Table 1.
Trials of Reduced Antimicrobial Durations in Multiple Infectious Syndromes
| Infectious Syndrome | Author | Study Design | Primary Outcome | No. of Patients | Inclusion Criteria | Exclusion Criteria | Patient Location | Severity of Illness | Short Course Antibiotic: Duration, d | Long Course Antibiotic: Duration, d | Outcomes | Comments |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| VAP | Chastre et al 2003 [19] | Multicenter, noninferiority RCT | 28-d mortality; microbiologically documented PNA recurrence; abx-free days | 197 | MV > 48 h; clinical suspicion of VAP; positive distal airway culture; appropriate abx within 24 h of culture | SAPSII > 65; immunosuppression or long-term corticosteroid therapy; concomitant extrapulmonary infection requiring >8 d abx | ICU | Short course: SAPSII 45 (SD, 15), SOFA 7.3 (4); vasporessors 33% long course: SAPSII 45 (15), SOFA 7.4 (4); vasopressors 35%; mechanical ventilation 100% | Adequate abx per physician discretion: 8 | Adequate abx per physician discretion: 15 | Primary ARRs: all-cause mortality 1.6 (90% CI, −3.7 to 6.9); pulmonary infection recurrence 2.9 (− 3.2 to 9.1); abx-free days 4.4 (3.1–5.6) | Noninferiority met |
| CAP | Dunbar et al 2003 [37] | Multicenter, double-blind, noninferiority RCT | Clinical response at follow-up; 7–14 d post medication completion | 530 | Mild-to-severe CAP | Levofloxacin-resistant organism; previous quinolone treatment failure; life expectancy < 72 h; neutropenia or HIV; empyema or effusion requiring chest tube | Inpatient or outpatient | PSI class I/II 58%; class III/IV 42% | Levofloxacin 750 mg: 5 | Levofloxacin 500 mg: 10 | Clinical success rate 92.4% vs 91.1% | Noninferiority met; short course (higher dose) group defervescence earlier than that longer course |
| CAP | Uranga et al 2016 [38] | Multicenter, noninferiority RCT | Clinical cure at 10 d; clinical cure at 30 d; CAP symptoms at 5 d and 10 d | 312 | Hospitalization for CAP | ICU admission before randomization; immunosuppression; HCAP; specific indication for longer duration; required chest tube | Ward | PSI short 81.8 (SD, 33.8); PSI long 83.7 (33.7); vasopressors 1.6%; mechanical ventilation 1% | Adequate abx per physician discretion: 5 | Adequate abx and duration per physician discretion | Clinical cure 10 d: 53.6% vs 48.6%; clinical cure 30 d: 91.9% vs 88.6%; CAP symptoms 5 d: 27.2 vs 24.7; CAP symptoms 10 d: 17.9 vs 18.6 | No difference in any primary outcomes; significant reduction in duration of antibiotics and hospital readmissions by 30 d |
| CAP; HCAP | Vaughn et al 2019 [39] | Multicenter, retrospective cohort | Rate of excess antibiotic treatment | 6481 | Adult medical patients with community-onset pneumonia (CAP or HCAP) | ICU admission; MV; severe immunocompromise; Legionella or fungal pathogen; bacteremia or empyema | Ward | qSOFA short >2 9.8% qSOFA long >2 8.8% | Adequate abx per physician discretion: 5–7 | Adequate abx per physician discretion: > 5–7 | Median excess duration: CAP 2 d (IQR, 0–4), HCAP 1 d (0–3) | Excess duration was only associated with patient-reported events (diarrhea, GI distress, thrush most common) |
| cUTI | Peterson et al 2008 [40] | Multicenter, double-blind, noninferiority RCT | Microbiologic eradication post therapy | 1093 | Acute pyelonephritis or cUTI | Complete obstruction; surgery or lithotripsy within 7 d; abx therapy for concurrent infection; quinolone-resistant pathogen; abscess, prostatitis, epidymitis | Inpatient or outpatient | NR | Levofloxacin 750 mg: 5 | Ciprofloxacin 400/500 mg: 10 | Microbiologic eradication: 79.8% vs 77.5% | Noninferiority met; clinical success comparable between groups |
| cUTI | Sandberg et al 2012 [41] | Multicenter, double-blind, noninferiority RCT | Clinical and bacteriologic efficacy 10–14 d after treatment | 156 | Women with diagnosis of community-acquired pyelonephritis | Systemic abx within 72 h; indwelling or intermittent bladder catheterization; CrCl < 0.5 mL/s | Inpatient or outpatient | NR | Ciprofloxacin 500 mg: 7 | Ciprofloxacin 500 mg: 14 | Clinical cure: 97% vs 96% | Noninferiority met; long course significantly higher rate of oral candidiasis |
| NF | Aguilar- Guisado et al 2017 [42] | Multicenter, open, superiority RCT | Number of EAT-free days | 157 | Hematologic malignancies or HSCT with febrile neutropenia without microbiologic diagnosis | Microbiologic diagnosis of infection or noninfectious etiology for fever; CrCl < 30 mL/min; receiving antibiotics for any reason prior to NF onset | Ward | NR | 72 h apyrexia, symptom resolution and normal vital signs | Apyrexia, symptom resolution, normal vital signs AND neutropenia resolved | Mean EAT-free days: 16.1 (SD, 6.3) vs 13.6 (7.2) | Mean fever days and all-cause mortality was not different; control group had more grade 3–4 adverse events than the short course |
