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PubMed2004

In vitro activities of the beta-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam alone or in combination with beta-lactams against epidemiologically characterized multidrug-resistant Acinetobacter baumannii strains.

Acinetobacter baumannii is an important nosocomial pathogen usually in the context of serious underlying disease. Multidrug resistance in these organisms is frequent. The beta-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam have intrinsic activity against Acinetobacter strains. To evaluate their potential therapeutic usefulness, we determined the in vitro activity of ampicillin, sulbactam, ampicillin-sulbactam, cefoperazone, cefoperazone-sulbactam, piperacillin, piperacillin-sulbactam, tazobactam, piperacillin-tazobactam, amoxicillin, clavulanic acid, amoxicillin-clavulanic acid, ticarcillin, and ticarcillin-clavulanic acid against multidrug-resistant A. baumannii. All isolates were epidemiologically characterized by RAPD [random(ly) amplified polymorphic DNA] analysis and/or pulsed-field gel electrophoresis and represented different strain types, including sporadic strains, as well as outbreak-related strains. The MICs were determined by agar dilution on Mueller-Hinton agar (using fixed concentrations, as well as fixed ratios for beta-lactamase inhibitors) and the E-test. The majority of E-test results were within two dilutions of those recorded by agar dilution, with the exception of piperacillin-tazobactam. Sulbactam was superior to clavulanic acid and tazobactam and may represent an alternative treatment option for infections due to multiresistant A. baumannii strains. beta-Lactamase inhibitors have intrinsic activity but do not enhance activity of beta-lactams against A. baumannii. Testing with the inhibitor added at a fixed concentration as recommended for piperacillin-tazobactam and ticarcillin-clavulanic acid by the National Committee for Clinical Laboratory Standards may falsely suggest high activity or gives uninterpretable results due to trailing. If combinations are used for testing, fixed ratios may give more useful results.

Acinetobacter Infections↗
PubMed1991

[The effect of sulbactam on the in vitro activity of mezlocillin, piperacillin and cefotaxime].

The in vitro activity of mezlocillin (MZL, CAS 51481-65-3), piperacillin (PIP, CAS 61477-96-1) and cefotaxim (CTX, CAS 63527-52-6) alone and in combination with sulbactam (SBT; CAS 68373-14-8) against mezlocillin-resistant pathogens was determined in a multicenter study. A total of 870 strains were investigated (481 Enterobacteriaceae, 57 Pseudomonas aeruginos, 41 Acinetobaster spp., 194 Bacteroides fragilis, and 97 Staphylococcus spp.). Determinations of MIC were performed according to DIN-guidelines (agar-dilution method for aerobes and microbroth-dilution method for anaerobes). Sulbactam was added in fixed concentrations of 5 mg/l and 10 mg/l. In all sulbactam-combinations examined mean MIC as well as MIC50 and MIC90 were reduced compared to the respective values for the antibiotics alone. Consequently, percentages of susceptible strains increased significantly: i.e. for Enterobacteriaceae: MZL 1% vs. MZL + 10 mg/l SBT 53%; PIP 4% vs. PIP + 10 mg/l SBT 54%; CTX 52% vs. CTX + 10 mg/l SBT 68%. The effect of sulbactam was most pronounced in Bacteroides spp. with an increase in susceptible strains from 2% to 97% for MZL, from 6% to 95% for PIP and from 7% to 98% for CTX. The results indicate that by adding sulbactam the in vitro activity of mezlocillin, piperacillin and cefotaxim against resistant pathogens is augmented significantly. In addition, the spectrum of antibacterial activity is extended to anaerobic pathogens such as Bacteroides spp. The availability of sulbactam as a monosubstance for combination with various beta-lactam-antibiotics thus represents a useful improvement of therapeutic options in bacterial infections.

Acinetobacter↗
PubMed1991

[Sulbactam in combination with mezlocillin, piperacillin or cefotaxime. Clinical and bacteriological results in the treatment of severe bacterial infections].

