Publication

• Title: Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest
• Acronym: ANTHARTIC (ANTibiotherapy during THerapeutic hypothermiA to pRevenT Infectious Complications)
• Year: 2019
• Journal published in: New England Journal of Medicine
• Citation: François B, Cariou A, Clère-Jehl R, Dequin PF, Renon-Carron F, Daix T, et al; CRICS-TRIGGERSEP Network and the ANTHARTIC Study Group. Prevention of early ventilator-associated pneumonia after cardiac arrest. N Engl J Med. 2019;381(19):1831-1842.

Context & Rationale

• Background

  • Early-onset pneumonia/ventilator-associated pneumonia (VAP) is common after out-of-hospital cardiac arrest (OHCA), driven by aspiration during resuscitation, mechanical ventilation, and post–cardiac arrest immune dysregulation.
  • VAP in this population increases antibiotic exposure and may prolong mechanical ventilation and ICU length of stay, yet attributable mortality is uncertain.
  • Prior observational studies and small trials suggested potential reductions in pneumonia with early/prophylactic antibiotics, but effects on patient-centred outcomes and antimicrobial resistance were unclear.
• Research Question/Hypothesis

  • Does a short course (48 hours) of early intravenous amoxicillin–clavulanate, started within 6 hours after OHCA in comatose patients treated with targeted temperature management (TTM), reduce the incidence of early VAP (within 7 days) compared with placebo?
  • Secondary hypothesis: reducing early VAP would translate into less non-study antibiotic use and shorter ICU stay without increasing antibiotic-resistant bacteria or serious adverse events.
• Why This Matters

  • If effective and safe, early targeted prophylaxis could reduce a frequent ICU complication and downstream broad-spectrum antibiotic exposure.
  • Conversely, routine prophylaxis risks overtreatment, ecological harm, and resistance selection; high-quality blinded evidence was needed.

Design & Methods

• Research Question: In comatose adults after OHCA with a shockable rhythm treated with TTM, does early 48-hour IV amoxicillin–clavulanate reduce early VAP (≤7 days) versus placebo?
• Study Type: Multicentre, randomised, double-blind, placebo-controlled, investigator-initiated trial in 16 ICUs (France).
• Population:
  • Setting: ICU admission after OHCA with planned TTM (32–34°C).
  • Inclusion criteria: ≥18 years; OHCA with shockable rhythm; Glasgow Coma Scale ≤8; intubated and mechanically ventilated; randomisation within 6 hours after cardiac arrest.
  • Key exclusion criteria: antibiotic therapy at baseline; suspected or confirmed infection at baseline; penicillin allergy; expected death within 24 hours (per treating clinician); non-shockable rhythm.
• Intervention:
  • Amoxicillin–clavulanate 1 g/200 mg IV every 8 hours for 48 hours, initiated immediately after randomisation (within 6 hours after arrest).
  • Renal dose adjustment according to prespecified thresholds; background VAP-prevention bundle applied in both groups.
• Comparison:
  • Matching placebo IV every 8 hours for 48 hours, with otherwise identical care (including VAP prevention, sedation, and TTM).
  • Subsequent antibiotics were clinically driven; VAP prevention measures were recommended/standardised.
• Blinding: Double-blind (patients, clinicians, investigators, and outcome adjudicators); identical preparation/administration schedule in both groups.
• Statistics: A total of 192 patients were required to detect a 25 percentage-point absolute reduction in day-7 VAP incidence (from 68% to 43%) with 90% power at a two-sided 5% significance level, targeting 91 VAP events and accounting for ~15% competing mortality; analysis was modified intention-to-treat (excluded patients who did not receive any trial drug), with competing-risk methods (Fine–Gray) for VAP.
• Follow-Up Period: Primary endpoint through day 7; key secondary outcomes to day 28; functional outcomes reported at 3 and 12 months.

Key Results

This trial was not stopped early. 198 patients underwent randomisation; 194 were analysed (99 intervention; 95 placebo).

• Early prophylactic amoxicillin–clavulanate reduced adjudicated early VAP from 34% to 19% (HR 0.53; 95% CI 0.31 to 0.92; P=0.03).
• Despite less VAP and less subsequent non-study antibiotic exposure, there was no clear signal for improved 28-day mortality or functional outcome.
• Resistant bacteria were uncommon and not increased in the intervention group by day 7 (1% vs 7%).

