Timing and clinical risk factors for early acquisition of gut pathogen colonization with multidrug resistant organisms in the intensive care unit

doi:10.21203/rs.3.rs-3547035/v1

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Research Article

Timing and clinical risk factors for early acquisition of gut pathogen colonization with multidrug resistant organisms in the intensive care unit

https://doi.org/10.21203/rs.3.rs-3547035/v1

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Journal Publication

published 21 Feb, 2024

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Background

Microbiome restitution therapies are being developed to prevent gut pathogen colonization among patients in the intensive care unit (ICU) and in other select populations. If preventive therapies are to be effective, they must be administered prior to pathogen acquisition. The timing and risk factors for early acquisition of gut pathogen colonization (within 72 hours) are currently unknown and could be helpful to guide ICU trial design.

Methods

This was a prospective cohort study. Patients in the ICU had deep rectal swabs performed at the time of ICU admission and exactly 72 hours later. Early gut pathogen colonization was classified as the new presence (based on culture of rectal swabs) of one or more of the following organisms of interest: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant (VRE), and Gram negative bacteria that showed multidrug resistance (MDR) or third generation Cephalosporin resistance (Ceph-R). Clinical risk factors for early acquisition of gut pathogen colonization were captured using the APACHE IV scoring system.

Findings

Among 131 patients who were swabbed at ICU admission and 72 hours later, the rates of gut pathogen colonization at ICU admission were 11.4%, 10.6%, 38.6%, and 8.3% for MRSA, VRE, MDR and Ceph-R Gram negatives respectively. Among the patients who were negative for a given pathogen at ICU admission, the rates of early acquisition of gut pathogen colonization were 7.8% for MRSA (95% CI 3.6 to 14.2%), 7.7% for VRE (95% CI 3.6 to 14.1%), 11.3% for MDR Gram negatives (95% CI 4.4 to 18.8%), and 4.2% for Ceph-R Gram negatives (95% CI 1.4 to 9.5%). There were no clinical risk factors which independently predicted early acquisition of gut pathogen colonization.

Interpretation

Early gut pathogen colonization is common in the ICU and may represent a target for future trials. Clinical risk factors are not likely to be useful in pre-selecting patients for trials.

Intensive care unit

Multidrug Resistant Bacteria

Methicillin-Resistant Staphylococcus Aureus

Vancomycin-Resistant Enterococcus

Extended-Spectrum B-Lactamase Resistance

Outcomes Research

Microbiome

Healthcare-associated infections caused by pathogenic (often MDR) bacteria are a significant concern in the medical ICU with mortality rates ranging from 26% and 80%.(1) Gut colonization with pathogenic bacteria is a risk factor for subsequent all-cause and pathogen-specific systemic infections.(2–7) Therefore, understanding the prevalence and dynamics of gut pathogen colonization is crucial for developing targeted interventions to mitigate the spread of these organisms and improve patient outcomes.

Previous studies have demonstrated that the prevalence of gut pathogen colonization is high at the time of ICU admission and that many previously uncolonized patients acquire gut pathogens during prolonged ICU stays.(3, 8–14) Specific estimates of gut colonization and acquisition range based on institution and organism. For example, the prevalence of gut colonization with VRE at ICU admission has been estimated at 3.6–10.6%, with acquisition rates from 3.0–10.2% during the ICU stay.(15, 16) Similarly, for carbapenem-resistant Enterobacteriaceae (CRE), prevalence of gut colonization at the time of ICU admission has been estimated at 2.1–28% with acquisition rates reaching up to 58.6% during prolonged ICU stays.(17, 18) Many studies show strong associations between fecal carriage of MDR organisms and subsequent systemic infections with the same organisms: e.g., 77% of patients who developed MDR A. baumanii infections were identified as fecal carriers.(19)

These prior studies are valuable but leave relatively wide estimates of confidence in rates of acquisition of gut pathogen colonization. Because many studies perform sampling at the end of the study period or immediately prior to ICU discharge, they do not always describe the dynamics of acquisition of gut pathogen colonization, which is crucial for the design of future ICU trials. Among ICU patients with sepsis, improvement or lack thereof during the early ICU period—typically defined as the first 72 hours after ICU admission—has been shown to be a powerful predictor of subsequent risk for death.(20, 21) To be clinically effective, interventions seeking to prevent acquisition of gut pathogen colonization may need to take action during this very short timeframe; yet relatively few prior studies have done such short-term sampling.

There are additional gaps in the existing literature. Prior studies have determined the clinical risk factors for gut colonization with pathogenic bacteria, but they have not always distinguished between prevalent colonization (colonization at the time of ICU admission) and incident colonization (acquisition of gut pathogen colonization during some predetermined time period in the ICU).(22, 23) Last, although prior studies of gut pathogen colonization in the ICU have often utilized protocolized sample collection—e.g., weekly after ICU admission—they have not always collected samples from the same individual patients, thus leaving some uncertainty related to whether there was a within-individual change in the gut pathogen colonization status of a given patient.(17)

In this study, we performed protocolized collection of rectal swabs at the time of ICU admission and exactly 72 hours later on the same patients. We used standard culture-based methods to define the within-individual changes in gut pathogen colonization status so that we could fully understand the acquisition rates and risk factors for gut pathogen colonization during the early period in ICU hospitalization. We focused on VRE, MRSA, and MDR Gram negative (GN) bacteria because these organisms account for a large proportion of ICU-acquired infections and are readily cultured.

