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Three Part Question

In [adult patients requiring endotracheal intubation for severe traumatic brain injury] do [early prophylactic IV antibiotics] reduce the later risks of [respiratory complications and/or mortality]

Clinical Scenario

You receive a major trauma patient to your emergency department. The history is of a 42 year old male who has fallen 8 foot from a balcony. On arrival, there is obvious evidence of head injury and Glasgow Coma Score is 4 (E1, V1, M2). You conduct a primary survey and find evidence of airway obstruction, but no other immediately life-threatening conditions. You undertake a drug assisted endotracheal intubation, which is uneventful. The patient is sedated, ventilated and escorted to radiology for definitive imaging. A full body trauma CT is reported within the hour as showing severe Traumatic Brain Injury (TBI) and 2 displaced right sided rib fractures. The case is discussed with the neurosurgical team who recommend admission to critical care for placement of an intracranial pressure bolt and a period of monitoring. As you are preparing for transfer, a colleague mentions recent evidence reporting that prophylactic antibiotics given within 12h of intubation can prevent subsequent pneumonia in patients with TBI. You have not heard of this before and are reluctant to prescribe anything, given the importance of antimicrobial stewardship. You escort the patient to Intensive Care, get a coffee and sit down to review any evidence on the topic.

Search Strategy

Medline (1946 to March 2025) and Embase (1980 to March 2025) databases were searched on 24th March 2025 via the OVID interface using the following search criteria:

[(exp traumatic brain injury/ OR traumatic brain lesion.ti,ab. OR brain adj2 trauma*.ti,ab OR TBI.ti,ab.) AND (exp pneumonia/ OR ventilator associated pneumonia/ OR ventilat* adj2 pneumoni*.ti,ab. OR VAP.ti,ab.) AND (exp antibiotic prophylaxis/ OR antibiotic*.ti,ab.) limit to (english language and yr=”2014 - Current”)


ventilator associated pneumonia/
(ventilat* adj2 pneumoni*).ti,ab.
VAP.ti,ab.
1 or 2 or 3
traumatic brain injury/
(traumatic brain injur* or traumatic brain lesion).ti,ab.
(brain adj2 trauma*).ti,ab.
TBI.ti,ab.
5 or 6 or 7 or 8
antibiotic prophylaxis/
antibiotic*.ti,ab.
10 or 11
4 and 9 and 12
limit 13 to (english language and yr=�2014 - 2024�)

Search Outcome

52 abstracts were initially identified. We discounted narrative review articles, case reports, conference abstracts, retrospective cohort studies of including less than 50 patients and individual studies already incorporated in more recent systemic review articles. After abstract sifting and review of relevant references, 4 research papers were selected for inclusion, all of which were deemed to be directly relevant to the original three-part question and are displayed in Table 1.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Prieto-Alvardo et al. February 2025 Colombia	1298 patients with TBI requiring mechanical ventilation for >48h.	Subgroup within a systematic review and meta-analysis of observational cohort studies. (Level 3)	Relationship between prophylactic antibiotic use and VAP	Prophylactic antibiotics significantly reduced VAP risk (OR 0.67, 95% CI 0.51-0.88, p ≤0.05)	Heterogeneity in the diagnostic criteria for VAP between studies. No randomised studies were used increasing risk of confounding and bias. Subgroup analysis rather than predefined hypothesis.
Dahyot-Fizelier et al. May 2024 France	319 adults with acute brain injury (27.9% TBI) and GCS <13, who had been intubated for <12 hours.	Randomised controlled trial comparing single dose of 2 grams ceftriaxone (intervention) against placebo. (Level 2)	Hazard ratio (HR) for early VAP (days 2-7)	Significant reduction with the intervention HR 0.60, 95% CI 0.38 to 0.95, p=0.03.	Majority of cases non traumatic subarachnoid haemorrhage, stroke etc.) Difference in baseline microbiological flora in the groups. Not appropriately powered to be more than hypothesis generating for secondary and stewardship outcomes.
			Mortality	Significant reduction in all-cause mortality with the intervention HR 0.62 (95% CI 0.39 to 0.97, p=0.036
			Safety of prophylactic antibiotic use	No serious adverse incidents were linked to the intervention.
Chen et al April 2023 China	1858 adult patients with TBI.	Meta-analysis of cohort studies. (Level 3)	Relationship between prophylactic antibiotic use and VAP	Significant reduction in VAP rate in those who received early antibiotic prophylaxis (RR = 0.53; 95% CI 0.18-0.88, p<0.001)	Non randomised studies therefore risk of confounding and bias. Variation in the diagnostic criteria for VAP between studies. 20 years between studies, implying changing standards of care.
Reizine et al. April 2019 USA	295 adults with severe TBI requiring mechanical ventilation.	Post-hoc analysis of study populations from 2 double blind randomised controlled trials (Level 2)	Incidence of VAP and association with prophylactic antibiotic use.	Significantly reduced VAP incidence in those who received early antibiotic prophylaxis. (RR = 0.33; 95% CI 0.19-0.56)	Underpowered to detect differences in the secondary outcomes. These trials were comparing different interventions in the prevention of VAP. Majority of prophylaxis was with penicillin (co-amoxiclav was the choice in 93%), 23% received a cephalosporin. There was also no standardisation of therapy duration.
			Duration of mechanical ventilation and total duration of antibiotic exposure	No difference in duration of mechanical ventilation. Overall duration of antibiotic exposure was significantly lower in the prophylaxis group
			Effect of antibiotics on other nosocomial infections	Incidence of other nosocomial infections was similar between the groups

