Ceftriaxone to Prevent Early-Onset Pneumonia in Comatose Patients Following Out-of-Hospital Cardiac Arrest

Abstract

BACKGROUND:

Antibiotic prophylaxis following out-of-hospital cardiac arrest (OHCA) reduces early-onset pneumonia. However, it has an uncertain impact on mortality and noninfectious outcomes, with ongoing concerns about the subsequent development of antibiotic resistance.

RESEARCH QUESTION:

Does prophylactic ceftriaxone reduce the incidence of early-onset pneumonia without increasing the acquisition of antibiotic resistance genes after OHCA?

STUDY DESIGN AND METHODS:

Comatose survivors of OHCA treated with targeted temperature management without a clinical diagnosis of pneumonia at admission were randomized to receive ceftriaxone 2 g or matching placebo every 12 hours for 3 days. The primary outcome was early-onset pneumonia occurring ≤ 4 days following intubation confirmed by masked adjudicators. Abundance of antibiotic resistance genes recovered from rectal swabs before and after study drug administration were analyzed with metagenomic sequencing.

RESULTS:

A total of 411 participants were screened; 53 (13%) were randomized to treatment, and 1 participant withdrew, leaving 26 in each group in the final analysis. Early-onset pneumonia was diagnosed in 10 (38%) participants receiving ceftriaxone and 18 (69%) participants receiving placebo (risk ratio, 0.57; 95% CI, 0.21-1.001; P = .05). Open-label antibiotics were administered to 14 (54%) participants receiving ceftriaxone and 22 (85%) receiving placebo (risk ratio, 0.64; 95% CI, 0.43-0.94); most of the antibiotics were broad-spectrum agents (93% and 100%, respectively). After adjusting for differences in abundance of antibiotic resistance genes prior to study drug administration, participants randomized to receive ceftriaxone acquired significantly fewer antibiotic resistance genes to frequently used antibiotics in the ICU compared with those randomized to receive placebo (incidence risk ratio, 0.30; 95% CI, 0.13-0.70). Serious adverse drug effects were not reported in either treatment group.

INTERPRETATION:

This trial was inconclusive regarding the impact of ceftriaxone prophylaxis on reducing the incidence of early-onset pneumonia following OHCA. However, ceftriaxone was associated with less frequent administration of open-label antibiotics and reduced acquisition of antibiotic resistance genes to frequently used antibiotics in the ICU.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov; No.: NCT04999592; URL: www.clinicaltrials.gov

Early-onset pneumonia (EOP) within 4 days of intubation occurs in up to 65% of comatose patients following out-of-hospital cardiac arrest (OHCA) and is associated with a longer time in the ICU, prolonged duration of mechanical ventilation, greater need for tracheostomy, and increased exposure to antibiotic treatment.^1,2 Controlled trials suggest that antibiotic prophylaxis reduces EOP following acute brain injury and OHCA,^3,4 but recommendations by major medical organizations and consensus groups regarding antibiotic prophylaxis following OHCA are inconsistent.^5,6 The American Heart Association and the Neurocritical Care Society proposed that antibiotic prophylaxis may be administered following OHCA,⁵ whereas the International Liaison Committee on Resuscitation suggested that antibiotic prophylaxis should not be used due to the risk of inducing antibiotic resistance and the lack of discernable effect on mortality, neurologic function, or ICU- and mechanical ventilator-free days.⁶ Consequently, all 3 organizations identified the need for a clinical trial to study these specific concerns.^5,6

The current study hypothesized that among comatose patients treated with targeted temperature management (TTM), prophylactic ceftriaxone administered for 3 days would reduce the incidence of EOP relative to placebo. Secondary objectives were to determine the abundance of new antibiotic resistance genes (ARGs) acquired following study drug administration and the rates of other important clinical endpoints to assist with planning and power calculations for a larger clinical trial.

Study Design and Methods

This randomized, masked, placebo-controlled pilot trial was conducted at Maine Medical Center, a 929-bed tertiary care academic hospital. It was performed in accordance with the amended Declaration of Helsinki. The MaineHealth institutional review board approved the protocol (#1661144) prior to commencement using the Exception from Informed Consent process.⁷ Patients were enrolled under the approved Exception from Informed Consent process or by written informed consent when the legally authorized representative was available. All participants who regained the capacity to consent for themselves were retrospectively reconsented or offered the opportunity to withdraw from the trial. The study was monitored by an independent Data Safety Monitoring Board and adhered to Consolidated Standards of Reporting Trials⁸ and Strengthening the Organizing and Reporting of Microbiome Studies⁹ checklists. The study design was published previously,¹⁰ and the trial was registered with the National Library Medicine at www.clinicaltrials.gov.¹¹ The full protocol is available in e-Appendix 1.

