Knowing when to stop: shorter duration of antibiotic therapy in the critically ill

Inappropriately prolonged use of antibiotics has several deleterious effects in critically ill patients. Injudicious administration of broad-spectrum antibiotics for an extended period may lead to new-onset infections with resistant organisms due to selective pressure. Besides adding to the cost of care, drug-related adverse effects resulting from prolonged use may also impact clinical outcomes. Let us consider the evidence behind the use of a short-duration antibiotic strategy in the treatment of infections commonly encountered in the critically ill. 

Empirical treatment for ventilator-associated pneumonia

Despite a surfeit of scoring systems and diagnostic criteria, the precise identification of ventilator-associated pneumonia (VAP) remains elusive. Early commencement of empirical antibiotic therapy is often necessary depending on the level of clinical suspicion. Singh et al. studied patients with a low likelihood of VAP, with a clinical pulmonary infection score (CPIS) <= 6. In the experimental group, patients received 3 days of ciprofloxacin followed by cessation of treatment if the CPIS remained <= 6. In the standard therapy group, the choice and duration of treatment were left to physician judgment. The 30-d mortality and ICU length of stay were not different between groups; antibiotic resistance and the incidence of superinfections were higher in the standard therapy group.1 In a recent observational study, patients suspected to have VAP, but on stable ventilator settings (FiO2 <= 0.4 and PEEP <= 5 cm H2O) received 1–3 days vs. > 3 days of antibiotic treatment. There was no difference in the time to extubation, death while on ventilation, time to hospital discharge, and death in hospital between groups.2

These studies support the early discontinuation of empirical antibiotic therapy in patients who are suspected to have VAP but remain clinically stable. In many of these patients, radiographic infiltrates may have been due to non-infectious causes, and antibiotic treatment may not have been necessary. 

Treatment of confirmed ventilator-associated pneumonia

What may the optimal duration of antibiotic therapy for microbiologically confirmed VAP? In a benchmark trial, Chastre et al.  compared 8 vs.15 days of treatment among patients with positive cultures of bronchoscopic specimens and underwent initial appropriate empirical antibiotic cover. A shorter duration of treatment did not result in increased 28-d mortality nor an increased incidence of recurrent infections. The incidence of recurrent infection with multidrug-resistant organisms was less with a shorter duration of treatment. Recurrent infection was more with a shorter duration of treatment in patients who had infection with non-fermenting gram-negative bacilli, including Pseudomonas aeruginosa.3 In another randomized controlled trial, among patients with early-onset VAP (between 24 h to 8 days of ventilation), there was no difference in the clinical cure rates, and mortality at 21 and 90 days with 8-day compared to 15-day antibiotic treatment.4 Based on available evidence, a prolonged course of antibiotic treatment may be unnecessary in microbiologically confirmed VAP, except in case of infection with non-fermenting gram-negative bacilli. 

Community-acquired pneumonia 

Severe community-acquired pneumonia (CAP) often leads to sepsis and multiorgan failure. Dual antibiotic therapy with a third-generation cephalosporin combined with a macrolide or fluoroquinolone is recommended, although the optimal duration of treatment is uncertain. In a Spanish multicentric study, Uranga et al. randomized patients with moderate to severe CAP on day 5 of treatment. In the intervention group, antibiotics were ceased at 5 days if the body temperature was =< 37.8 C or less for 48 h and patients were clinically stable; in the control group, the duration of antibiotic therapy was left to physician judgment. The clinical success rate was comparable at days 10 and 30, suggesting that a shorter duration of antibiotic therapy based on clinical stability is safe and effective in patients with CAP.5 A multicentric Italian study compared cessation of antibiotics 48 h after attaining clinical stability with a physician-determined duration of treatment. This study was stopped early on interim analysis due to an apparent increase in early treatment failure and 30-d mortality in the experimental group. The Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) recommend a minimum of 5 days antibiotic treatment for CAP. A longer duration of treatment may be required in case of extrapulmonary infection, infection due to Pseudomonas aeruginosa or unusual organisms (e.g., Burkholderia pseudomallei), and in the presence of necrotizing pneumonia, empyema, or lung abscess.6

