Sultamicillin

Abstract: The parenteral kinetics of sulbactam, a potent synergist with ampicillin against a broad range of clinically important organisms in humans, are similar to those of ampicillin. The kinetics of ampicillin were not affected by co-administration of sulbactam, and high levels of both agents were attained: 15-min infusions of 2 g of ampicillin plus 1 g of sulbactam produced peak serum concentrations of approximately 120 micrograms of ampicillin/ml plus 60 micrograms of sulbactam/ml; intramuscular injections of 1 g of ampicillin plus 0.5 g of sulbactam produced peak concentrations of 18 micrograms of ampicillin/ml plus 13 micrograms of sulbactam/ml. The drugs had similar half-lives (approximately 1 hr), and both drugs were excreted primarily in the urine (greater than 75%). Although the kinetics of sulbactam in postpartem women and in surgical patients were similar to the kinetics in young men, the half-life of sulbactam (like that of ampicillin) was altered in the elderly, during labor, in neonates, and in patients with renal impairment. After distribution of the agents in the body, the concentrations of both drugs in blister and parenteral fluid were similar to those in serum. Furthermore, useful antibacterial concentrations of both drugs were found in pus, sputum, and middle-ear fluid. The normally low penetration of sulbactam and ampicillin into cerebrospinal fluid was increased in patients with bacterial meningitis.

Abstract: Sulbactam is a semisynthetic beta-lactamase inhibitor which when combined with certain beta-lactam antibacterials extends their activity against bacteria that are normally resistant to the antibiotic due to production of beta-lactamases. In combination with ampicillin it extends the antibacterial activity of ampicillin to include beta-lactamase-producing strains which are otherwise resistant, including Bacteroides fragilis, and increases the susceptibility of many sensitive strains. Sulbactam is poorly absorbed after oral administration and sulbactam/ampicillin is therefore administered parenterally, although another linked sulbactam-ampicillin compound, sultamicillin, has been developed which is well absorbed after oral administration. The basic pharmacokinetic characteristics of sulbactam after parenteral administration are similar to those of ampicillin. Multiple-dose therapy with sulbactam/ampicillin is clinically and bacteriologically effective in infections of the urinary tract, skin and soft tissue, bones and joints, respiratory tract, ears, nose and throat, as well as intra-abdominal and obstetric and gynaecological infections and septicaemia. In addition, single intramuscular doses of sulbactam/ampicillin administered with oral probenecid are therapeutically effective in gonorrhoea, including infections due to penicillinase-producing and/or ampicillin-resistant Neisseria gonorrhoeae. In the prophylaxis of infectious complications of surgery sulbactam/ampicillin is superior to placebo and appears to be similar in efficacy to several alternative antibacterial regimens. Further studies involving larger numbers of patients are needed to clarify the comparative therapeutic and prophylactic efficacy of sulbactam/ampicillin and alternative antibacterial drugs. Nonetheless, sulbactam/ampicillin improves the therapeutic and prophylactic efficacy of an antibacterial of familiar safety, and must be seen as a worthwhile advance.

Abstract: The antibacterial effectiveness of penicillins, cephalosporins, and other β-lactam antibiotics depends on the inactivation of transpeptidases involved in bacterial cell wall synthesis. Bacteria that are resistant to β-lactam antibiotics often produce enzymes called β-lactamases that inactivate the antibiotics by catalyzing the hydrolytic opening of the β-lactam ring to give products devoid of antibacterial activity. One approach to combating antibiotic resistance caused by β-lactamase is to inhibit the enzyme. Effective combinations of enzyme inhibitors with β-lactam antibiotics such as penicillins or cephalosporins result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. The most important β-lactamases to inhibit clinically are the gram-positive penases, the gram-negative TEM, which are Richmond-Sykes type III, and the gram-negative chromosomal cephalosporinases–cephases which are Richmond-Sykes type I. These enzymes may be referred to as penase, TEM(III), and cephase(I). These clinically important β-lactamases are serine proteases that form an acyl enzyme intermediate with β-lactam substrates and β-lactam-derived β-lactamase inhibitors. A number of β-lactamase-resistant penicillins and cephalosporins were found to be β-lactamase inhibitors. No clinically useful inhibitors have been identified from this class. Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important β-lactamases, including penases and Richmond-Sykes types II, III, IV, V, VI (Bacteroides). Carbapenems are another class of natural product β-lactamase inhibitors. Many penem β-lactamase inhibitors are potent antibacterials. Penicillanic acid sulfone, (2(S)-cis)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylic acid (sulbactam) (, ), C8H11NO5S, is a weak antibacterial, but is a potent irreversible inactivator of many β-lactamases, including penases and Richmond-Sykes type II, III, IV, V, and VI (Bacteroides) β-lactamases. Sulbactam is better than clavulanic acid against type I cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sulfones have been reported to be β-lactamase inhibitors. Among penam β-lactamase inhibitors, of 6-β-bromopenicillanic acid, a potent inhibitor, has progressed to clinical trials. Although a broad range of β-lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid manufactured by SmithKline Beecham is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin, C15H16N2O6S, has the trade name, Timentin. The oral version of sulbactam in combination with ampicillin, produced by Pfizer is called Unasyn Oral, which is the mutual prodrug sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any β-lactam antibiotic as Betamaze. Keywords: Carbenem; Clavulanic acid; Penems; Mechanisms; Antibiotics; Enzymes; Bacteria; Penicillins; Cephalosporins; Monobactams

Abstract: Sulbactam (1) is a beta-lactamase inhibitor with limited oral bioavailability. Lipophilic double-ester prodrug sulbactam pivoxil (2) significantly improves the oral absorption of sulbactam, as does the mutual prodrug double ester sultamicillin (3). We have found that double-ester prodrugs of sulbactam terminating in a carboxyl group (8) also were effective oral-delivery vehicles in rats. Carboxyl-terminated double esters have several potential advantages over their nonionizable lipophilic counterparts, including water solubility, crystallinity, choice of salts for dosage forms, and formation of innocuous byproducts on hydrolysis.