Laporte-Amargos, J. (J.)
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- Efficacy of extended infusion of β-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE)(2020) Garcia-Vidal, C. (C.); Arnan, M. (M.); Tebe, C. (C.); Padullés, A. (A.); Puerta-Alcalde, P. (Pedro); NO USAR del-Pozo, J.L. (José Luis); Parody, R. (Rocío); Carmona-Torre, F. (Francisco de A.); Videla, S. (S.); Muñoz, C. (C.); Laporte-Amargos, J. (J.); Tubau, F. (F.); Huguet, M. (M.); Rigo-Bonnin, R. (R.); Carratalà, J. (Jordi); Batlle, M. (M.); Gudiol, C. (Carlota); Sureda-Balari, A. M. (Anna Maria); Albasanz-Puig, A. (Adaia)Background: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal βlactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. Methods: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. Discussion: Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes. Trial registration: European Clinical Trials Database: EudraCT 2018–001476-37. ClinicalTrials.gov, ID: NCT04233996.
- Real-life use of ceftolozane/tazobactam for the treatment of bloodstream infection due to Pseudomonas aeruginosa in neutropenic hematologic patients: a matched control study (ZENITH study)(2022) Garcia-Vidal, C. (C.); Doernberg, S.B. (Sarah B.); Clerici, T.D. (Teresa Daniela); Capilla, S. (Silvia); González-Barca, E. (Eva); Fernández-Cruz, A. (Ana); Puerta-Alcalde, P. (Pedro); Drgona, L. (Lubos); Machado, M. (Marina); Fortún, J. (Jesús); Petrikova, L. (Lucía); Pozo, J.L. (José Luis) del; DeVoe, C. (Catherine); Carmona-Torre, F. (Francisco de A.); Laporte-Amargos, J. (J.); Oltolini, C. (Chiara); Van-Duin, D. (David); Durà-Miralles, X. (Xavier); Hakki, M. (Morgan); Gasch, O. (Oriol); Martín-Dávila, P. (Pilar); Ruiz-Camps, I. (Isabel); Carratalà, J. (Jordi); Gudiol, C. (Carlota); Peghin, M. (Maddalena); Mikulska, M. (Malgorzata); Álvarez-Uría, A. (Ana); Magnasco, L. (Laura); Pallarès, N. (Natàlia); Novo, A. (Andrés); Bergas, A. (Alba); Castaldo, N. (Nadia); Aguilar-Company, J. (Juan); Albasanz-Puig, A. (Adaia)We sought to assess the characteristics and outcomes of neutropenic hematologic patients with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) treated with ceftolozane-tazobactam (C/T). We conducted a multicenter, international, matched-cohort study of PA BSI episodes in neutropenic hematologic patients who received C/T. Controls were patients with PA BSI treated with other antibiotics. Risk factors for overall 7-day and 30-day case fatality rates were analyzed. We compared 44 cases with 88 controls. Overall, 91% of episodes were caused by multidrug-resistant (MDR) strains. An endogenous source was the most frequent BSI origin (35.6%), followed by pneumonia (25.8%). There were no significant differences in patient characteristics between groups. C/T was given empirically in 11 patients and as definitive therapy in 41 patients. Treatment with C/T was associated with less need for mechanical ventilation (13.6% versus 33.3%; P = 0.021) and reduced 7-day (6.8% versus 34.1%; P = 0.001) and 30-day (22.7% versus 48.9%; P = 0.005) mortality. In the multivariate analysis, pneumonia, profound neutropenia, and persistent BSI were independent risk factors for 30-day mortality, whereas lower mortality was found among patients treated with C/T (adjusted OR [aOR] of 0.19; confidence interval [CI] 95% of 0.07 to 0.55; P = 0.002). Therapy with C/T was associated with less need for mechanical ventilation and reduced 7-day and 30-day case fatality rates compared to alternative agents in neutropenic hematologic patients with PA BSI. IMPORTANCE Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited. Our study is unique because it is focused on extremely immunosuppressed hematological patients with neutropenia and bloodstream infection (BSI) due to PA (mainly multidrug resistant [MDR]), a scenario which is often associated with very high mortality rates. In our study, we found that the use of C/T for the treatment of MDR PA BSI in hematological neutropenic patients was significantly associated with improved outcomes, and, in addition, it was found to be an independent risk factor associated with increased survival. To date, this is the largest series involving neutropenic hematologic patients with PA BSI treated with C/T. Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited.
