What data are available regarding short versus long duration of antibiotic treatment for uncomplicated Enterobacteriaceae bacteremia?

Introduction

Enterobacteriaceae are Gram-negative facultative anaerobes that primarily reside in the lower gastrointestinal tract, and also colonize the genitourinary tract and oropharynx.1 Enterobacteriaceae cause a variety of community-acquired and nosocomial infections, including bacteremia. Antibiotic resistance is an increasing concern with Enterobacteriaceae, with resistant strains including those that produce extended-spectrum β-lactamase, metallo-β-lactamase, and carbapenem-resistant Enterobacteriaceae.

Gram-negative bacteremia is most commonly caused by the Enterobacteriaceae Escherichia coli, followed by Klebsiella pneumoniae.1 E. coli may cause bacteremia due to intestinal overgrowth, immunosuppression, and intestinal mucosa damage. The most common source of E. coli bacteremia is the urinary tract (approximately 50 to 66%) followed by the abdomen (approximately 25%).2 E. coli bacteremia may lead to sepsis, septic shock, or death.2,3 Patients with Gram-negative bacteremia should be treated immediately with antibiotic therapy, the choice of which depends on patient-specific factors (eg, comorbidities, previous culture results), health-care exposure, and local resistance patterns.3

Standard of Care

The Infectious Diseases Society of America (IDSA) does not have guidelines specifically on duration of antibiotic therapy for bacteremia. Although now they are archived, the 2009 IDSA guideline on intravascular catheter-related infections recommended a treatment duration of 7 to 14 days for intravascular catheter-related Gram-negative bacteremia.4,5 Duration in patients without catheters was not defined.

Typically, duration of antibiotic treatment for Enterobacteriaceae bacteremia is dependent on the patient’s clinical condition, the infection source, and severity of infection.3 Duration usually ranges from 7 to 14 days, but is not well established and is an area of active investigation. Advantages to shorter treatment duration may be lower rates of resistant organisms and adverse events.6 The purpose of this review is to summarize a recent meta-analysis and randomized controlled trial evaluating the appropriate duration of antibiotic therapy for Enterobacteriaceae bacteremia.

Literature evaluation

A literature search was performed to identify randomized controlled trials, meta-analyses, or systematic reviews evaluating duration of therapy for Enterobacteriaceae bacteremia. A 2019 meta-analysis and a recent randomized controlled trial were identified and are presented in the Table.5,6 Retrospective studies were included in the meta-analysis but are not included individually in the Table.

A 2019 meta-analysis included 4 retrospective cohort studies7-10 and 1 randomized controlled trial6 comparing short- versus long-duration of antibiotic therapy for Enterobacteriaceae bacteremia.5 The meta-analysis included studies that compared treatment for ≤ 10 days versus > 10 days. Forty-one percent of patients had uncomplicated bacteremia. Mortality at 30 days, mortality at 90 days, clinical cure, and relapse at 90 days were not significantly different between the short- and long-duration of therapy. However, by including retrospective studies, the meta-analysis has limitations.11,12 For example, selection bias may be present in retrospective studies leading to the choice of shorter duration of antibiotic treatment for certain patients (eg, patients with a good response to treatment).5,11 Another limitation includes a short duration of follow-up  (30 days instead of 90 days) in certain studies.5,12 Severity of bacteremia, comorbidities, and antibiotic regimens were not available in all studies.5

Furthermore, this article discussed 4 additional studies (2 randomized controlled trials, 1 retrospective cohort study, and 1 retrospective case control study) as part of a systematic review.5,13-16 These studies were not included in the meta-analysis because either they had treatment time frames different than the ≤ 10 days versus > 10 days that was used to evaluate duration in the meta-analysis (eg, ≤ 7 versus > 7 days or < 14 days versus ≥ 14 days) or bacteremia was the result of one source of infection (ie, pyelonephritis or cholangitis). In these studies, clinical outcomes including clinical cure,14-16 eradication rates,14 and mortality13 were not different between short- and long-course duration. However, in one study, relapse was higher when treatment was ≥ 14 days versus < 14 days.13 The randomized controlled trials from the systematic review are not included in the Table because the focus of these studies was on pyelonephritis and not bacteremia; therefore, they included a small number of patients with bacteremia.15,16