Population and rationale

The study enrolled adult patients aged 18 or more years who were newly admitted to an ICU (medical, surgical, or specialty ICU), provided informed consent for rectal swab collection (delayed patient or surrogate consent accepted) (24), and survived for a minimum of 72 hours in the ICU after admission so that they could provide a follow-up rectal swab. The rationale for selecting 72 hours as the sampling interval was based on prior ICU literature related to sepsis, including the APACHE studies. (25, 26) This literature suggests that ICU interventions must be deployed during the first 72 hours to be most effective at altering patient outcomes. Because the focus of the study was on early acquisition of gut pathogen colonization, we excluded data from subjects who were swabbed at ICU admission and could not be swabbed again due to death or discharge. Our overall goal was to study a heterogeneous ICU population, the same population that would be targeted for future trials testing therapies to prevent acquisition of gut pathogen colonization.

Rectal swabs

Rectal swabs were performed by an ICU nurse, within 4 hours of ICU admission and then again 72 hours later (+/- 4 hours). Fecal soilage/staining was used to verify that swabs were adequate. With the patient in the left lateral decubitus position, flocked nylon swabs (Eswab, Copan Diagnostics, Murrieta, CA) were inserted at least 6 cm into the rectum and spun clockwise five times while moving them longitudinally.

Cultures for multi-drug resistant organisms

The organisms of interest in this study were MRSA, VRE, and MDR or Ceph-R Gram-negative bacteria. These organisms were selected because they are readily culturable and cause up to 40% of all culture-proven infections in the ICU.(27) Aliquoted rectal swab specimens were plated onto chromogenic agars for MRSA (Spectra MRSA agar, Remel, San Diego, CA)and VRE (Spectra VRE agar, Remel, San Diego, CA)), as well MacConkey agar for Gram-negative bacteria. Gram-negative colonies were selected from MacConkey based on predominant colony morphology, with identification and antimicrobial susceptibility testing performed using the Vitek 2 system with AST-N010/020 cards with confirmatory testing as needed. Current Clinical and Laboratory Standards Institute (CLSI) breakpoints were used for categorical interpretations of susceptibility. For this study, Gram-negative bacteria were classified as MDR if they were non-susceptible to three or more antimicrobial categories. (28, 29) Gram-negative bacteria were classified as Ceph-R if they showed non-susceptibility to 3rd generation cephalosporins (ceftriaxone or ceftazidime). (30) All organisms of interest were classified as present or absent at ICU admission and again after 72 hours.

Early acquisition of gut pathogen colonization

Early acquisition of gut pathogen colonization was defined categorically, in a pathogen-specific manner for each individual patient. For the organisms of interest—MRSA, VRE, and the Gram negative bacteria—patients were defined as having acquired gut pathogen colonization if the organism was absent at the time of ICU admission but present after 72 hours.

Clinical risk factors for early acquisition of gut pathogen colonization

We were interested in testing clinical variables as potential risk factors for early acquisition of gut pathogen colonization. The APACHE IV score was used to assess acute severity of illness, and was calculated at the time of ICU admission and again after 72 hours. APACHE-IV is calculated by incorporating a comprehensive set of variables including age, sex, admission date to the ICU, vital signs, laboratory findings, and various clinical parameters to assess the severity of illness in critically ill patients. APACHE-IV scores were grouped into three categories: low (≤ 42), middling (43–73), and high (> 73). We gathered the following co-variables in addition to the APACHE component variables: age (organized into tertiles), gender, ICU type (cardiac, medical, neurological, or surgical), ICU admission diagnosis, and pre-ICU hospital days.

Clinical outcomes: death or culture-proven infection

To examine the downstream impact of gut pathogen colonization, we examined a composite outcome of death and culture-proven infection within 30 days from ICU admission, an outcome that we and others have utilized previously.(2) The rationale for this composite outcome is that death and culture-proven infection function as competing risks because a patient might die from infection before the infection can be diagnosed. Operationalization of this outcome followed previously described methods.

Statistical approach

Continuous measures were divided into tertiles. An exact binomial calculation was used to estimate the 95% confidence intervals for proportions. Chi-squared tests were used to compare co-variables based on early acquisition of gut pathogen colonization. A logistic regression model was constructed for the outcome of early acquisition of gut pathogen colonization. APACHE IV score was included in this model a priori, with additional predictor variables added stepwise and retained in the model if they had an independent association (p < 0.10) with the outcome. An additional model was examined which interrogated the component measures within APACHE IV as predictors. To examine the relationship between early acquisition of gut pathogen colonization and the composite outcome of death and culture-proven infection, we constructed a Cox proportional hazards model. This model had three exposure groups: patients who were not colonized at either ICU admission or 72 hours later, patients who were colonized at ICU admission (with or without colonization at 72 hours), and patients who were not colonized at admission but acquired one or more pathogens after 72 hours. Last, a sample size calculation was performed to guide future ICU trials; this calculation was performed as a two-sided test of two proportions with alpha 0.05.