- Pseudomonas aeruginosa bloodstream infections in patients with cancer: differences between patients with hematological malignancies and solid tumors(2022) Isler, B. (Burcu); Manzur, A. (Adriana); Kern, W. (Winfried); Calik, S. (Sebnem); Yáñez, L. (Lucrecia); Pena, M. (Marta); Herrera, F. (Fabián); Montejo, M. (Miguel); Márquez-Gómez, I. (Ignacio); Puerta-Alcalde, P. (Pedro); Brunel, A.S. (Anne Sophie); Drgona, L. (Lubos); Kanj, S. (Souha); NO USAR del-Pozo, J.L. (José Luis); Akova, M. (Murat); Maestro-de-la-Calle, G. (Guillermo); Laporte-Amargos, J. (J.); Oltolini, C. (Chiara); Royo-Cebrecos, C. (Cristina); Hemmatti, P. (Philipp); Marin, J.I. (Jorge Iván); Tilley, R. (Robert); Gasch, O. (Oriol); Martín-Dávila, P. (Pilar); Ruiz-Camps, I. (Isabel); Carratalà, J. (Jordi); Araos, R. (Rafael); Gudiol, C. (Carlota); García, E. (Estefania); Peghin, M. (Maddalena); Mikulska, M. (Malgorzata); Paz-Morales, H.M. (Hugo Manuel); Montero, M.M. (Maria Milagro); Novo, A. (Andrés); Palacios-Baena, Z.R. (Zaira R.); Abdala, E. (Edlon); Sipahi, O. (Oguz); Gomes, M.Z.R. (Marisa Z. R.)Objectives: To assess the clinical features and outcomes of Pseudomonas aeruginosa bloodstream infection (PA BSI) in neutropenic patients with hematological malignancies (HM) and with solid tumors (ST), and identify the risk factors for 30-day mortality. Methods: We performed a large multicenter, retrospective cohort study including onco-hematological neutropenic patients with PA BSI conducted across 34 centers in 12 countries (January 2006-May 2018). Episodes occurring in hematologic patients were compared to those developing in patients with ST. Risk factors associated with 30-day mortality were investigated in both groups. Results: Of 1217 episodes of PA BSI, 917 occurred in patients with HM and 300 in patients with ST. Hematological patients had more commonly profound neutropenia (0.1 x 10(9) cells/mm) (67% vs. 44.6%; p < 0.001), and a high risk Multinational Association for Supportive Care in Cancer (MASCC) index score (32.2% vs. 26.7%; p = 0.05). Catheter-infection (10.7% vs. 4.7%; p = 0.001), mucositis (2.4% vs. 0.7%; p = 0.042), and perianal infection (3.6% vs. 0.3%; p = 0.001) predominated as BSI sources in the hematological patients, whereas pneumonia (22.9% vs. 33.7%; p < 0.001) and other abdominal sites (2.8% vs. 6.3%; p = 0.006) were more common in patients with ST. Hematological patients had more frequent BSI due to multidrug-resistant P. aeruginosa (MDRPA) (23.2% vs. 7.7%; p < 0.001), and were more likely to receive inadequate initial antibiotic therapy (IEAT) (20.1% vs. 12%; p < 0.001). Patients with ST presented more frequently with septic shock (45.8% vs. 30%; p < 0.001), and presented worse outcomes, with increased 7-day (38% vs. 24.2%; p < 0.001) and 30-day (49% vs. 37.3%; p < 0.001) case-fatality rates. Risk factors for 30-day mortality in hematologic patients were high risk MASCC index score, IEAT, pneumonia, infection due to MDRPA, and septic shock. Risk factors for 30-day mortality in patients with ST were high risk MASCC index score, IEAT, persistent BSI, and septic shock. Therapy with granulocyte colony-stimulating factor was associated with survival in both groups. Conclusions: The clinical features and outcomes of PA BSI in neutropenic cancer patients showed some differences depending on the underlying malignancy. Considering these differences and the risk factors for mortality may be useful to optimize their therapeutic management. Among the risk factors associated with overall mortality, IEAT and the administration of granulocyte colony-stimulating factor were the only modifiable variables.