Sulbactam/Ampicillin

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Abstract
Sulbactam is a semisynthetic β -lactamase inhibitor which when combined with certain β-lactam antibacterials extends their activity against bacteria that are normally resistant to the antibiotic due to production of β -lactamases. In combination with ampicillin 1 it extends the antibacterial activity of ampicillin to include β-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. Sulbactam is an effective inhibitor of β-lactamases of the Richmond types II, III, IV and V. Some isolated type I β-lactamases have been inhibited by sulbactam, although this is variable and less marked. Sulbactam appears to be generally less potent than clavulanic acid against β-lactamases on a weight-for-weight basis. However, the higher tissue concentrations of sulbactam, its greater stability and lesser likelihood of inducing chromosomal β-lactamases than clavulanic acid tends to offset the difference in potency. Sulbactam alone has only weak antibacterial activity against most bacterial species except Neisseria gonorrhoeae and Neisseria meningitidis. However, the addition of sulbactam to ampicillin in vitro increases the susceptibility to ampicillin of ampicillin-resistant (penicillinase-producing) strains of Gram-positive and Gram-negative aerobic bacteria and anaerobic bacteria. The combination of sulbactam plus ampicillin in a 1:2 ratio is inhibitory [minimum inhibitory concentration (MIC) ⩽ 8 mg/L] against ampicillin-resistant strains of Staphylococcus aureus, Haemophilus influenzae and Bacteroides species, and results in several-fold reductions in the MICs of ampicillin alone for most species of Enterobacteriaceae and methicillin-resistant staphylococci. The minimum bactericidal concentrations of sulbactam plus ampicillin against ampicillin-resistant strains of S. aureus, H. influenzae and B. fragilis are generally only 1-fold dilution higher (i.e. twice as high) than the MICs except for strains of S. aureus which are tolerant of β-lactam antibacterial drugs. Sulbactam is poorly absorbed orally. However, sulfamicillin, the tosylate salt of the double ester of sulbactam and ampicillin which is intended for oral administration (not discussed in this review), is well absorbed after oral administration. Following administration of single intravenous doses of sulbactam 0.5g or 1g to healthy volunteers the data fit a 2-compartment pharmacokinetic model. Coadministration of sulbactam plus ampicillin by intravenous bolus injection results in no significant changes in serum concentrations, areas under the serum concentration/time curve and urinary recoveries for both drugs from those reported with the administration of each drug alone. Following 15-minute infusions of sulbactam 1g plus ampicillin 2g to healthy male volunteers, mean peak serum sulbactam concentrations were approximately 60 and 120 mg/L, respectively. Sulbactam plus ampicillin is completely bioavailable following intramuscular administration; doses of sulbactam 0.5g plus ampicillin 1g resulted in mean peak serum sulbactam concentrations of 13 and 18 mg/L, respectively. When multiple doses of sulbactam 0.5g were administered 6-hourly for 3 days to healthy volunteers no significant accumulation was seen. The apparent volume of distribution of sulbactam at steady-state was 17.2L following infusion of 0.5g or 1g over 15 minutes. In volunteers administered sulbactam plus ampicillin in a 1:2 ratio intravenously over 15 minutes the volume of distribution of ampicillin (1g or 2g) was almost identical to that of sulbactam. Sulbactam achieves concentrations in blister fluid, intraperitoneal fluid and intestinal mucosa of approximately double the ampicillin concentrations when equivalent doses are administered, but the reverse relationship is seen in female genital tissues and bile. Sulbactam also distributes into the sputum and cerebrospinal fluid, passes into the placenta and is excreted into breast milk. The elimination half-life of sulbactam, approximately 1 hour, is almost identical to that of ampicillin when the drugs are administered simultaneously in a 1: 1 or 1: 2 ratio. Sulbactam is not metabolised, but is excreted primarily in the urine (glomerular filtration and tubular secretion) with a small amount being recovered in bile and faeces. Probenecid decreases renal elimination and increases the half-lives of sulbactam and ampicillin, as does renal function impairment. These pharmacokinetic variables are similarly affected in premature neonates, paediatric patients and elderly colorectal surgery patients, whereas in pregnant women at term the half-lives of sulbactam and ampicillin are reduced (30 to 40 minutes). Cumulated results in several hundred adult and paediatric patients included in open and comparative studies from Europe, North America and Asia reveal therapeutic efficacy (defined as clinical cure or improvement, plus eradication of the initial pathogen) in 79% of gynaecological infections, 83% of respiratory tract infections and over 90% of urinary tract, skin and skin structure, bone and joint, intra-abdominal, ear, nose and throat and blood infections. 