Triple combination effective for hospital- and ventilator-acquired pneumonia

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INFECTIOUS DISEASE

Medical writer: Kirsty LEE | Last updated: 10 September 2020 | In: Critical Care Medicine, Pneumonia, Infectious Disease

Article Keywords

cilastatin, VAP, Gram-negative, β-lactam antimicrobial, Gram-positive, β-lactamase, HAP, Imipenem, intra-abdominal infection, piperacillin, relebactam, resistance, tazobactam, carbapenem, urinary tract infection

Pneumonia is the second leading cause of death in Hong Kong as of 2019, with annually increasing death rates.¹ Hospital-acquired pneumonia (HAP) and ventilator-acquired pneumonia (VAP) are associated with substantial mortality of 20-30%.² Gram-negative bacteria are responsible for the majority of HAP/VAP infections and Pseudomonas aeruginosa and Acinetobacter baumannii are the most frequently reported bacteria.² Antimicrobial resistance among these organisms has increased in recent years, leaving few therapeutic options. Carbapenem-resistant bacteria, in particular, are associated with substantial morbidity and mortality.^2,3

Imipenem is a carbapenem β-lactam antimicrobial agent with broad activity against Gram-negative bacteria and certain Gram-positive organisms.³ However, its clinical efficacy has decreased over the recent years due to resistance.³ It is typically combined with cilastatin which prevents imipenem metabolism by renal dehydropeptidase.³ The imipenem/cilastatin combination was approved in 1985 by the US Food and Drug Administration (FDA) for the treatment of severe or complicated skin, tissue, respiratory tract, intra-abdominal (IAI), and urinary tract infection (UTI), as well as meningitis, endocarditis, and sepsis due to susceptible organisms.³

Relebactam is a novel β-lactamase that restores some of imipenem’s activity against certain Gram-negative bacterial infections.³ It was approved by the US FDA in combination with imipenem-cilastatin for the treatment of complicated UTIs and complicated IAIs.³ Recently, results of imipenem/cilastatin/relebactam (IMI/REL) use in HAP/VAP from the RESTORE-IMI 2 trial were published in Clinical Infectious Diseases.⁴

The RESTORE-IMI 2 trial was a phase 3, randomised, double-blind, noninferiority trial evaluating IMI/REL vs piperacillin/tazobactam (PIP/TAZ) for the treatment of HAP/VAP.⁴ The modified intention-to-treat population (MITT) consisted of 531 patients who were aged ≥18 requiring intravenous antibacterial therapy for nonventilated HAP, ventilated HAP, or VAP.⁴ These patients were randomised 1:1 to receive either IMI/REL 500mg/500mg/250mg or PIP/TAZ 4g/500mg, which were administered every 6 hours as 30-minute intravenous infusions.⁴ The primary efficacy endpoint was all-cause mortality (ACM) at day 28, and key secondary endpoint was favourable clinical response at early follow-up visit (EFU), both in the MITT population.⁴ Other secondary endpoints were day 28 mortality and microbiologic response at the end of therapy in the microbiologic MITT population (mMITT).⁴

Baseline clinical and demographic characteristics were similar between treatment arms, with 66.1% of MITT patients in the intensive care unit (ICU), 47.5% having an APACHE II score ≥15, and 48.6% having ventilated HAP/VAP.⁴ Moderate or severe renal impairment was observed in 24.7% of patients.⁴ Baseline lower respiratory tract specimens were also similar between treatment arms, with the most frequent species being Klebsiella pneumoniae (25.6%), P. aeruginosa (18.9%), Acinetobacter calcoaceticus-baumannii complex (15.7%), and Escherichia coli (15.5%).⁴

For the primary endpoint of day 28 ACM, IMI/REL was found to be non-inferior to PIP/TAZ, with 15.9% and 21.3% rates for ACM, respectively (adjusted treatment difference -5.3%, 95% CI: -11.9%—1.2%, noninferiority p<0.001).⁴ Mortality rates for patient subpopulations were comparable between treatment arms apart from patients with a primary diagnosis of ventilated HAP/VAP and with APACHE II scores ≥15, where mortality was lower with IMI/REL than PIP/TAZ.⁴

The key secondary endpoint of favourable clinical response was observed in 61.0% of IMI/REL patients and 55.8% of PIP/TAZ patients, demonstrating noninferiority (adjusted treatment difference 5.0%, 95% CI: -3.2%—13.2%, noninferiority p<0.001).⁴ Incidence of release or clinical failure was also comparable between IMI/REL (14.4%) and PIP/TAZ (12.0%).⁴ Other secondary endpoints, such as the overall microbiologic response at EFU and favourable clinical response rate at EFU also showed similar efficacy across treatment arms.⁴ Baseline pathogen susceptibility to the study drug did not impact the primary and key secondary efficacy outcomes.⁴

Most patients experienced at least 1 adverse event (AE), with rates of 85.0% and 86.6% for IMI/REL and PIP/TAZ, respectively.⁴ However, the incidence of specific drug-related AEs was similar between treatment arms.⁴ Most reported AEs in the IMI/REL treatment arm were diarrhoea, increased aspartate aminotransferase (AST), and increased alanine aminotransferase (ALT).⁴ Discontinuation due to drug-related AEs was observed in only 2.3% and 1.5% of patients in the IMI/REL and PIP/TAZ treatment arms, respectively.⁴ Serious drug-related AEs were reported in 1.1% of IMI/REL and 0.7% of PIP/TAZ patients, and no death was considered drug-related.⁴

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Reference

Centre for Health Protection, Department of Health. Number of Deaths by Leading Causes of Death, 2001 – 2019.

Cillóniz C et al. Curr Opin Infect Dis. 2019;32(6):656-662.

McCarthy MW. Clin Pharmacokinet. 2020;59(5):567-573.

Titov I et al. Clin Infect Dis. Doi: 10.1093/cid/ciaa803.

Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).