Knowing when to stop: duration of antibiotic therapy in critical illness

Introduction

Antibiotic therapy is often continued for an extended period, beyond the optimal duration in critically ill patients. Although there is emphasis on early administration and choice of appropriate antibiotics in septic patients, the evidence regarding duration of treatment is sparse. Ideally, the duration of antibiotic therapy should maximize clinical efficacy while reducing the risks of untoward effects including Clostridioides difficile infection, toxicity, the emergence of resistant strains, and increased cost of health care. The duration of antibiotic prescription in septic patients may be highly variable among clinicians, ranging from 3–5 days to more than 10 days depending on the clinical circumstances.(1)

What is the available evidence regarding the optimal duration of antibiotic therapy in critically ill patients with suspected or proven infection?

Duration of antibiotic therapy: intra-abdominal infections 

Conventionally, antibiotics are prescribed for 7–14 days in patients in complicated intra-abdominal infections, once the systemic inflammatory response has resolved. However, once source control is achieved, the duration of antibiotic therapy may be curtailed, depending on the clinical response; a short duration of therapy of 3–5 may suffice following source control.(2) Several recent studies have evaluated the optimal duration of antibiotic therapy following complicated intra-abdominal infections. 

A French multicenter study included patients who underwent intra-abdominal surgery with evidence of pus collection in the peritoneal cavity.(3) Source control was achieved with appropriate surgical intervention. On postoperative day 8, patients were randomized to the cessation of antibiotic therapy or continued administration for 15 days. The 8-day antibiotic regimen included 120 patients and the 15-day regimen, 116 patients. The number of antibiotic-free days from day 8 to 28, was significantly more in patients who were randomized to the shorter antibiotic regimen (15 [6–20] vs. 12 [6–13] days, P <0.0001). Mortality at 45 days was 9.1% with the 8-day compared with 13.6% in the 15-day regimen; the difference was not statistically significant. The duration of stay in the ICU and hospital, the emergence of multidrug-resistant bacteria, and re-exploration rates were also similar between the two groups. This study suggested that a shorter, 8-day antibiotic regimen, compared to a 15-day regimen, is safe and effective following surgery for intra-abdominal infections when source control was achieved. 

The STOP-IT trial also evaluated the efficacy of a short-course antibiotic therapy in intra-abdominal infection following source control.(4) Patients were randomized to receive 4 days of antibiotic therapy after source control (short-course) or continued therapy until 2 days after resolution of the systemic inflammatory response (control). The primary outcome was a composite of surgical-site infection, recurrent infection, or death within 30 days of the source control intervention. Fifty-six of 257 patients (21.8%) suffered the primary outcome in the short-course antibiotic therapy group compared to 58 of 260 patients (22.3%) in the control group; the difference was not statistically significant. The incidence of the individual components of the composite primary outcome was also similar between groups. The median duration of antibiotic treatment was significantly lower with short-course treatment compared to the control arm [4.0 (4.0–5.0) vs. 8.0 (5.0–10.0 days)]. 

A single-center, retrospective study evaluated the duration of antibiotic therapy and outcomes in patients with complicated intra-abdominal infections.(5) In the short-duration therapy group, antibiotics were administered for 7 days or less; in the longer-duration therapy group, antibiotics were administered for more than 7 days. The primary outcome was treatment failure, defined as a composite of recurrent infection, secondary extra-abdominal infection, and all-cause hospital mortality. Two-hundred and forty patients were included in the study, with 103 in the short and 137 in the longer duration treatment groups. Treatment failure occurred in significantly fewer patients in the short-duration therapy group (39% vs. 63%, P <0.001). On logistic regression analysis, longer duration therapy was associated with treatment failure; however, it was not associated with mortality. 

Duration of antibiotic therapy: ventilator-associated pneumonia 

Ventilator-associated pneumonia (VAP) is among the commonest nosocomial infections in critically ill patients. The diagnosis of VAP is often unclear; besides, often, there is pressure on the clinician to prescribe antibiotics early, considering the perceived adverse outcomes associated with delayed treatment. Many patients initially diagnosed with possible VAP may not, in fact, have pneumonia and undergo inappropriately prolonged antibiotic treatment.(6) A shorter duration of antibiotic administration has favorable effects on bacterial ecology and the emergence of resistant strains.(7)  

What does the available evidence suggest regarding the duration of antibiotic therapy for VAP? 