Bacteremia 

Bacteremia occurs in 15% of critically ill patients commonly due to pneumonia, urosepsis, intra-abdominal infections, and catheter-related bloodstream infections and carries a high mortality. In a Canadian retrospective cohort study, the median duration of antibiotic treatment in bacteremia was 14 days (interquartile range, 9–17.5). Most pathogens, except coagulase-negative staphylococcus aureus, were treated for a relatively long duration. Urosepsis was often treated for a shorter duration; unknown primary foci were associated with a longer duration of treatment.7 In a meta-analysis of 13 studies, including 227 patients with bacteremia, no difference was observed in clinical and microbiological cure rates, and survival with 5–7 days compared to 7–21 days of antibiotic treatment. The BALANCE randomized controlled trial comparing 7 vs. 15 days treatment for bloodstream infections in the critically ill is currently recruiting patients,8 following successful completion of a pilot feasibility study.9

Intra-abdominal infections

The management of severe intra-abdominal infection involves initial resuscitation, source control, and antimicrobial therapy. Conventionally, antibiotics are administered for 7–14 days after source control; however, a shorter duration of treatment may be safe and effective. In a recent randomized controlled trial, patients with complicated intra-abdominal infection were randomized to receive antibiotics for 2 days after resolution of fever and ileus and normalization of the leukocyte count; this was compared to an experimental group who received antibiotics for 4 ± 1 calendar days after source control. There was no difference in the composite primary outcome of surgical site infection, recurrent intra-abdominal infection, or 30-d mortality between groups. The duration of antibiotic therapy was significantly less in the experimental group.10 Antibiotic therapy for 8 vs. 15 days was compared among critically ill patients with postoperative intra-abdominal infections in a randomized controlled trial. The 45-d mortality, ICU and hospital length of stay, emergence of multidrug-resistant bacteria, and re-exploration rates were similar in both study groups.11 These studies suggest that a shorter duration of antibiotic therapy is efficacious once source control has been achieved in critically ill patients with intra-abdominal infections. 

Urinary infections

The optimal duration of antimicrobial treatment in patients with urosepsis, including pyelonephritis is uncertain. Eliakim-Raz et al. performed a meta-analysis of 10 randomized controlled trials, including 2,515 patients with acute pyelonephritis. Antibiotic therapy for 7 days or less was compared with a longer duration of treatment. There was no difference in clinical or microbiological failure during the follow-up period, including among patients who had bacteremia. Microbiological failure occurred more commonly with a shorter duration of treatment in a small subgroup of patients with urogenital abnormalities.12 This study suggests that a 7-d course of antibiotics is appropriate in most patients with urosepsis due to acute pyelonephritis. 

When is a longer duration of treatment required? 

There are some infections that demand longer-term antibiotics, including infective endocarditis and bone and joint infections. Infection related to prosthetic material also require prolonged treatment. VAP with non-fermenting gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumanni, and Stenotrophomonas maltophilia also require a longer duration of antimicrobial treatment. Bacteremia with Staphylococcus aureus may require more than 2 weeks of antibiotic treatment. Recurrent bacteremia or deep-seated infection with shorter courses of antibiotics would also require a longer than a conventional period of treatment. In candidemia, although guidelines suggest 2 weeks of treatment after blood cultures become negative, there is no strong evidence to support this recommendation. Augmented renal clearance, observed in younger patients with less severe illness, may lead to enhanced renal elimination of antibiotics, including beta-lactams, and may require more prolonged treatment.  

Biomarkers to guide the duration of antibiotic treatment

C-reactive protein had been conventionally used to evaluate the efficacy and guide the duration of antibiotic treatment. Procalcitonin has been extensively evaluated to guide therapy in various infective illnesses. A meta-analysis13 and a randomized controlled trial14 have supported the use of procalcitonin as a tool to guide the duration of antimicrobial therapy. However, at the end of the day, the decision to cease antibiotic therapy needs to be based on the clinical picture and microbiological data, perhaps in combination with biomarker levels. Table 1 depicts the suggested duration of antibiotic therapy for common infections among critically ill patients.15   

Table 1. Suggested duration of antibiotic therapy for common infections in critically ill patients 