An open multicenter study on inpatients of 12 german hospitals was performed to investigate efficacy and safety of sulbactam in combination with mezlocillin, piperacillin or cefotaxim in severe bacterial infections. In total 155 patients were enrolled. The following infections were diagnosed: 48 lower respiratory tract infections, 66 intraabdominal infections, 34 skin/soft tissue infections including post operative wound infections and 5 complicated urinary tract infections. 55 patients received 3 daily doses of 4 g mezlocillin + 1 g sulbactam, 52 patients received 3 daily doses of 4 g piperacillin + 1 g sulbactam and 48 patients received 3 daily doses of 2 g cefotaxim + 1 g sulbactam. Antibiotics and sulbactam were administered concomitantly via intravenous short infusion. Mean duration of therapy was 8 days. Endpoints for assessment of therapeutic efficacy were cure (complete resolution of pretreatment signs and symptoms of the infection) or improvement (marked reduction or partial disappearance or pretreatment signs and symptoms, no further antibiotic therapy required) as well as eradication of pretreatment pathogens. 141 (92%) of 153 evaluable patients were successfully treated (98 cures and 43 improvements), therapy failed in 12 patients (7.8%). Success rates of the 3 sulbactam combinations were almost identical: 91% for mezlocillin/sulbactam, 92% for piperacillin/sulbactam and 93% for cefotaxim/sulbactam. 106 patients (68.4%) were also bacteriologically evaluable. In these patients 192 bacterial pathogens were isolated prior to study therapy, 55 patients had mixed infections. In 96 patients (90%) pretreatment pathogens were eradicated (180 strains = 94%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Stability of aztreonam and ampicillin sodium-sulbactam sodium in 0.9% sodium chloride injection.

The stability of aztreonam, ampicillin sodium, and sulbactam sodium admixed in 0.9% sodium chloride injection and stored at room temperature and under refrigeration was studied. Each of the following admixtures was prepared in 0.9% sodium chloride injection: (1) aztreonam 10 mg/mL; (2) ampicillin 20 mg/mL (as the sodium salt) and sulbactam 10 mg/mL (as the sodium salt); and (3) aztreonam 10 mg/mL, ampicillin 20 mg/mL, and sulbactam 10 mg/mL. Three minibags of each admixture were stored at room temperature and three were refrigerated. Every 12 hours, up to 96 hours, the admixtures were visually inspected and 5-mL samples were withdrawn for high-performance liquid chromatography and pH testing. No color change or precipitation was observed in any sample. In admixtures containing ampicillin, ampicillin was the first or only drug to lose more than 10% of initial concentration. In the ampicillin-sulbactam admixture, ampicillin was stable for 32 hours at room temperature and 68 hours refrigerated. In the aztreonam-ampicillin-sulbactam admixture, ampicillin was stable for 30 hours at room temperature and 94 hours refrigerated. Aztreonam 10 mg/mL, ampicillin 20 mg/mL (as the sodium salt), and sulbactam 10 mg/mL (as the sodium salt) in 0.9% sodium chloride injection were stable in combination for up to 30 hours at room temperature and 94 hours under refrigeration.

Ampicillin↗
PubMedDate not supplied

Pharmacoeconomic analysis of ampicillin-sulbactam versus cefoxitin in the treatment of intraabdominal infections.

We conducted a retrospective pharmacoeconomic analysis of a prospective, multicenter, double-blind, randomized, controlled trial comparing the beta-lactamase inhibitor combination ampicillin-sulbactam (96 patients) and the cephalosporin cefoxitin (101) in the treatment of intraabdominal infections. An institutional perspective was adopted for the analysis. The primary outcomes of interest were cure and failure rates, development of new infection, and antibiotic-related adverse events. Epidemiologic data pertaining to outcomes was retrieved primarily from the trial, although results of other published studies were taken into consideration through extensive sensitivity analyses. Data pertaining to potential resource use and economic impact were retrieved mainly from the University Health Consortium and hospital-specific sources. When considering only costs associated with drug acquisition through cost-minimization analysis, a potential savings of $37.24/patient may be realized with ampicillin-sulbactam relative to cefoxitin based on an average 7-day regimen. Outcome data collected for the entire hospitalization during the trial revealed an approximately 9% greater frequency of failure with cefoxitin relative to ampicillin-sulbactam. When considering all outcomes of interest in the initial base-case analysis, a potential cost savings of approximately $890/patient may be realized with ampicillin-sulbactam relative to cefoxitin. In assessing the impact of the significant variability in probability and cost estimates, Monte Carlo analysis revealed a savings of $425/patient for ampicillin-sulbactam over cefoxitin (95% CI -$618 to $1516 [corrected]). Given the model assumptions, our analysis suggests a 78% certainty level that savings will be experienced when ampicillin-sulbactam is chosen over cefoxitin.