In their landmark trial, Chastre et al. compared 8 vs. 15 days of antibiotic therapy for VAP in 51 French ICUs.(8) In this study, 197 patients were randomized to receive an 8-day antibiotic course; 204 patients received a 15-day course. The 28-day mortality was similar between the 8- and 15-day treatment groups (18.8% vs. 17.2%; 90% CI, −3.7% to 6.9%). The incidence of recurrent infection was similar between groups. Mechanical ventilation-free days, organ failure-free days, and duration of ICU stay were also not significantly different. However, patients allocated to the shorter regimen had significantly more antibiotic-free days (13.1 vs. 8.7 days, P <0.001). Among patients who had infection with non-fermenting gram-negative bacteria including Pseudomonas aeruginosa, the recurrence rate was higher with the shorter duration of antibiotic therapy. Among patients with recurrent infection, multidrug-resistant organisms were less frequent with a shorter duration of treatment. 

Hendrik et al. specifically evaluated the efficacy of a shorter duration of antibiotic therapy in VAP caused by non-fermenting gram-negative bacteria against the background of the previous study by Chastre et al.(9) In a retrospective analysis, the authors analyzed data on patients who underwent treatment for VAP in a surgical and trauma ICU. Overall, 452 episodes of VAP were observed during the study period. Infection with non-fermenting gram-negative bacilli occurred in 154 patients; 127 patients underwent antibiotic treatment for 9 or more days, while 27 patients were treated for 3–8 days. In contrast to the Chastre et al. study, the authors observed no significant difference in the rate of recurrent infection between patients who underwent short compared to a longer duration of antibiotic treatment in VAP caused by non-fermenting gram-negative bacilli (22% vs. 34%; P = 0.27). The mortality rate was also not significantly different between the two groups. However, this study is limited by its retrospective design; besides, it is possible that sicker patients received a longer duration of treatment, as the decision to cease therapy was based entirely on clinician judgment. 

An 8-day compared to a 15-day antibiotic therapy was evaluated for early-onset VAP in 13 ICUs in France.(10) Patients who developed VAP within the first 8 days of ventilation were randomized to the 8- or 15-day antibiotic regimen. All included patients received beta-lactams for 8 or 15 days; an aminoglycoside was administered until day 5 of treatment. The study included 225 patients; 109 in the 15-day regimen and 116 in the 8-day regimen. The primary outcome was clinical cure on day 21. Clinical cure occurred in 92/109 (84.4%) patients in the 15-day regimen and 99/116 (85.3%) patients in the 8-day regimen, demonstrating equivalence between the two regimens. The 21-day mortality was also comparable between both patient cohorts.

In a retrospective study, an ultra-short antibiotic course of 1–3 days was compared with >3 days of treatment in patients with suspected VAP.(11) Patients were on an FiO2 of ≤0.4 or less, and a PEEP level of ≤5 cm H2O on the day of commencement of antibiotics and for the following two days. Sensitivity analyses were performed using propensity scores to match patients in both cohorts. Among 1,290 patients with suspected VAP who remained on minimal, stable ventilator settings, 259 received antibiotics for 1–3 days; 1031 patients received antibiotics for >3 days. Hospital mortality, duration of mechanical ventilation, and hospital length-of-stay were not significantly different between the two groups of patients. The median duration from commencement of antibiotic treatment to extubation and hospital discharge was longer among patients who received >3 days of antibiotics. This study underlines the importance of early cessation of antibiotics in patients who are initially suspected to have VAP, but may have an alternate, non-infective event. 

