Sulbactam sodium is a semisynthetic beta-lactamase inhibitor obtained by oxidation of the thiazolidine sulfur of penicillanic acid (English et al., 1978). It exhibits good activity against the clinically important plasmid-mediated beta-lactamases most frequently responsible for transferred drug resistance. It is somewhat less potent than clavulanic acid in that respect. Unlike clavulanic acid, it is active against inducible chromosomally mediated enzymes which cause resistance to third-generation cephalosporins (Jacobs et al., 1986; Klastersky and Van der, 1989; Sawai and Yamaguchi, 1989).

The medication is marketed in combination with ampicillin (trade name Unasyns in the USA), which is generally administered parenterally. The structure of sulbactam is shown in Figure 12.1.

For intravenous use, ampicillin–sulbactam (AMP/S) is available in vials containing 1 g ampicillin and 0.5 g sulbactam or 2 g ampicillin and 1 g sulbactam. Data from comparative studies justify the use of the combination of drugs in a 2:1 ratio (Foulds, 1986). Orally, the medication is usually administered in the form of the mutual prodrug sultamicillin.
Cefoperazone, a third-generation cephalosporin, can also be combined with sulbactam (Bodey et al., 1989). In clinical trials, the two drugs were combined both in a 1:1 ratio (Horiuchi et al., 1989) and in a 2:1 ratio (Bodey et al., 1993).

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

Sulbactam alone possesses moderate antibacterial activity related to its affinity for penicillin-binding proteins (Aswapokee and Neu, 1978). It mainly acts against Neisseria and Acinetobacter spp. The antibacterial activity of AMP/S is much broader, including penicillinase- and nonpenicillinase-producing staphylococci and streptococci, Gramnegative pathogens including Neisseria, Moraxella, Haemophilus, and Enterobacteriaceae, and anaerobes such as anaerobic streptococci, clostridia, and Bacteroides spp. 

MECHANISM OF DRUG ACTION

Sulbactam inhibits the hydrolysis of a variety of beta-lactams, but the exact mechanism of action is not well understood (English et al., 1978; Fu and Neu, 1979; Wise et al., 1980). The drug is recognized by betalactamases and forms an acyl enzyme by reacting with the active site serine hydroxyl group. The intermediate then leads to an irreversibly inhibited enzyme form.

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

For intravenous usage, ampicillin and sulbactam are administered in a 2:1 ratio. For adults, doses have ranged from 1 g of ampicillin plus 0.5 g of sulbactam every 8 hours to 2 g of ampicillin plus 1 g of sulbactam every 6 hours (see Chapter 15, Ampicillin–Sulbactam) (Foulds, 1986). For resistant organisms, higher dosages may be considered, including up to 24 g ampicillin/12 g sulbactam daily (Betrosian et al., 2007).

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

The pharmacokinetics of ampicillin is not affected by co-administration of sulbactam (Foulds et al., 1983). Approximately 28% of ampicillin and 38% of sulbactam is bound to human serum protein. 

b. Drug distribution

Sulbactam is distributed in bile, bronchial secretions, cartilage, cerebrospinal fluid, and peritoneal fluid. Although sulbactam appears in breast milk, the concentration is too low to be clinically significant. For a broader discussion regarding the drug distribution of AMP/S.

c. Clinically important pharmacokinetic and pharmacodynamic features

There are few data regarding the pharmacokinetics and pharmacodynamics of sulbactam alone. Most information relates to AMP/S.

d. Excretion

Between 75% and 85% of ampicillin and sulbactam is excreted by the kidneys. Sulbactam is also excreted in bile.

e. Drug interactions

Most drug–drug interaction data regarding sulbactam are related to the AMP/S combination (see Chapter 15, Ampicillin–Sulbactam), including the fact that concurrent use of allopurinol and ampicillin has been associated with an increase in the frequency of rash due to ampicillin (Jick and Porter, 1981).