Participants and Randomization

Adult patients ≥ 18 years of age were eligible if they were unable to follow simple verbal commands following resuscitation from OHCA due to both shockable and non-shockable heart rhythms and were treated with TTM (33 °C-36 °C). Individuals were excluded for in-hospital cardiac arrest, a delay > 6 hours from ICU admission to study drug administration, severe beta-lactam antibiotic allergy, or if the bedside treatment team planned antibiotic administration due to a suspected or confirmed infection. A complete list of exclusion criteria is provided in e-Appendix 1.

A computer-generated allocation sequence was used to randomize participants in a 1:1 ratio to receive ceftriaxone or placebo in blocks of 6. Participants, bedside treatment teams, pneumonia adjudicators, data analysts, outcome assessors, and the Data Safety Monitoring Board remained masked to the treatment group for the duration of the study.

Intervention

Participants received IV ceftriaxone 2 g every 12 hours for 3 days or matching 0.9% sodium chloride placebo. The dose and duration were selected to optimize methicillin-sensitive Staphylococcus aureus coverage according to local response data and to study ceftriaxone’s potential antiinflammatory benefits.¹⁰ All individuals were managed with clinical practice guideline-recommended post-resuscitation cardiac arrest care,^5,6 including moderate-dose sedation,¹² enteral nutrition, and sucralfate for stress ulcer prophylaxis. Following enrollment in the trial, study drug was immediately discontinued if bedside treatment teams prescribed open-label antibiotics, but the blind was maintained. A ventilator-associated pneumonia bundle was used in all individuals; these interventions included head-of-bed elevation at 30°, sucralfate for stress ulcer prophylaxis, oral care with chlorhexidine every 4 hours, and sedation interruption with an assessment for extubation readiness at least daily after the 24-hour TTM period, when clinically appropriate.

Efficacy Outcomes

The primary outcome was the incidence of adjudicator-confirmed clinical EOP, defined as occurring ≤ 4 days following intubation. This time frame was selected based on multiple clinical trials using this definition in participants with acute brain-injury^13,14 and a higher preponderance of resistant Gram-negative bacilli following 4 days of mechanical ventilation.¹⁵ All participants underwent pneumonia adjudication regardless of bedside treatment team diagnosis of pneumonia to reduce the risk of bias. Making a clinical diagnosis of pneumonia in hospitalized patients is challenging,¹⁶ more so following OHCA due to similar presentations with common co-existing diagnoses (eg, pulmonary edema, ARDS, pulmonary contusion, aspiration pneumonitis) and blunting of febrile responses during TTM.^5,6,17,18

Pneumonia following OHCA was not addressed in guidance for either community-acquired pneumonia^19-22 or ventilator-associated pneumonia,^23-25 and expert reviews have not provided validated diagnostic criteria.^17,18,26 We therefore adapted our criteria from published definitions in this patient population (Table 1).^3,27-30

TABLE 1 ].

Early-Onset Pneumonia Adjudication Criteria

Hours 0-72 following intubation (during TTM)

New or progressive focal lung consolidation and at least 1 clinical symptom (a or b)

a. New purulent secretions or change in quantity or quality of sputum

b. Worsening gas exchangea

Following 72 h of intubation

New or progressive focal lung consolidation and at least 2 clinical symptoms (a through e)

a. New purulent secretions or change in quantity or quality of sputum

b. Worsening gas exchangea

c. Cough, dyspnea, tachypnea, rales, or bronchial breath sounds

d. Body temperature ≥ 38.3 °C

e. Leukopenia (< 4,000 cells/mm3) or leukocytosis (> 12,000 cells/mm3)

TTM = targeted temperature management.

^aThe definition of worsening gas exchange is presented in the trial protocol.

The diagnosis of EOP was adjudicated by the agreement of 2 blinded, board-certified pulmonologists performing independent assessments; discrepancies were resolved by a third adjudicator with similar training. Secondary outcomes included late-onset pneumonia (LOP) > 4 days following intubation, microbiologically confirmed EOP or LOP from flexible fiber optic bronchoscopy, protected mini-bronchoalveolar lavage, or expectorated sputum, non-pulmonary infections, ICU- and mechanical ventilator-free days in the first 28 days, ICU and in-hospital mortality, hospital discharge disposition, and cerebral performance category and modified Rankin scale (mRS) scores determined by a standardized telephone interview at 6 months following OHCA. Open-label antibiotic exposure was also monitored, and broad-spectrum antibiotics were defined according to criteria from the National Healthcare Safety Network.³¹

Safety Outcomes

Three adverse drug effects related to ceftriaxone were classified a priori as Clostridioides difficile-associated diarrhea,³² type one (immediate-type) hypersensitivity reaction,³³ and gallbladder disease.³⁴ Serious adverse events were defined as per Good Clinical Practice guidance, and death was considered a serious adverse event only if it was determined that it was related to the study (e-Appendix 1).

