Difficult-to-treat (DTR) Pseudomonas aeruginosa harboring Verona-Integron metallo-β-lactamase (blaVIM): infection management and molecular analysis

Abstract

Pseudomonas aeruginosa harboring Verona Integron-encoded metallo-β-lactamase enzymes (VIM-CRPA) have been associated with infection outbreaks in several parts of the world. In the US, however, VIM-CRPA remain rare. Starting in December 2018, we identified a cluster of cases in our institution. Herein, we present our epidemiological investigation and strategies to control/manage these challenging infections. This study was conducted in a large academic healthcare system in Miami, FL, between December 2018 and January 2022. Patients were prospectively identified via rapid molecular diagnostics when cultures revealed carbapenem-resistant P. aeruginosa. Alerts were received in real time by the antimicrobial stewardship program and infection prevention teams. Upon alert recognition, a series of interventions were performed as a coordinated effort. A retrospective chart review was conducted to collect patient demographics, antimicrobial therapy, and clinical outcomes. Thirty-nine VIM-CRPA isolates led to infection in 21 patients. The majority were male (76.2%); the median age was 52 years. The majority were mechanically ventilated (n = 15/21; 71.4%); 47.6% (n = 10/21) received renal replacement therapy at the time of index culture. Respiratory (n = 20/39; 51.3%) or bloodstream (n = 13/39; 33.3%) were the most common sources. Most infections (n = 23/37; 62.2%) were treated with an aztreonam-avibactam regimen. Six patients (28.6%) expired within 30 days of index VIM-CRPA infection. Fourteen isolates were selected for whole genome sequencing. Most of them belonged to ST111 (12/14), and they all carried bla_VIM-2 chromosomally. This report describes the clinical experience treating serious VIM-CRPA infections with either aztreonam-ceftazidime/avibactam or cefiderocol in combination with other agents. The importance of implementing infection prevention strategies to curb VIM-CRPA outbreaks is also demonstrated.

Keywords: Pseudomonas aeruginosa; Verona Integron metallo-beta-lactamase; antimicrobial stewardship; carbapenemase; infection prevention.

Fig 1

Microbiology automatic reflex testing for multi-drug resistant Pseudomonas aeruginosa. Abbreviations: C/T, ceftolozane-tazobactam; CZA, ceftazidime-avibactam; I/R, imipenem-cilastatin-relebactam.

Fig 2

(A) Tree depicting relatedness among isolates; (B) map depicting genetic context of bla_VIM-2 and its position within two representative P. aeruginosa chromosomes.

Fig 3

Isolate susceptibilities and targeted VIM therapies. Includes all infectious episodes treated per patient; only the first isolate per infection. For bacteremia cases, the source isolate also listed when applicable. All doses adjusted for renal impairment by our ASP pharmacists. Abbreviations: BAL, bronchoalveolar lavage; DDKT, deceased donor kidney transplant; EOT, end of therapy; ET, endotracheal; inh, inhaled; IU, international units; IV, intravenous; MIC, minimum inhibitory concentration; OM, osteomyelitis; PNA, pneumonia; PO, by mouth drugs; AMK, amikacin; GEN, gentamicin; TOB, tobramycin; MEM, meropenem; LVX, levofloxacin; FOF = fosfomycin. ^aTotal duration of ATM plus CZA, or FDC backbone; alternative agents used empirically or as adjunction therapy are listed with their total durations in parenthesis. ^bCefiderocol and imipenem–cilastatin–relebactam approved and first available at our institution. ^cLevofloxacin breakpoint changed for Pseudomonas. ^dCLSI breakpoints for polymyxin B changed for Pseudomonas beginning Jan 2020: <2, intermediate; >4, resistant; no susceptible breakpoint. ^eSecond hospitalization during the study period.

Fig 4

Timeline and epidemiological curve of VIM-CRPA cases by month of onset. Includes only the first isolate identified per patient; POU: point-of-use.