Internal Validity

• Randomisation and allocation: Central web-based randomisation with fixed blocks of 4; allocation concealment appears robust.
• Dropout/exclusions: 198 randomised; 194 analysed; all 4 post-randomisation exclusions occurred in the placebo group (2 withdrew consent; 2 did not receive placebo), introducing potential (though likely small) bias from modified intention-to-treat analysis.
• Performance/detection bias: Double-blinding reduced co-intervention and ascertainment bias; however, VAP diagnosis remains clinically complex in post-arrest patients (sedation, aspiration, atelectasis), even with adjudication.
• Protocol adherence: Intervention was administered on a tight timeline (randomisation within 6 hours), and the prophylaxis course was short and standardised; both groups received similar TTM and VAP-prevention bundles.
• Baseline characteristics: Groups were well balanced (e.g., age median 63 vs 61 years; bystander CPR 78% vs 77%; no-flow time median 2 vs 1 min; time from arrest to randomisation median 185 vs 182 min).
• Heterogeneity: Multicentre design (16 ICUs) increases heterogeneity in usual care; standardised bundle recommendations and blinded design likely mitigated differential management.
• Timing: Antibiotics started early (≤6 hours post-arrest), aligned with the hypothesised aspiration/microaspiration window and the high early VAP incidence.
• Dose: Amoxicillin–clavulanate 1 g/200 mg IV q8h for 48 hours targets aspiration flora; short duration may reduce ecological pressure but may be insufficient if infection is established rather than prophylactic.
• Separation of the variable of interest: Clear separation in early VAP (19% vs 34%) and overall VAP (23% vs 39%); downstream antibiotic exposure was lower in the intervention group (median 23% vs 50% of ICU days on non-study antibiotics).
• Outcome assessment: Primary outcome used predefined clinical, radiographic, and microbiological criteria with independent adjudication; competing risk methods were appropriate given early mortality.
• Statistical rigour: Power assumptions (control event rate 68%) exceeded observed placebo early VAP (34%), which may reduce precision for some secondary endpoints; primary effect estimate remained statistically significant with reported CI.

Conclusion on Internal Validity: Overall internal validity is moderate-to-strong: allocation concealment and blinding were robust and the primary analysis handled competing risks appropriately, but modified intention-to-treat exclusions and the inherent diagnostic uncertainty around VAP modestly limit confidence in the exact magnitude of effect.

External Validity

• Population representativeness: Restricted to OHCA with shockable rhythms, coma (GCS ≤8), and planned TTM at 32–34°C; findings may not apply to non-shockable rhythms, in-hospital arrests, ECMO/ECPR pathways, or contemporary normothermia-focused protocols.
• Antibiotic ecology: The regimen (amoxicillin–clavulanate for 48 hours) reflects local aspiration flora coverage; external applicability depends on local resistance patterns and baseline VAP epidemiology.
• Healthcare system context: Conducted in French ICUs with protocolised bundles and intensive microbiological sampling; settings with different ventilation practices or antimicrobial stewardship may see different absolute effects.

Conclusion on External Validity: External validity is moderate for similar post-OHCA shockable-rhythm populations managed with early ICU admission and structured VAP prevention, but limited when extrapolated to broader cardiac arrest cohorts and current post-resuscitation temperature strategies.

Strengths & Limitations

• Strengths:
  • Double-blind, placebo-controlled design with central randomisation and prespecified competing-risk analysis for VAP.
  • Early administration (≤6 hours) and short, standardised antibiotic course with renal adjustment and systematic microbiological surveillance.
  • Independent adjudication of the primary endpoint and clinically relevant secondary outcomes (antibiotic exposure, ICU stay, mortality, neurological outcome).
• Limitations:
  • Modified intention-to-treat analysis with post-randomisation exclusions confined to the placebo group.
  • Primary endpoint (VAP) is a partially subjective diagnosis in a complex post-arrest physiology; misclassification remains plausible despite adjudication.
  • Planned control event rate (68%) substantially exceeded observed early VAP (34%), potentially limiting power for some secondary outcomes and precision of subgroup inferences.
  • Restricted population (shockable rhythm, TTM 32–34°C) may not match current practice patterns and broader cardiac arrest epidemiology.

