background: ANTHARTIC trial
Prophylaxis against VAP (ventilator-associated pneumonia) is already supported by a few studies in the literature, perhaps most notably the ANTHARTIC trial. That was a multicenter RCT evaluating 48 hours of therapy with amoxicillin/clavulanate for patients intubated following cardiac arrest. Antibiotic therapy reduced early-onset VAP, with a trend towards more ventilator-free days (further discussion here).
background: the SuDDICU trial
The SuDDICU trial was an investigation of “Selective Decontamination of the Digestive Tract” among critically ill, intubated patients. That involves empiric administration of a bevy of enteral and intravenous antibiotics intended to suppress bacterial pathogens in the gastrointestinal tract – with a goal of reducing iatrogenic infections. I'm using the term “Selective Decontamination of the Digestive Tract” in quotation marks because patients received four days of systemic antibiotic therapy (e.g., ceftriaxone or ciprofloxacin). You can't tell the ceftriaxone molecules to selectively go to the gut and not the lung.
The details of this trial are aptly summarized at The Bottom Line website here. Despite recruiting a whopping 5,982 patients the study was overall neutral.
However, a post-hoc analysis of SuDDICU focused on 2,061 patients admitted with acute brain injuries. (37982826) This included patients with cardiac arrest, intracranial hemorrhage, stroke, seizure, traumatic brain injury, or coma. Among these patients, antibiotic therapy caused a reduction in mortality (32% vs. 38%, p = 0.004), and improvements in ventilator-free days, hospital-free days, and ICU-free days. The subgroup of patients with brain injury seemed to derive a unique benefit from antibiotic therapy:
I'm skeptical of selective decontamination of the digestive tract due to concerns regarding antimicrobial stewardship and the long-term emergence of drug-resistant organisms (effects that may be impossible to evaluate during the duration of a single trial, as discussed further here).
Nonetheless, SuDDICU is a large multicenter RCT that does show a signal of benefit for empiric antibiotic therapy among intubated patients with acute brain injury.
PROPHY-VAP trial: design
The trial involved patients intubated for airway protection due to neurological injury from head trauma, stroke, or subarachnoid hemorrhage. Some notable inclusion criteria were:
- Anticipated length of ventilation >48 hours.
- Absence of an infectious disease.
- No ongoing antibiotic therapy.
- Not admitted to the hospital for >48 hours.
- Not already intubated for >12 hours.
319 patients were included in the final analysis from eight university hospitals in France. The causes of coma were subarachnoid hemorrhage (42%), traumatic brain injury (28%), hemorrhagic stroke (22%), and ischemic stroke (9%).
Patients were randomized to receive placebo or a single dose of two grams of IV ceftriaxone. The average time from intubation to ceftriaxone administration was seven hours.
results: efficacy
The primary endpoint was the rate of early VAP (between 2-7 days after intubation). This was lower in the treatment group (14% vs. 32%; p = 0.03). That's a good sign, but given the vagaries of VAP diagnosis the clinical significance of this endpoint could be debated.
More importantly, patient-centered endpoints were also positive. There were statistically significant improvements in the number of ventilator-free days, ICU-free days, and hospital-free days. Mortality and neurological endpoints were improved after 28 days, but after 60 days these differences lost statistical significance.
Early VAP (within seven days of intubation) was much more common than late VAP. This suggests that a major driver of pneumonia in this patient population may be aspiration of oropharyngeal secretions prior to intubation.
results: safety & antimicrobial stewardship
Prophylactic ceftriaxone actually increased the number of antibiotic-free days. This makes sense: a single day of ceftriaxone reduced the rate of VAP by 16%. Current guidelines recommend a seven-day course of antibiotics for VAP, which would lead to a roughly neutral exposure to antibiotics (0.16 x 7 days = 1, so one day of ceftriaxone could avoid an average of ~1 day of antibiotics). However, if patients were treated for VAP for longer than seven days (which commonly occurs), then ceftriaxone could lead to an improvement in antibiotic-free days.
The ability of ceftriaxone to reduce VAP without causing an increase in overall antibiotic exposure suggests that this intervention could be applied without increasing the risk of drug-resistant organisms.
Ventilator-associated pneumonias are often treated with combination antibiotic therapy (e.g., vancomycin plus piperacillin-tazobactam). It's conceivable that ceftriaxone prophylaxis could lead to lower utilization of these broad-spectrum antibiotics – which would support the ability to prophylax against VAP without exacerbating antimicrobial resistance.
There were no measurable differences in the rate of C. difficile diarrhea nor acquisition of ESBL-producing Enterobacteriaceae. However, the study was grossly underpowered to evaluate these events. Consequently, overall antibiotic exposure (in terms of antibiotic-free days) might be a more robust metric to consider in terms of antimicrobial stewardship.
integration of PROPHY-VAP, ANTHARTIC, and SuDDICU
These are obviously quite different studies. I'm sure that methodological purists would bristle at any attempts to combine their results.
However, a common theme that seems to run through all three trials is that a short course of antibiotics for patients intubated due to acute brain injury is safe and beneficial. The PROPHY-VAP trial implies that only a single dose of ceftriaxone may be adequate (noting that ceftriaxone has a relatively long half-life, so this amounts to ~24 hours of antimicrobial therapy).
- PROPHY-VAP is a multicenter RCT demonstrating benefit from a single two-gram dose of IV ceftriaxone among patients intubated due to coma resulting from stroke, intracranial hemorrhage, or traumatic brain injury.
- Prophylactic ceftriaxone reduced the total duration of antibiotic exposure, due to a prevention of VAP. This suggests that VAP prophylaxis may be performed in a manner that is neutral or beneficial with regards to antimicrobial stewardship.
- PROPHY-VAP, ANTHARTIC, and SuDDICU are three multicenter RCTs which all lend some support to the concept of prophylactic antibiotics among patients who are intubated due to acute brain injury.
- VAP prophylaxis among patients intubated due acute brain injury using a single two-gram dose of ceftriaxone seems to be reasonable (as recommended by the authors of the study below). However, the benefits of VAP prophylaxis haven't been established with complete certainty, so further data on this topic would be welcome.
Full article: PROPHY-VAP trial
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First off, I have to admit I thought I was going to dislike this study from the start, I’m still recovering from reading the prophylactic inhaled AG study that NEJM last year. It seems like the study was well performed in a specific population high risk for VAP. Some big things for me are missing that I’m worried people will generalize. Generalization #1: “Patient will get off the vent sooner if we administer prophylactic cephalosporins” – 2018 BMJ proposal suggested time between inclusion and the first spontaneous ventilation test but this is missing in the supplemental data. Bottom line: Reported… Read more »
Hello!
In the amikacin trial you criticised the high VAP rate. Since the rate in this trial was similar, how would you consider it in this case?
In the Prophy-VAP study, the placebo group had a statistically higher 28 day modified Rankin and a trend towards a higher 60 day modified Rankin score, indicating a neurologically sicker group. It’s possible that worse neurological damage could result in longer ventilator days and ICU days rather than prophylactic antibiotics leading to shorter ventilator days and ICU days.