ARG Assessment

ARGs were measured in material recovered from rectal swabs collected prior to study drug initiation, following study drug completion (3 days), and 1 week following the first dose of study drug. Total nucleic acids were extracted by using a ZymoBIOMICS DNA/RNA plus extraction kit (Zymo Research; 2024). Sequencing libraries were prepared by using the Kapa BioSystems HyperPlus Kit (KR1145, version 3.16; Roche Sequencing). Sequencing was completed on a NovaSeq 6000 with an SP flow cell (paired-end 250 bps reads; Illumina). A complete description of the approach to metagenomic sequencing is presented in e-Appendix 1.

Statistical Analysis

Sample size was calculated assuming an absolute reduction in the incidence of EOP of 25%, from 55% in participants receiving placebo to 30% in ceftriaxone-treated individuals, with 80% power at a 2-tailed 5% level of significance; this yielded 60 participants to be randomized to each group (120 total).^35-37 Continuous data are reported as median (interquartile range) and categorical variables as number (%). All data were analyzed on an intention-to-treat basis, using risk ratio (RR) with 95% CIs for treatment effect tested with the χ² or Fisher exact test and the U test for independent samples, as appropriate; P < .05 was considered statistically significant.

After identifying imbalances between treatment groups despite randomization, post hoc analyses were conducted. For the primary outcome of EOP, the Fisher exact test was used to estimate the unadjusted RR among patients randomized to receive ceftriaxone vs placebo. Poisson generalized linear regression was used to adjust for baseline covariate imbalance for previously healthy vs not previously healthy, COPD, witnessed cardiac arrest, bystander CPR, time to return of spontaneous circulation, and initial heart rhythm. The same approach was used to evaluate the risk for mortality according to treatment group. Posttreatment new ARG abundance was estimated by using generalized linear models with hurdle components and incidence rate ratios, with both treatment group (placebo vs ceftriaxone) and pretreatment ARG count as model predictors.

All statistical analyses were performed by using R version 4.2.1 (R Core Team; 2022).^37-40

Results

From August 10, 2021, to January 16, 2024, a total of 411 participants were screened, and 53 (13%) were randomized to treatment (Fig 1). One participant withdrew consent after awakening; the remaining 52 participants (26 in each treatment group) were included in the analyses. The trial was terminated early due to slow enrollment during the COVID-19 pandemic leading to an expiration of funding; 53 (44%) of a planned 120 participants were enrolled. Sixteen (62%) individuals randomized to receive ceftriaxone and 17 (65%) participants randomized to receive placebo completed all study drug doses.

Figure 1 –

Consolidated Standards of Reporting Trials trial flow diagram showing patient screening and recruitment from August 10, 2021, to January 16, 2024. EFIC = Exception from Informed Consent; LAR = legally authorized representative; MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant Enterococcus.

A numerically higher proportion of participants in the ceftriaxone group experienced a witnessed OHCA, bystander CPR rate, shorter time to return of spontaneous circulation, and lower Acute Physiology and Chronic Health Evaluation IV score (Table 2). Most (83%) participants were treated with a TTM goal of 33 °C for 24 hours. Three days of study drug were completed by 16 (62%) participants receiving ceftriaxone and 17 (65%) participants receiving placebo. Incomplete dosing of study drug only occurred when open-label antibiotics were started by the bedside treatment team.

TABLE 2 ].