Interpretation & Why It Matters

• Clinical signal

  Short-course early amoxicillin–clavulanate reduced early VAP and decreased subsequent antibiotic exposure, suggesting prophylaxis can meaningfully alter early infectious trajectories in selected post-arrest patients.
• Patient-centred outcomes

  Absent improvement in mortality or neurological outcomes implies that preventing early VAP may not translate into large, measurable gains in survival or function, or that the trial was not powered for these endpoints.
• Stewardship trade-off

  A targeted 48-hour regimen reduced downstream antibiotic days (23% vs 50% of ICU days) and did not increase resistant bacteria by day 7, but ecological effects beyond short follow-up and in higher-resistance settings remain uncertain.
• Practice integration

  For most systems, this trial supports prioritising high-quality VAP-prevention bundles and reserving antibiotics for clinically suspected infection, rather than routine prophylaxis, unless future evidence identifies a clearly benefitting subgroup.

Controversies & Subsequent Evidence

• Endpoint and diagnostic uncertainty: Correspondence highlighted that differentiating aspiration pneumonitis, colonisation, and true VAP early after arrest (especially under sedation and temperature management) is challenging, raising concern that outcome misclassification could influence effect estimates.¹
• Event-rate assumptions and interpretability: Observed placebo early VAP incidence (34%) was far below the assumed 68%, and while the primary endpoint reached statistical significance, this divergence complicates interpretation of power and generalisability for secondary outcomes.¹
• Patient-centred benefit remains unproven: A systematic review/meta-analysis including ANTHARTIC and earlier trials found reductions in pneumonia outcomes without convincing improvement in mortality or neurological recovery, supporting caution with routine prophylaxis.²
• Guideline position: European post-resuscitation care guidelines recommend against routine prophylactic antibiotics in comatose post-arrest patients, citing uncertain patient-centred benefit and stewardship concerns.³
• Newer trials broaden the evidence base: PROPHY-VAP (ceftriaxone prophylaxis in mechanically ventilated acute brain injury) and PROTECT (ceftriaxone prophylaxis after OHCA with microbiome/resistome endpoints) extend evaluation to different populations/regimens, but have not yet established a clear survival or functional benefit.⁴⁵

Summary

• In comatose OHCA survivors with shockable rhythms treated with TTM, 48 hours of early IV amoxicillin–clavulanate reduced early adjudicated VAP (19% vs 34%; HR 0.53).
• Overall adjudicated VAP was also lower (23% vs 39%; HR 0.55), with less downstream non-study antibiotic exposure (median 23% vs 50% of ICU days).
• No clear differences were observed in 28-day mortality (41% vs 37%) or neurological outcomes at 90 days.
• Short-course prophylaxis did not increase resistant bacteria by day 7 (1% vs 7%), but ecological certainty is limited by follow-up and sample size.
• Guidelines and pooled evidence remain cautious, generally advising against routine prophylactic antibiotics after cardiac arrest.

Further Reading

Other Trials

• 2026Gagnon DJ, Benken ST, Tanski A, et al. Ceftriaxone to prevent early-onset pneumonia in comatose patients after out-of-hospital cardiac arrest: a pilot randomized controlled trial and resistome assessment. Chest. 2026;169(1):115-127.
• 2017Ribaric SF, Turel M, Knafelj R, Gorjup V, Stanic R, Dzelalija B. Prophylactic versus clinically-driven antibiotics in comatose survivors of out-of-hospital cardiac arrest: a randomized pilot study. Resuscitation. 2017;111:103-109.
• 2024Dahyot-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 trial. Lancet Respir Med. 2024;12(5):375-385.
• 2015Westendorp WF, Vermeij JD, Zock E, et al. The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial. Lancet. 2015;385(9977):1519-1526.
• 2015Kalra L, Irshad S, Hodsoll J, et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint trial. Lancet. 2015;386(10006):1835-1844.

