Sultamicillin

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Abstract
Sultamicillin is the tosylate salt of the double ester of sulbactam plus ampicillin. Sulbactam is a semisynthetic β-lactamase inhibitor which, in combination with ampicillin, extends the antibacterial activity of the latter to include some β-lactamase-producing strains of bacteria that would otherwise be resistant. The combination ofsulbactam plus ampicillin for parenteral use has previously been shown to be clinically and bacteriologically effective in a variety of infections. The chemical linkage of sulbactam and ampicillin has now produced an orally effective compound, sultamicillin, with antibacterial activity and clinical efficacy which are similar to those of the parenteral formulation. Sultamicillin has been shown to be clinically effective in non-comparative trials in patients with infections of the respiratory tract, ears, nose and throat, urinary tract, skin and soft tissues, as well as in obstetric and gynaecological infections, and in the treatment of gonorrhoea. In a small number of controlled trials, sultamicillin has shown comparable clinical efficacy to phenoxymethyl penicillin (penicillin V) and to amoxycillin (alone and in combination with clavulanic acid) in the treatment of paediatric streptococcal pharyngitis and acute otitis media, respectively; to cefaclor in the treatment of acute otitis media in adults; and to bacampicillin, cloxacillin and flucloxacillin plus ampicillin in skin and soft tissue infections in adults, children and adult diabetic patients, respectively. Sultamicillin was superior in efficacy to bacampicillin in the treatment of chronic respiratory infections, to cefaclor in the treatment of acute otitis media in adults, and to cefadroxil in the treatment of patients with complicated urinary tract infections. However, in single-dose treatment of uncomplicated gonorrhoea, sultamicillin (1500mg plus probenecid 1g) was inferior to a 2g intramuscular dose of spectinomycin. While in several studies the incidence of diarrhoea associated with sultamicillin was greater than that with comparative antibacterials, sultamicillin-associated diarrhoea was generally mild and transitory, although occasionally severe enough to necessitate discontinuation of treatment. Further studies in larger groups of patients are needed to clarify the therapeutic efficacy and safety of sultamicillin in comparison with other antibacterial regimens, and to determine the optimum single dosage for the treatment of gonorrhoea. Nonetheless, sultamicillin appears to provide a similar pharmacodynamic and pharmacokinetic profile to that of parenteral sulbactam plus ampicillin and, as such, will extend the therapeutic efficacy of ampicillin, with the further advantage of allowing treatment of patients with an oral formulation, thus avoiding the potentially adverse clinical and financial effects of prolonged parenteral therapy. Sulbactam effectively inhibits β-lactamases of Richmond & Sykes types II, III, IV and V, and to a lesser degree Richmond and Sykes type I. Although 2 to 5 times less potent an inhibitor of β-lactamases than clavulanic acid on a weight-for-weight basis, equivalent inhibition can be achieved at the dosage levels of sulbactam used clinically. The in vitro protein binding of sulbactam and ampicillin was 29.2 and 25.6%, respectively, and the mean volumes of distribution of both sulbactam and ampicillin were similar. Distribution of both drugs after oral administration of single doses of sultamicillin has been demonstrated in sputum, sinus aspirates, bile, purulent ascites, wound exudates and middle ear effusions, as well as in tissue from various organs, including tonsils, gallbladder, appendix and genital organs. Sulbactam and ampicillin cross the placenta and are present in maternal milk for up to 6 hours after a dose of sultamicillin. in several-fold reductions in the MIC of ampicillin for most species of Enterobacteriaceae and methicillin-resistant staphylococci, although methicillin-resistant staphylococci should be considered resistant clinically regardless of whether the MIC indicates susceptibility. The 1 : 1 ratio of sulbactam plus ampicillin has also demonstrated inhibitory activity against strains of Branhamella catarrhalis, Acinetobacter spp. and penicillinase-producing strains of Neisseria gonorrhoeae. The bactericidal activity of sultamicillin is considered to be largely due to the ampicillin component, although sulbactam alone has inhibitory activity in vivo against strains of N. gonorrhoeae, Neisseria meningitidis and Acinetobacter calcoaceticus. The minimum bactericidal concentrations of sulbactam plus ampicillin are generally only 1 dilution higher than the MIC, except for the few strains of S. aureus which are tolerant of β-lactam antibacterial drugs. Sultamicillin is hydrolysed by enzymes in the intestinal wall, releasing sulbactam and ampicillin in equimolar proportions. No intact sultamicillin reaches the portal circulation at the doses used clinically. A close relationship exists between the pharmacokinetic handling of both sulbactam and ampicillin. Both time to peak plasma concentrations (approximately 1 hour) and profile of elimination are similar for the 2 drugs. However, the peak plasma concentration of ampicillin administered as sultamicillin is higher than that achieved with an equivalent dose of ampicillin alone, yielding an in vivo plasma ratio of ampicillin : sulbactam of 1.6 : 1 to 2.5 : 1 in some studies. Peak plasma concentrations of both sulbactam and ampicillin are proportional to dose, and accumulation has not occurred in short term multiple-dose trials. The in vitro protein binding of sulbactam and ampicillin was 29.2 and 25.6%, respectively, and the mean volumes of distribution of both sulbactam and ampicillin were similar. Distribution of both drugs after oral administration of single doses of sultamicillin has been demonstrated in sputum, sinus aspirates, bile, purulent ascites, wound