Imipenem Resistance of Enterobacter aerogenes Mediated by Outer Membrane Permeability

Abstract

Multidrug-resistant Enterobacter aerogenes strains are increasingly isolated in Europe and especially in France. Treatment leads to imipenem resistance, because of a lack of porin. We studied the evolution of resistance in 29 strains isolated from four patients during their clinical course. These strains belonged to the prevalent epidemiological type observed in France in previous studies (C. Bosi, et al., J. Clin. Microbiol. 37:2165–2169, 1999; A. Davin-Regli et al., J. Clin. Microbiol. 34:1474–1480, 1996). They also harbored a TEM-24 extended-spectrum β-lactamase-coding gene. Thirteen strains were susceptible to gentamicin and resistant to imipenem and cefepime. All of the patients showed E. aerogenes strains with this resistance after an imipenem treatment. One patient showed resistance to imipenem after a treatment with cefpirome. Twelve of these 13 strains showed a lack of porin. Cessation of treatment with imipenem for three patients was followed by reversion of susceptibility to this antibiotic and the reappearance of porins, except in one case. For one patient, we observed three times in the same day the coexistence of resistant strains lacking porin and susceptible strains possessing porin. The emergence of multidrug-resistant E. aerogenes strains is very disquieting. In our study, infection by E. aerogenesincreased the severity of the patients' illnesses, causing a 100% fatality rate.

Membrane permeability, a pivotal function involved in antibiotic resistance and virulence in Enterobacter aerogenes clinical isolates

“…In the third stage, the isolate was resistant to imipenem and presented an over-expression of efflux pumps conjointly with loss of the main porins, and an alteration of LPS. The complete loss of the two major porins and the LPS alteration were clearly involved in strains exhibiting a high level of resistance to imipenem and polymyxin as previously suggested [5,6].…”

“…After treatment including imipenem, the collected E. aerogenes isolates were devoid of porin and resistant to b-lactams. When the antibiotic treatment was removed, the imipenem susceptibility and the expression of porins were recovered [5,6]. This suggests the involvement of a regulator controlling their expression and a pivotal role of these outer membrane proteins in bacterial survival in the patient body, as recently mentioned for Salmonella enterica, Klebsiella pneumoniae and Escherichia coli strains [1,3,4].…”

Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria

“…It should be mentioned that similar observations have been made with E. aerogenes and Enterobacter cloacae (Lavigne et al, 2011Pérez et al, 2007Glatz et al, 2010). It is also noted that imipenem treatment is able to select resistant isolates exhibiting a step-by-step adaptative phenotype with first, an efflux overproduction, and second, an efflux overproduction associated with a downexpression of porin (Bornet et al, 2000(Bornet et al, , 2003. These results may explain some previous reports describing a paradoxical b-lactam resistance without the consistent identification of a specific enzyme production or demonstration of a porin alteration and evoking a possible role of efflux in resistant enterobacterial isolates or possibly reflecting AmpC activity based on interpretive reading of wider antibiogram data (Hornsey et al, 2010).…”

“…These isolates are imipenem resistant due to a porin deficiency and express active efflux pumps expelling various unrelated antibiotics including quinolones, tetracycline and chloramphenicol. All strains overexpressed AcrA, indicating the involvement of the AcrAB pump in response to imipenem therapy (Bornet et al, 2000(Bornet et al, , 2003.…”

Cellular impermeability and uptake of biocides and antibiotics in Gram-negative bacteria

“…aeruginosa, antibiotic resistance has been associated with a deficient OprF and OprD (Buscher et al 1987;Godfrey and Bryan 1987;Piddock et al 1987;Quinn et al 1988;Gimeno et al 1996;Dubois et al 2001). In Enterobacter aerogenes, the emergence of multi-drug resistance has been associated with a decrease in outer membrane permeability associated with changes in porins (Charrel et al 1996;Chevalier et al 1999;De et al 2001), although the alteration in porins might be reversible when the selective pressure is removed (Bornet et al 2000). Loss of OmpF has been shown to be among one of the resistance mechanisms elaborated by E. coli against b-lactam antibiotics and fluoroquinolones (Tavio et al 1999).…”