Individualized short antibiotic course non-inferior to usual course in VAP

Key takeaways:

• Mortality and pneumonia recurrence at day 60 did not significantly differ between short-course vs. usual antibiotic treatment.
• Fewer patients receiving the short-course experienced antibiotic side effects.

An individualized short antibiotic course was non-inferior to usual care in those with ventilator-associated pneumonia when assessing mortality and pneumonia recurrence at day 60, according to study results.

This study was published in The Lancet Respiratory Medicine and presented at the Society of Critical Care Medicine’s 2024 Critical Care Congress.

“Individualized short-course antibiotic duration for ventilator-associated pneumonia based on simple clinical criteria is non-inferior to usual care,” Gyan K. Kayastha, MD, MPH, professor at Patan Hospital in Nepal, said during his presentation at the meeting. “This can be used in developing country setting [and] low-income setting as well.”

In a multicenter, individually randomized, open-label, non-inferiority phase 4 trial (REGARD-VAP), Kayastha and colleagues assessed 460 adults with ventilator-associated pneumonia (VAP) in low- or middle-income countries, who had received culture-directed antibiotics and mechanical ventilation for at least 48 hours, to compare mortality/pneumonia recurrence at 60 days among those who received short-course antibiotic treatment vs. usual long-course treatment.

“Given that VAP is a major driver of antibiotic consumption in the intensive care setting, and in the absence of gold-standard diagnostics, a pragmatic approach to minimize antibiotic treatment duration is needed,” Kayastha and colleagues wrote in the study.

Of the total cohort, 231 patients (median age, 63 years; 42% women) received the individualized short-course treatment, given for a maximum of 7 days, and 229 patients (median age, 64 years; 37% women) received the long-course usual treatment, given for a minimum of 8 days. In the usual care group, clinicians determined the length of treatment.

Notably, Kayastha said they waited to assign treatment groups until patients’ fever resolved for 48 hours and they had stable hemodynamics.

Researchers assessed the two treatment durations against one another in two analyses. The first analysis, known as the intention-to-treat analysis, involved the total cohort, whereas the second analysis (the per-protocol analysis) included 435 patients “who fulfilled the eligibility criteria, met fitness criteria for antibiotic discontinuation and who received antibiotics for the duration specified by their allocation group.”

Of the total per-protocol cohort, 221 received the short-course treatment, and 224 received the long-course usual treatment.

Switching to the intention-to-treat population, researchers found a higher percentage of gram-negative vs. gram-positive bacterial isolates (94% vs. 4%). Within the gram-negative classification, Kayastha said 34% of bacterial isolates were carbapenem-resistant and 17% were cephalosporin-resistant.

Aligning with the defining principle of each group, patients receiving the short-course treatment had a shorter median length of antibiotic treatment vs. patients receiving usual treatment (6 days vs. 14 days).

Primary outcome

The percentage of patients who died or experienced pneumonia recurrence at day 60 was comparable between the short-course group and the usual care group (41% vs. 44%; adjusted absolute risk difference, –2), and this result was also observed in the per-protocol analysis (short-course, 41% vs. usual care, 44%; adjusted absolute risk difference, –2).

With the non-inferiority margin prespecified at 12%, researchers deemed that short-course treatment was non-inferior to the usual, long-course treatment in both unadjusted and adjusted analyses of each population.

On the other hand, superiority of the short-course treatment, signaled when the upper bound of the one-sided 97.5% confidence interval is less than zero, was not found, according to researchers.

Secondary outcomes

Out of the several secondary outcomes assessed, only two significantly differed between the treatment courses in the per-protocol population.

“Mean duration of mechanical ventilation during admission, mean duration of ICU admission ... mean duration of hospital stay, readmission, pneumonia recurrence, bloodstream infection as well as carbapenem-resistant bacteria [were] not that different between the two [groups],” Kayastha said during his presentation.

Firstly, patients receiving usual care had a significantly longer median length of antibiotics during admission vs. patients receiving short-course treatment (25.7 days vs. 20.5 days; adjusted estimates, –5.2 days; 95% CI, –7.8 to –2.8).

Additionally, more patients receiving usual care had antibiotic side effects than patients receiving short-course treatment (38% vs. 8%; adjusted estimate, –31%; 95% CI, –37% to –25%).

Patients reported several side effects, including acute kidney injury, liver injury, diarrhea and allergy due to antibiotics. Of these, researchers found that acute kidney injury occurred the most in both groups, with significantly more patients in the usual care vs. the short-course group experiencing this outcome (35% vs. 5%; adjusted estimate, –30%; 95% CI, –36% to –24%).

“[A short-course antibiotic strategy] is non-inferior at less than 12% absolute risk; however, there is no difference in outcomes, but short-course has less side effects, less antibiotic use, definitely lower costs and the risk of antimicrobial resistance is also lower,” Kayastha said.

When concluding his presentation, Kayastha said one notable limitation of this study is that usual care duration is longer than what is recommended in guidelines.

“The CDC recommends only 7 to 8 days, but in practice, it’s usually 14 [days], 15 days or more,” he said.

Reference:

• Kayastha GK. Late-breaking studies affecting patient outcomes II. Presented at: Society of Critical Care Medicine’s Critical Care Congress; Jan. 21-23, 2024; Phoenix.