Patient baseline characteristics

177 patients donated a rectal swab at ICU admission and 131 (74%) survived 72 hours and donated a second rectal swab. Among the 131 patients studied who provided serial rectal swabs, most were over 50 years old, with approximately equal numbers of females and males (Table 1). Patients were admitted to a variety of ICU types (medical, surgical, etc.) and were predominantly admitted directly to the ICU from the emergency room (74.0%). Acute severity of illness was high, with a median APACHE IV score of 52 (IQR 38 to 89).

Table 1

Baseline characteristics at the time of ICU admission, stratified by early gut colonization.
Characteristics at the Time of ICU Admission		No Early Gut Colonization N = 104	Early Gut Colonization N = 27	P-value
Age (tertiles)	≤ 56 years	30 (75.0%)	10 (25.0%)	0.177
	57–67 years	39 (88.6%)	5 (11.4%)
	≥ 68 years	35 (74.5%)	12 (25.5%)
Gender	female	59 (79.7%)	15 (20.3%)	0.913
Gender	male	45 (78.9%)	12 (21.1%)
ICU Type	Cardiac	23 (82.1%)	5 (17.9%)	0.884
	Medical	31 (77.5%)	9 (22.5%)
	Neurological	11 (73.3%)	4 (26.7%)
	Surgical	39 (81.3%)	9 (18.8%)
Admission Diagnosis, by System	Cardiovascular	35 (85.4%)	6 (14.6%)	0.735
	Digestive	28 (73.7%)	10 (26.4)
	Respiratory	18 (75.0%)	6 (25.0%)
	Genitourinary	7 (100%)	0 (0.0%)
	Neurologic	6 (75.0%)	2 (25.0%)
	Neurosurgery	5 (71.4%)	2 (28.6%)
	Metabolic	1 (100%)	0 (0.0%)
	Other	4 (80.0%)	1 (20.0%)
Pre-ICU Days in Hospital	0 days	78 (80.4%)	19 (19.6%)	0.719
	1–2 days	13 (72.2%)	5 (27.8%)
	> 2 days	13 (81.3%)	3 (18.8%)
Receiving Dialysis	Yes	2 (66.7%)	1 (33.3%)	0.582
Receiving Dialysis	No	102 (79.7%)	26 (20.3%)
Receiving Ventilation	Yes	38 (84.4%)	7 (15.6%)	0.301
Receiving Ventilation	No	66 (76.7%)	20 (23.3%)
Vital Signs	Temperature > 38°C	1 (50.0%)	1 (50.0%)	0.300
	Heart Rate ≥ 120/min	8 (80.0%)	2 (20.0%)	0.960
	Resp. Rate > 20/min	32 (76.2%)	10 (23.8%)	0.534
	MAP ≤ 65	9 (81.8%)	2 (18.2%)	0.835
Lab values	WBC (10⁹/L) > 10	63 (81.8%)	14 (18.2%)	0.412
	Hct (%) ≤ 40	81(77.9%)	23 (22.1%)	0.403
	Albumin (g/dL) ≤ 3.4	43 (78.2%)	12 (21.8%)	0.771
	Creatinine (mg/dL) > 1.2	37 (82.2%)	8 (17.8%)	0.562
Glasgow coma scale	< 5	27 (79.4%)	7 (20.6%)	0.973
	5–10	10 (76.9%)	3 (23.1%)
	> 10	67 (79.8%)	17 (20.2%)
APACHE IV score (tertiles)	Low (≤ 42 points)	35 (79.5%)	9 (20.5%)	0.842
	Middling (43–73 points)	36 (81.8%)	8 (18.2%)
	High (> 73 points)	33 (76.7%)	10 (23.3%)

Gut pathogen colonization

Rates of gut colonization at ICU admission were 11.4%, 10.6%, 38.6%, and 8.3% for MRSA, VRE, MDR Gram negatives, and Ceph-R Gram negatives respectively (Fig. 1). 48.1% of patients were colonized with one or more of these organisms at ICU admission. After 72 hours in the ICU, rates of gut colonization were 14.4%, 16.7%, 34.8%, and 9.1% for the same organisms and 51.1% of patients were colonized with one or more organisms. Among 116 patients who were negative for MRSA at ICU admission, rates of early gut MRSA acquisition were 9/116 (7.8%, 95% CI 3.6 to 14.2%). Similarly, rates for early acquisition of VRE were 9/117 (7.7%, 95% CI 3.6 to 14.1%); rates for early acquisition of MDR Gram negatives were 9/80 (11.3%, 95% CI 4.4 to 18.8%); rates for early acquisition of Ceph-R Gram negatives were 5/120 (4.2%, 95% CI 1.4 to 9.5%).

Characteristics of colonizing Gram negatives

The most common Gram negative bacteria cultured from rectal swabs were E. coli, followed by K. pneumoniae and Enterobacter (Table 2). The comparison of the antimicrobial resistance patterns within Gram negative bacteria showed minimal differences comparing the overall resistance pattern at ICU admission versus 72 hours later (Fig. 2). The largest increase in resistance was observed with nitrofurantoin, followed by cefoxitin and cefazolin. However, the proportion of Gram negatives showing non-susceptibility was similar for most antibiotics over this short timeframe.