Systematic Review & Meta Analysis

• 2019Couper K, Laloo R, Field RA, Perkins GD, Thomas M, Yeung J. Prophylactic antibiotic use following cardiac arrest: a systematic review and meta-analysis. Resuscitation. 2019;141:166-173.
• 2025Hadley-Brown K, Rowland MJ, Wang K, et al. Prophylactic antibiotics in adults with acute brain injury who are invasively ventilated in ICU: systematic review and meta-analysis. Chest. 2025;168(3):822-833.
• 2023Zha S, Zhao X, Liu X, et al. Prophylactic antibiotics for preventing ventilator-associated pneumonia: a pairwise and Bayesian network meta-analysis. Chest. 2023;164(2):397-410.
• 2017Righy C, Do BP, Valles J, et al. Systemic antibiotics for preventing ventilator-associated pneumonia in comatose patients: a systematic review and meta-analysis. Ann Intensive Care. 2017;7(1):67.
• 2023Wang Y, Lin JD, Xiao WB. Preventive antibiotic therapy for acute stroke: a systematic review and meta-analysis. Br J Clin Pharmacol. 2023;89(9):2951-2962.

Observational Studies

• 2011Perbet S, Mongardon N, Dumas F, et al. Early-onset pneumonia after cardiac arrest: characteristics, risk factors, and influence on prognosis. Am J Respir Crit Care Med. 2011;184(9):1048-1054.
• 2013Pabst D, Römer S, Samol A, et al. Predictors and outcome of early-onset pneumonia after out-of-hospital cardiac arrest. Respir Care. 2013;58(9):1514-1520.
• 2015Gagnon DJ, Nielsen N, Fraser GL, et al. Prophylactic antibiotics are associated with a lower incidence of pneumonia in cardiac arrest survivors treated with targeted temperature management. Resuscitation. 2015;92:154-159.
• 2015Kakavas S, Mongardon N, Cariou A, et al. Early-onset pneumonia after out-of-hospital cardiac arrest. J Infect. 2015;70(6):553-562.
• 2013Davies KJ, Walters JH, Kerslake IM, Greenwood R, Thomas MJ. Early antibiotics improve survival following out-of-hospital cardiac arrest. Resuscitation. 2013;84(5):616-619.

Guidelines

• 2021Nolan JP, Sandroni C, Böttiger BW, et al. European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Resuscitation. 2021;161:220-269.
• 2021Nolan JP, Sandroni C, Böttiger BW, et al. European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Intensive Care Med. 2021;47(4):369-421.
• 2020Berg KM, Soar J, Andersen LW, et al. Adult advanced life support: 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2020;142(16_suppl_2):S366-S468.
• 2024Hirsch KG, et al. Critical care management of patients after cardiac arrest: a scientific statement from the American Heart Association. Circulation. 2024;149(5):e372-e407.
• 2024Seder DB, Hirsch KG, Reynolds JC, et al. Canadian Cardiovascular Society and Canadian Cardiovascular Critical Care Society clinical practice update on optimal post–cardiac arrest and refractory cardiac arrest patient care. Can J Cardiol. 2024;40(4):524-539.

Notes

• When interpreting VAP outcomes, consider local diagnostic practices, baseline VAP prevention bundle adherence, and antimicrobial resistance ecology.

Overall Takeaway

ANTHARTIC showed that a short, early course of amoxicillin–clavulanate can reduce adjudicated early VAP after shockable-rhythm OHCA treated with TTM, and may reduce downstream antibiotic exposure. However, the absence of demonstrable survival or neurological benefit, combined with diagnostic and stewardship uncertainties, has meant that routine prophylactic antibiotics have not been adopted into standard post-arrest care for most systems.

Bibliography

• 1Llitjos JF, Reignier J, Lascarrou JB. Prevention of early ventilator-associated pneumonia after cardiac arrest. N Engl J Med. 2020;382(17):1672-1674. DOI
• 2Couper K, Laloo R, Field RA, Perkins GD, Thomas M, Yeung J. Prophylactic antibiotic use following cardiac arrest: a systematic review and meta-analysis. Resuscitation. 2019;141:166-173. DOI
• 3Nolan JP, Sandroni C, Böttiger BW, Cariou A, Cronberg T, Friberg H, et al. European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Resuscitation. 2021;161:220-269. DOI
• 4Dahyot-Fizelier C, Lasocki S, Kerforne T, Perrigault PF, Geeraerts T, Asehnoune K, et al. Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2024;12(5):375-385. DOI
• 5Gagnon DJ, Benken ST, Tanski A, et al. Ceftriaxone to prevent early-onset pneumonia in comatose patients after out-of-hospital cardiac arrest: a pilot randomized controlled trial and resistome assessment. Chest. 2026;169(1):115-127. DOI