Prostatic Pharmacokinetic/Pharmacodynamic Evaluation of Ampicillin-Sulbactam for Bacterial Prostatitis and Preoperative Prophylaxis.

This study aims to define the penetration of ampicillin and sulbactam into prostate tissue, develop a prostatic pharmacokinetic model of each drug, and assess the appropriateness of ampicillin-sulbactam regimens for the treatment of prostatitis and the prophylaxis of postoperative infection, based on a pharmacokinetic and pharmacodynamic simulation. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-hour infusion of 1.5 g (1:0.5 g) or 3 g (2:1 g) ampicillin-sulbactam before transurethral resection of the prostate. Ampicillin and sulbactam concentrations in plasma and prostate tissue were measured. The prostate tissue/plasma ratios of both ampicillin and sulbactam were approximately 0.37 (area under the drug concentration-time curve), and penetration was similar. The prostatic population pharmacokinetic model, which included a covariate analysis, adequately predicted prostate tissue concentrations in our patient population. For therapeutic use, aiming for a bactericidal target of 50% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability against only Enterococcus faecalis in typical patients with a creatinine clearance (CLcr ) of 30 mL/min. For prophylactic use, aiming for a bacteriostatic target of 30% T > MIC, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability of attaining the bacteriostatic target against E. faecalis and Proteus species when CLcr was 30 mL/min. Based on prostatic simulations, the present study provides helpful recommendations for the treatment of bacterial prostatitis and preoperative prophylaxis in prostatectomy.

Population pharmacokinetics and Monte Carlo simulations of sulbactam to optimize dosage regimens in patients with ventilator-associated pneumonia caused by Acinetobacter baumannii.

BACKGROUND: Ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) Acinetobacter baumannii remains one of the leading causes of the high mortality rate in critically ill patients. Sulbactam has been considered as an alternative concomitant medication with other effective antimicrobial agents for the treatment of these MDR microorganisms. The aims of this study were (i) to characterize the population pharmacokinetics (PK) and (ii) to assess the efficacy of various dosage regimens of sulbactam in terms of probability of target attainment (PTA). METHODS: The PK studies were carried out following administration of 2 g of sulbactam every 12 h on the 7th dose of drug administration in 16 patients with VAP, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% and 60% the exposure time during which the total plasma drug concentration remained above the MIC (T>MIC). RESULTS: The volume of distribution and total clearance of sulbactam were 22.17 ±â€¯1.60 L and 6.76 ±â€¯2.37 L/h, respectively. For pathogens with a MIC of 8 µg/mL, the high PTAs of achieving (≥90%) 60% T>MIC in patients with serum albumin 1.7-2.4 g/dL and CLCR 90-120 mL/min following administration of sulbactam as a 4-h infusion of 1 g every 6 h, 2 g every 12 h, and 2 g every 8 h were 98.65%, 78.07% and 98.23%, respectively. For pathogens with a MIC of 16 µg/mL, the high PTAs of achieving (≥90%) 60% T>MIC in patients with serum albumin 1.7-2.4 g/dL and CLCR 90-120 mL/min following administration of sulbactam as a 4-h infusion of 2 g every 6 h, and 3 g every 8 h were 98.83% and 95.59%, respectively. CONCLUSION: These findings indicate that high dosage combination regimens are required for the treatment of life-threatening infections in critically ill patients with VAP.

Population Pharmacokinetics and Pharmacodynamics Modeling To Optimize Dosage Regimens of Sulbactam in Critically Ill Patients with Severe Sepsis Caused by Acinetobacter baumannii.

Sulbactam is being considered as an alternative concomitant medication with other effective antibiotics for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii infections. Pathophysiological changes in critically ill patients with severe sepsis, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors in determining therapeutic success. The aims of this study were (i) to examine the population PK parameters and (ii) to assess the probability of target attainment (PTA) for sulbactam in patients with severe sepsis caused by A. baumannii PK studies were carried out following administration of 2 g of sulbactam every 12 h on the 4th day of drug administration in 27 patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentration remained above the MIC (T>MIC) and 60% T>MIC The central and peripheral volumes of distribution were 14.56 and 9.55 liters, respectively, and total clearances of sulbactam were 2.26 liters/h and 7.64 liters/h in patients aged >65 years and ≤65 years, respectively. The high PTAs (≥90%) for targets of 40% T>MIC and 60% T>MIC with a MIC of 4 µg/ml were observed when sulbactam was administered by a 4-h infusion of 1 g every 12 h and 1 g every 8 h, respectively. Sulbactam would be an alternative antibiotic option to coadminister with colistin for the treatment of infections caused by MDR A. baumannii However, for pathogens with MICs of >4 µg/ml, higher dosage regimens of sulbactam are required.

Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques.

The pharmacokinetics of cefuroxime, cefotiam, cefamandole, and ampicillin/sulbactam were randomly measured in 40 patients undergoing major orthopedic surgery associated with high blood and volume turnover and intraoperative blood salvage. Serum and bone concentrations and the pharmacokinetics occurring in the context of these procedures were measured. No changes in elimination half-life relative to a normal population occurred with cefuroxime, cefotiam, and ampicillin. Serum and tissue concentrations were slightly lower with cefamandole and sulbactam, but reapplication of the initial dose was required with all antibiotics 4 hours after the first application.

Sulbactam efficacy in experimental models caused by susceptible and intermediate Acinetobacter baumannii strains.

Sulbactam and imipenem were compared in an experimental pneumonia model in immunocompetent mice, using a susceptible strain of Acinetobacter baumannii, and in an experimental endocarditis model in rabbits, using an intermediately susceptible strain. In the former, sulbactam was as efficacious as imipenem in terms of survival, sterility of lungs and in the bacterial clearance from lungs and blood, provided that the t > MIC for sulbactam (1.84 h) was similar to that for imipenem (2.01 h). In the endocarditis model, imipenem (t > MIC, 2.12 h) was more efficacious than sulbactam (t > MIC, 1.17 h) in bacterial clearance from vegetations. These results show the efficacy of sulbactam in infections caused by susceptible strains of A. baumannii, with an MIC up to 4 mg/L, provided that doses reach a t > MIC similar to that of imipenem. The activity of sulbactam was time dependent.

Antibiotic penetration of experimental intra-abdominal abscesses.

Intra-abdominal abscess is seldom adequately treated by systemic antibiotics alone and often requires surgical or computed tomography-guided drainage for resolution. Abscess penetration of six currently used antibiotics was examined in a murine intra-abdominal abscess model. Ampicillin/sulbactam, cefmetazole, clindamycin, and trospectomycin penetrated intra-abdominal abscesses to a greater degree than cefoxitin and ceftriaxone. Abscess pus antibiotic levels were not significantly higher after multiple doses than after a single dose. Pus antibiotic levels below the MIC90 for Bacteroides and E. coli within intra-abdominal abscess were observed for most antibiotics with the doses used in this study. Selection of antibiotics with a greater ability to penetrate abscess may be important in optimally treating patients with abdominal infection.

Comparison of cefoperazone plus sulbactam with clindamycin plus gentamicin as treatment for intra-abdominal infections.

This study compared the safety and efficacy of cefoperazone plus sulbactam with that of clindamycin plus gentamicin in the treatment of intra-abdominal infection. Seventy-six patients were included in the analysis of an open, randomized, comparative, single-site trial. Forty-seven patients received cefoperazone-sulbactam, and 29 patients received clindamycin plus gentamicin. Thirty-three patients (70%) who received cefoperazone-sulbactam and 15 patients (52%) who received clindamycin plus gentamicin were cured of infection, did not suffer a relapse within one month after the end of treatment, and did not receive any other antibiotics during the follow-up period (P = 0.17). In patients treated with cefoperazone-sulbactam there were four cases of superinfection, one patient had a prolonged prothrombin time, six patients had a poor response, two patients received antibiotics during follow-up, and one patient died during follow-up because of cancer. Treatment with clindamycin plus gentamicin was associated with five cases of superinfection, four patients had a poor response, four patients had a drug reaction, and one patient required antibiotics in the follow-up period. Serum levels of cefoperazone-sulbactam measured at one and three hours after dosing were consistent with earlier findings in normal volunteers. Two hundred and one pathogens were isolated, and 17 of 122 aerobic isolates (14%) were resistant to cefoperazone-sulbactam, and 17 of 122 (14%) were resistant to both clindamycin and gentamicin. Eleven of 79 (14%) anaerobic isolates were resistant to cefoperazone, none was resistant to cefoperazone-sulbactam, and 10 of 79 (13%) were resistant to clindamycin. The results of this study show that cefoperazone-sulbactam is an effective and safe alternative to clindamycin plus gentamicin in the treatment of intra-abdominal infections.