Duration of antibiotic therapy: gram-negative bacteremia 

The optimal duration of antibiotic therapy for patients with gram-negative bacteremia is unclear. Yahav et al. evaluated the duration of antibiotic therapy and outcomes in patients with gram-negative bacteremia who were afebrile and hemodynamically stable.(12) Patients were randomized to a 7-day or 14-day treatment regimen. The primary focus of infection was urinary in the majority (68%) of patients. Patients with an uncontrolled source were excluded from the trial. The primary outcome, assessed at 90 days,  was a composite of all-cause mortality, relapse of infection, remote complications, and readmission or prolonged hospitalization of more than 14 days. The primary outcome occurred in 45.8% of patients in the 7-day treatment group and 48.3% of patients in the 14-day treatment group; the difference was not statistically significant. Besides, there was no significant difference in the incidence of new infections, development of bacterial resistance, or duration of stay in hospital between the two groups. 

Chotiprasitsakul et al. compared outcomes of patients between a short-course (6-10 days) compared to prolonged-course (11-16 days) of antibiotic therapy in patients with Enterobacteriaceae bacteremia.(13) In this retrospective cohort study, 1:1 propensity score matching, followed by regression analysis was carried out to evaluate all-cause mortality at 30 days after cessation of antibiotic treatment. No difference in mortality was observed between the two treatment groups; a trend towards reduced emergence of multidrug-resistant gram-negative bacteria was observed with the shorter course of treatment.

Procalcitonin to guide the duration of antibiotic therapy 

Procalcitonin (PCT) is often used by clinicians to decide on the duration of antibiotic therapy in septic patients. However, the utility of PCT in this situation is controversial. An RCT from the Netherlands included critically ill patients with proven or suspected sepsis. In the PCT-guided group, antibiotics were continued until the PCT level had reduced to 20% of baseline or 0·5μg/l; in the control arm, the duration of treatment was guided by local protocols. The median duration of therapy was significantly lower in the PCT-guided group. Furthermore, the 1-year mortality was also lower in the PCT-guided treatment arm.(14) However, a multicentric RCT from 11 Australian ICUs revealed contrasting findings. This RCT included patients with bacterial infection or sepsis with an expected ICU stay of more than 24 hours. A cut-off PCT value of <0.10 ng/ml was used to cease antibiotic therapy; in the standard care arm, the duration of treatment was based on clinician judgment. The overall median duration of antibiotic therapy was similar in the PCT-guided and standard care groups. The 90-day all-cause mortality was not significantly different between the two groups. On logistic regression analysis, the initial PCT level was not a predictor of mortality; however, a slow reduction in PCT levels was an independent predictor of hospital and 90-day mortality.(15) Meta-analyses comparing PCT-guided compared to standard care do not support the utility of PCT levels to guide the duration of antibiotic therapy. PCT guidance may not minimize mortality, or reduce the duration of mechanical ventilation.(16,17)

Key points

  • Limiting exposure to antibiotics to an optimal duration is one of the cornerstones of  treatment of infections in critically ill patients. Although there is an emphasis on early, appropriate antibiotic administration, there is a relative lack of focus on the duration of therapy. An unnecessarily long duration of therapy may result in Clostridioides difficile infection, toxicity, the emergence of resistant strains, and an increase in the cost of health care
  • VAP is often difficult to diagnose; a significant number of patients who are initially suspected to have VAP may have experienced a non-infective, alternate event. Continued vigilance at the bedside may enable cessation of therapy at an early stage. There is reasonably strong evidence to support antibiotic therapy for a week or less in patients with VAP
  • Source control is all-important in complicated intra-abdominal infections. Once source control is achieved, an extended duration of therapy is unnecessary; in fact, treatment failure may be less common with a shorter duration of therapy 
  • In gram-negative bacteremia, a shorter duration of therapy of 7–10 days has been shown to be as effective as more prolonged therapy
  • PCT may be a useful biomarker of bacterial infection; although some studies support its use to reduce the duration of antibiotic therapy, the evidence has generally been inconclusive 

References 

1.         admin. Results of ESCAVO’s Survey on Antibiotic Use in Sepsis [Internet]. Escavo. 2019 [cited 2022 Jul 10]. Available from: https://escavo.com/2019/07/18/antibiotic-use-in-sepsis-survey/

2.         Schein M, Assalia A, Bachus H. Minimal antibiotic therapy after emergency abdominal surgery: a prospective study. Br J Surg. 1994 Jul;81(7):989–91. 

