This was a prospective, multicenter, randomized, unblinded clinical trial conducted in the Intensive Care Unit (ICU) involving patients with infections receiving antibiotic therapy. The blinding of the teams in this study would be challenging due to the variety of medications used in the treatment, as well as the prescription modifications based on the individualized characteristics of each patient. The study compared sequential IV therapy to EN therapy, with one group (EN group) transitioning to EN antibiotics, while the other group (IV group) maintained standard IV therapy. The term “enteral” encompasses oral administration, as well as orogastric, nasogastric, and naso-enteric tubes. We considered a non-inferiority study with a sample power of 70 %, confidence interval of 90 %, and non-inferiority limit of 15 % for calculation the study population. In this study, 60 patients were considered in each group (Group 1 and 2) and randomized in a 1:1 ratio of IV and EN antibiotics. The percentage 'success' in control group would be 80 % (survival). See https://www.sealedenvelope.com/power/binary-noninferior/.

Patient enrollment took place at two Brazilian hospitals, both specializing in trauma, neurosurgery, general surgery, and medical patients. A total of 120 ICU beds were included in this study. The local ethics committee approved the study prior to randomization, which occurred from April 23, 2020, to April 2022 (ethical committee approval n° 3.987.566). Informed consent was obtained from conscious patients or their legal representatives in the case of unconscious patients.

The sample size was determined based on convenience, with 60 patients allocated to each group (EN and IV) using a 1:1 randomization ratio.

Inclusion criteria

• 1)

  Age > 18-years;

• 2)

  Admission to the ICU;

• 3)

  Clinical diagnosis of infection;

• 4)

  Regular oral or enteral feeding;

• 5)

  Availability of enteral antibiotics with equipotency to IV alternatives;

• 6)

  Signed consent from the patient or ICU team;

• 7)

  At least 24-hours of clinical improvement.

Exclusion Criteria:

• 1)

  Life expectancy < 24-hours;

• 2)

  Treatment considered futile;

• 3)

  Diet intolerance or refusal of EN medications;

• 4)

  High gastrointestinal bleeding;

• 5)

  Lack of suitable EN antibiotic alternatives due to microbiological results;

• 6)

  Patients with COVID-19 were also excluded.

After fulfilling the inclusion criteria, patients were randomized using an online randomization system (www.random.org). A clinical pharmacist oversaw the randomization process. In the EN group, patients transitioned from IV to EN antibiotics as determined by the attending physician in collaboration with the antimicrobial stewardship team (including a clinical pharmacist and an infectious disease specialist). Patients in the IV group continued their IV therapy. The researcher did not influence the attending physician's decisions regarding the duration of therapy. Supplementary Tables 1 and 2 detail the commercially available options for EN use and the method of administration (oral or via EN tube), respectively. The antimicrobial stewardship team was responsible for screening and assessing patients.

The decision to switch back to intravenous therapy was based on well-established clinical criteria to ensure it is justified and avoids unnecessary biases. Some key aspects were considered: i) True therapeutic failure: The need to return to IV antibiotics confirmed by objective signs, such as the persistence or worsening of symptoms, prolonged fever, increased inflammatory markers (CRP, ESR, procalcitonin), and positive microbiological cultures indicating treatment failure; ii) Conservative medical decision: In some cases, physicians have opt for an early return to IV therapy due to excessive precautions, even without clear evidence of failure.

Clinical and laboratory data collected included sex, age, total duration of IV and EN antibiotic therapy, duration of mechanical ventilation, length of hospital and ICU stay, use of vasoactive drugs, comorbidities (Charlson index), and clinical outcomes. The Acute Physiology and Chronic Health Disease Classification System II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were assessed on the day of randomization. All identified microorganisms and infection sites were evaluated, and antimicrobial adequacy was assessed according to susceptibility tests. Empirical antibiotics with negative culture results were excluded from this subgroup analysis.

The severity of infection was classified using the following sepsis criteria:

• •

  Sepsis ‒ Organ dysfunction resulting from a dysregulated host response to infection, indicated by an acute increase of ≥ 2 points in SOFA scores due to infection.

• •

  Septic Shock ‒ Hypotension requiring vasopressors to maintain a mean arterial pressure > 65 mmHg and a serum lactate level > 2 mmoL/L despite adequate fluid resuscitation11

Infection definitions adhered to CDC criteria, as all patients presented with healthcare-associated infections12

The primary outcome was patient mortality, with in-hospital and 30-day mortality and survival curves evaluated. Secondary outcomes included clinical response, while tertiary outcomes encompassed the length of hospital and ICU stay. Microbiological failure was assessed, defined as the persistence of the same microorganism at the infection site. Patients requiring a return to IV therapy due to treatment failure were classified as clinical failures. The cost analysis for each group included the costs of the drugs, syringes, needles, diluents, and carrier fluids.

