Shorter antibiotic dosing for pneumonia holds up against usual care in Asians

In the treatment of Asian patients with ventilator-associated pneumonia (VAP), shortened antibiotic treatment duration guided by clinical response compares favourably with longer treatment durations used in usual care in terms of 60-day mortality and pneumonia recurrence, as shown in the open-label REGARD-VAP trial.

Death or pneumonia recurrence at 60 days occurred in 41 percent of participants in the short-course group and in 44 percent of those in the usual-care group (risk difference, –3 percent, 95 percent confidence interval [CI], −∞ to 5 percent) both in the intention-to-treat (n=460) and per-protocol (n=435) populations. [Lancet Respir Med 2024;doi:10.1016/S2213-2600(23)00418-6]

The results established the noninferiority of short-course antibiotic treatment, although superiority was not met, according to the investigators.

“[T]he overall all-cause mortality was 37 percent, and mortality attributable to pneumonia was 12 percent. These are [similar] with global estimates among critically ill patients with VAP,” they added. [PLoS One 2021;16e0247832]

Accordingly, short-course treatment reduced the overall mean antibiotic treatment duration during hospitalization by 5.2 days (95 percent CI, –7.5 to –2.8; p=0.0003), with significantly fewer participants experiencing antibiotic-related side effects relative to the usual-care group (per-protocol population: 8 percent vs 38 percent; risk difference, –31 percent, 95 percent CI, –37 percent to –25 percent; p<0.0001). Participants in the short-course group particularly benefitted from a substantially lower risk of acute kidney injury (5 percent vs 35 percent).

When to stop antibiotic treatment?

In the trial, participants in the short-course group received antibiotic treatment for at least 7 days and as short as 3–5 days, while those in the usual-care group received treatment for at least 8 days with the precise duration determined by the primary clinicians.

For participants in the short-course group, a strict set of criteria determined when to discontinue antibiotics. This included maintaining a normal body temperature (below 38.3 °C orally or rectally, or 38.0 °C axillary) for 48 hours and having stable blood pressure (systolic blood pressure ≥90 mm Hg without inotropic support).

“When these fitness criteria were met, the protocol specified that all antibiotics for participants randomly assigned to the short-course group were to be stopped as early as day 3 if the respiratory culture was negative, as early as day 5 if the respiratory culture was positive, and, in all cases, within 7 days of starting treatment for VAP,” the investigators said.

“The clinical response criteria, based on normalization of body temperature and blood pressure, are simple and reproducible, and can be adopted by both prescribing clinicians and other healthcare professionals to guide antibiotic stewardship policies, including in resource-limited settings,” they continued.

The investigators believe that by taking a personalized approach to how long patients take antibiotics, the overall prescribing of these medications can be reduced, which helps combat the growing threat of antibiotic resistance especially among the most vulnerable patients.

REGARD-VAP

REGARD-VAP included 460 adult patients from 39 intensive care units across six hospitals in Nepal, Singapore, and Thailand. All patients met the US Centers for Disease Control and Prevention National Healthcare Safety Network criteria for VAP, had been mechanically ventilated for at least 48 hours, and received culture-directed antibiotics. Empirical antibiotic choices in culture-negative cases depended on local hospital antibiograms reported by the respective microbiology laboratories or prevailing local guidelines.

Following 48 hours of fever resolution and haemodynamic stability, the patients were randomly assigned to receive individualized short-course antibiotic treatment (n=232, median age 63 years, 42 percent women) or usual care (n=229, median age 64 years, 37 percent women). A total of 491 bacterial pathogens were isolated from 320 index episodes of VAP, with 94 percent of bacterial isolates being Gram-negative and 34 percent (including Acinetobacter spp, Pseudomonas spp, and Enterobacterales) being carbapenem-resistant.

The median antibiotic treatment duration was 6 days in the short-course group and 14 days in the usual-care group. The most common antibiotic regimen for carbapenem-resistant Gram-negative bacilli was colistin-based or polymyxin-B-based combinations (41 percent in the short-course group and 49 percent in the usual-care group). No significant between-group differences were observed in the duration of hospital and intensive care unit stays.

“An important finding in this trial was that the usual care antibiotic treatment duration was longer than most current guideline recommendations of 7–8 days. This observation reflects real-world practice, in which antibiotic treatment tends to be prolonged for VAP, especially those associated with Gram-negative nonfermenting and carbapenem-resistant Gram-negative bacilli,” the investigators noted. [Eur Respir J 2017;50:1700582; Clin Infect Dis 2016;63:e61-111; https://www.who.int/publications-detail-redirect/9789240062382]

In addition, the antibiotic prescriptions reflected the epidemiology of bacteria causing VAP and the limited access to newer-generation antibiotics (eg, novel β-lactam–β-lactamase inhibitors or cefiderocol) in many areas where the trial was conducted, as pointed out by the investigators, adding that very few trials have been done in such settings, where rates of VAP are higher than in high-resource settings.

“The high rates of VAP are a major driver for antibiotic prescription and are likely to contribute to the high prevalence of multidrug-resistant organisms… [Hence,] individualized, short-course antibiotic treatment for VAP could help to reduce the burden of side-effects and the risk of antibiotic resistance [especially in] resource-limited settings,” they said.