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

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

Disclosures

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

In This Article

Management of Skin and Soft Tissue Infection by Carbapenem-resistant Enterobacteriaceae

The frequency of CRE in SSTIs is estimated to be around 1%.[7] The Consortium on Resistance Against Carbapenem in Klebsiella pneumoniae and Other Enterobacteriaceae (CRACKLE-1) encompassed a cohort of 142 patients with a documented CRE skin or soft tissue culture and found that the most common wound type with CRE infection or colonization were pressure ulcers (34%) and surgical site infections (30%).[8] Patients who were admitted from long-term care facilities were more prone to CRE SSTIs and were less likely to undergo surgical debridement.

Treatment of SSTIs in patients who had a long course of antibiotics prior to hospitalization, admission from a long-term facility, pressure ulcers, wounds in the lower extremities, abdomen or perineum, and a history of diabetes mellitus require coverage for CRE.[9] In view of the limited data on the management of MDR-GNB SSTIs, physicians often rely on combination therapy or therapy with novel antibiotics.

Tigecycline has an excellent activity against CREs and CRAB and can be used at a high dose or in combination to achieve a good response.[10] When novel antibiotics are not available, the extended infusion of carbapenems can be used when the minimal inhibitory concentration (MIC) is 8 mg/l or less.

Ceftazidime–avibactam was found in the REPRISE trial to be effective in the treatment of MDR-GNB when compared with the best available therapy (BAT).[11] Three hundred and seventeen out of the 333 enrolled patients had CRE infections, mostly complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs), and ceftazidime–avibactam was found to be effective, especially when the mechanism of resistance is KPC or OXA-48 production. Table 2 summarizes the activity of novel antibiotics, such as ceftazidime–avibactam, on multidrug-resistant organisms.

Polymyxins have activity against both KPC and MBL-producing CREs. Recent observational studies demonstrated an improvement in the clinical success rates and an added benefit with the addition of carbapenems to polymyxins in the management of KPC and VIM-producing CRE.[12] Due to the recent increase in polymyxin resistance, epidemiological patterns should tailor second-line therapies in combining polymyxins with a carbapenem, tigecycline, or aminoglycoside. A recent study demonstrated that the combination of polymyxin B and ceftazidime–avibactam was successful in the treatment of polymyxin B heretoresistant K. pneumoniae in vitro.[13]

Cefiderocol is a novel cephalosporin conjugated with a catechol siderophore on its side chain. It is active against all classes of β-lactamases, including KPC and OXA-producers, and MBLs. Its characteristically efficient cell entry and stability to β-lactamase hydrolysis allows it to overcome all mechanisms of β-lactamases.[14] A large study demonstrated potent in-vitro activity and an inhibition of 96% of clinical isolates of CRE, MDR A. baumannii, MDR P. aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia.[15]

Eravacycline is a synthetic fluorocycline antibiotic that inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit, and covers a broad range of GNB including MDR E. coli, K. pneumoniae, A. baumannii, and Bacteroides spp. It is superior to tetracyclines in its increased potency in vitro, fewer drug interactions, and good activity in biofilm.[16] The Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE1) trial compared eravacycline to ertapenem in the management of cIAI and showed noninferiority to ertapenem and potent activity against MDR Enterobacteriaceae.[17] The IGNITE4 trial showed noninferiority to meropenem with a clinical cure rate of 87.5% in patients with MDR Enterobacteriaceae cIAI.[18] IGNITE2 and IGNITE3 compared oral and intravenous eravacycline to levofloxacin in the treatment of cUTIs but have both failed to result in noninferiority to date (ClinicalTrials.gov identifiers NCT01978938 and NCT03032510).

Plazomicin is a next-generation semisynthetic aminoglycoside that inhibits bacterial protein synthesis. Contrary to traditional aminoglycosides, it evades aminoglycoside-modifying enzymes (AMEs), and provides effective activity against Enterobacteriaceae, including CREs.[19–23] Plazomycin was approved by the Federal and Drug Administration (FDA) for the management of cUTI in June 2018. A trial examined plazomicin versus colistin in patients with CRE infection combined with meropenem or tigecycline.[24] Although the study was prematurely terminated because of low enrollment, preliminary findings indicated that plazomicin was associated with a reduced all-cause mortality at 28 days compared with colistin for CRE bloodstream infections and with a safer adverse effect profile.[24] A recent study found plazomicin to be active against CRE isolates from SSTI,[25] but robust trials are required to contextualize the therapeutic role of this agent in SSTIs.

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