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Combination beta-lactamase inhibitors, carbapenems, and monobactams

Alyssa R Letourneau, MD
Stephen B Calderwood, MD
Section Editor
David C Hooper, MD
Deputy Editor
Allyson Bloom, MD


The spectrum of activity and pharmacology of combination beta-lactamase inhibitors, carbapenems, and monobactams will be reviewed here. The mechanisms of action and resistance and major adverse reactions of the beta-lactam antibiotics, issues related to penicillins and cephalosporins are discussed separately. (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects" and "Penicillin, antistaphylococcal penicillins, and broad-spectrum penicillins" and "Cephalosporins".)


Clavulanate, sulbactam, tazobactam, avibactam, and vaborbactam are beta-lactamase inhibitors that have little intrinsic antibacterial activity but inhibit the activity of a number of plasmid-mediated beta-lactamases [1]. Only avibactam inhibits chromosomally mediated AmpC beta-lactamases, and none inhibit the class B metallo-carbapenemases, such as New Delhi metallo-beta-lactamase [2]. Combination of these agents with ampicillin, amoxicillin, piperacillin, ceftolozane, ceftazidime, and meropenem results in antibiotics with an enhanced spectrum of activity against many, but not all, organisms containing plasmid-mediated beta-lactamases. The addition of avibactam to ceftazidime and vaborbactam to meropenem results in enhanced activity against many, but not all, organisms producing carbapenemases. In addition, sulbactam and tazobactam inhibit the chromosomal beta-lactamase of many Bacteroides species, extending the spectrum of coverage of combinations with these compounds to include Bacteroides as well.

Dosing of combination beta-lactam beta-lactamase inhibitors is listed separately, and the dosing should be modified in the setting of renal failure (table 1). For piperacillin-tazobactam, an extended infusion (eg, 3.375 g infused over four hours every eight hours) is an alternative to standard dosing; in particular, this strategy has been used for critically ill patients or for pathogens with elevated but susceptible minimum inhibitory concentrations. The benefits of extended infusion over standard dosing have been suggested by some studies but not all [3,4]. Overall, this dosing regimen is at least equivalent and may be superior to standard dosing in appropriate patient populations. (See "Prolonged infusions of beta-lactam antibiotics".)

Amoxicillin-clavulanate — Amoxicillin-clavulanate will inhibit most strains of oxacillin-sensitive Staphylococcus aureus and beta-lactamase producing Haemophilus influenzae in addition to the usual organisms inhibited by amoxicillin alone (see "Penicillin, antistaphylococcal penicillins, and broad-spectrum penicillins"). At the high drug concentrations achieved in urine, the combination is also active against certain beta-lactamase producing Enterobacteriaceae. Amoxicillin-clavulanate (250 to 500 mg PO Q 8h or 875 mg PO Q12h) can be used as oral therapy for patients with otitis media, sinusitis, lower respiratory infections, bite wounds, and urinary tract infections [5], although there are no data that this combination is superior to other antibiotics (such as trimethoprim-sulfamethoxazole or the second or third generation oral cephalosporins). (See "Soft tissue infections due to dog and cat bites".)

Ampicillin-sulbactam — Ampicillin-sulbactam is a parenteral formulation that expands the spectrum of ampicillin to include most strains of S. aureus and beta-lactamase producing H. influenzae, some Enterobacteriaceae, and anaerobes (including Bacteroides fragilis). The sulbactam component of ampicillin-sulbactam has activity against many strains of Acinetobacter baumannii. Ampicillin-sulbactam has been used to treat patients with diabetic foot ulcers [6]. This combination has also been used for prophylaxis and therapy of intra-abdominal and pelvic infections instead of cefoxitin. Randomized, double-blind trials showed ampicillin-sulbactam to be equivalent to cefoxitin in prophylaxis for abdominal surgery and in the treatment of intra-abdominal and pelvic infections [7,8]. However, increasing resistance worldwide to ampicillin-sulbactam of both Enterobacteriaceae and B. fragilis in intra-abdominal infections renders this drug combination less useful for this purpose [9-11].

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Literature review current through: Nov 2017. | This topic last updated: Sep 27, 2017.
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