Demographic and Baseline Characteristics

Characteristic	Ceftriaxone (n = 26)	Placebo (n = 26)
Age, y	60 (52-67)	59 (52-65)
Male sex	22 (85)	24 (92)
Race
White	25 (96)	25 (96)
Black/African American	1 (4)	0 (0)
Asian/multiple races	0 (0)	1 (4)
Ethnicity
Non-Hispanic/Latino	26 (100)	25 (96)
Unknown	0 (0)	1 (4)
Weight, kg	87 (75-100)	89 (77-106)
Medical history
Previously healthy	8 (31)	4 (15)
Coronary disease	9 (35)	3 (12)
Myocardial infarction	7 (27)	3 (12)
COPD	7 (27)	3 (12)
Heart failure	7 (27)	3 (12)
Hypertension	7 (27)	12 (46)
Kidney disease	4 (15)	2 (8)
Diabetes	2 (8)	2 (8)
Cerebrovascular disease	1 (4)	1 (4)
Cognitive impairment	1 (4)	0 (0)
Cancer	1 (4)	3 (12)
Liver disease	0 (0)	1 (4)
Out-of-hospital cardiac arrest
Witnessed, yes	20 (77)	13 (50)
Bystander CPR, yes	22 (85)	16 (62)
Time to ROSC, min	23 (13-31)	27 (21-36)
Initial heart rhythm
Shockable	11 (42)	15 (58)
Non-shockable	13 (50)	11 (42)
Unknown	2 (8)	0 (0)
Defibrillation, yes	15 (58)	16 (62)
Hospital admission
Glasgow Coma Scale, motor	1 (1-4)	1 (1-1)
SOFA score	11 (7-14)	11 (9-13)
APACHE IV score	71 (54-99)	102 (70-112)
Shock on admission, yes	9 (35)	13 (50)
Lactate, mM	4.0 (2.1-7.9)	5.4 (3.2-9.2)
Target temperature 33°C	21 (81)	22 (85)
Target temperature 36°C	5 (19)	4 (15)

Data are presented as median (interquartile range) or No. (%). APACHE = Acute Physiology and Chronic Health Evaluation; ROSC = return of spontaneous circulation; SOFA = Sequential Organ Failure Assessment.

Efficacy Outcomes

Blinded adjudicators diagnosed EOP in 10 (38%) participants receiving ceftriaxone and 18 (69%) participants receiving placebo, an absolute risk reduction of 31% in the unadjusted analysis (RR, 0.57; 95% CI, 0.21-1.001; P = .05). After adjusting for baseline covariates, the difference in the incidence of EOP between treatment groups was similar (RR, 0.37; 95% CI, 0.12-1.08; P = .09) (e-Table 1).

Microbiologically confirmed EOP was diagnosed in 6 (23%) individuals receiving ceftriaxone and 13 (50%) receiving placebo (RR, 0.46; 95% CI, 0.20-1.02) (Table 3). Agreement on the presence or absence of the diagnosis of EOP between the bedside treatment teams and the adjudicators occurred in 77% of participants randomized to receive ceftriaxone and 85% of participants randomized to receive placebo. Blinded adjudicators diagnosed LOP in 3 (12%) participants receiving ceftriaxone and 6 (23%) individuals receiving placebo (RR, 0.5; 95% CI, 0.14-1.8), with microbiologic confirmation in 1 (4%) individual and in 4 (15%) participants receiving ceftriaxone and placebo, respectively (RR, 0.25; 95% CI, 0.03-2.1). The organisms isolated from respiratory samples diagnostic for EOP or LOP are summarized in Table 4; there was no suggestion of a higher incidence of resistant bacteria in either treatment group. There were no non-pulmonary infections identified in either the ceftriaxone or placebo group.

TABLE 3 ].

Efficacy Outcomes

Outcome	Ceftriaxone (n = 26)	Placebo (n = 26)	RR (95% CI)
Primary infectious outcomes
Unadjusted adjudicator-confirmed EOP	10 (38)	18 (69)	0.57 (0.21-1.001), P = .05
Adjusted adjudicator-confirmed EOPa	NA	NA	0.37 (0.12-1.08), P = .09
Secondary infectious outcomes
Adjudicator microbiologically confirmed EOP	6 (23)	13 (50)	0.46 (0.20-1.02)
Treatment team clinically diagnosed EOP	8 (31)	20 (77)	0.40 (0.21-0.74)
Treatment team microbiologically confirmed EOP	5 (19)	16 (62)	0.31 (0.13-0.73)
Open-label antibiotic treatment	14 (54)	22 (85)	0.64 (0.43-0.94)
Time to open-label antibiotic treatment, d	1 (1-2)	3 (2-4)	NA
Broad-spectrum antibiotic treatment	10 (38)	20 (77)	0.50 (0.29-0.85)
Clinical outcomes
ICU-free days to day 28	16 (0-24)	0 (0-2)	NA
Mechanical ventilator-free days to day 28	25 (0-26)	0 (0-8)	NA
CPC at 6-month follow-up	5 (1-5)	5 (5-5)	NA
mRS at 6-month follow-up	6 (1-6)	6 (6-6)	NA
Unadjusted in-hospital mortality	11 (42)	19 (73)	0.59 (0.22-0.998)
Adjusted in-hospital mortalitya	NA	NA	0.56 (0.16-1.68)
Neurologic/brain death	9 (82)	16 (84)	0.97 (0.69-1.36)
Cardiac/circulatory	2 (18)	3 (16)	1.03 (0.20-5.19)

Data are presented as No. (%) or median (interquartile range). CPC = cerebral performance category; EOP = early-onset pneumonia; mRS = modified Rankin scale; NA = not applicable; RR = relative risk.