One randomized controlled trial was included in the 2019 meta-analysis. The open-label, multicenter, randomized controlled trial compared 7 days versus 14 days of antibiotic treatment in 604 patients with uncomplicated, Gram-negative bacteremia.6 Patients were included in the study if they were afebrile and hemodynamically stabile for ≥ 48 hours on day 7 of treatment. Exclusion criteria included an uncontrolled infection source, polymicrobial growth, and immunosuppression. The majority of patients had Enterobacteriaceae as the causative pathogen (90%) with a urinary source (68%). Seven-day treatment was noninferior to 14 day-treatment for the primary outcome, a composite of all-cause mortality, relapse, suppurative or distant complications, and readmission or extended hospitalization at 90 days.

Table. Literature Evaluating Short- Versus Long-Treatment of Enterobacteriaceae Bacteremia.5,6

Citation and study design Subjects Interventions Results Conclusions
Meta-analysis
Tansarli 20195

MA

 Included 4 retrospective cohort studies and 1 RCT (N=2865) evaluating antibiotic duration

Majority of bacteremia cases resulted from UTIs due to E. coli followed by K. pneumoniae

 

41% of patients had uncomplicated bacteremia

 Treatment for ≤ 10 days versus > 10 days

Antibiotic choice was not specified

 Mortality at 30 days was not significantly different between short- (7.5%) and long- (7.6%) duration therapy (RR, 0.99; 95% CI, 0.69 to 1.66; I2=0%)

Mortality at 90 days was not significantly different between short- (6.7%) and long- (5.6%) duration therapy (RR, 1.16; 95% CI, 0.81 to 1.66; I2=33%)

Clinical cure was not significantly different between short- (81.6%) and long- (81.4%) duration therapy (RR, 1.02; 95% CI, 0.96 to 1.08; I2=0%)

Relapse at 90 days was not significantly different between short- (4.5%) and long- (4.5%) duration therapy (RR, 1.08; 95% CI, 0.69 to 1.67; I2=0%)

 Clinical outcomes were not significantly different between short- and long- duration of therapy
Randomized Controlled Trial
Yahav 20196

NI, MC, OL, RCT

 N=604 patients with Gram-negative bacteremia on day 7 of treatment (afebrile and hemodynamically stable for ≥ 48 hours)

Main infection source was urinary tract (68%)

Majority of causative pathogens were Enterobacteriaceae (90%)

 7 days (n=306) or 14 days (n=298) of antibiotics

Antibiotic regimen was chosen by treating physicians

 Primary outcome:

Composite of all-cause mortality; relapse, suppurative or distant complications; and readmission or extended hospitalization (> 14 days) occurred in 45.8% with 7 days and 48.3% with 14 days (RD, -2.6%; 95% CI, -10.5 to 5.3%; NI margin: 10%)

Secondary outcomes:

Individual primary endpoint components were not significantly different between groups

90-day all-cause mortality was 11.8% with 7 days and 10.7% with 14 days (RD, 1.0%; 95% CI, -4.0 to 6.1%)

14-day mortality was 2.3% with 7 days and 1.3% with 14 days (RD, 0.95%; 95% CI, -1.42 to 3.44%)

28-day mortality was 4.9% with 7 days and 4.4% with 14 days (RD, 0.54; 95% CI, -2.98 to 4.06%)

Resistance development was 10.8% with 7 days and 9.7% with 14 days (RD, 1.0; 95% CI, -3.7 to 5.9%)

AEs were not significantly different between groups

 Short duration of antibiotics was non-inferior to long duration for treatment of Gram-negative bacteremia in patients who are afebrile and hemodynamically stable ≥ 48 hours at 7 days
Abbreviations: AE=adverse event; CI=confidence interval; I2=heterogeneity; MA=meta-analysis; MC=multicenter; NI=noninferiority; OL=open-label; RCT=randomized controlled trial; RD=risk difference; RR=relative risk; UTI=urinary tract infection.