Table 2

Gram negative bacteria cultured from rectal swabs at ICU admission and 72 hours later.
Gram Negative Organisms	Admission N (%)	72 Hours N (%)
E. coli	94 (71.2%)	83 (62.9%)
K. Pneumoniae	21 (21.2%)	24 (18.2%)
Enterobacter	3 (2.3%)	11 (8.3%)
Citrobacter	3 (2.2%)	6 (4.5%)
Proteus	1 (0.8%)	4 (3.0%)
S. Fonticola	1 (0.8%)	2 (1.5%)
Shigella	2 (1.5%)	1 (0.8%)
H. Alvei	1 (0.8%)	1 (0.8%)
Burkholderia	0 (0.0%)	1 (0.8%)
Raoutella	1 (0.8%)	0 (0.0%)
Morganella	1 (0.8%)	0 (0.0%)

Clinical risk factors for acquisition of early gut pathogen colonization

Baseline patient characteristics including acute severity of illness (APACHE IV) at ICU admission were compared between those who did versus those who did not acquire early gut pathogen colonization (Table 1). None of these clinical risk factors was associated with acquisition of early gut pathogen colonization. Neither APACHE IV score nor any other co-variables from the time of ICU admission predicted early gut pathogen colonization (odds ratio (OR) 0.86, 95% CI 0.30–2.49 for a middling vs. low APACHE IV score and OR 1.18, 95% CI 0.43–3.26 for a high vs. low APACHE IV score).

Death and culture-proven infection

There were 11 deaths (8.4%) and 21 (16.0%) culture-proven infections within 30 days of ICU admission; 29 (22.1%) of patients had the combined outcome of death or infection within 30 days. The most common infection sites were urine (N = 10), respiratory (N = 7), and bloodstream (N = 7) (Table 3). The most common infection-causing organisms were Klebsiella spp. (N = 5) followed by E. coli, Pseudomonas spp., and Enterobacter (N = 4 each). Out of the 5 patients with Klebsiella infections, 1 was previously colonized with Klebsiella (1/5, 20%), 4/4 (100%) were previously colonized with E. coli, and 0/4 (0%) were previously colonized with Enterobacter.

Table 3

Culture-proven infections within 30 days of ICU admission, organized by infection source and organism type.
		Organism
Infection Source	Total	E. coli	Klebs-iella	MRSA	Entero-bacter	Pseudomonas spp.	E. faecalis	VRE	Citro-bacter	Candida	A. xylox-idans	MSSA
Respiratory	7	0	0	2	2	1	1	0	0	0	1	0
Biliary Fluid	1	0	1	0	0	0	0	0	0	0	0	0
Urine	10	2	2	0	1	1	2	1	1	0	0	0
Blood	7	0	2	0	1	0	0	1	0	1	0	1
Wound	4	1	0	0	0	1	1	1	0	0	0	0
Abdominal Fluid	1	1	0	0	0	0	0	0	0	0	0	0
Totals	29	4	5	2	4	3	4	3	1	1	1	1

Acquisition of early gut pathogen colonization and risk for death or infection

Patient characteristics after 72 hours in the ICU were examined to explore their association with subsequent occurrences of death or infection (Table 4). Longer pre-ICU hospital stays (> 2 days), receipt of dialysis, and receipt of mechanical ventilation, was associated with increased risk for the composite outcome. Elevated heart rate, respiratory rate, and creatinine levels were also associated with higher rates of death or infection, as was lower Glasgow Coma Scale scores (< 5 points) and higher APACHE IV score. Neither receipt of antibiotics nor receipt of PPIs was associated with the composite outcome.

Table 4

Characteristics after 72 hours in the ICU, stratified by subsequent death or culture-proven infection.
Characteristics after 72 Hours		No Death or Infection N = 102	Death or Infection N = 29	P-value
Age (tertiles)	≤ 56 years	29 (72.5%)	11 (27.5%)	0.612
	57–67 years	35 (79.5%)	9 (20.5%)
	≥ 68 years	38 (80.9%)	9 (19.1%)
Gender	female	60 (81.1%)	14 (18.9%)	0.312
Gender	male	42 (73.7%)	15 (26.3%)
ICU Type	Cardiac	24 (85.7%)	4 (14.3%)	0.402
	Medical	28 (70.0%)	12 (30.0%)
	Neurological	11 (73.3%)	4 (26.7%)
	Surgical	39 (81.3%)	9 (18.8%)
Admission Diagnosis, by System	Cardiovascular	38 (92.7%)	3 (7.3%)	0.108
	Digestive	28 (73.7%)	10 (26.3%)
	Respiratory	17 (70.8%)	7 (29.2%)
	Genitourinary	5 (71.4%)	2 (28.6%)
	Neurologic	6 (75.0%)	2 (25.0%)
	Neurosurgery	4 (57.1%)	3 (42.9%)
	Metabolic	0 (0.0%)	1 (100.0%)
	Other	4 (80.0%)	1 (20.0%)
Pre-ICU Days in Hospital	0 days	82 (84.5%)	15 (15.5%)	0.007
	1–2 days	10 (55.6%)	8 (44.4%)
	> 2 days	10 (62.5%)	6 (37.5%)
Receiving Dialysis	Yes	4 (44.4%)	5 (55.6%)	0.012
Receiving Dialysis	No	98 (80.3%)	24 (19.7%)
Receiving Ventilation	Yes	11 (50.0%)	11 (50.0%)	< 0.001
Receiving Ventilation	No	91 (83.5%)	18 (16.5%)
Vital Signs	Temperature > 38°C	0 (0.0%)	1 (100.0%)	0.060
	Heart Rate ≥ 120/min	7 (70.0%)	3 (30.0%)	0.533
	Resp. Rate > 20/min	30 (69.8%)	13 (30.2)	0.119
	MAP ≤ 65	6 (60.0%)	4 (40.0%)	0.157
Lab values	WBC (10⁹/L) > 10	49 (73.1%)	18 (26.9%)	0.182
	Hct (%) ≤ 40	90 (75.6%)	29 (24.4%)	0.053
	Albumin (g/dL) ≤ 3.4	59 (73.8%)	21 (26.3%)	0.156
	Creatinine (mg/dL) > 1.2	33 (67.3%)	16 (32.7%)	0.025
Glasgow coma scale	< 5	2 (25.0%)	6 (75.0%)	< 0.001
	5–10	7 (58.3%)	5 (41.7%)
	> 10	93 (83.3%)	18 (16.2%)
APACHE IV score	≤ 42 points	59 (90.8%)	6 (9.2%)	< 0.001
	43–73	34 (73.9%)	12 (26.1%)
	> 73	9 (45.0%)	11 (55.0%)