Abdominal Abscess↗
PubMed2006

Simultaneous determination of rifampicin and sulbactam in mouse plasma by high-performance liquid chromatography.

A simple and rapid high-performance liquid chromatographic (HPLC) method with ultraviolet detection has been developed and validated for the simultaneous determination of rifampicin and sulbactam in mouse plasma. Plasma samples were deproteinized with acetonitrile and separated by HPLC on a RP-18 (125 x 4 mm, 5 microm) column and gradient elution with potassium dihydrogen phosphate solution (pH 4.5; 50 mm) and acetonitrile at a flow-rate of 1.0 mL/min. Rifampicin and sulbactam were monitored at 230 nm and confirmed by means of their UV spectra using a diode-array detector. The method was linear at plasma levels from 1 to 100 microg/mL for rifampicin and from 5 to 200 microg/mL for sulbactam. The limits of quantification were 0.6 microg/mL for rifampicin and 4.2 microg/mL for sulbactam. The intra- and inter-day precisions of the method (RSD) were lower than 5% for both compounds. Average recoveries of rifampicin and sulbactam from mice plasma were 98.2 and 89.3%, respectively. The developed method was successfully applied to the determination of the pharmacokinetic profile of both compounds in mice.

Animals↗
PubMedDate not supplied

In-vitro susceptibility of cefoperazone-susceptible and -resistant gram-negative rods to cefoperazone plus sulbactam, other beta-lactams, aminoglycosides and quinolone.

We compared the in-vitro activity of cefoperazone-sulbactam (2:1), other beta-lactams, amino-glycosides and ciprofloxacin against cefoperazone-susceptible and -resistant nosocomial gram-negative bacilli. Resistant isolates including Pseudomonas aeruginosa were susceptible to cefoperazone-sulbactam; the susceptible isolates had modestly increased susceptibility to the combination. Sulbactam, by itself, was poorly active. Among others tested, ciprofloxacin and imipenem were the most active. No inoculum effect was seen with cefoperazone-sulbactam and this drug combination had a prolonged post-antibiotic effect. Cefoperazone-sulbactam is an attractive candidate for evaluation in the treatment of nosocomial infections due to aerobic gram-negative bacilli.

4-Quinolones↗
PubMed1983

Concentrations of ampicillin plus sulbactam in serum and intestinal mucosa and effects on the colonic microflora in patients undergoing colorectal surgery.

Ampicillin and sulbactam were administered intravenously in 2 g and 1 g doses respectively every 8 h for two days to ten patients undergoing colorectal surgery. Drug concentrations were determined in serum, intestinal mucosa and faeces. The first dose was given at induction of anesthesia. The serum half-life was 2.1 h for ampicillin and 2.0 h for sulbactam on the first day. The concentrations in intestinal mucosa were in most cases 50% or more of the serum concentrations and there was no statistical difference between the two drugs. Faecal concentrations of both drugs were found in eight patients: a mean of 10.5 micrograms/g for ampicillin and a mean of 7.5 micrograms/g for sulbactam. Faecal samples were also collected during the investigation period for culture of aerobic and anaerobic bacteria. Among the aerobic bacteria enterococci, streptococci and enterobacteria decreased markedly during the prophylaxis period. Anaerobic bacteria were also suppressed significantly during the same period. The changes in colonic microflora were related to the concentrations of ampicillin and sulbactam in the intestinal mucosa and faeces. Overgrowth of yeasts was observed in six patients and overgrowth of Pseudomonas fluorescens in two others. These strains were resistant to the combination ampicillin and sulbactam. The microflora normalized in all patients after two weeks. No postoperative infections occurred.

Aged↗
PubMed1997

Pharmacokinetics of mezlocillin and sulbactam under continuous veno-venous hemodialysis (CVVHD) in intensive care patients with acute renal failure.