DurationType of infection
5–7 daysEarly VAP with susceptible pathogens, bacteremia with coagulase-negative Staphylococcus aureus, urinary tract infections. 
7–10 daysBloodstream infection with gram-negative bacteria, anaerobes, and Enterococcus spp; meningitis, community-acquired pneumonia 
14 days or more VAP with non-fermenting gram-negative bacilli, candida bloodstream infections, Staphylococcus aureus bloodstream infections, nosocomial meningitis

The bottom line

  • Inappropriately prolonged use of antibiotics can adversely impact clinical outcomes, including new-onset infections with multidrug-resistant organisms.
  • In clinical situations with a high index of suspicion for an infective illness, it is reasonable to commence empirical antibiotics. However, the appropriateness of continued antibiotic therapy must be reconsidered early if a non-infectious etiology seems more likely.  
  • There is robust evidence that a short duration of antibiotic treatment is appropriate in VAP, except in case of infection with non-fermenting gram-negative bacilli. 
  • The clinical situation and microbiological data should guide the duration of antibiotic therapy; biomarkers may support the decision-making process.
  • Besides the adverse impact on clinical outcomes, unnecessarily prolonged antibiotic treatment adds to the overall cost of care. 

References

1.         Singh N, Rogers P, Atwood CW, et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription: Infect Dis Clin Pract. 2001;10(4):230. doi:10.1097/00019048-200105000-00015

2.         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. Clin Infect Dis. December 2016:ciw870. doi:10.1093/cid/ciw870

3.         Chastre J, Wolff M, Fagon J-Y, et al. Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-Associated Pneumonia in Adults: A Randomized Trial. JAMA. 2003;290(19):2588. doi:10.1001/jama.290.19.2588

4.         Capellier G, Mockly H, Charpentier C, et al. Early-Onset Ventilator-Associated Pneumonia in Adults Randomized Clinical Trial: Comparison of 8 versus 15 Days of Antibiotic Treatment. Spellberg B, ed. PLoS ONE. 2012;7(8):e41290. doi:10.1371/journal.pone.0041290

5.         Uranga A, España PP, Bilbao A, et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA Intern Med. 2016;176(9):1257. doi:10.1001/jamainternmed.2016.3633

6.         Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis Off Publ Infect Dis Soc Am. 2007;44 Suppl 2:S27-72. doi:10.1086/511159

7.         Daneman N, Rishu AH, Xiong W, et al. Duration of Antimicrobial Treatment for Bacteremia in Canadian Critically Ill Patients: Crit Care Med. 2016;44(2):256-264. doi:10.1097/CCM.0000000000001393

8.         Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness – Full Text View – ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03005145. Accessed October 17, 2019.

9.         Daneman N, Rishu AH, et al. on behalf of the Canadian Critical Care Trials Group. Seven versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial. Trials. 2018;19(1):111. doi:10.1186/s13063-018-2474-1

10.       Sawyer RG, Claridge JA, Nathens AB, et al. Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection. N Engl J Med. 2015;372(21):1996-2005. doi:10.1056/NEJMoa1411162

11.       Montravers P, Tubach F, et al., for the DURAPOP Trial Group. Short-course antibiotic therapy for critically ill patients treated for postoperative intra-abdominal infection: the DURAPOP randomised clinical trial. Intensive Care Med. 2018;44(3):300-310. doi:10.1007/s00134-018-5088-x

12.       Eliakim-Raz N, Yahav D, Paul M, Leibovici L. Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection— 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2013;68(10):2183-2191. doi:10.1093/jac/dkt177

13.       Prkno A, Wacker C, Brunkhorst FM, Schlattmann P. Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock – a systematic review and meta-analysis. Crit Care. 2013;17(6):R291. doi:10.1186/cc13157

14.       de Jong E, van Oers JA, Beishuizen A, 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;16(7):819-827. doi:10.1016/S1473-3099(16)00053-0

15.       Garnacho-Montero J, Arenzana-Seisdedos A, De Waele J, Kollef MH. To which extent can we decrease antibiotic duration in critically ill patients? Expert Rev Clin Pharmacol. 2017;10(11):1215-1223. doi:10.1080/17512433.2017.1369879

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