Cox proportional hazards model for death or infection

Finally, we examined the relationship between new gut pathogen colonization and death or culture-proven infection using time-to-event methods (Fig. 3). Patients were divided into three groups: not colonized, colonized at admission (with or without colonization after 72 hours), and new colonization. The highest rates of death or infection were among those who were newly colonized, followed by those with baseline colonization, and those without colonization had the lowest rates (Log-Rank not statistically significant, p = 0.257). Next, we constructed a Cox proportional hazards model for the outcome of death or culture-proven infection within 30 days of ICU admission. In this model, we compared three categories of patients: those who were never gut pathogen colonized, those who were colonized at ICU admission (regardless of colonization status after 72 hours), and those who had early acquisition of gut pathogen colonization. Compared versus a reference group who was never colonized, the crude hazard ratio for death or infection was 1.69 (95% CI 0.70–4.09) for those who were colonized at ICU admission and was 2.19 (95% CI 0.82–5.84) for those who had early gut acquisition of colonization. APACHE IV score was a strong independent predictor for death or infection, but adjusting for APACHE score did not substantially alter the relationship between early gut colonization and death or infection.

Sample size calculation for future studies

The point estimates from the study can be used for power calculations for future studies that may wish to test interventions which decolonize and/or prevent colonization. If an intervention had a 50% relative benefit over placebo in decolonizing ICU patients (i.e., eradicating colonization that was either present at admission or acquired early thereafter), a future study testing this intervention would need to enroll a total of 112 patients to show benefit (assuming alpha 0.05 and equal sample sizes in intervention groups). If an intervention had 50% relative benefit over placebo in preventing acquisition of gut pathogen colonization, the future study would need to enroll a total of 328 patients, assuming that the study pre-selected for treatment only the patients who were not colonized at ICU admission. If the future study treated all patients without pre-selection, it would need to enroll a total of 700 patients.

This study assessed early acquisition of gut pathogen colonization by performing protocolized deep rectal swabs on patients at the time of ICU admission and exactly 72 hours later. Focusing on acquisition of VRE, MRSA, or MDR/Ceph-R Gram negative bacteria, we found that rates of early acquisition varied from 4.2 to 11.3% across the organisms of interest. Among patients who were not previously gut pathogen colonized, one in every five patients became colonized during this period of short-term follow-up. One caveat to this finding is that there was “noise” in our data, with some patients who were classified as colonized at ICU admission then testing negative three days later. This intermittent intestinal carriage has been observed in previous studies and may represent false negatives or true changes in carriage due to administration of antibiotics or natural clearance.(31–33)

Interestingly, the observed rates of 30-day death or infection were worse among patients who had early acquisition of gut pathogen colonization compared to those who were already colonized at the time of ICU admission, although this result was not statistically significant. Overall, our findings highlight the need for early interventions aimed at preventing acquisition of gut pathogen colonization in the ICU, particularly for patients at high risk for sepsis. The early hours of an ICU admission are a critical window during which interventions can have the most substantial impact on patient outcomes (e.g., in treatment of sepsis where in-hospital mortality can be reduced by early interventions by up to 16%).(34) Our study demonstrates that substantial, likely clinically relevant, changes are taking place in terms of gut colonization status during this same early ICU time period.

