REVIEW

Sulbactam-containing b-lactamase inhibitor combinationsM. Akova

Department of Medicine, Section of Infectious Diseases, Hacettepe University School of Medicine,Ankara, Turkey

ABSTRACT

Sulbactam irreversibly inhibits the hydrolytic activity of b-lactamases. This compound is commerciallyavailable in combination with either ampicillin or cefoperazone. In each instance, the activity of thepartner antibiotic against b-lactamase-producing bacteria is restored. One of the particular advantages ofusing sulbactam-containing combinations is that sulbactam itself has inherent activity against someAcinetobacter baumannii. Sulbactam combinations have not demonstrated strong selective pressures forextended-spectrum b-lactamase-producing Enterobacteriaceae and vancomycin-resistant enterococci. Incontrast to clavulanate, sulbactam does not induce class I (Ampc) chromosomal b-lactamases inEnterobacteriaceae.

Keywords Ampicillin, b-lactamase inhibitors, cefoperazone, sulbactam

Clin Microbiol Infect 2008; 14 (Suppl. 1): 185188

INTRODUCTION

b-Lactamase inhibitors are themselves b-lactamantibiotics, usually with minimal or no antibac-terial activity. When combined with certainb-lactam antibiotics, they augment the potencyof these against b-lactamase-producing bacteria.Three b-lactamase inhibitors (sulbactam, clavula-nate and tazobactam) are commercially available.Sulbactam is combined with either ampicillin orcefoperazone and this review briefly outlines thein-vitro and clinical characteristics of these com-binations.

CHEMICAL STRUCTURE ANDRELATED ACTIVITY

Sulbactam is chemically a penicillanic acidsulphone and shows particular activity againstclass A enzymes. However, compared with cla-vulanate and tazobactam, sulbactam is a lesspotent inhibitor of this class, particularly forSHV-1 [1]. Against class C b-lactamases, sulbac-

tam is more potent than clavulanate, whereasactivity against class D enzymes is less potentthan against class A b-lactamases. Similarly,OXA-type enzymes are not as well inhibitedby sulbactam as TEM-1 and other clinically usedinhibitors.

In general, b-lactamase inhibitors have negligi-ble antimicrobial activity themselves, but restoreantimicrobial activity to other b-lactams whenused in combination. However, sulbactam isexceptional in that it has intrinsic activity againstAcinetobacter spp. [2,3] and Bacteroides fragilis.High-affinity binding to penicillin-binding pro-tein 2 of these organisms is responsible for thisactivity [2].

Paradoxically, b-lactamase inhibitors, particu-larly clavulanate, may induce production ofb-lactamases in some Gram-negative bacteria,causing autagonism of their partner b-lactamases[4]. No such activity has been described withsulbactam [5].

IN-VITRO ACTIVITY

Early studies reported that more than 90% ofstrains, among a variety of organisms, wereinhibited at 4 mg L with a fixed ratio (1:2) ofsulbactam and ampicillin [6]. These includedmethicillin-susceptible Staphylococcus aureus,

Corresponding author and reprint requests: M. Akova,Department of Medicine, Section of Infectious Diseases,Hacettepe University School of Medicine, Ankara 06100,TurkeyE-mail: makova@hacettepe.edu.tr

2008 The AuthorJournal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 1), 185188

Staphylococcus epidermidis, B. fragilis, Haemophilusinfluenzae, Moraxella catarrhalis, Escherichia coli,Klebsiella pneumoniae and Proteus spp. However,recent trials have indicated increasing resistanceto sulbactamampicillin. In a study with a total of3134 aerobic and facultative Gram-negative bacil-li, sulbactamampicillin was the least active agentamong the 12 antibiotics tested against E. coli andKlebsiella spp., with susceptibility rates of 56%and 73%, respectively [7]. Extended-spectrum b-lactamases (ESBLs) were detected in 7% of E. coliand 13% of Klebsiella spp. isolates.

In the absence of CLSI criteria, in-vitro stud-ies have used cefoperazone breakpoints forreporting the susceptibility results for sulbac-tamcefoperazone. Thus, resistance was definedas 64 mg L with a fixed ratio (2:1) of cefope-razone and sulbactam (the latter was used at8 mg L), intermediate susceptibility as32 16 mg L and susceptibility as

supplemental doses are recommended after dial-ysis [13]. However, only 4% of cefoperazone isremoved with the same intervention, and themain route of excretion for this drug is via thebiliary tract. Thus, in patients with a creatinineclearance of

tious in using sulbactam combinations for infec-tions due to these organisms.

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2008 The AuthorJournal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 1), 185188