^aAdjusted for previously healthy vs not, COPD, witnessed cardiac arrest, bystander CPR, time to return of spontaneous circulation, and initial heart rhythm.

TABLE 4 ].

Bacteria Isolated From Sputum Samples

Pneumonia Organism	Ceftriaxone (n = 5 Bacteria)	Placeboa (n = 24 Bacteria)
Early-onset pneumonia organisms
Gram positive
Methicillin-sensitive Staphylococcus aureus	2 (40)	10 (42)
Streptococcus pneumoniae	0 (0)	2 (8)
Group B streptococcus	0 (0)	2 (8)
Gram negative
Haemophilus influenzae	1 (20)	3 (13)
Moraxella catarrhalis	1 (20)	1 (4)
Citrobacter koseri	1 (20)	0 (0)
Klebsiella pneumoniae	0 (0)	2 (8)
Escherichia coli	0 (0)	2 (8)
Pseudomonas aeruginosa	0 (0)	1 (4)
Enterobacter cloacae	0 (0)	1 (4)
Late-Onset Pneumonia Organisms	Ceftriaxone (n = 2 Bacteria)	Placeboa (n = 3 Bacteria)
Gram positive
Methicillin-sensitive S aureus	1 (50)	0 (0)
Gram negative
H influenzae	0 (0)	1 (33)
K pneumoniae	0 (0)	1 (33)
E cloacae	0 (0)	1 (33)
Serratia marcescens	1 (50)	0 (0)

Data are presented as No. (%).

^aSeven individuals in the placebo group grew multiple organisms; percentages may not add up to 100% due to rounding.

The per-protocol sputum sample obtained prior to study drug initiation yielded normal oropharyngeal flora in a similar frequency between study groups: 14 (54%) among participants randomized to receive ceftriaxone and 9 (35%) among participants randomized to receive placebo (Fig 2). Adjudicator-confirmed EOP was diagnosed in 5 (36%) of these 14 participants receiving ceftriaxone compared with all 9 (100%) participants receiving placebo.

Figure 2 –

Results of prestudy drug sputum samples and subsequent pneumonia development. Microbiologic results of sputum sample obtained prior to study drug administration and ultimate incidence of EOP and MP. EOP = early-onset pneumonia; MP = microbiologically confirmed pneumonia.

Open-label antibiotic treatment was prescribed by bedside treatment teams to 14 (54%) participants receiving ceftriaxone compared with 22 (85%) individuals receiving placebo (RR, 0.64; 95% CI, 0.39-0.90), and they were started earlier among individuals receiving ceftriaxone (1 [1-2] days) compared with individuals receiving placebo (3 [2-4] days). Almost all open-label antibiotics met broad-spectrum criteria in both the ceftriaxone (13 of 14 [93%]) and placebo (22 of 22 [100%]) treatment groups (RR, 0.93; 95% CI, 0.80-1.07).

Participants receiving ceftriaxone experienced more days alive and ICU-free (16 [0-24] days vs 0 [0-2] days) and more days alive and mechanical ventilator-free (25 [0-26] days vs 0 [0-8] days) compared with participants receiving placebo. Unadjusted in-hospital mortality was lower in the ceftriaxone group (42% vs 73%; RR, 0.59; 95% CI, 0.22-0.998), with wider CIs after adjusting for baseline covariates (RR, 0.56; 95% CI, 0.16-1.68) (e-Table 2). Six-month postdischarge cerebral performance category was similar for participants receiving ceftriaxone or placebo (5 [1-5] vs 5 [5-5]), as was 6-month mRS (6 [1-6] vs 6 [6-6]). In-hospital mortality was lower in the ceftriaxone group compared with the placebo group (42% vs 73%; RR, 0.58; 95% CI, 0.35-0.96). There were no instances of C difficile-associated diarrhea, type one (immediate-type) hypersensitivity reactions, gallbladder disease, or serious adverse events in either treatment group.