In terms of specific organisms, our study results are similar to previous studies, although variation in the ICU population, local pathogen prevalence, and the timeframe of testing make exact comparisons challenging.(3) A prior meta-analysis estimated the acquisition rate of VRE to be 10.2% within the United States,(16) which is similar to our finding of a VRE acquisition rate of 10.6% within the first 72 hours. However, acquisition rates of VRE can vary greatly between studies based on frequency and type of screening. (15, 35) Our study had an MRSA acquisition rate of 7.8% during the initial 72 hours of ICU admission and Thompson et al. similarly found an MRSA acquisition rate of 7.5%; however, this study and many others re-tested for colonization after one week or more instead of 72 hours.(36–38) For Gram negative bacteria, our study had an Ceph-R acquisition rate of 4.2% within the first 72 hours of ICU admission which is similar to the 3% acquisition rate in the Americas estimated by a previous meta-analysis.(3) However, these studies screened weekly after admission,(39, 40) so it is again unclear what proportion was acquired within 72 hours. Given the similar rates of acquisition in our study after 72 hours and other studies that screen after a greater time interval, it is likely that much pathogen acquisition takes place during the first few days after ICU admission.

Our results also can be used as the basis for sample size calculations for future trials seeking to intervene to decolonize patients or prevent colonization and emphasize that the appropriate design for future trials will depend on the hypothesized mechanism of the intervention. Sample sizes for trials seeking to decolonize patients who are already colonized at ICU admission will require about 3-fold fewer patients than studies seeking to prevent early colonization, although the latter may be a more clinically important outcome. Pre-selection of patients based on rapid testing for colonization at the time of ICU admission is likely to enhance the efficiency of future trials design. Clinical variables, on the other hand, are less likely to be useful in pre-selecting patients for future trials; none of them—including APACHE IV score—were associated with acquisition of gut pathogens in this study.

This study has some strengths. The emphasis on early acquisition of gut pathogen colonization (within 72 hours) is unusual. This approach provides unique insights into the rapid dynamics of gut colonization in critically ill patients, a timeframe that has been less explored in previous research. By narrowing the window of observation, the study highlights the urgency of addressing colonization during the initial stages of an ICU stay, which informs the timing of future interventions. Sample acquisition was strictly protocolized, was done in real time, and used low cost, readily accessible culture-based methods (as opposed to sequencing) that could be easily replicated across institutions. The study also has limitations. We did not have the resources to extend sample collection beyond 72 hours; we have ongoing studies which will address this by taking protocolized samples on ICU days 0, 3, 7, 14, and 30. Our findings are derived from a diverse range of ICU types, but in a single institution, and the gut colonization characteristics of the background population are likely to influence ICU colonization and impact study generalizability. Last, the sample size was relatively small, with a consequent effect on the confidence for our estimates of acquisition of gut pathogen colonization.

In sum, this prospective cohort study found that over one in five ICU patients acquired gut pathogen colonization within 72 hours of ICU admission (MRSA, VRE, or MDR/Ceph-R GN bacteria). By describing the dynamics of early gut pathogen colonization in the ICU, these results may guide future trials seeking to test ICU interventions to reduce or prevent gut pathogen colonization.

ICU: Intensive Care Unit

MRSA: Methicillin-Resistant Staphylococcus Aureus

VRE: Vancomycin-Resistant Enterococcus

MDR: Multidrug Resistance

Ceph-R: Third Generation Cephalosporin-resistant

CRE: Carbapenem-Resistant Enterobacteriaceae

GN: Gram Negative

CLSI: Clinical and Laboratory Standards Institute

Ethics approval and consent to participate

This study was approved by the Columbia University Institutional Review Board (IRB #AAAS2583).

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

Dr. Freedberg was funded in part by the Department of Defense (PR181960).

Authors' contributions

LS: Formal analysis, interpretation of patient data regarding gut colonization and clinical outcomes, major contributor in writing the manuscript. MH: review and editing. EL: data collection. DAG: review and editing. AGS: Review and editing. DF: conceptualization, methodology, review and editing, supervision, and funding acquisition. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