| BSI | Daneman et al 2018 [43] | Multicenter, open pilot RCT | Feasibility (recruitment, adherence) | 115 | Positive blood culture result with pathogenic bacteria while in ICU | Immunocompromise; prosthetic heart valve or endovascular grafts; established requirement for extended treatment; Staphylococcus aureus or fungal BSI | ICU | APACHEII 22 (IQR, 18–26); vasopressors 52% | Adequate abx per physician discretion: 7 | Adequate abx per physician discretion: 14 | Median recruitment rate 0.7 patients/mo (IQR, 0.3– 1.5); median adherence 71% (50%–85%) | 90-d mortality 15%, ICU mortality 7%, hospital mortality 13%; duration MV 8 d (3–21); relapse BSI 4%; CDI 4%; secondary AMR infection 9% |
| BSI | Yahav et al 2019 [44] | Mulicenter, open, noninferiority RCT | Composite: 90-d mortality, clinical failure, readmission, or LOS >14 d | 604 | Hospitalized adults with gram-negative bacteremia surviving to day 7 of treatment and clinically stable | Uncontrolled source; polymicrobial infection; immunosuppression | Ward; ICU | Presentation SOFA: short course 2 (IQR, 1–3), long 2 (1–3)Randomization SOFA: short 1 (0–2), long 2 (0–2) | Adequate abx per physician discretion: 7 | Adequate abx per physician discretion: 14 | Primary composite: risk difference −2.6 (CI, − 10.5 to 5.3) | Noninferiority met; secondary endpoints not different except time to return to baseline activity, duration of antibiotic therapy, and total antibiotic days (P < .001) |
| IAI | Sawyer et al 2015 [22] | Multicenter, open, superiority RCT | Composite: surgical site infection, recurrent IAI, 30-d mortality | 518 | Complicated IAI having undergone an intervention for source control | Inadequate source control; high likelihood of death within 72 h; SBP | NR | APACHE II: 10.1 ± 0.3 (range 0–29) | Adequate abx per physician discretion: 4 after source control | Adequate abx per physician discretion: 2 after resolution of SIRS | Primary composite: ARR −0.5% (CI, −7.0% to 8.0%; P = .92) | Secondary: no difference except for duration of therapy and abx-free days |
| ABSSTI | Prokocimer et al 2013 [45] | Multinational, double-blind, noninferiority RCT | Early clinical response at 48–72 h assessment | 667 | Skin or soft tissue infection accompanied by regional or systemic signs of infection; gram-positive organism suspected/documented | Uncomplicated ABSSTI or association with prosthetic device or vascular catheter site, gram-negative pathogen suspected or documented (unless wound infection); any necrotizing process; septic shock or severe sepsis; immunosuppression | NR | NR | Tedizolid PO: 6 | Linezolid: 10 | Early clinical response: 79.5% vs 79.4% | Noninferiority was met for primary and secondary endpoints |
| ABSSTI | Moran et al 2014 [46] | Multinational, double-blind, noninferiority RCT | Early clinical response at 48–72 h assessment | 666 | Skin or soft tissue infection accompanied by regional or systemic signs of infection; gram-positive organism suspected/documented | Uncomplicated ABSSTI or associated with prosthetic device or vascular catheter site; gram-negative pathogen suspected or documented (unless wound infection); any necrotizing process; septic shock or severe sepsis; immunosuppression | NR | NR | Tedizolid IV to PO: 6 | Linezolid: 10 | Early clinical response: 85% vs 83% | Noninferiority was met for primary and secondary endpoints |
| Acute pyogenic osteomyelitis | Bernard et al 2015 [47] | Multicenter, open, noninferiority RCT | Clinical cure 1 y posttreatment | 359 | Microbiologically confirmed pyogenic vertebral osteomyelitis | Life expectancy < 1 y; fungal, brucellar, mycobacterial infection; death within 1 wk of treatment | NR | NR | Adequate abx per physician discretion: 42 | Adequate abx per physician discretion: 84 | Clinical cure: 90.9% vs 90.9% | Noninferiority met |
Abbreviations: ABSSTI, acute bacterial skin and soft tissue infection; abx, antibiotics; AMA, against medical advice; AMR, antimicrobial resistance; APACHE II, acute physiology + age points + chronic health points score; ARR, absolute risk reduction; BSI, bloodstream infection; CAP, community-acquired pneumonia; CI, confidence interval; CrCl, creatinine clearance; cUTI, complicated urinary tract infection; CVC, central venous catheter; DFI, diabetic foot infection; EAT, empiric antibiotic therapy (consisted of antipseudomonal β-lactam monotherapy or in combination with other agents per institutional protocol); EOT, end of therapy; HCAP, health care-associated pneumonia; HIV, human immunodeficiency virus; HSCT, hematopoetic stem cell transplantation; IAI, intraabdominal infection; ICU, intensive care unit; IQR, interquartile range; ITT, intention to treat; LOS, length of stay; MV, mechanical ventilation; NF, neutropenic fever; NR, not reported; PD, peritoneal dialysis; PNA, pneumonia; PSI, pneumonia severity index; qSOFA, quick sequential organ failure assessment score; RCT, randomized controlled trial; SAPS II, simplified acute physiology score; SBP, spontaneous bacterial peritonitis; SOFA, sequential organ failure assessment score.
Number of patients diagnosed with sepsis not reported but number of patients for whom sepsis was the reason for MV was reported.