79% of Haemophilus species, 83% of staphylococci and over 85% of streptococci, Enterobacteriaceae, Neisseriaciae and Bacteroides species were eradicated. In 2 double-blind comparative studies in patients with intra-abdominal infections (perforated or gangrenous appendicitis and peritonitis, respectively) clinical efficacy rates (clinical cure or improvement) with sulbactam 1g plus ampicillin 2g 6-hourly were approximately 88%, versus efficacy rates of 97% or more with gentamicin 1.5 mg/kg 8-hourly plus clindamycin 600mg 6-hourly. However, in the appendicitis study a greater percentage of patients with perforated appendix were randomised to the sulbactam plus ampicillin group, which could have affected the results. In this study Pseudomonas species were isolated from 5 of the 8 (62.5%) sulbactam plus ampicillin treatment failures but from only 12 of the 57 (21%) patients who were cured with this antibacterial combination. Pseudomonas species are not usually susceptible to this combination. Several small comparative studies which did not provide statistical analyses of their results have assessed the clinical efficacy of sulbactam 2g to 4g daily plus ampicillin 4g to 8g daily (1:2 ratio) in obstetric and gynaecological infections (mostly acute salpingitis); the percentages of patients cured or improved with sulbactam plus ampicillin were generally within approximately 10% of the percentages obtained with cefoxitin or with gentamicin plus metronidazole or clindamycin, suggesting at least a similar therapeutic efficacy. Sulbactam 2g to 4g daily plus ampicillin 4g to 8g daily (1:2 ratio) also appeared to be similar in therapeutic efficacy to several alternative antibacterial regimens in small studies of skin, soft tissue, bone and joint infections. Single intramuscular doses of sulbactam 0.5 or 1g plus ampicillin 1 or 2g (1:2 ratio) administered concurrently with oral probenecid 1g have proven to be an effective treatment for Neisseria gonorrhoeae infections, including those due to penicillinase-producing strains and strains showing relative resistance to ampicillin. In a study in 81 infants and children with bacterial meningitis, due in most instances to β-lactamase-producing Haemophilus influenzae type B, Streptococcus pneumoniae or Neisseria meningitidis, sulbactam 50 mg/kg/day plus ampicillin 400 mg/kg/day appeared to be similar in clinical efficacy to ampicillin 400 mg/kg/day plus chloramphenicol 100 mg/kg/day. In the prophylaxis of infectious complications of surgery, sulbactam plus ampicillin, administered shortly prior to or concurrently with the induction of anaesthesia, appears to be superior in efficacy to placebo and similar in efficacy to several alternative antibacterial regimens, such as gentamicin plus metronidazole, latamoxef (moxalactam), cefoxitin, and metronidazole plus cephazolin or cefotaxime (gastrointestinal surgery); ampicillin plus metronidazole (gynaecological surgery); and cefoxitin (transurethral surgery). While in many of these studies the prophylactic regimen was continued for the 24 hours following surgery, in several of the studies sulbactam/ampicillin efficacy was demonstrated with the single preoperative dose. Overall, sulbactam plus ampicillin is well tolerated. Among 1764 patients administered the combination, injection site pain, which can be minimised by diluting the intramuscular dose with lignocaine (lidocaine), was the most frequently reported adverse effect (3.6% of patients). Diarrhoea (1.9% of patients) and phlebitis (1.2% of patients) are the only other side effects reported with a frequency greater than 1%. The most frequently reported laboratory abnormalities associated with sulbactam/ampicillin administration are transiently elevated liver function tests (ALT, AST and lactic dehydrogenase). As with many antibacterial drugs, the possibility of superinfection with mycotic or bacterial pathogens exists during therapy or prophylaxis with sulbactam/ampicillin. Sulbactam plus ampicillin in a 1: 2 concentration ratio is available as a combination product for parenteral (intravenous or intramuscular) injection. The recommended adult therapeutic dosage of the combination is 1.5 to 12g daily (representing 0.5 to 4g sulbactam plus 1g to 8g ampicillin) in divided doses every 6 to 8 hours. In less severe infections the interval between doses may be increased to 12 hours. For children, infants and neonates the recommended therapeutic dosage of the combination is 150 mg/kg/day (sulbactam 50 mg/kg/day plus ampicillin 100 mg/kg/day). For prophylaxis of surgical infections in adults 1.5 to 3g of the combination product is recommended at induction of anaesthesia and may be repeated up to 6-hourly for up to 24 hours. Sulbactam/ampicillin can be given by bolus intravenous injection over at least 3 minutes or intravenous infusion over 15 to 30 minutes. Sulbactam plus ampicillin may also be administered by deep intramuscular injection; if pain is experienced the dose may be dissolved in 0.5% lignocaine. Sulbactam/ampicillin is contraindicated in individuals with a history of allergy to the penicillins and in patients with mononucleosis. Sulbactam/ampicillin should not be administered to patients receiving allopurinol or disulfiram.

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