Combination Therapy for Carbapenem-resistant Gram-negative Bacteria

Alexandre P Zavascki; Jurgen B Bulitta; Cornelia B Landersdorfer


Expert Rev Anti Infect Ther. 2013;11(12):1333-1353. 

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Other Agents


Sulbactam is a β-lactamase inhibitor with a chemical structure similar to β-lactams. It is commercially available mainly in combination with ampicillin or cefoperazone. However, sulbactam clearly has intrinsic activity against A. baumannii isolates by binding to penicillin-binding proteins and contributes the major part of the activity in the combinations with ampicillin or cefoperazone.[197] There is reasonable clinical experience with sulbactam against A. baumannii,[39,198,199] but few studies have assessed the PK/PD of this agent, particularly against CR A. baumannii. Nonetheless, an experimental study demonstrated that fT>MIC is the PK/PD index that best correlates with sulbactam efficacy.[200] Although no specific target has been defined, sulbactam was as efficacious as imipenem against A. baumannii, when the sulbactam fT>MIC was similar to that of imipenem.[200] In a recent in vitro PD model of A. baumannii infection with human-simulated exposures of ampicillin/sulbactam, the fT>MIC of sulbactam against the three sulbactam non-susceptible isolates (MIC: 16–32 mg/l) was 50–65% with 3 g sulbactam every 8 h as 4 h infusion, compared with 5–30% with 1 g of sulbactam every 6 h over 30 min.[201] Extended infusion regimens achieved significantly more bacterial reduction against these non-susceptible isolates than standard 30 min infusions[201] .

Only recently, a study has evaluated the PK/PD of sulbactam using Monte Carlo simulations.[202] This study predicted that doses of 2 g sulbactam given as 4 h infusions every 8 h had a probability of 97% to achieve concentrations above the MIC of 4 mg/l (CLSI susceptibility breakpoint) over 40% of the dosing interval.[202] With this extended infusion, administration of 4 g every 8 h achieved a probability of target attainment (PTA) for fT>MIC ≥40% of 97% for an MIC of 8 mg/l. Considering these recent data and that sulbactam presents a relatively good stability at 37°C for up to 24 h[203] it should be considered as an adjuvant drug when the MIC is ≤4 mg/l, and potentially when the MICs are 8 or 16 mg/l. Extended infusion is recommended.


Aztreonam is a monobactam antibiotic with a similar mechanism of action compared with other β-lactams such as cephalosporins.[204] The monobactam class is 'unique' among the clinically available β-lactams in its capacity of not being hydrolyzed by metallo-β-lactamases;[11] thus, aztreonam is an important therapeutic option against metallo-β-lactamase-producing CR GNB.[11,205] The major cause for its limited use is that the vast majority of metallo-β-lactamase-producing isolates also produce extended spectrum β-lactamases and/or AmpC enzymes that can hydrolyze aztreonam.[11] In practice, it is only an option for a few isolates that produce metallo-β-lactamase and do not express other broad spectrum β-lactamases that inactivate aztreonam. However, considering its low potential for AmpC induction,[206] it may be a good option even for Enterobacteriaceae isolates with inducible chromosomal AmpC β-lactamases, if there is susceptibility in vitro. Aztreonam may also be a valuable component of β-lactam plus aminoglycoside combination therapies.[207,208]

There are few PK/PD studies available with aztreonam, but in a murine thigh infection model with human simulated doses, 2 g aztreonam every 6 h over 30 min was able to reach a fT>MIC of 100, 90, 65 and 38% against isolates with aztreonam MICs ≤4 (CLSI susceptibility breakpoint), 8, 16 and 32 mg/l, respectively.[209] Hence, aztreonam might be considered even for some non-susceptible isolates, in particular for combination therapies.