Nosocomial pneumonia, which is often associated with mechanical ventilation, is one of the most common hospital-acquired infections and is associated with high mortality.1, 2 Crude mortality estimates range from 20% to 50%;3 infections caused by multidrug-resistant bacteria are associated with a particularly high mortality risk.4 Rising multidrug resistance among Gram-negative pathogens, including Pseudomonas aeruginosa and Enterobacteriaceae (Enterobacterales), is widely recognised as a major public health issue globally.5, 6, 7 Resistant pathogens are especially problematic in critically ill patients, who are at high risk of adverse clinical outcomes,7 and in whom up to 20–30% of cases of ventilator-associated pneumonia due to P aeruginosa are caused by multidrug-resistant strains.8 New treatment options for nosocomial pneumonia are therefore urgently needed.
Previous large phase 3 trials9, 10, 11 in patients with nosocomial pneumonia have been unable to show non-inferiority of several novel drugs (eg, tigecycline, doripenem, and ceftobiprole) to established therapies. However, underdosing of these novel drugs might have contributed to the negative results.12, 13, 14 Many patients with nosocomial pneumonia are critically ill, and the pharmacokinetic and pharmacodynamic profiles for antimicrobials in such patients are frequently complex, potentially leading to rapid drug elimination and changes in volume of distribution.12 Additionally, drug concentrations in the lungs are often lower than those in plasma,12 and causative pathogens in nosocomial pneumonia often have reduced antibacterial susceptibility.15, 16, 17 The combination of these factors could lead to insufficient drug concentrations at the infection site, and thus antibacterial dosing regimens in patients with nosocomial pneumonia should be carefully optimised.12
Research in context
Evidence before this study
Nosocomial pneumonia is one of the most common and serious hospital-acquired infections (crude mortality 20–50%). We searched PubMed with terms including “hospital-acquired pneumonia”, “ventilator-associated pneumonia”, “phase 3”, and “randomised” for randomised, controlled trials published in any language between July 1, 2009, and July 1, 2019, that assessed antibacterial agents for the treatment of nosocomial pneumonia. Full details of the search are provided in the appendix (p 33). Previous clinical trials showed higher mortality at 28 days in patients with ventilated hospital-acquired pneumonia than in those with ventilator-associated pneumonia. Nosocomial pneumonia is frequently caused by Gram-negative pathogens, including Pseudomonas aeruginosa and Enterobacteriaceae. Selection of appropriate antibacterial therapy is increasingly complicated by the rising incidence of multidrug resistance among these key causative pathogens, and this problem is widely recognised as a major, global public health issue. New safe and effective antibacterial drugs are thus urgently needed, but phase 3 trials of novel drugs tigecycline, doripenem, and ceftobiprole were unsuccessful. Ceftolozane–tazobactam, a novel combination of a potent anti-pseudomonal cephalosporin and a β-lactamase inhibitor, is approved for complicated urinary tract and intra-abdominal infections. Its profile suggests that it would also be an efficacious treatment for Gram-negative nosocomial pneumonia.
Added value of this study
This trial is the first randomised, controlled study to assess the efficacy and safety of ceftolozane–tazobactam for nosocomial pneumonia, an infection for which additional treatment options are urgently needed. Unlike most non-inferiority studies of other novel antibacterial agents in the same clinical setting, we enrolled only mechanically ventilated patients—specifically, those with ventilator-associated pneumonia or ventilated hospital-acquired pneumonia, who have higher mortality than non-ventilated patients with nosocomial pneumonia. Notably, on the basis of pharmacokinetic–pharmacodynamic modelling, we selected a dose of ceftolozane–tazobactam that was twice that approved for other indications. Ceftolozane–tazobactam was non-inferior to meropenem in both the primary endpoint of 28-day all-cause mortality and the key secondary endpoint of clinical response at the test-of-cure visit, irrespective of causative pathogens (most commonly Enterobacteriaceae and P aeruginosa). It also seemed to be well tolerated in this critically ill population, with a low incidence of treatment-related adverse events.
Implications of all the available evidence
High-dose ceftolozane–tazobactam can be used to treat nosocomial pneumonia caused by P aeruginosa (including multidrug-resistant strains), Enterobacteriaceae (including producers of extended-spectrum β-lactamases), and other Gram-negative pathogens.
Ceftolozane–tazobactam is a novel combination anti-bacterial consisting of ceftolozane (a potent anti-pseudomonal cephalosporin) and tazobactam (a β-lactamase inhibitor).18 It is approved for complicated urinary tract and intra-abdominal infections at a dose of 1·5 g (ie, 1 g ceftolozane and 0·5 g tazobactam) every 8 h.19 Ceftolozane–tazobactam is active in vitro against many important pathogens associated with nosocomial pneumonia, including multidrug-resistant pseudomonal species and Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs),15, 19 and had good lung penetration in two phase 1 trials20, 21 (one of which was done in critically ill patients undergoing mechanical ventilation). These findings suggest that the combination would be efficacious against Gram-negative nosocomial pneumonia.
We therefore aimed to assess the efficacy and safety of ceftolozane–tazobactam compared with meropenem (an established, broad-spectrum, first-line treatment) in patients with nosocomial pneumonia. To ensure sufficient drug concentrations in patients' lungs, we used a new dosing regimen for ceftolozane–tazobactam (ie, double the dose approved for other indications).21, 22, 23
