Which trial do we need? One or two antimicrobials with anti-pseudomonal activity for the empirical treatment of ventilator-associated pneumonia due to Gram-negative bacteria

Ventilator-associated pneumonia (VAP) is the second most common nosocomial infection in the intensive care unit (ICU), and it is associated with significant morbidity and mortality [ 1 Kollef M.H. Shorr A.F. Bassetti M. Timsit J.F. Micek S.T. Michelson A.P. et al. Timing of antibiotic therapy in the ICU. Crit Care. 2021; 25: 1-10https://doi.org/10.1186/s13054-021-03787 Crossref PubMed Scopus (0) Google Scholar ]. Inadequate antibiotic therapy for VAP has been associated with twice higher risk of death [ 1 Kollef M.H. Shorr A.F. Bassetti M. Timsit J.F. Micek S.T. Michelson A.P. et al. Timing of antibiotic therapy in the ICU. Crit Care. 2021; 25: 1-10https://doi.org/10.1186/s13054-021-03787 Crossref PubMed Scopus (0) Google Scholar ]. Gram-negative bacteria are the most common pathogens causing VAP, particularly Pseudomonas aeruginosa, which is responsible for around 25% of VAP [ 2 Kollef M.H. Chastre J. Fagon J.Y. François B. Niederman M.S. Rello J. et al. Global prospective epidemiologic and surveillance study of ventilator-associated pneumonia due to pseudomonas aeruginosa. Crit Care Med. 2014; 42: 2178-2187https://doi.org/10.1097/ccm.0000000000000510 Crossref PubMed Scopus (0) Google Scholar ]. Due to its importance, both the Infectious Disease Society of America (IDSA) and the European Society for Infectious Diseases, suggests that combination therapy with two antimicrobials with activity against P. aeruginosa should be used as empirical therapy in patients with specific conditions, which are generally similar in both guidelines and include the presence of risk factors for multidrug-resistant (MDR) bacteria and a more severe presentation of VAP, such as acute severe distress syndrome and/or septic shock [ 3 Torres A. Niederman M.S. Chastre J. Ewig S. Fernandez-Vandellos P. Hanberger H. et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur Respir J. 2017; 501700582https://doi.org/10.1183/13993003.00582-2017 Crossref Scopus (753) Google Scholar , 4 Kalil A.C. Metersky M.L. Klompas M. Muscedere J. Sweeney D.A. Palmer L.B. et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016; 63 (–111): e61https://doi.org/10.1093/cid/ciw353 Crossref PubMed Scopus (2177) Google Scholar ]. Yet, this recommendation from both guidelines is conditional and based on low-quality evidence. The rationale for the recommendation is that double therapy would increase the probability of early appropriate antibiotic coverage [ 3 Torres A. Niederman M.S. Chastre J. Ewig S. Fernandez-Vandellos P. Hanberger H. et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur Respir J. 2017; 501700582https://doi.org/10.1183/13993003.00582-2017 Crossref Scopus (753) Google Scholar , 4 Kalil A.C. Metersky M.L. Klompas M. Muscedere J. Sweeney D.A. Palmer L.B. et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016; 63 (–111): e61https://doi.org/10.1093/cid/ciw353 Crossref PubMed Scopus (2177) Google Scholar ] which has been shown to decrease mortality in severely ill patients with sepsis or septic shock [ 5 Kumar A. Safdar N. Kethireddy S. Chateau D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study. Crit Care Med. 2010; 38: 1651-1664https://doi.org/10.1097/ccm.0b013e3181e96b91 Crossref PubMed Scopus (0) Google Scholar ]. Moreover, synergy can be expected by adding a second anti-pseudomonal drug, which is most commonly reported with in vitro the combination of a β-lactam and an aminoglycoside [ 6 Giamarellou H. Aminoglycosides plus β-lactams against gram-negative organisms: evaluation of in vitro synergy and chemical interactions. Am J Med. 1986; 80: 126-137https://doi.org/10.1016/0002-9343(86)90490-0 Abstract Full Text PDF PubMed Scopus (93) Google Scholar ], but no clinical replication has validated these in vitro data. Another potential benefit is the prevention of the development of mutational resistance, as shown in vitro [ 7 Mouton J.W. Combination therapy as a tool to prevent emergence of bacterial resistance. Infection. 1999; 27 (S24–8)https://doi.org/10.1007/bf02561666 Crossref PubMed Scopus (100) Google Scholar ]. However, the addition of a second drug may increase the incidence of adverse effects, such as pharmacodermies, nephrotoxicity, Clostridioides difficile infection, and it might increase the development of MDR bacteria due to selective pressure secondary to more antibiotic exposure with combination therapy [ 8 Paul M. Leibovici L. Editorial commentary: combination therapy for Pseudomonas aeruginosa bacteraemia: where do we stand?. Clin Infect Dis. 2013; 57: 217-220https://doi.org/10.1093/cid/cit220 Crossref PubMed Scopus (29) Google Scholar ]. This is of particular concern with P. aeruginosa infections because, in addition to acquired resistance, these microorganisms pursue multiple constitutive efflux pumps that affect a broad range of antimicrobial classes, mainly fluoroquinolones, but also aminoglycosides [ 9 Potron A. Poirel L. Nordmann P. Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: mechanisms and epidemiology. Int J Antimicrob Agents. 2015; 45: 568-585https://doi.org/10.1016/j.ijantimicag.2015.03.001 Crossref PubMed Scopus (514) Google Scholar ]. Notably, both recommendations were made previously to the recent changes in aminoglycosides breakpoints of both the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (https://www.eucast.org/eucastguidancedocuments) and Clinical & Laboratory Standards Institute (CLSI) (CLSI document M100Ed33; 2023).