OBJECTIVE: In intensive care medicine, continuous detoxication methods, such as continuous veno-venous hemodialysis (CVVHD), are used for treating acute renal failure. However, in contrast to conventional hemodialysis, little is known about the pharmacokinetics of many drugs administered in this setting and guidelines for dosages of drugs often do not exist. This holds particularly true for broad-spectrum antibiotics, which are often required during intensive care. METHODS: In this study, we investigated the pharmacokinetics of the acylureidopenicillin mezlocillin and the beta-lactamase inhibitor sulbactam during CVVHD and deduced dosage recommendations from the kinetic parameters with the goal of maintaining trough levels of above 10 mg.l-1 for mezlocillin and 5 mg.l-1 for sulbactam. Six intensive care patients with acute renal failure, receiving mezlocillin (n = 5) and/or sulbactam (n = 4), were examined during CVVHD and during intervals between CVVHD. The serum concentrations and the amounts of the drugs excreted into the dialyzate and into the urine within one dosage interval were measured using high performance liquid chromatography (HPLC). Three of the patients were jaundiced, indicating functional impairment of the liver. RESULTS: The clearances by CVVHD (CLCVVHD) for mezlocillin ranged between 11.0 and 44.9 ml.min-1 and the half lives ranged between 1.12 and 8.84 h. Low CL and long half lives were observed in the patients with jaundice. For sulbactam, CLCVVHD ranged between 10.1 and 22.8 ml.min-1 and serum half lives were 4.25-6.11 h, independent of liver function. CONCLUSION: Due to high hepatobiliary clearance of mezlocillin, dosage adjustments in patients with acute renal failure, treated by CVVHD, are needed only with concurrent impaired liver function. For sulbactam, the optimal dose was found to be 0.5 g, administered every 12 h, regardless of liver function.

Acute Kidney Injury↗
PubMed1995

Latency period after preterm premature rupture of membranes: a comparison of ampicillin with and without sulbactam.

OBJECTIVE: To compare ampicillin with and without sulbactam with respect to the effect on the latency period after preterm premature rupture of membranes (PROM). METHODS: Patients with PROM at 25-35 weeks' gestation were offered participation in a randomized blinded trial comparing ampicillin-sulbactam with ampicillin. Evaluations for cervical pathogens were performed on admission and patients were followed-up with daily maternal and fetal evaluation. Maternal and neonatal outcomes were analyzed using indicated techniques. RESULTS: Fifty-three women were studied, with 25 receiving ampicillin-sulbactam and 28 receiving ampicillin. The ampicillin-sulbactam group had a significantly longer latency period (433 +/- 625 versus 143 +/- 165 hours, P = .03) and significantly fewer neonatal complications (five versus 20, P < .001). Although no neonatal infectious complications were observed in sulbactam-treated cases, there were four cases of neonatal sepsis and two of neonatal pneumonia in the ampicillin group. Also, significantly more neonates in the ampicillin group required prolonged oxygen and ventilatory support. There was no significant difference in maternal morbidity. CONCLUSIONS: In our population with preterm PROM, a broad-spectrum antibiotic that provides anaerobic coverage appears to extend latency and decrease neonatal morbidity without increasing adverse maternal outcome.

Adult↗
PubMedDate not supplied

In vitro assessment of sulbactam plus cefoperazone in the treatment of bacteria isolated from cancer patients.

Cefoperazone is a broad-spectrum cephalosporin that has been used extensively to treat infections in cancer patients. A recent survey demonstrated only a 6% resistance to this drug among Gram-negative bacteria. The combination of cefoperazone plus sulbactam was studied in vitro against consecutive isolates causing bacteremia in cancer patients as well as those selected for resistance to cefoperazone. Both a fixed ratio of sulbactam/cefoperazone (2:1 w/w) and selected concentrations of sulbactam (2, 4, 8, and 16 micrograms/ml) were studied. Sulbactam was shown to increase the susceptibility of various unselected Gram-negative bacilli; this effect increased with larger concentrations of sulbactam. The addition of sulbactam at optimum concentration levels made 29 of 65 cefoperazone-resistant Gram-negative bacilli susceptible. This effect was seen most markedly for Acinetobacter spp.