Inactivación de ß-lactamasas por sulbactam en presencia de anticoagulante y en anaerobiosis / ß-lactamase inactivation by sulbactam in aerobiosis and anticoagulant

Se aislaron cepas de Staphylococcus aureus resistentes a penicilina y productoras de ß-lactamasas. Mediante el método de dilución en tubos, se calculó la concentración inhibitoria CIM para amoxicilina-sulbactam, con diferente tensión de oxígeno y frente a heparina. Los valores de CIM se redujeron significativamente al sumar sulbactam al antibiótico. La disminución del oxígeno no afectó la capacidad inhibidora de ß-lactamasas del sulbactam, del mismo modo que la presencia de heparina no interfirió en su efecto protector sobre la amoxicilina. Estos resultados reafirmaron el concepto de efectividad de la combinación amoxicilina-sulbactam sobre los procesos infecciosos a S. aureus productores de ß-lactamasas, aun en afecciones donde se genera anaerobiosis relativa y también en enfermos con tratamiento simultáneo con heparina

Inactivación de ß-lactamasas por sulbactam en presencia de anticoagulante y en anaerobiosis / ß-lactamase inactivation by sulbactam in aerobiosis and anticoagulant

Se aislaron cepas de Staphylococcus aureus resistentes a penicilina y productoras de ß-lactamasas. Mediante el método de dilución en tubos, se calculó la concentración inhibitoria CIM para amoxicilina-sulbactam, con diferente tensión de oxígeno y frente a heparina. Los valores de CIM se redujeron significativamente al sumar sulbactam al antibiótico. La disminución del oxígeno no afectó la capacidad inhibidora de ß-lactamasas del sulbactam, del mismo modo que la presencia de heparina no interfirió en su efecto protector sobre la amoxicilina. Estos resultados reafirmaron el concepto de efectividad de la combinación amoxicilina-sulbactam sobre los procesos infecciosos a S. aureus productores de ß-lactamasas, aun en afecciones donde se genera anaerobiosis relativa y también en enfermos con tratamiento simultáneo con heparina (AU)

[Sulacillin in the treatment of bronchopulmonary diseases]. / Sulatsillin v lechenii bronkholegochnykh zabolevanii.

Antibiotic susceptibility of 279 strains of gram-positive and gram-negative isolates from patients with bronchopulmonary infections was tested. It was shown that the frequency of resistance to ampicillin and sulacillin amounted to 36.5 and 28.8 per cent respectively. The highest clinical efficacy of sulacillin was observed in the treatment of acute pneumonia (good and satisfactory results in 76.2 and 19 per cent of the cases respectively) and chronic nonobstructive bronchitis (good and satisfactory results in 80 and 16 per cent respectively). The clinical efficacy of sulacillin was somewhat lower in the treatment of chronic obstructive bronchitis (good and satisfactory results in 50 and 30 per cent of the cases respectively). In the treatment of chronic purulent bronchitis no clinical effect was detected in 30 per cent of the cases and in 70 per cent of the cases the results were satisfactory. The total frequency of adverse reactions to sulacillin amounted to 18.8 per cent.

Ampicillin/sulbactam in lower respiratory tract infections: a review.

The pathophysiology and microbiology of lower respiratory tract infections are outlined and diagnostic and therapeutic problems considered. The use of sulbactam/ampicillin in the treatment of these infections is evaluated. The two drugs have similar pharmacokinetic characteristics; predictable and dose-dependent peak serum concentrations of both agents are achieved after parenteral administration. More than 90% of strains of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella sp, Escherichia coli, and Acinetobacter sp were inhibited by ampicillin/sulbactam concentrations of 16/8 micrograms/ml. Serum concentrations of ampicillin and sulbactam were 18 to 28 micrograms/ml and 13 micrograms/ml, respectively, after intramuscular administration of 1 gm/0.5 gm of ampicillin/sulbactam and 58 micrograms/ml and 30 micrograms/ml, respectively, after intravenous administration of the same dose. Good distribution of ampicillin/sulbactam into lung tissue, sputum, and bronchial fluid has been demonstrated. In over 2,250 patients treated with ampicillin/sulbactam, the rate of discontinuance of treatment because of side effects was less than 1%. Satisfactory clinical and bacteriologic outcome has been reported in over 80% of patients treated with ampicillin/sulbactam. The cost of ampicillin/sulbactam treatment is generally lower than that of other comparable antibiotic regimens.