Definition of clinical improvement

Each infection type has specific signs and symptoms for evaluation. Therefore, general criteria for clinical improvement of sepsis were considered on days 3, 5, and 1013 Patients demonstrating at least 24 h of clinical improvement or stability were defined by criteria including temperature < 37.8 °C, heart rate < 100 beats/min, respiratory rate < 24 breaths/min, systolic blood pressure > 90 mmHg, arterial oxygen saturation > 90 % or pO2 > 60 mmHg in room air, the ability to maintain EN intake, and a normal mental status (according to the Glasgow scale)14

Descriptive data were reported as percentages, with quantitative data presented as means or medians, depending on the distribution pattern. Standard deviations and interquartile ranges (25th and 75th percentiles) were used for mean and median distributions, respectively. Associations between variables and outcomes were analyzed using the Student's t-test, Mann-Whitney test, Chi-Square test, or Fisher's exact test, with a p-value < 0.05 considered statistically significant. For multivariate analysis, all variables showing significance in univariate analysis were included in binary logistic regression. Survival curves (Kaplan-Meier) were constructed from the initiation of antibiotic therapy until patient death or discharge. Overall and 30-day mortality curves were generated, and the Gehan-Breslow-Wilcoxon test was conducted. All analyses were performed using SPSS version 23.

Of the 142 eligible patients, 15 were excluded prior to randomization. The primary reasons for exclusion included: (i) Clinical deterioration on the day of randomization (53 %); (ii) Fasting for examinations (33 %); and (iii) Withdrawal of antimicrobial therapy on the day of randomization (13 %) (Fig. 1). After exclusions, 67 patients were included in the EN and 60 in the IV group. Baseline patient characteristics at the time of randomization are summarized in Table 1. The groups were comparable in terms of age, sex, total length of hospital and ICU stay, comorbidities, and severity scores (SOFA and APACHE II).

Fig. 1.

Flowchart of patients randomized to maintain IV antibiotic or switch to enteral route admitted into the ICU with a diagnosis of infection.

(0.31MB).

The most common site of infection was the respiratory tract (77.1 %), followed by soft tissues (7.0 %). Based on sepsis criteria, the majority of patients were classified as having an infection (66.1 %), followed by sepsis (33.1 %), with only one patient meeting the criteria for septic shock (0.8 %). Approximately 25 % of all patients were receiving vasoactive drugs at baseline, though only one patient fulfilled the criteria for septic shock. There were no significant differences in sepsis classification between the IV and EN groups (p = 0.385).

The predominant pathogens identified were Gram-positive cocci, primarily Staphylococcus aureus (49 %), followed by Enterobacterales (34 %), with Klebsiella spp. (12 %) and Escherichia coli (10 %) being the most common. Only 13 % of infections were polymicrobial (Supplementary Tables). Culture results by infection site are detailed in Supplementary Table 3.

The sole difference observed between the IV and EN groups was in the type of antibiotic therapy received, with microbiologically guided treatment more frequently employed in the IV group compared to the EN group (68 % vs. 52 %, p = 0.047). Empirical therapy was utilized in 48 % of the EN group and 32 % of the IV group. The duration of antibiotic use was similar between both groups.

Before randomization, the most commonly used antibiotics were quinolones (levofloxacin or ciprofloxacin) at 37 %, followed by ceftriaxone at 21 % (Table 2). Monotherapy was more prevalent, particularly in cases of respiratory tract infections. Following randomization, quinolones remained the most prescribed antibiotics in the EN group (47 %), followed by amoxicillin with clavulanate (24 %) and sulfamethoxazole-trimethoprim (18 %). Among patients with microbiological identification of their infections, treatment was deemed adequate in 86 % (65/76) prior to randomization.

The in-hospital mortality rates were comparable between the two groups, with 31 % in the EN group and 30 % in the IV group. Additionally, clinical outcomes assessed on days 3, 5, and 10 ‒ categorized as improvement, failure, or indifferent ‒ showed no significant differences between the groups. The 30-day survival Kaplan-Meier curve is presented in Fig. 2, illustrating similar survival rates for both the IV and EN groups (p = 0.992).

Fig. 2.

Survival curve of patients randomized to maintain IV antibiotic or switch to enteral route admitted into the ICU with a diagnosis of infection. Dashed line represents the Hazard Ratio (HR) with a 95 % Confidence Interval.

(0.14MB).

In the IV group, only two patients experienced microbiological failure. Among the 67 patients in the EN group, 7 (10.5 %) required a return to the IV route of antibiotics. The reasons for this transition included two treatment failures without microbiological identification, two cases where bacteria were susceptible only to IV antibiotics, and three patients who experienced gastric stasis. Those patients who needed to revert to IV therapy due to treatment failure were classified as clinical failures.

The total cost of antibiotics in the EN group was USD 1243.00, which included pre-randomization IV antibiotics. The total cost of IV group was USD 2575.35, with an increase of 107 %.