Bacterial Infections↗
PubMedDate not supplied

Antibacterial activity of cefoperazone and cefoperazone plus sulbactam in a neutropenic site model.

Efficacy of cefoperazone versus cefoperazone plus sulbactam was studied in a rabbit neutropenic site infection model against a broad range of clinical isolates including six isolates each of staphylococci, enterococci, pneumococci, Enterobacteriaceae, and Pseudomonas aeruginosa. Therapy of cefoperazone plus sulbactam demonstrated enhanced efficacy against the staphylococci, pseudomonads, and Enterobacteriaceae. The activity of cefoperazone against enterococci and pneumococci was not enhanced or inhibited by the addition of sulbactam. Increased concentrations of cefoperazone found at the infection sites when sulbactam was added to the therapeutic regimen indicates that sulbactam provided a protection to cefoperazone from beta-lactamases produced by staphylococci and Enterobacteriaceae. The combination improved the efficacy of cefoperazone in this animal model.

Animals↗
PubMed1985

High-performance liquid chromatographic assay of sulbactam using pre-column reaction with 1,2,4-triazole.

A high-performance liquid chromatographic (HPLC) method for the determination of sulbactam in human and rat plasma and urine has been developed. Sulbactam was reacted with 1,2,4-triazole to yield a product having an ultraviolet absorption maximum at 326 nm. The product was separated using reversed-phase HPLC from the regular components of plasma and urine with an ion-pair buffer at 50 degrees C and detected at the ultraviolet maximum. The limits of accurate determination were 0.2 and 1.0 micrograms/ml in plasma and urine, respectively. The coefficients of variation of inter- and intra-assays in human plasma spiked at 4.0 micrograms/ml (n = 5) were 1.02 and 3.05%, respectively. Coexisting cefoperazone, penicillins, or the alkaline degradation product(s) of sulbactam did not interfere in the sulbactam assay. The pharmacokinetic behaviour of sulbactam and cefoperazone coadministered to rats was estimated by moment analysis.

Animals↗
PubMed1994

A structure-based analysis of the inhibition of class A beta-lactamases by sulbactam.

From the crystal structure of the Bacillus licheniformis 749/C beta-lactamase, energy-minimized structures for the precatalytic, the acyl-enzyme intermediate, and the acylated linear inactivating species for sulbactam--a clinically useful mechanism-based inactivator for class A beta-lactamases--were generated. The effect of individual Ser-235-Ala and Arg244-Ser point mutations on the inactivation and turnover processes was consistent with the existence of hydrogen bonds between the side chains of these residues and the sulbactam species. The departure of the sulfinate leaving group from the acyl-enzyme intermediate of sulbactam is believed to be a prerequisite for the inactivation process. In order to explore the influence of the leaving group, penicillanic acid (2), penicillanic acid alpha-S-oxide (3), and penicillanic acid beta-S-oxide (4) were synthesized and studied in kinetic experiments with the TEM-1 beta-lactamase. Penicillanic acid is only a substrate, but penicillanic acid S-oxides were both substrates and inactivators for the enzyme. An argument is presented to rationalize these observations on the basis of the leaving ability of thiolate, sulfenate, and sulfinate from the acyl-enzyme intermediates of penicillanic acid (2), the penicillanic acid S-oxides (3 and 4), and sulbactam, respectively. The departure of the leaving group does not appear to be rate limiting in the inactivator process, but is an indispensable component of the irreversible inactivation of the enzyme. Molecular dynamics calculations of the putative inactivating species suggest that Lys-73, Lys-234, and Ser-130 are three likely residues that may be modified in the course of the inactivation chemistry. A discussion is presented of the mechanism of formation of the transiently inhibited enzyme species, which comes about as a consequence of the tautomerization of the double bond of the inactivating iminium moiety. In addition, the mechanistic details presented for sulbactam are compared and contrasted with those of clavulanic acid, another clinically used inactivator for class A beta-lactamases.

Acylation↗
PubMedDate not supplied

Sulbactam: biochemical factors involved in its synergy with ampicillin.