Use of ampicillin-sulbactam for treatment of experimental meningitis caused by a beta-lactamase-producing strain of Escherichia coli K-1.

We evaluated the pharmacokinetics and therapeutic efficacy of ampicillin combined with sulbactam in a rabbit model of meningitis due to a beta-lactamase-producing strain of Escherichia coli K-1. Ceftriaxone was used as a comparison drug. The MIC and MBC were 32 and greater than 64 micrograms/ml (ampicillin), greater than 256 and greater than 256 micrograms/ml (sulbactam), 2.0 and 4.0 micrograms/ml (ampicillin-sulbactam [2:1 ratio, ampicillin concentration]) and 0.125 and 0.25 micrograms/ml (ceftriaxone). All antibiotics were given by intravenous bolus injection in a number of dosing regimens. Ampicillin and sulbactam achieved high concentrations in cerebrospinal fluid (CSF) with higher dose regimens, but only moderate bactericidal activity compared with that of ceftriaxone was obtained. CSF bacterial titers were reduced by 0.6 +/- 0.3 log10 CFU/ml/h with the highest ampicillin-sulbactam dose used (500 and 500 mg/kg of body weight, two doses). This was similar to the bactericidal activity achieved by low-dose ceftriaxone (10 mg/kg), while a higher ceftriaxone dose (100 mg/kg) produced a significant increase in bactericidal activity (1.1 +/- 0.4 log10 CFU/ml/h). It appears that ampicillin-sulbactam, despite favorable CSF pharmacokinetics in animals with meningitis, may be of limited value in the treatment of difficult-to-treat beta-lactamase-producing bacteria, against which the combination shows only moderate in vitro activity.

[Laboratory and clinical study of sulbactam/cefoperazone (SBT/CPZ) on bacterial prostatitis].

The cefoperazone and sulbactam concentrations in human prostatic fluid were measured following intravenous administration of sulbactam/cefoperazone (SBT/CPZ) and its clinical efficacy and safety in the treatment of 11 patients with acute or chronic bacterial prostatitis were evaluated. Cefoperazone concentrations in prostatic fluid (PF) one hour after an intravenous infusion of SBT/CPZ at a dose of 1 g and 2 g were 0.57 +/- 0.26 micrograms/ml and 1.37 +/- 0.86 micrograms/ml, respectively, both exceeding the MIC against most of the isolated strains from expressed prostatic secretion (EPS). The sulbactam levels in PF at doses of 1 g and 2 g of SBT/CPZ were 0.30 +/- 0.18 micrograms/ml and 0.38 +/- 0.13 micrograms/ml, respectively, both of which were high enough to potentiate antimicrobial activity of cefoperazone. The peak of MIC distribution of sulbactam/cefoperazone against E. coli (14 strains) and S. epidermidis (21 strains) isolated from EPS of patients with bacterial prostatitis was in a range of 0.1-0.2 micrograms/ml and 0.2-0.78 micrograms/ml as described for the cefoperazone concentration, respectively, which were superior to those of cefoperazone, ceftazidime and piperacillin, all compared as control, SBT/CPZ exhibited 8 fold or more potent antimicrobial activity than cefoperazone against beta-lactamase producing E. coli and CNS. Clinically, SBT/CPZ was given to 11 patients diagnosed as having bacterial prostatitis in a daily dose of 2-4 g for 5 to 8 days. The drug was found to be effective in all (100%) of 5 patients with acute prostatitis and in 3 (75.0%) of 4 patients who were judged to be assessable among 6 chronic patients. No side effects of any kind were observed in any of the patients treated. In laboratory tests, a transient thrombocytopenia was reported for one patient. SBT/CPZ is particularly useful in the treatment of acute bacterial prostatitis caused by GNR. This drug is useful for chronic prostatitis those, caused primarily by CNS which is susceptible to this agent. This drug is available as an injectable form, subjects for its appropriate usage will be those who show acute exacerbation of infection or who do not respond to oral therapy.