exudates and middle ear effusions, as well as in tissue from various organs, including tonsils, gallbladder appendix and genital organs. Sulbactam and ampicillin cross the placenta and are present in maternal milk for up to 6 hours after a dose of sultamicillin. Sultamicillin is excreted primarily in the urine as sulbactam and ampicillin. Metabolism has not been reported in humans. Percentage urinary recovery over 8 hours after a single dose ranged from 41 to 66% for sulbactam and from 46 to 80% for ampicillin, and peak urine concentrations were 200 mg/L and 400 mg/L, respectively. Neither food nor antacid affected the rate or extent of elimination of either drug; however, coadministration of sultamicillin with probenecid delayed the renal excretion and prolonged the serum half-lives of both sulbactam and ampicillin. Small amounts of both drugs have been recovered in bile and faeces. The mean elimination half-life of sulbactam ranged from 0.65 to 1.20 hours and was similar to that of ampicillin (0.74 to 1.33 hours) in healthy volunteers. The elimination half-life is prolonged in patients with renal disease. Cumulated results in 2,187 adult and paediatric patients included in non-comparative therapeutic trials provided an overall efficacy rate (defined as a good to excellent clinical response to treatment) of 80%. Percentage efficacy by type of infection was 79% for respiratory tract infections, 81% for urinary tract infections (including gonorrhoea), 58% for ear, nose and throat infections, 84% for soft tissue infections, 97% for obstetric and gynaecological infections, and 80% for ophthalmic infections. The bacteriological eradication rate was 83% of 1,872 strains tested, including 65% of ampicillin-resistant strains. In non-comparative studies sultamicillin was clinically effective in the treatment of acute purulent exacerbations of chronic bronchitis in adults and in H. influenzae infections in children with cystic fibrosis or other chronic obstructive pulmonary disease. In addition, in a randomised, double-blind, placebo-controlled comparison in parallel groups of patients with various respiratory infections, sultamicillin was superior to bacampicillin (an ester of ampicillin), producing a good to excellent clinical response in 83% of patients as opposed to 70% in the latter group (p = 0.03); when patients were grouped according to type of infection, sultamicillin was superior to bacampicillin in patients with chronic infections (p = 0.0177) but not in those with acute infections (pneumonia or lung abscess). However, a lower than usual dosage of bacampicillin was used in this study. In several controlled comparative trials in paediatric patients with ear, nose and throat infections, sultamicillin was similar in efficacy to oral phenoxymethyl penicillin in the treatment of streptococcal pharyngitis, and to oral amoxycillin, with or without clavulanic acid, in acute otitis media. However, relapses and reinfections were common. In adult patients, sultamicillin was similar in efficacy to cefaclor in acute lacunar tonsillitis, but superior to the cephalosporin (p N. gonorrhoeae (96 and 100% cure rates), but much less effective against penicillinase-producing strains (64 and 71% cure rates). Further comparative trials using higher single doses of sultamicillin in combination with probenecid for the treatment of gonorrhoea are needed. Sultamicillin was generally effective in the treatment of various skin and soft tissue infections of surgical and non-surgical origin with most studies reporting cure rates of 75% or more. It was as effective as oral cloxacillin in the treatment of children with impetigo and other soft tissue infections due to S. aureus and Streptococcus pyogenes, although neither regimen was considered optimum. Sultamicillin was also similar in efficacy to bacampicillin in adult patients with skin and soft tissue infections, and to flucloxacillin plus ampicillin in adult diabetic patients whose treatment for various skin and soft tissue infections had been initiated with the parenteral formulations of the antibacterial drugs. The overall incidence of adverse effects reported in a total of 3,005 patients in Japanese clinical trials was 7.2%, the only symptoms with an incidence of greater than 1% being diarrhoea (3.7%) and soft stools (1.1%). However, in non-Japanese clinical trials, most of which assessed paediatric patients, the incidence of diarrhoea was much higher, generally ranging from 10 to more than 50%. Diarrhoea was usually mild and transitory, resolving either during treatment with sultamicillin or soon after the end of therapy. However, in a few cases diarrhoea was severe or prolonged and required cessation of treatment. Haemorrhagic colitis due to Clostridium difficile was a rare complication. The diarrhoea appears to be due to a reduction in the number of anaerobic bacteria. The only laboratory abnormalities of note associated with sultamicillin administration were transient elevations in liver function tests (ALT, AST) in 2.7% of patients, and rare reports of eosinophilia and hypoprothrombinaemia. Sultamicillin is available in a tablet dosage form containing 375mg sultamicillin tosylate. The usual adult dose is 375mg administered orally 2 to 3 times daily, taken with an adequate amount of water to avoid lodgement in the oesophagus and potential ulceration. No information on paediatric dosages is available. Sultamicillin is contraindicated in patients with a history of allergy to any of the penicillins and in patients with infectious mononucleosis, the latter contraindication suggesting caution in its administration to patients with pharyngitis of unknown aetiology. Caution should be exercised in administering sultamicillin to patients receiving allopurinol and to malnourished or debilitated patients in whom symptoms of vitamin K deficiency may occur. Patients with renal dysfunction should receive reduced dosages of sultamicillin in accordance with the usual practice for ampicillin.