Morris S, Cerceo E. Trends, Epidemiology, and Management of Multi-Drug Resistant Gram-Negative Bacterial Infections in the Hospitalized Setting. Antibiotics (Basel). 2020;9(4).
Freedberg DE, Zhou MJ, Cohen ME, Annavajhala MK, Khan S, Moscoso DI, et al. Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection. Intensive Care Med. 2018;44(8):1203-11.
Detsis M, Karanika S, Mylonakis E. ICU Acquisition Rate, Risk Factors, and Clinical Significance of Digestive Tract Colonization With Extended-Spectrum Beta-Lactamase–Producing Enterobacteriaceae. Critical Care Medicine. 2017;45(4):705-14.
Massart N, Camus C, Benezit F, Moriconi M, Fillatre P, Le Tulzo Y. Incidence and risk factors for acquired colonization and infection due to extended-spectrum beta-lactamase-producing Gram-negative bacilli: a retrospective analysis in three ICUs with low multidrug resistance rate. European Journal of Clinical Microbiology & Infectious Diseases. 2020;39(5):889-95.
Prado V, Hernández-Tejero M, Mücke MM, Marco F, Gu W, Amoros A, et al. Rectal colonization by resistant bacteria increases the risk of infection by the colonizing strain in critically ill patients with cirrhosis Graphical abstract Rectal colonization by multidrug-resistant organism Predominant colonizing strain. Journal of Hepatology. 2022;76:1079-89.
Falcone M, Tiseo G, Galfo V, Giordano C, Leonildi A, Marciano E, et al. Bloodstream infections in patients with rectal colonization by Klebsiella pneumoniae producing different type of carbapenemases: a prospective, cohort study (CHIMERA study). Clinical Microbiology and Infection. 2022;28(2):298.e1-.e7.
Oostdijk EAN, De Smet AMGA, Kesecioglu J, Bonten MJM, editors. The role of intestinal colonization with Gram-negative bacteria as a source for intensive care unit-acquired bacteremia. Critical Care Medicine; 2011: Lippincott Williams and Wilkins.
Maamar E, Ferjani S, Jendoubi A, Hammami S, Hamzaoui Z, Mayonnove-Coulange L, et al. High Prevalence of Gut Microbiota Colonization with Broad-Spectrum Cephalosporin Resistant Enterobacteriaceae in a Tunisian Intensive Care Unit. Frontiers in Microbiology. 2016;7:1859-.
Razazi K, Derde LPG, Verachten M, Legrand P, Lesprit P, Brun-Buisson C. Clinical impact and risk factors for colonization with extended-spectrum β-lactamase-producing bacteria in the intensive care unit. Intensive care medicine. 2012;38(11):1769-78.
Warren DK, Kollef MH, Seiler SM, Fridkin SK, Fraser VJ. The epidemiology of vancomycin-resistant Enterococcus colonization in a medical intensive care unit colonization in a medical intensive care unit. Infection Control and Hospital Epidemiology. 2003;24(4):257-63.
Alves M, Lemire A, Decré D, Margetis D, Bigé N, Pichereau C, et al. Extended-spectrum beta-lactamase--producing enterobacteriaceae in the intensive care unit: acquisition does not mean cross-transmission. BMC Infect Dis. 2016;16:147.
Boutrot M, Azougagh K, Guinard J, Boulain T. Antibiotics with activity against intestinal anaerobes and the hazard of acquired colonization with ceftriaxone-resistant Gram-negative pathogens in ICU patients: A propensity score-based analysis. Journal of Antimicrobial Chemotherapy. 2019;74(10):3095-103.
Kluytmans-van den Bergh MFQ, van Mens SP, Haverkate MR, Bootsma MCJ, Kluytmans J, Bonten MJM, et al. Quantifying Hospital-Acquired Carriage of Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae Among Patients in Dutch Hospitals. Infection Control and Hospital Epidemiology. 2018;39(1):32-9.
Papadimitriou-Olivgeris M, Drougka E, Fligou F, Kolonitsiou F, Liakopoulos A, Dodou V, et al. Risk factors for enterococcal infection and colonization by vancomycin-resistant enterococci in critically ill patients. Infection. 2014;42(6):1013-22.
Kampmeier S, Kossow A, Clausen LM, Knaack D, Ertmer C, Gottschalk A, et al. Hospital acquired vancomycin resistant enterococci in surgical intensive care patients - a prospective longitudinal study. Antimicrob Resist Infect Control. 2018;7:103.
Ziakas PD, Thapa R, Rice LB, Mylonakis E. Trends and Significance of VRE Colonization in the ICU: A Meta-Analysis of Published Studies. PLOS ONE. 2013;8(9):e75658-e.
Armand-Lefevre L, Angebault C, Barbier F, Hamelet E, Defrance G, Ruppe E, et al. Emergence of imipenem-resistant gram-negative bacilli in intestinal flora of intensive care patients. Antimicrob Agents Chemother. 2013;57(3):1488-95.
McConville TH, Sullivan SB, Gomez-Simmonds A, Whittier S, Uhlemann AC. Carbapenem-resistant Enterobacteriaceae colonization (CRE) and subsequent risk of infection and 90-day mortality in critically ill patients, an observational study. PLoS One. 2017;12(10):e0186195.
Corbella X, Pujol M, Ayats J, Sendra M, Ardanuy C, Dominguez MA, et al. Relevance of digestive tract colonization in the epidemiology of nosocomial infections due to multiresistant Acinetobacter baumannii. Clin Infect Dis. 1996;23(2):329-34.
Jee W, Jo S, Lee JB, Jin Y, Jeong T, Yoon JC, et al. Mortality difference between early-identified sepsis and late-identified sepsis. Clin Exp Emerg Med. 2020;7(3):150-60.
Oami T, Imaeda T, Nakada TA, Abe T, Takahashi N, Yamao Y, et al. Mortality analysis among sepsis patients in and out of intensive care units using the Japanese nationwide medical claims database: a study by the Japan Sepsis Alliance study group. J Intensive Care. 2023;11(1):2.
Ochotorena E, Hernandez Morante JJ, Canavate R, Villegas RA, Viedma I. Methicillin-Resistant Staphylococcus aureus and Other Multidrug-Resistant Colonizations/Infections in an Intensive Care Unit: Predictive Factors. Biol Res Nurs. 2019;21(2):190-7.