ARG Assessment

Rectal swabs with usable material for metagenomic sequencing were obtained from 17 (65%) participants in both treatment groups (e-Fig 1, e-Tables 3-4). The analysis of ARG abundance prior to study drug initiation identified 86 total ARGs in 12 (71%) participants randomized to receive ceftriaxone compared with 59 ARGs from 12 (71%) participants randomized to receive placebo; this represents 2 (0-4) ARGs per individual receiving ceftriaxone and 4 (0-9) ARGs per individual receiving placebo. After administering study drug, there were 143 ARGs from 14 (82%) ceftriaxone-treated individuals compared with 187 ARGs from 14 (82%) participants in the placebo group; this represents 8 (2-12) ARGs per individual receiving ceftriaxone and 12 (3-17) ARGs per individual receiving placebo (Fig 3 and e-Tables 3-4). Participants randomized to receive ceftriaxone had no change in total ARG abundance prior to vs following study drug administration (2 [0-4] vs 8 [2-12]; P = .18), whereas participants in the placebo group exhibited a significant increase (4 [0-9] vs 12 [3-17]; P = .01). After adjusting for differences in abundance of ARGs prior to study drug administration, participants randomized to receive ceftriaxone acquired a similar number of new ARGs compared with those randomized to receive placebo (incidence RR, 0.66; 95% CI, 0.35-1.25) (e-Table 5).

Figure 3 –

Distribution of unique ARGs and their antibiotic or antibiotic class target. New unique ARGs and their antibiotic or antibiotic class targets isolated after study drug administration in patients randomized to receive ceftriaxone (blue bars) and placebo (red bars). If 2 or more participants had the same gene it was only counted once. Common ICU antibiotics include macrolides, beta-lactams, fluoroquinolones, sulfamethoxazole-trimethoprim, and vancomycin. ARG = antibiotic resistance gene; SMZ-TMP = sulfamethoxazole-trimethoprim.

Abundance of ARGs targeting commonly prescribed antibiotics in the ICU isolated prior to study drug initiation was similar between groups, with 23 ARGs from 7 (41%) participants in the ceftriaxone group compared with 15 ARGs from 8 (47%) participants in the placebo group; this represents 1 (0-3) ARG in participants randomized to receive ceftriaxone and 1 (0-1) ARG in participants randomized to receive placebo.

After administering study drug, 33 ARGs targeting commonly administered antibiotics were isolated from 12 (71%) participants randomized to receive ceftriaxone compared with 77 ARGs from 12 (71%) participants randomized to receive placebo; this represents 1 (0-4) ARG in participants in the ceftriaxone group and 4 (0-9) ARGs in participants in the placebo group. For participants randomized to receive ceftriaxone, no change in the abundance of ARGs targeting commonly administered antibiotics in the ICU was seen comparing prior to and following study drug administration (1 [0-3] vs 1 [0-4]; P = .30) vs an increase in ARG abundance in individuals randomized to receive placebo (1 [0-1] vs 4 [0-9]; P < .01). After adjusting for differences in abundance of ARGs prior to study drug administration, participants randomized to receive ceftriaxone acquired significantly fewer ARGs to frequently used antibiotics compared with those randomized to receive placebo (incidence RR, 0.30; 95% CI, 0.13-0.70) (e-Table 6). Among the participants with genetically intact material recovered from rectal swabs, open-label antibiotic treatment was prescribed by bedside treatment teams to 5 (29%) participants who initially received ceftriaxone compared with 15 (88%) participants who initially received placebo (RR, 0.29; 95% CI, 0.13-0.64) (Fig 4).

Figure 4 –

ARGs targeting common ICU antibiotics in participants randomized to receive ceftriaxone (A) or placebo (B). For participants randomized to receive ceftriaxone, no change in the number of ARGs targeting commonly administered antibiotics in the ICU was seen comparing prior to and following study drug administration (1 [0-3] vs 1 [0-4]; P = .30) vs an increase in ARGs in participants randomized to receive placebo (1 [0-1] vs 4 [0-9]; P < .01). Open-label antibiotic treatment was prescribed by bedside treatment teams to 5 (29%) of 17 participants receiving ceftriaxone compared with 15 (88%) of 17 participants receiving placebo (risk ratio, 0.29; 95% CI, 0.13-0.64). ARG = antibiotic resistance gene.

Discussion

This randomized, placebo-controlled pilot trial was terminated early and was inconclusive regarding the impact of ceftriaxone prophylaxis to reduce the incidence of EOP after OHCA. However, it was associated with less frequent administration of open-label antibiotics, as well as reduced acquisition of ARGs to frequently used antibiotics in the ICU. These important secondary outcomes must be considered hypothesis generating, and rather than considering the study definitive to confirm efficacy or futility of antibiotic prophylaxis, we feel it should generate further study with increased focus on open-label antibiotics and ARG acquisition.

