Treatment of Multidrug-resistant Gram-Negative Skin and Soft Tissue Infections

Jean-Francois Jabbour; Sima L. Sharara; Souha S. Kanj


Curr Opin Infect Dis. 2020;33(2):146-154. 

In This Article

Management of Skin and Soft Tissue Infection by Klebsiella Pneumoniae Carbapenemase-producing Carbapenem-resistant Enterobacteriaceae

The favored drug of choice for SSTIs with KPC-producing CREs is ceftazidime–avibactam given that the MIC 8 mg/l or less.[26,27] Compared with colistin, ceftazidime–avibactam was shown to have a lower all-cause 30-day hospital mortality and a better outcome at 30-day disposition.[26] Although relatively infrequent, resistance to ceftazidime–avibactam is being observed, with rates up to 3.7% in China.[28] There are no current guidelines for ceftazidime–avibactam-resistant CRE SSTI treatment, but combination therapy with meropenem was found to be effective.[29]

Other antibiotics that can be used for KPC-producing CREs include the prolonged infusion of agents, such as meropenem–vaborbactam, imipenem/cilastatin–relebactam, or polymyxins. The recent TANGO II randomized trial, which investigated the efficacy and safety of meropenem–vaborbactam versus BAT for CRE infections showed that meropenem–vaborbactam significantly improved clinical cure rates and had lower nephrotoxicity risk and mortality compared with BAT.[30] However, this trial did not include CRE SSTIs, had a small sample size, and the data and safety monitoring board advised to stop randomization to the BAT arm as it was resulting in high risks. In vitro, meropenem–vaborbactam was very active against 99.5% of KPC producers.[31]

Relebactam is a novel β-lactamase inhibitor related to avibactam that has been combined with imipenem/cilastatin to provide effective activity to class A and C β-lactamases.[32] Imipenem/cilastatin-relebactam has demonstrated potent antimicrobial activity against KPC-producers, in vitro and in vivo.[33–36] A trial comparing imipenem/relebactam to colistin and imipenem in patients with imipenem-nonsusceptible bacterial infections found that imipenem/relebactam resulted in higher clinical response rates and lower 28-day mortality compared with colistin, although the study was not powered for statistical inference.[37] As of July 2019, the FDA approved the use of imipenem/cilastatin-relebactam for adults with cUTI and cIAI wherever limited or no alternative treatment options are available.

Ceftaroline fosamil–avibactam has an extended activity to infections caused by Enterobacteriaceae, including strains producing extended spectrum beta-lactamases, KPC, or AmpC.[33,38] Ceftaroline fosamil has been specifically studied in the context of SSTI (mainly for its anti-staphylococcal activity),[39,40] yet there have not been any studies examining the combination with avibactam in the management of MDR-GNB SSTIs.

Intravenous fosfomycin can also be an alternative agent for the treatment of select cases of KPC infections, although studies on SSTIs are scarce. Due to this drug's high predisposition to confer resistance, it is always recommended that fosfomycin be used in combination with either tigecycline or colistin.[41] The combination of fosfomycin with colistin was shown to result in an improved microbiological response in bacteremia and respiratory infections, but there was no effect on survival.[10]