Is Early Antibiotic Administration for Hospital-Acquired Pneumonia Debatable?

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) account for 22% of healthcare-associated infections.¹ Nearly every international society, including the Infectious Diseases Society of America, American Thoracic Society, Society of Critical Care Medicine, and European Respiratory Society, advocate for early and appropriate antimicrobial treatment to curtail infection-associated morbidity and mortality.

This Concise Critical Appraisal reviews a multicenter cohort study by Barbier et al on the prognostic impact of early appropriate antibiotic therapy (EAAT) in patients with gram-negative HAP.² EAAT was defined by the authors as the administration of monotherapy or combination therapy with in vitro activity against the causative gram-negative bacteria at day 0 and/or day 1 of the pneumonia diagnosis . For patients with polymicrobial infections, two antimicrobial agents with activity against all the isolated pathogens must be used. 

The authors retrospectively analyzed 880 patients with HAP or VAP admitted from 2008 through 2019 to 32 French intensive care units to evaluate the impact of EAAT on 28-day all-cause mortality, Sepsis-Related Organ Failure (SOFA) scores, 14-day clinical cure, mechanical ventilation days, and length of stay.

Of the 804 first-episode pneumonias and 252 subsequent episodes of pneumonias, EAAT was used in 61.6% and 37.5% episodes, respectively. The majority (69.2%) of pneumonias were first-episode VAP. Enterobacterales (49.9%) was the predominant gram-negative organism, followed by Pseudomonas (40.3%), for which most of the patients received beta-lactam monotherapy. 

Of the single-episode HAPs, 23.5% were caused by multidrug-resistant gram-negative organisms or polymicrobial infections (14.5%). There was no significant impact on 28-day all-cause mortality, 28-day SOFA score changes using the daily clinical and biological variables, 14-day clinical cure rate, mechanical ventilation days, or length of stay. These findings held true regardless of pneumonia type, causative pathogen, or characteristics of the antimicrobial regimen.

These findings seem to contradict the robust amount of literature directly correlating EAAT with improved morbidity and mortality. This contradiction might be explained by this article’s significant limitations. The data from the relatively small sample size did not capture supportive efforts often used in conjunction with antibiotics (e.g., vasopressors, antibiotic dosing, infection control measures) that have advanced since the data were analyzed. HAP/VAP patients have heterogeneous presentations that cannot be generalized to all critically ill patients with HAP/VAP. The mortality data is heavily impacted by competing risks, including comorbidities, hemodynamic stability, cointerventions, degree of hypoxia or pulmonary involvement, degree of multisystem organ failure, and/or concomitant hospitalization complications. 

The authors found that patients who did not receive EAAT had higher SOFA scores and an increased incidence of infection with multidrug-resistant gram-negative organisms. This, in addition to the higher incidence of septic shock and acute respiratory distress syndrome in the EAAT group, would explain the neutral results. Although most of the patients met the criteria of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), this does not mean they were truly infected. Because the authors did not establish whether the patients were truly infected, misdiagnoses may have confounded the treatment effect.

While the findings of Barbier et al are certainly noteworthy, critical care practitioners must still appreciate the detrimental effects of delayed antimicrobial therapy on clinical outcomes. Particularly in septic patients, clinicians should continue to use rapid diagnostic measures, early appropriate antibiotic prescription, pharmacy and infectious disease involvement, optimal dosing regimens, effective antimicrobial stewardship efforts, and efficient infection control measures.


References:

1. Magill SS, O’Leary E, Janelle SJ, et al.; Emerging Infections Program Hospital Prevalence Survey Team. Changes in prevalence of health care-associated infections in U.S. hospitals. N Engl J Med. 2018 Nov 1;379(18):1732-1744.
2. Barbier F, Buetti N, Dupuis C, et al.; OutcomeRéa Study Group. Prognostic impact of early appropriate antimicrobial therapy in critically ill patients with nosocomial pneumonia due to gram-negative pathogens: a multicenter cohort study. Crit Care Med. 2025 May 1;53(5):e1066-e1079.