With lower than planned enrollment, the current study was underpowered to detect a treatment benefit (a type II error). A reduction in EOP with antibiotic prophylaxis has been reported in previous trials,^3,4 but the decreased ARG acquisition in the current trial was unexpected, and if confirmed, refutes the frequently expressed concern that antibiotic prophylaxis after OHCA should not be used because it selects for microbial resistance.^5,6,17,26,41 Antibiotic resistance is a global health emergency with an estimated 1.1 million attributable deaths in 2021 and is anticipated to increase markedly by 2050.⁴² Prior studies did not consider the impact of open-label antibiotics started as rescue therapy by bedside treatment teams or evaluate ARGs in assessing antibiotic resistance.^1,3,4,13,14 The use of metagenomic sequencing in the current study to assess the resistome is novel and previously unreported following OHCA or any trial including participants with acute brain injury.^{3,4,13,14,17,26} In addition to potentially affecting the incidence of EOP, antibiotic prophylaxis with ceftriaxone following OHCA may paradoxically decrease total antibiotic exposure and measurably reduce the acquisition of ARGs.

Two randomized trials of antibiotic prophylaxis following acute brain injury reported reductions in the incidence of pneumonia similar to the current study results. The Antibiotherapy During Therapeutic Hypothermia to Prevent Infectious Complications (ANTHARTIC) trial reported a reduction in EOP (19% vs 34%; P = .03) with IV amoxicillin-clavulanate 1 g and 200 mg administered for 2 days following OHCA.³ Unlike the current study, the ANTHARTIC trial defined EOP as occurring within the first 7 days and excluded participants with non-shockable initial heart rhythms, who comprise at least 45% of patients with OHCA in the United States.⁴³ ANTHARTIC reported no increase in multidrug-resistant bacteria using solid selective media cultures of stool samples prior to and following the intervention,³ with a similar trend to the current study results; multidrug-resistant bacteria were isolated from 2 participants prior to the intervention and 1 patient following antibiotic treatment, compared with 5 participants prior to placebo and 7 following placebo use. ANTHARTIC also reported a greater percentage of days with antibiotic use among the placebo group (50% vs 23%) but did not specifically describe the frequency of broad-spectrum antibiotic use.

The Prevention of Early Ventilation Acquired Pneumonia (VAP) in Brain Injured Patients by a Single Dose of Ceftriaxone (PROPHY-VAP) trial reported a reduction in EOP (14% vs 32%; P = .03), increased mechanical ventilator-, ICU-, and antibiotic-free days, and improved mRS and mortality following a single 2 g dose of ceftriaxone compared with placebo among participants with acute stroke or traumatic brain injury.⁴ The current study similarly identified an increase in ICU- and mechanical ventilator-free days, as well as a higher survival rate with ceftriaxone compared with placebo. PROPHY-VAP isolated extended-spectrum beta-lactamase-producing Enterobacteriaceae from the gut in only 2 participants, both in the placebo group, leaving the question of subsequent antibiotic resistance incompletely answered.

Recent scientific statements, expert reviews, and clinical practice guidelines have recommended that antibiotic prophylaxis be used either with caution or not at all due to concerns about the subsequent development of antibiotic resistance and the lack of improvement in noninfectious clinical outcomes.^5,6,17,26 These recommendations are based on low certainty evidence resulting in “weak” recommendations. Additional research to evaluate the impact on antibiotic resistance and other meaningful outcomes has been recommended.^5,6,17,26 The pooled results of ANTHARTIC, PROPHY-VAP, and the current trial provide consistent results and a biologically plausible mechanism by which antibiotic prophylaxis may reduce the incidence of EOP, decrease the use of open-label antibiotics, and reduce the risk of acquired antibiotic resistance in survivors of OHCA with brain injuries compared with no prophylaxis.^3,4 The findings refute recommendations to avoid antibiotic prophylaxis following OHCA. Additional characterization of postresuscitation ceftriaxone prophylaxis is needed to optimize the potential benefits and minimize the potential harms of treatment.

Despite a similar reduction in the incidence of pneumonia in ANTHARTIC, PROPHY-VAP, and our trial, an effect on mortality has only been shown in the 2 studies using ceftriaxone.^{3,4,13,14,17,26} Ceftriaxone may have neuroprotective and antiinflammatory properties,^10,44 and whether these discordant results may be explained by these mechanisms requires additional research. The results of the immunomodulatory studies embedded within the current trial will be reported separately.

