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 Carbapenem-resistant Pseudomonas Aeruginosa

Pseudomonas aeruginosa is a known cause of many dermatologic manifestations, including severe and even fatal infections such as ecthyma gangrenosum and burn wound infections. CRPA is a serious and growing pathogen and is mostly seen in neutropenic cancer patients. Risk factors for acquiring CRPA infections includes a prolonged hospitalization and intensive care unit stay, diabetes mellitus, and prior surgery. The strongest predictors for CRPA infection are history of CRPA infection, tracheostomy, and carbapenem use within 30 days.[49]

A suitable option for the treatment of CRPA SSTIs is ceftazidime–avibactam or ceftolozane–tazobactam. The INFORM Surveillance Program identified that 98.7% of CRPA SSTI isolates were susceptible to ceftazidime–avibactam in the United States[7] and that ceftazidime–avibactam and ceftolozane–tazobactam were the most active compounds against P. aeruginosa after colistin.[50] For CRPA isolates, however, their susceptibility rates to both drugs dropped by 27 and 21%, respectively, whereas colistin retained a susceptibility rate of 99%.[50] Resistance to ceftazidime mostly occurs through AmpC induction and resistance to both antibiotics simultaneously was because of AmpD mutations.[51] Although these studies were not directly related to SSTIs, it would be appropriate to test the susceptibility of CRPA isolates against ceftazidime–avibactam and ceftolozane–tazobactam and initiate treatment whenever possible. If found to be resistant, polymyxins are an indispensable alternative, despite their nephrotoxicity and ototoxicity.

Imipenem–relebactam has excellent activity against CRPA because of the ability of relebactam to inhibit the imipenem-hydrolyzing AmpC enzymes and evade the up-regulated efflux pumps.[34–36,52,53]

Cefiderocol was found to have the strongest activity against MDR P. aeruginosa strains when compared with other antipseudomonal agents. It was shown to be more potent in vitro compared with ceftazidime–avibactam and ceftolozane–tazobactam.[54] Delafloxacin and finafloxacin are novel fluoroquinolones that exhibit antipseudomonal activity. Delafloxacin received FDA approval in June 2017 for the treatment of acute SSTIs and was found to be noninferior to other antibacterial agents against MRSA and P. aeruginosa in phase 3 trials.[55,56]

Murepavadin, a first-in-class antibiotic targeting outer membrane proteins, was shown to be very potent against CRPA, as well as ceftolozane–tazobactam-resistant and colistin–resistant strains. This agent retained potent in-vitro activity against MDR and extensively drug-resistant strains of P. aeruginosa and was four-to-eight-folds more active than polymyxins.[57,58] There were two clinical trials investigating murepavadin's safety and efficacy in respiratory infections that were prematurely terminated because of the high rates of renal failures in the murepavadin arm ( identifiers NCT02096315 and NCT02096328). A topical formulation of the drug is currently being developed and may have a promising role in the future of CRPA SSTI treatment[54]