In vitro activity of imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from ICU patients in Spain and Portugal (SUPERIOR and STEP studies)

Abstract

Objectives To study the in vitro activity of imipenem/relebactam and comparators and the imipenem/relebactam resistance mechanisms in a Pseudomonas aeruginosa collection from Portugal (STEP, 2017–18) and Spain (SUPERIOR, 2016–17) surveillance studies. Methods P. aeruginosa isolates (n = 474) were prospectively recovered from complicated urinary tract (cUTI), complicated intra-abdominal (cIAI) and lower respiratory tract (LRTI) infections in 11 Portuguese and 8 Spanish ICUs. MICs were determined (ISO broth microdilution). All imipenem/relebactam-resistant P. aeruginosa isolates (n = 30) and a subset of imipenem/relebactam-susceptible strains (n = 32) were characterized by WGS. Results Imipenem/relebactam (93.7% susceptible), ceftazidime/avibactam (93.5% susceptible) and ceftolozane/tazobactam (93.2% susceptible) displayed comparable activity. The imipenem/relebactam resistance rate was 6.3% (Portugal 5.8%; Spain 8.9%). Relebactam restored imipenem susceptibility to 76.9% (103/134) of imipenem-resistant isolates, including MDR (82.1%; 32/39), XDR (68.8%; 53/77) and difficult-to-treat (DTR) isolates (67.2%; 45/67). Among sequenced strains, differences in population structure were detected depending on the country: clonal complex (CC)175 and CC309 in Spain and CC235, CC244, CC348 and CC253 in Portugal. Different carbapenemase gene distributions were also found: VIM-20 (n = 3), VIM-1 (n = 2), VIM-2 (n = 1) and VIM-36 (n = 1) in Spain and GES-13 (n = 13), VIM-2 (n = 3) and KPC-3 (n = 2) in Portugal. GES-13-CC235 (n = 13) and VIM type-CC175 (n = 5) associations were predominant in Portugal and Spain, respectively. Imipenem/relebactam showed activity against KPC-3 strains (2/2), but was inactive against all GES-13 producers and most of the VIM producers (8/10). Mutations in genes affecting porin inactivation, efflux pump overexpression and LPS modification might also be involved in imipenem/relebactam resistance. Conclusions Microbiological results reinforce imipenem/relebactam as a potential option to treat cUTI, cIAI and LRTI caused by MDR/XDR P. aeruginosa isolates, except for GES-13 and VIM producers.

In vitro activity of antibiotics potentially effective against difficult-to-treat strains of Gram-negative rods: retrospective study

“…There were distinct differences between DTR and non-DTR groups A. baumannii with all DTR being resistant due to OXA carbapenemase production and all non-DTR were susceptible. There are several susceptible strains of DTR P. aeruginosa and Enterobacterales, including producers of class A carbapenemases and carbapenemase non-producers 24 , 25 , 27 , 28 .…”

Rationale and evidence for the use of new beta-lactam/beta-lactamase inhibitor combinations and cefiderocol in critically ill patients

“… From references [ 31 – 35 , 38 , 40 , 42 – 45 , 50 , 51 , 54 , 56 – 60 , 63 , 64 , 66 , 68 , 69 , 74 , 75 ] Susceptibility profiles are indicated for carbapenem-resistant isolates only KPC: Klebsiella pneumoniae carbapenemase; MBL: metallo-β-lactamase; NDM: New-Delhi MBL; MIC: minimal inhibitory concentration a OXA-48 and derivatives (e.g., OXA-181 and OXA-232)—note that these β-lactamases hydrolyze penicillins and carbapenems but not broad-spectrum cephalosporins; b NDM is the main MBL type in Enterobacterales (other types such as VIM are less common); c main efflux pump systems implicated in carbapenem resistance in P. aeruginosa are MexAB-OprM and MexEF-OprN; d various MBL types (VIM, IMP, NDM, SPM)—other carbapenemase types are occasionally documented in P. aeruginosa , including class A (KPC and GES) and C (OXA-48-like) carbapenemases; e mainly OXA-23-, OXA-24/40-, and OXA-58–like enzymes; f ceftolozane–tazobactam is not active against carbapenemase-producing isolates of P. aeruginosa ; g intrinsic resistance or limited susceptibility (species); h activity resting on the combination of aztreonam and avibactam (see the text for explanations); i no defined EUCAST breakpoint (insufficient data) …”

“…From references [ 31 – 35 , 38 , 40 , 42 – 45 , 50 , 51 , 54 , 56 – 60 , 63 , 64 , 66 , 68 , 69 , 74 , 75 ]…”

Management strategies for severe Pseudomonas aeruginosa infections

“…It is effective against class A b-lactamase-producing PA, AmpCproducing PA, and OprD PA (by inducing a downregulation of the OprD expression). It can enhance imipenem activity against imipenem-nonsusceptible isolates of PA, that is, isolates with an eightfold reduction in the MIC of imipenem with a restoration of activity in 70.3-76.9% of the cases [56][57][58].…”