Ceftriaxone-sulbactam combination in rabbit endocarditis caused by a strain of Klebsiella pneumoniae producing extended-broad-spectrum TEM-3 beta-lactamase.

We studied the activity of the combination of sulbactam and ceftriaxone against a Klebsiella pneumoniae strain producing TEM-3, a new extended-broad-spectrum beta-lactamase, in an endocarditis model. In vitro, ceftriaxone was strongly inactivated in the presence of TEM-3 (MBC, 128 micrograms/ml with an inoculum of 5 x 10(5) CFU/ml). A marked inoculum effect was demonstrated with sulbactam: effective concentrations of inhibitor needed to reduce the MIC and MBC of ceftriaxone to similar levels increased from 1 microgram/ml in the presence of an inoculum of 5 x 10(5) CFU/ml to 20 micrograms/ml in the presence of an inoculum of 1 x 10(7) CFU/ml. In vivo, sulbactam given at 200 mg/kg of body weight every 12 h, a dosage higher than that previously reported to be effective against rabbit endocarditis caused by other microorganisms, was not sufficient to restore the complete activity of ceftriaxone given at 30 mg/kg once daily for 4 days. This insufficient activity may be correlated with the presence of a high level of beta-lactamase inside the vegetations, as indicated by a quantitative in vitro assay of beta-lactamase activity in the cardiac vegetation, suggesting an insufficient inactivation of the extended-broad-spectrum beta-lactamase in vivo.

Perioperative systemic antibiotics for prophylaxis of infections in breast surgery: sulbactam/ampicillin versus mezlocillin/oxacillin.

In a prospective, randomized, open trial, efficacy of one dose of sulbactam/ampicillin (1 g:2 g) was compared to three doses of mezlocillin/oxacillin (2 g:1 g), starting with induction of anesthesia in 80 breast surgery patients with an increased risk of postoperative infection. No infections at the site of operation were seen in either group. Fever due to postoperative pulmonary complications occurred in one patient in the sulbactam/ampicillin group. The only side effect was a moderate exanthema observed in one patient in the mezlocillin/oxacillin group. In this study of the prophylaxis of patients with an increased risk of postoperative infections having the potential to jeopardize the results of surgery, a single dose of sulbactam/ampicillin was as effective as a short term course of three doses of mezlocillin/oxacillin.

Studies on the synergism of sulbactam and beta-lactam antibiotics under in vitro conditions and in healthy volunteers after intravenous administration. Antibacterial activity in vitro, compatibility and pharmacokinetics of the drugs in combination.

Sulbactam, a new beta-lactam inhibitor, increased the in vitro activity of cefotaxime, mezlocillin and piperacillin against 803 clinical bacterial isolates. The synergism of sulbactam and these antibiotics was particular marked against 467 beta-lactamase positive strains, both aerobic and anaerobic. In the presence of sulbactam the mean minimal inhibitory concentrations (MICs) of the antibiotics against beta-lactamase positive bacteria were greatly reduced: with cefotaxime by 58%, with mezlocillin by 64% and with piperacillin by 70%. Sulbactam alone at low concentrations inhibited the growth of only a few strains (Neisseria spp., Acinetobacter spp.). The inhibitor proved to be very stable in infusion media under a variety of conditions and was compatible in vitro with 14 different beta-lactam antibiotics. The pharmacokinetics profiles of sulbactam and the antibiotics cefotaxime, mezlocillin and piperacillin were similar after infusion to healthy volunteers. The relevant pharmacokinetic parameters of the single substances were essentially unchanged when administered in combination. The general similarity between the pharmacokinetics of sulbactam and of the beta-lactam antibiotics appears to be an essential precondition for the therapeutic success of such a synergistic combination. Thus the physicochemical and pharmacological properties of sulbactam apparently permit flexible dosage in combination with different penicillins or cephalosporins and sulbactam can be administered as non-fixed combination in the clinical treatment of bacterial infections.