Fouda R, Soliman MS, ElAnany MG, Abadeer M, Soliman G. Prevalence and risk factors of MRSA, ESBL and MDR bacterial colonization upon admission to an Egyptian medical ICU. J Infect Dev Ctries. 2016;10(4):329-36.
Terry MA, Freedberg DE, Morris MC. An Alternative Consent Process for Minimal Risk Research in the ICU. Crit Care Med. 2017;45(9):1450-6.
Barie PS, Hydo LJ, Fischer E. Comparison of APACHE II and III scoring systems for mortality prediction in critical surgical illness. Arch Surg. 1995;130(1):77-82.
Kruse JA, Thill-Baharozian MC, Carlson RW. Comparison of Clinical Assessment With APACHE II for Predicting Mortality Risk in Patients Admitted to a Medical Intensive Care Unit. JAMA. 1988;260(12):1739-42.
Tosi M, Roat E, De Biasi S, Munari E, Venturelli S, Coloretti I, et al. Multidrug resistant bacteria in critically ill patients: a step further antibiotic therapy. Journal of Emergency and Critical Care Medicine. 2018;2.
Pop-Vicas A, Strom J, Stanley K, D'Agata EM. Multidrug-resistant gram-negative bacteria among patients who require chronic hemodialysis. Clin J Am Soc Nephrol. 2008;3(3):752-8.
Macesic N, Gomez-Simmonds A, Sullivan SB, Giddins MJ, Ferguson SA, Korakavi G, et al. Genomic Surveillance Reveals Diversity of Multidrug-Resistant Organism Colonization and Infection: A Prospective Cohort Study in Liver Transplant Recipients. Clin Infect Dis. 2018;67(6):905-12.
Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18(4):657-86.
Grohs P, Podglajen I, Guerot E, Bellenfant F, Caumont-Prim A, Kac G, et al. Assessment of five screening strategies for optimal detection of carriers of third-generation cephalosporin-resistant Enterobacteriaceae in intensive care units using daily sampling. Clin Microbiol Infect. 2014;20(11):O879-86.
Bar-Yoseph H, Hussein K, Braun E, Paul M. Natural history and decolonization strategies for ESBL/carbapenem-resistant Enterobacteriaceae carriage: Systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy: Oxford University Press; 2016. p. 2729-39.
Haverkate MR, Derde LPG, Brun-Buisson C, Bonten MJM, Bootsma MCJ. Duration of colonization with antimicrobial-resistant bacteria after ICU discharge. Intensive Care Medicine. 2014;40(4):564-71.
Jones AE, Brown MD, Trzeciak S, Shapiro NI, Garrett JS, Heffner AC, et al. The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis. Crit Care Med. 2008;36(10):2734-9.
Zhou MJ, Li J, Salmasian H, Zachariah P, Yang YX, Freedberg DE. The local hospital milieu and healthcare-associated vancomycin-resistant enterococcus acquisition. Journal of Hospital Infection. 2019;101(1):69-75.
Thompson DS. Methicillin-resistant Staphylococcus aureus in a general intensive care unit. J R Soc Med. 2004;97(11):521-6.
Jolivet S, Lolom I, Bailly S, Bouadma L, Lortat-Jacob B, Montravers P, et al. Impact of colonization pressure on acquisition of extended-spectrum β-lactamase-producing Enterobacterales and meticillin-resistant Staphylococcus aureus in two intensive care units: a 19-year retrospective surveillance. J Hosp Infect. 2020;105(1):10-6.
Bloemendaal ALA, Fluit AC, Jansen WMT, Vriens MR, Ferry T, Argaud L, et al. Acquisition and Cross-Transmission of Staphylococcus aureus in European Intensive Care Units. Infection Control and Hospital Epidemiology. 2009;30(2):117-24.
Harris AD, Kotetishvili M, Shurland S, Johnson JA, Morris JG, Nemoy LL, et al. How important is patient-to-patient transmission in extended-spectrum β-lactamase Escherichia coli acquisition. American Journal of Infection Control. 2007;35(2):97-101.
Ajao AO, Johnson JK, Harris AD, Zhan M, McGregor JC, Thom KA, et al. Risk of acquiring extended-spectrum β-lactamase-producing Klebsiella species and Escherichia coli from prior room occupants in the intensive care unit. Infect Control Hosp Epidemiol. 2013;34(5):453-8.
Ajao AO, Johnson JK, Harris AD, Zhan M, McGregor JC, Thom KA, et al. Risk of Acquiring Extended-Spectrum beta-Lactamase-Producing Klebsiella Species and Escherichia coli from Prior Room Occupants in the Intensive Care Unit. Infection Control and Hospital Epidemiology. 2013;34(5):453-8.
Kim J, Lee JY, Kim SI, Song W, Kim JS, Jung S, et al. Rates of Fecal Transmission of Extended-Spectrum beta-Lactamase-Producing and Carbapenem-Resistant Enterobacteriaceae Among Patients in Intensive Care Units in Korea. Annals of Laboratory Medicine. 2014;34(1):20-5.

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Timing and clinical risk factors for early acquisition of gut pathogen colonization with multidrug resistant organisms in the intensive care unit

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Journal Publication

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Abstract

Figures

INTRODUCTION

METHODS

Population and rationale

Rectal swabs

Cultures for multi-drug resistant organisms

Early acquisition of gut pathogen colonization

Clinical risk factors for early acquisition of gut pathogen colonization

Clinical outcomes: death or culture-proven infection

Statistical approach

RESULTS

Patient baseline characteristics

Gut pathogen colonization

Characteristics of colonizing Gram negatives

Clinical risk factors for acquisition of early gut pathogen colonization

Death and culture-proven infection

Acquisition of early gut pathogen colonization and risk for death or infection

Cox proportional hazards model for death or infection

Sample size calculation for future studies

DISCUSSION

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1