This trial had several important limitations. It was conducted at a single center, had a limited sample size, was partially recruited during the COVID-19 pandemic, and was terminated early due to enrollment delays and funding expiration. Incomplete enrollment lowered sample size, reduced power, and increased the chance for overestimation of treatment effect. Despite a randomized design, nominal imbalances between treatment groups were seen, which may have been clinically relevant. The mortality rate in the current trial was high (58% overall), due mainly to severe hypoxicischemic encephalopathy, and reflecting enrollment of participants with all initial heart rhythms. In contrast, ANTHARTIC excluded participants with non-shockable rhythms and reported a lower mortality rate of 39%,³ and the Targeted Temperature Management (TTM-2) trial excluded participants asystole with unwitnessed arrest and known non-cardiac etiologies, with a lower mortality rate of 49%.³⁵ Withdrawal of lifesustaining therapy after OHCA due to severe hypoxicischemic encephalopathy is a competing risk that confounds the impact of antibiotic prophylaxis,⁴⁵ including a more heterogeneous group of patients with OHCA may enhance the generalizability of the trial but also complicate outcome interpretation. Study drug was administered to all comers, and heterogeneity of treatment effect is possible with antibiotic prophylaxis after OHCA; triage excluding clearly moribund patients or using an individualized EOP risk score may improve benefit and minimize risk to patients and warrants further study. All participants were treated with TTM at 33 °C or 36 °C, meaning the current results may not be representative of patients treated with normothermia or fever prevention. Whether specific subsets of cardiac arrest survivors may benefit or be harmed by TTM at 33 °C or 36 °C or fever prevention remain controversial.^46-48

The current resistome analysis assessing abundance of ARGs was novel but did not assess ARG expression or the organism associated with the ARG; future trials evaluating these endpoints using metatranscriptomics are needed. The high incidence of open-label antibiotic use likely contributed to ARG acquisition; whether these rates and choices reflect medical care at other centers is unknown, but data from community-acquired pneumonia studies suggest similar patterns.^16,49 Finally, stratifying randomization according to severity of brain injury, addressing the complex issue of diagnosing pneumonia in this critically ill patient population, and advancing the evaluation and reduction of antibiotic resistance is needed in future research efforts.

Interpretation

In this pilot study, antibiotic prophylaxis with ceftriaxone was inconclusive regarding the incidence of EOP in OHCA survivors treated with TTM, likely representing inadequate power related to the reduced enrollment, but was associated with reduced acquisition of ARGs to frequently used antibiotics, potentially through a reduction in subsequent antibiotic exposure.

Improved mortality may have been biased by group imbalances but could also reflect specific benefits of ceftriaxone relative to other antibiotics. Although further study is needed, these findings challenge recommendations and support similar findings in recent trials of patients with acute brain injury, including OHCA, suggesting that antibiotic may both prevent pneumonia and protect against the development of antibiotic resistance.

Supplementary Material

Additional information: The e-Tables and e-Figure are available online under “Supplementary Data.”

Take-Home Points.

Study Question:

Does prophylactic ceftriaxone reduce the incidence of early-onset pneumonia without increasing the acquisition of antibiotic resistance genes after out-of-hospital cardiac arrest?

Results:

Early-onset pneumonia was diagnosed in 10 (38%) participants receiving ceftriaxone and 18 (69%) participants receiving placebo (risk ratio, 0.57; 95% CI, 0.21-1.001; P = .05), and after adjusting for differences in abundance of antibiotic resistance genes prior to study drug administration, participants randomized to receive ceftriaxone acquired significantly fewer antibiotic resistance genes to frequently used antibiotics in the ICU compared with those randomized to receive placebo (incidence risk ratio, 0.30; 95% CI, 0.13-0.70).

Interpretation:

This trial was inconclusive regarding the impact of ceftriaxone prophylaxis to reduce the incidence of early-onset pneumonia after out-of-hospital cardiac arrest; however, ceftriaxone was associated with less frequent administration of open-label antibiotics and reduced acquisition of antibiotic resistance genes to frequently used antibiotics in the ICU.

ABBREVIATIONS:

ANTHARTIC

Antibiotherapy During Therapeutic Hypothermia to Prevent Infectious Complications

ARG

antibiotic resistance gene

EOP

early-onset pneumonia

LOP

late-onset pneumonia

mRS

modified Rankin Scale

OHCA

out-of-hospital cardiac arrest

PROPHY-VAP

Prevention of Early Ventilation Acquired Pneumonia (VAP) in Brain Injured Patients by a Single Dose of Ceftriaxone

RR

risk ratio

TTM

targeted temperature management