Sulbactam is a time-dependent irreversible inhibitor of various beta-lactamases by reversible formation of a Michaelis-type enzyme-inhibitor complex and progressive evolution of this complex into inactivated protein(s). This process is either irreversible (true inactivation) or quasi-irreversible (stable acyl-enzyme). In this way, sulbactam efficiently protects ampicillin from degradation by beta-lactamases. Sulbactam itself exhibits a moderate antibacterial activity that is related to an affinity for the penicillin-binding proteins of various bacterial strains, which is similar to the affinity of penicillins such as ampicillin. However, sulbactam binding differs according to the bacterial species involved. In strains producing either low levels of beta-lactamase or none at all, a synergistic effect, minor but not negligible, can be observed when sulbactam is associated with a beta-lactam antibiotic with a complementary affinity for the target sites.

Ampicillin↗
PubMedDate not supplied

Pharmacokinetic study of sulbactam and ampicillin administered concomitantly by intraarterial or intravenous infusion in the newborn.

The combination of sulbactam and ampicillin was administered to 16 newborn infants, 15 preterm and one term, who required umbilical arterial or venous catheterization and prophylactic antibiotics. The aims were to determine an appropriate dosage regimen and to study the pharmacokinetics. Satisfactory plasma concentrations were achieved with administration of a bolus injection of 50 mg of each drug/kg every 12 hr (mean concentrations: sulbactam, 110 mg/liter; ampicillin, 87 mg/liter 3 hr after dosing; and sulbactam, 105 and 135 mg/liter; ampicillin, 320 and 310 mg/liter 30 min after dosing in two infants. Mean elimination half-lives were longer than those in adults (sulbactam, 7.9 hr; ampicillin, 9.4 hr), and urinary excretion over 12 hr varied considerably (range: sulbactam, 7%-91%; ampicillin, 5%-132%), rates reflecting the immature renal function in the newborn and the relative oliguria characteristic of preterm infants with idiopathic respiratory distress syndrome. There was little evidence of accumulation of either drug, and both were well tolerated. This combination and dosage should be suitable for a trial of therapy for infection in the newborn.

Ampicillin↗
PubMedDate not supplied

Biliary pharmacokinetics of sulbactam plus ampicillin in humans.

The biliary pharmacokinetics of sulbactam and ampicillin was investigated in 19 patients with normal liver function who were undergoing surgery of the biliary tract. The combination of sulbactam (0.5 g) plus ampicillin (1 g) was given intravenously to five patients with T-tube drainage of the common bile duct. Mean peak concentrations of sulbactam (19.4 micrograms/ml) and ampicillin (471 micrograms/ml) in the bile occurred 0.5-1 hr after administration. Biliary excretion was estimated to account for approximately 0.24% of the sulbactam dose and 2.8% of the ampicillin dose. Fourteen other patients received the same dose of sulbactam/ampicillin immediately before elective cholecystectomy. Respective mean concentrations of sulbactam and ampicillin at the time of gallbladder removal were 4.3 micrograms/ml and 15.9 micrograms/ml in gallbladder bile and 6.3 micrograms/g and 7.7 micrograms/g in gallbladder wall tissue. These results, together with the antibacterial spectrum and potency of the combination, suggest that sulbactam/ampicillin is suitable for prophylactic use in biliary tract surgery.

Ampicillin↗
PubMedDate not supplied

Penetration of sulbactam into the cerebrospinal fluid of patients with bacterial meningitis receiving ampicillin therapy.

Concentrations of sulbactam in the CSF of 18 patients with bacterial meningitis who were undergoing treatment with intravenous (iv) ampicillin were determined. Six patients received single doses of sulbactam (1 g) and 12 patients received multiple doses (four times daily) by the iv route at various intervals before lumbar punctures were performed to monitor their condition. Concentrations of sulbactam up to 12 micrograms/ml were detected in the CSF between 1 and 4 hr after dosing, the higher levels being present in the CSF of patients with the most severe meningeal inflammation. There were no significant differences in the concentrations achieved after single or multiple doses of sulbactam, and the concentrations were generally similar to the concurrent concentrations of ampicillin. It is concluded that these results as well as the antibacterial properties of sulbactam plus ampicillin support the evaluation of this combination as an alternative in the treatment of bacterial meningitis.

Ampicillin↗