Conclusion

Overall, a shorter duration of antibiotic treatment is supported by a recent meta-analysis and randomized controlled trial in patients with uncomplicated Enterobacteriaceae bacteremia. Importantly, patients included in the randomized controlled trial were afebrile and hemodynamically stable for at least 48 hours on day 7 of antibiotic treatment, were not immunocompromised, and did not have uncontrolled infection sources. Additional research in other patient populations is required. A study examining length of antibiotic treatment in critically ill patients with bacteremia (BALANCE) is ongoing.17,18

 

References

  1. Nelson GE, Greene MH. Enterobacteriaceae. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infections Diseases. 9th ed. Philadelphia, PA: Elsevier; 2020. https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323482554002186?indexOverride=GLOBAL. Accessed September 19, 2019.
  2. Russo TA, Johnson JR. Diseases caused by gram-negative enteric bacilli. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill; 2018. http://accesspharmacy.mhmedical.com/content.aspx?bookid=2129&sectionid=192022222. Accessed September 19, 2019.
  3. Moehring R, Anderson DJ. Gram-negative bacillary bacteremia in adults. UpToDate website. http://www.uptodate.com. Updated July 17, 2019. Accessed September 19, 2019.
  4. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009 Jul 1;49(1):1-45.
  5. Tansarli GS, Andreatos N, Pliakos EE, Mylonakis E. A systematic review and meta-analysis of antibiotic treatment duration for bacteremia due to Enterobacteriaceae. Antimicrob Agents Chemother. 2019;63(5):e02495-18.
  6. Yahav D, Franceschini E, Koppel F, et al; Bacteremia Duration Study Group. Seven versus 14 days of antibiotic therapy for uncomplicated gram-negative bacteremia: a noninferiority randomized controlled trial. Clin Infect Dis. 2019;69(7):1091-1098.
  7. Chotiprasitsakul D, Han JH, Cosgrove SE, 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;66(2):172-177.
  8. Giannella M, Pascale R, Toschi A, et al. Treatment duration for Escherichia coli bloodstream infection and outcomes: retrospective single-centre study. Clin Microbiol Infect. 2018;24(10):1077-1083.
  9. Nelson AN, Justo JA, Bookstaver PB, Kohn J, Albrecht H, Al-Hasan MN. Optimal duration of antimicrobial therapy for uncomplicated Gram-negative bloodstream infections. Infection. 2017;45(5):613-620.
  10. Mercuro NJ, Stogsdill P, Wungwattana M. Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones versus β-lactams. Int J Antimicrob Agents. 2018;51(5):687-692.
  11. Tochitani K, Ikenoue T, Yamamoto S, Yamamoto Y. Impairment of validity of comparison between short-course and prolonged-course antibiotic therapy using propensity score matching. Clin Infect Dis. 2018;66(12):1978.
  12. Al-Hasan MN, Albrecht H, Bookstaver PB, Kohn J, Justo JA. Duration of antimicrobial therapy for Enterobacteriaceae bacteremia: using convenient end points for convenient conclusions. Clin Infect Dis. 2018;66(12):1978-1979.
  13. Uno S, Hase R, Kobayashi M, et al. Short-course antimicrobial treatment for acute cholangitis with Gram-negative bacillary bacteremia. Int J Infect Dis. 2017;55:81-85.
  14. Swamy S, Sharma R. Duration of treatment of Gram-negative bacteremia: are shorter courses of antimicrobial therapy feasible? Infect Dis Clin Pract. 2016;24:155-160.
  15. Sandberg T, Skoog G, Hermansson AB, et al. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet. 2012;380(9840):484-490.
  16. Talan DA, Stamm WE, Hooton TM, et al. Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial. JAMA. 2000;283(12):1583-1590.
  17. Daneman N, Rishu AH, Xiong W, et al; Canadian Critical Care Trials Group. Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE): study protocol for a pilot randomized controlled trial. Trials. 2015;16:173.
  18. Daneman N, Fowler RA. Shortening antibiotic treatment durations for bacteremia. Clin Infect Dis. 2019;69(7):1099-1100.

Prepared by:
Patricia Hartke, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2019

The information presented is current as September 19, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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