3.         For the DURAPOP Trial Group, Montravers P, Tubach F, Lescot T, Veber B, Esposito-Farèse M, et al. Short-course antibiotic therapy for critically ill patients treated for postoperative intra-abdominal infection: the DURAPOP randomised clinical trial. Intensive Care Med. 2018 Mar;44(3):300–10. 

4.         Sawyer RG, Claridge JA, Nathens AB, Rotstein OD, Duane TM, Evans HL, et al. Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection. N Engl J Med. 2015 May 21;372(21):1996–2005. 

5.         Smith SE, Rumbaugh KA, May AK. Evaluation of a Short-course of Antimicrobial Therapy for Complicated Intra-Abdominal Infections in Critically Ill Surgical Patients. Surg Infect (Larchmt). 2017 Sep;18(6):742–50. 

6.         Nussenblatt V, Avdic E, Berenholtz S, Daugherty E, Hadhazy E, Lipsett PA, et al. Ventilator-associated pneumonia: overdiagnosis and treatment are common in medical and surgical intensive care units. Infect Control Hosp Epidemiol. 2014 Mar;35(3):278–84. 

7.         Bottery MJ, Pitchford JW, Friman VP. Ecology and evolution of antimicrobial resistance in bacterial communities. ISME J. 2021 Apr;15(4):939–48. 

8.         Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003 Nov 19;290(19):2588–98. 

9.         Hedrick TL, McElearney ST, Smith RL, Evans HL, Pruett TL, Sawyer RG. Duration of antibiotic therapy for ventilator-associated pneumonia caused by non-fermentative gram-negative bacilli. Surg Infect (Larchmt). 2007 Dec;8(6):589–97. 

10.       Capellier G, Mockly H, Charpentier C, Annane D, Blasco G, Desmettre T, et al. Early-Onset Ventilator-Associated Pneumonia in Adults Randomized Clinical Trial: Comparison of 8 versus 15 Days of Antibiotic Treatment. Spellberg B, editor. PLoS ONE. 2012 Aug 31;7(8):e41290. 

11.       Klompas M, Li L, Menchaca JT, Gruber S, for the CDC Prevention Epicenters Program. Ultra short-course antibiotics for patients with suspected ventilator-associated pneumonia but minimal and stable ventilator settings. CLINID. 2016 Dec 29;ciw870. 

12.       Yahav D, Franceschini E, Koppel F, Turjeman A, Babich T, Bitterman R, et al. Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial. Clin Infect Dis. 2019 Sep 13;69(7):1091–8. 

13.       Chotiprasitsakul D, Han JH, Cosgrove SE, Harris AD, Lautenbach E, Conley AT, et al. Comparing the Outcomes of Adults With Enterobacteriaceae Bacteremia Receiving Short-Course Versus Prolonged-Course Antibiotic Therapy in a Multicenter, Propensity Score-Matched Cohort. Clin Infect Dis. 2018 Jan 6;66(2):172–7. 

14.       de Jong E, van Oers JA, Beishuizen A, Vos P, Vermeijden WJ, Haas LE, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016 Jul;16(7):819–27. 

15.       Shehabi Y, Sterba M, Garrett PM, Rachakonda KS, Stephens D, Harrigan P, et al. Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. Am J Respir Crit Care Med. 2014 Nov 15;190(10):1102–10. 

16.       Andriolo BN, Andriolo RB, Salomão R, Atallah ÁN. Effectiveness and safety of procalcitonin evaluation for reducing mortality in adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev. 2017 Jan 18;1:CD010959. 

17.       Arulkumaran N, Khpal M, Tam K, Baheerathan A, Corredor C, Singer M. Effect of Antibiotic Discontinuation Strategies on Mortality and Infectious Complications in Critically Ill Septic Patients: A Meta-Analysis and Trial Sequential Analysis. Crit Care Med. 2020 May;48(5):757–64. 

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