TOXICITY

Almost all toxicity data regarding sulbactam relate to its use in combination with ampicillin as AMP/S. Overall, however, the drug is generally well tolerated, other than occasional pain at the site of intravenous injection. Severe rare reactions include erythema multiforme, exfoliative dermatitis, and toxic epidermal necrolysis (Arca et al., 2005). Hypersensitivity reactions in the form of anaphylactic reactions, angioedema, and urticaria have been described. The most common adverse event is diarrhea, which occurs in approximately 3% of patients. Other gastrointestinal adverse events include nausea and vomiting. The use of the antibiotic has been associated with pseudomembranous colitis (Bartlett, 1981). Interstitial nephritis has been reported as an adverse event (Gilbert et al., 1970). Ampicillin at high doses has been associated with seizures (Hodgman et al., 1984); however, seizures have not been reported with the use of AMP/S.  
Ampicillin–sulbactam is classified as a pregnancy category B medication since there are no well-controlled studies in humans. Both ampicillin and sulbactam are considered compatible with breastfeeding. Although sulbactam appears in breast milk, the concentration is too low to be clinically significant.  

CLINICAL USES OF THE DRUG

a. Multidrug-resistant Acinetobacter calcoaceticus–baumannii

Sulbactam is effective in treating severe nosocomial infections caused by multidrug-resistant (MDR) Acinetobacter calcoaceticus–baumannii, including carbapenem-resistant Acinetobacter. Its use as a sole agent has not been approved by the US Food and Drug Administration (FDA).

Bacteremia

The treatment of choice for bacteremia due to Acinetobacter spp. has not been established. There are no clinical trials comparing the use of a beta-lactam with or without the use of an aminoglycoside. Current evidence supports the use of AMP/S for bacteremia if the organism is susceptible to the drug. In a retrospective study of 48 patients with bacteremia conducted at a university hospital, AMP/S was deemed to be at least as effective as imipenem–cilastatin (Jellison et al., 2001). There was no statistically significant difference between days of bacteremia and success or failure during or at the end of treatment.

Pneumonia

In a single case series report, AMP/S was used for the treatment of imipenem-resistant Acinetobacter pneumonia (Urban et al., 1993). The medication was suggested to be effective as nine of ten patients improved clinically; however, the data were limited by the diagnostic techniques used. Moreover, there was no comparison group. In a retrospective study, a total of 77 episodes of Acinetobacter ventilatorassociated pneumonia (VAP) in 75 patients were evaluated. Fourteen patients were treated with AMP/S and 63 with imipenem/cilastatin. The two drugs had similar efficacy in this small group of critically ill trauma patients (Wood et al., 2002). Patients in the sulbactam group tended to have longer hospital stays; however, this was thought to be due to the later onset of pneumonia and not to lower efficacy of the antibiotic. Adjunctive aminoglycoside therapy was more frequently used in the sulbactam group.

Meningitis

In a report of eight cases of nosocomial meningitis related to head trauma or neurosurgical procedures and due to Acinetobacter, the MIC of these isolates to AMP/S was o8/4 mg/ml (i.e. susceptible) (Jimenez-Mejias et al., 1997). All A. baumannii isolates were resistant to cefotaxime, ceftriaxone, ceftazidime, ureidopenicillins, ciprofloxacin, and gentamicin; seven isolates were resistant to imipenem. Six patients were cured and two died of the disease. All extermal or ventriculoperitoneal cerebrospinal fluid (CSF) shunts were removed. The mortality rate was similar to that reported in previous studies (Siegman-Igra et al., 1993). The authors concluded that sulbactam may be an effective treatment option for carbapenem-resistant Acinetobacter meningitis.

b. Other uses

AMP/S in combination with probenecid has been used in the treatment of uncomplicated gonorrhoea (Kim et al., 1986; Odugbemi, 1988; Ngeow et al., 1991). However, sulbactam or AMP/S administered alone are not clinically effective despite their in vitro activity.

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