Comment(s)

Traumatic brain injury (TBI) is a leading international cause of injury related death and disability.[5,6] The consequences of TBI can be further exacerbated by development of complications, such as pneumonia. Ventilator associated pneumonia (VAP), conventionally defined as developing after 48h mechanical ventilation, is common in Critical Care patients.[7, 8] The TBI population appear to be highly susceptible to VAP, with an estimated incidence of between 20.4 to 36%.[9, 10] Hypotheses for this increased risk include an altered immune profile following TBI, concurrent thoracic injury in trauma and increased aspiration risk in the context of brain injury.[7] VAP is often associated with an increased duration of mechanical ventilation and increased duration of critical care stay.[9, 10] Systemic antibiotic prophylaxis for the prevention of VAP has previously been contentious. Brain Trauma Foundation guidelines from 2016 do not recommend antibiotics for VAP prevention, citing the limited evidence base and generic antimicrobial stewardship concerns.[11] However, a number of subsequent randomised studies now provide evidence that early prophylactic use of antibiotics may significantly reduce VAP rates in critically ill patients requiring endotracheal intubation. In a 2019 study of 198 patients admitted to Intensive care following out of hospital cardiac arrest, François et al. observed a significant reduction in VAP rates within 7 days in patients randomised to an early course of co-amoxiclav.[12] Following this, the 2024 PROPHY-VAP study reported a statistically significant improvement in VAP rate with a single dose of ceftriaxone within 12h of endotracheal intubation for patients with neurological injury.[1] Neither study reported any significant harm with the intervention, including no difference in subsequent culture rates for resistant bacteria. Two recent observational meta-analyses report the use of prophylactic antibiotics to significantly reduce the risk of VAP following TBI. [2,4] This recent evidence suggests that a short course of early prophylactic antibiotics appears clinically effective at reducing VAP incidence for TBI patients who require mechanical ventilation and does not appear to convey additional harms. However, the current evidence base is limited by use of observational cohort data, limitations in generalisability and lack of consensus definition for VAP. Questions also remain regarding the potential impact on antibiotic resistance patterns; this issue is a secondary outcome within the prospective trials reported; none were sufficiently powered or appropriately designed to provide conclusive evidence; and longer term challenges with antimicrobial resistance could have a significant impact on the cost effectiveness of such an intervention.

Clinical Bottom Line

Early prophylactic antibiotics for people with severe traumatic brain injury who require endotracheal intubation may reduce the rate of subsequent ventilator associated pneumonia. Further randomised studies are required to investigate the potential effects on microbiological resistance following VAP prevention courses and to evaluate the broader cost effectiveness of antimicrobial prophylaxis in TBI.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Prieto-Alvarado DE, Parada-Gereda HM, Molano D, et al Risk factors and outcomes of ventilator-associated pneumonia in patients with traumatic brain injury: a systematic review and meta-analysis. J Crit Care 2025;85:154922
2. Dahyot-Fizelier C, Lasocki S, Kerforne T, et al Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled, assessor-masked superiority trial Lancet Respir Med 2024;12(5):375–85.
3. Chen S, Gao G, Xia Y, et al. Incidence rate and risk factors of ventilator-associated pneumonia in patients with traumatic brain injury: a systematic review and meta-analysis of observational studies J Thorac Dis 2023;15(4):2068–78
4. Reizine F, Asehnoune K, Roquilly A, et al. Effects of antibiotic prophylaxis on ventilator-associated pneumonia in severe traumatic brain injury: a post hoc analysis of two trials J Crit Care 2019;50:221–6