Pseudomonas aeruginosa ExoU-associated virulence in HCT recipients and patients with hematologic malignancies

Pseudomonas aeruginosa remains a signi ﬁ cant pathogen in patients undergoing chemotherapy for hematologic malignancies (HMs) and hematopoietic cell transplant (HCT) recipients. 1,2 Studies on the outcome determinants of P. aeruginosa infections in these patients have largely focused on host factors, initiation of appropriate antibacterial therapy, and resistance to antibiotics. 1,3-7 In contrast, there is a relative paucity of data pertaining to the role of intrinsic P. aeruginosa virulence factors in disease severity and outcomes in these speci ﬁ c patient populations. The P. aeruginosa ExoU enzyme is a phospholipase that causes cell membrane damage, leading to cell death, and is 1 of 4 enzymes delivered into the host cell by the type 3 secretion system, with the others being ExoS, ExoT, and ExoY. 8,9 Of these, ExoU plays the greatest role in P. aeruginosa pathogenesis and disease severity; 10,11 however, not all P. aeruginosa isolates contain exoU . 12 In vitro infection with exoU+ isolates results in greater cytotoxicity and increased virulence in mouse models of infection. 10,11,13-15 In humans, the exoU+ genotype has been associated with increased early (5 day) mortality during bacteremia. 16,17 However, not all studies have recapitulated these ﬁ ndings. 18,19 Furthermore, although some studies have included oncology and patients with HCT as minority subsets of the overall study population, 16-19 no study, to our knowledge, has examined the role of ExoU in disease severity exclusively in patients with HMs and recipients of HCT, in whom unique host factors preclude the extrapolation of data from existing studies. Therefore, we performed this study to determine whether the exoU+ genotype is associated with early disease severity of P. aeruginosa in HCT recipients and patients with HMs. We conducted a retrospective review of P. aeruginosa bloodstream infections (BSIs) and pneumonia that occurred between 1 October 2016 and 30 June 2020 in adult (age ≥ 18 years) patients with HMs and recipients of HCT at Oregon Health and Science University (OHSU). The study was approved by the OHSU institutional review board and conducted in accordance with the Declaration of Helsinki. The de ﬁ nitions and criteria for BSI episodes, pneumonia, appropriate empirical antimicrobial therapy, and multidrug resistant P. aeruginosa have been previously published. 20,21 At OHSU, levo ﬂ oxacin is used for neutropenic prophylaxis, unless contraindicated. Cefepime is the ﬁ rst-line agent for the empirical treatment of febrile neutropenia, with piperacillin-tazobactam and meropenem being second-and third-line agents, respectively. Adjunctive empirical tobramycin is used at the discretion of medical teams, typically for patients with septic shock and/or suspicion of infection with multidrug resistant P. aeruginosa , while awaiting susceptibility data to guide de ﬁ nitive therapy; combination therapy for the duration of de ﬁ nitive therapy is not standard practice. P. aeruginosa isolates from blood cultures and bronchoalveolar lavage ﬂ uid (BALF) from patients meeting the de ﬁ nition of pneumonia were obtained from the OHSU Clinical Microbiology Laboratory.