinetics of this antibiotic combination were determined in patients receiving continuous ambulatory peritoneal dialysis (CAPD). The pharmacodynamic activity of this drug was also determined by use of mean bactericidal titers against selected bacterial strains. Six noninfected CAPD patients in a randomized two-way crossover study were given a fixed dose of ampicillin (2 gm) and sulbactam (1 gm) either intravenously or intraperitoneally. The mean peak ampicillin and sulbactam serum concentrations following intravenous dosing were 170.3 and 87.5 micrograms/mL, respectively. The mean peak serum concentrations of ampicillin and sulbactam following intraperitoneal dosing were 48.0 and 27.8 micrograms/mL, respectively. Absolute bioavailabilities of the intraperitoneal ampicillin and sulbactam doses were 60% and 68%. Both drugs exhibited similar distribution and elimination characteristics. Renal failure markedly reduced drug elimination. Intraperitoneal administration of ampicillin/sulbactam provided satisfactory inhibitory and bactericidal antibiotic titers for most organisms in dialysate at 6 h but not 24 h. Ampicillin/sulbactam (2 gm/1 gm) should be administered every 12 h to patients with peritoneal dialysis-related peritonitis.

Adult↗

Pharmacokinetics of sulbactam and ampicillin in mice and in dogs.

Sulbactam is a new beta-lactamase inhibitor. The pharmacokinetic characteristics of sulbactam was similar to ampicillin after a single intravenous injection of 200 mg/kg in mice with a half-life of approximately 50 min. The two drugs appear to equilibrate rapidly between central and peripheral compartments. The Vc and Vd suggest that they are widely distributed in the extracellular fluid and into tissues. Co-administration of sulbactam and ampicillin in mice and in dogs showed essentially no change on the kinetics of either ampicillin or sulbactam.

Ampicillin↗

In vitro activity against clinically important gram-positive and gram-negative bacteria of sulbactam, alone and in combination with ampicillin, cefotaxime, mezlocillin, and piperacillin.

The in vitro effects of the single agents, and the synergistic/antagonistic action of three different combinations of ampicillin (AMP, CAS 69-53-4), cefotaxime (CTX, CAS 63527-52-6), mezlocillin (MEZ, CAS 51481-65-3), and piperacillin (PIP, CAS 61477-96-1) with the beta-lactamase inhibitor sulbactam (SUL, CAS 68373-14-8) were determined against 675 gram-positive and gram-negative, both aerobic and anaerobic bacteria. All the combinations of sulbactam and the antibiotics (1: 1, 1:2 and 1:4) exhibited very similar synergistic action. The percentage of the total strains tested for which synergistic activity was found was 51% with SUL + AMP (1:1), 24% with SUL + CTX (1:1), 31% with SUL + MEZ (1:1), and 28% with SUL + PIP (1:1). A fourfold or greater reduction of MIC's in the comparison with the antibiotics alone was found with 23% of the total strains tested for the SUL + AMP, with 9% of the strains tested with SUL + CTX, with 11% of the strains tested with SUL + MEZ, and with 15% of the strains tested with the SUL + PIP-combination. In the presence of sulbactam, 18% of the strains tested showed a significant reduction in the number of resistant strains with ampicillin, 7% with cefotaxime, 16% with mezlocillin, 14% with piperacillin, and in parallel there was an increase in the number of fully susceptible strains (shift from resistant or moderately sensitive to sensitive) by about 14%. In comparison with the antibiotic alone, the most marked reductions in the number of resistant strains on combination with sulbactam were as follows (the percentage of reduction is shown in brackets): for SUL + AMP and Acine-tobacter spp. (39% fewer resistant strains). Citrobacter spp. (-60%), Enterobacter aerogenes (-48%), Klebsiella oxytoca (-49%), Klebsiella pneumoniae (-63%), Morganella morganii (-74%), and Proteus vulgaris (-55%); for SUL + CTX and Acinetobacter spp. (-38%), Enterobacter cloacae (-6%), Klebsiella pneumoniae (-16%), Serratia marcescens (-9%), and Bacteroides fragilis (-31%); for SUL + MEZ and Acinetobacter spp. (-68%), Citrobacter spp. (-27%), Enterobacter spp. (-23%), Klebsiella pneumoniae (-32%), and Serratia marcescens (-19%); for SUL + PIP and Acinetobacter spp. (-41%), Citrobacter spp. (-30%), Klebsiella spp. (-30%), and Serratia marcescens (-33%).

Ampicillin↗

[A combination of ampicillin and sulbactam: effect on aerobic and anaerobic gram-negative bacteria].

The antibacterial activity of the association of ampicillin and sulbactam (2:1) upon strains of aerobic and anaerobic Gram negative agents was assayed. Inhibition of B-lactamases from intact and disrupted cells of some selected strains by sulbactam was also determined. Susceptibility was found in 34% and partial inhibition in 48%; 18% were fully resistant. Synergy between ampicillin and sulbactam was found upon ampicillin susceptible strains. This effect might reflect higher degree of binding of the inhibitor to PBP's in the absence of a trapping effect produced by B-lactamases. Anaerobic microorganisms were found to be highly susceptible to this association of B-lactams. Adequate penetration of the inhibitor into periplasmic space of Gram negative bacilli was deduced by the similar decrease of B-lactamase activity observed in intact and disrupted cells treated with sulbactam.

Ampicillin↗

Synergy of sulbactam and ampicillin against methicillin-resistant staphylococci.

Methicillin resistance in staphylococci is an increasing problem both for Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), which cause infections of the heart and after central nervous system surgery. Resistance seems to be due primarily to production of altered penicillin-binding proteins. The present study determined whether a combination of beta-lactamase inhibitor sulbactam and ampicillin or sulbactam and cefazolin would inhibit MRSA and MRSE. Sulbactam, ampicillin and cefazolin at 32 micrograms/ml did not inhibit MRSA or MRSE. At 8 micrograms/ml of each agent all isolates were inhibited. Synergy of sulbactam and ampicillin could be demonstrated against MRSA by the agar fixed ratio method, checkerboard dilution and by killing curves. This suggests that in certain situations MRSA and MRSE may be effectively eliminated by this method.

Ampicillin↗

Pharmacokinetics of sulbactam and ampicillin intravenously applied in combination to healthy volunteers and patients. Determination of the ratio of the two drugs in serum and in various tissues.

The pharmacokinetics of sulbactam, a new beta-lactamase inhibitor, and ampicillin were investigated in 9 healthy volunteers and 125 patients. The two drugs were administered intravenously in combination (Unacid). Each subject received 1 g sulbactam and 2 g ampicillin. The two drugs showed a similar pharmacokinetic profile in humans. Relevant pharmacokinetic parameters were calculated using a 2-compartment model on the basis of the serum and urine concentrations determined in healthy volunteers. The ratio of sulbactam to ampicillin was found to be nearly constant (approx. 1:2), both in the blood, in several tissues and at various time points. The two compounds apparently penetrated well into the myometrium, renal cortex and medulla, the gall bladder wall, the tonsils and the cutis of the skin. The sulbactam/ampicillin ratios in the bile ranged from 1:3 to 1:13 over 2 h after the infusion. The concentrations of the two compounds measured in the various fluids and tissues of the body reached levels which are effective against beta-lactamase producing bacteria. The similar pharmacokinetics of sulbactam and ampicillin in humans are considered an essential prerequisite for the therapeutic efficacy of such a combination product.

Adult↗