3 Days β-lactam for CAP
Discontinuing β-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial.
Dinh A, Ropers J, Duran C, et al. Pneumonia Short Treatment (PTC) Study Group.
Lancet. 2021 Mar 27;397(10280):1195-1203. [Full text]
The 2019 ATS and IDSA guidelines for community-acquired Pneumonia (CAP) recommend a minimum of 5 days of antibiotics [1], a strong recommendation with moderate quality evidence [2]. When prescribing practice is reviewed, the median length of duration has been 10 days, with over 70% likely over prescribed [3] or elsewhere a quarter receiving antibiotics without cardinal features of pneumonia [4]. Any evidence of shortened antibiotic duration that is safe is likely to improve stewardship.
In this non-inferiority trial, the authors aimed to assess whether 3 days of β-lactam was similar to 3 days followed by an additional 5-day course of treatment for patients hospitalized for CAP.
Patient population
Immunocompetent patients with moderately severe community-acquired pneumonia (ie, admitted to a non-critical care unit, without serious respiratory insufficiency, and without septic shock) were eligible if stable after 72hr of β-lactam (amoxicillin-clavulonate of 3rd generation cephalosporin) by Halm’s criteria (afebrile, HR<100, RR<24, SPo2≥90%, SBP >90, normal mental status). CAP diagnosis required at least one acute clinical sign (dyspnea, cough, purulent sputum, or crackles), temperature >38°C , and a new pulmonary infiltrate on imaging. Those with complicated pneumonia (abscess, parapneumonic effusion), suspected or confirmed legionella, or those with CKD 4 or worse (CrCl <30) were excluded.
Outcomes
This was a double-blind, randomized, placebo-controlled, non-inferiority trial with two parallel groups undertaken in 16 French hospitals. Patients with randomized 1:1, stratified by site and PSI (≤70 or >70) to receive either an additional 5 days of amoxicillin-clavulonate 1000 mg TID or matched placebo.
The primary outcome was cure 15 days after the start of antibiotic treatment, requiring a patient be afebrile, have resolution of clinical signs or symptoms and receiving no additional antibiotic treatment. The secondary outcomes were: cure at day 30; all-cause mortality on day 30; frequency and severity of adverse events and length of hospital stay assessed at day 15.
Results
Of the 706 potentially eligible, 17% were not stable at the 72 hr mark so were not eligible. Otherwise, 310 patients were enrolled, though 7 subsequently withdrew consent. About 69% were male with an average age was 73 and average PSI in the 80s (risk class 2). A total of 39% required oxygen on admission.
In the ITT analysis 117 of 152 (77%) of patients in the 3 day β-lactam group (placebo) were cured compared to 102 of 151 (68%) of patients in the 8 day β-lactam group for a 9.42% difference (95 % CI -0.38 – 20.04). A similar finding of non-inferiority was found in the per protocol analysis.
In the subgroup analysis, all findings tended to favor the 3 day β-lactam group; however, the confidence interval for two groups, age <65 years or PSI ≥90, extended low enough that favoring 8 day β-lactam group was more possible.
There was no difference in death rate, adverse advents, length of hospital stay, or median recovery time.
Discussion
In this small randomized trial of patients with moderately severe CAP, 3 days of β-lactam only compared to 8 days total β-lactam was non-inferior. The results tended to even favor the 3 day group and there were no differences in adverse events. It is notable that though patients met stability criteria at 72 hours, only about 70% in either group were “cured” at 15 days.
How can one apply these findings in practice? These patients were not very ill, with most having PSI ≤90. Almost 20% of patients screened were not eligible as they were not clinically stable at the 72 hour mark. Therefore, possibly only a subset of patients admitted with CAP will be similar to this population in that they are only moderately ill and reach 72 hour stability. Yet, for mildly to moderately ill patients, 3 days potentially may be sufficient.
Additionally, the ATS and IDSA US guidelines still advocate empiric atypical coverage for patients admitted with CAP [1], while in this French study only β-lactam monotherapy was used with suspected legionella excluded. There is some evidence that empiric atypical coverage offers no benefit to β-lactam monotherapy, though this predominantly was a comparison to fluoroquinoloes, not macrolides [5].
In the end this trial may not be a major change from the minimum of 5 days of antibiotics recommended By ATS/IDSA [1]. Anything that safely shortens duration of treatment will likely move the needle on antibiotics stewardship. And at the least, the trial reminds us that providers should likely be prescribing duration of therapy to endpoints like reaching clinical stability, more so than just using a fixed duration based on diagnosis.
| F: Follow up | 3 days IP, 8 day phone call, 15 and 30 day f/u appointments |
| R: Randomization | Yes |
| I: Intention to treat | Yes, ITT and per-protocol |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes |
| S: Source (funding) | French Ministry of Health. |
- Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, Cooley LA, Dean NC, Fine MJ, Flanders SA, Griffin MR, Metersky ML, Musher DM, Restrepo MI, Whitney CG. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67. doi: 10.1164/rccm.201908-1581ST.
- Uranga A, España PP, Bilbao A, Quintana JM, Arriaga I, Intxausti M, Lobo JL, Tomás L, Camino J, Nuñez J, Capelastegui A. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA Intern Med. 2016 Sep 1;176(9):1257-65.
- Yi SH, Hatfield KM, Baggs J, Hicks LA, Srinivasan A, Reddy S, Jernigan JA. Duration of Antibiotic Use Among Adults With Uncomplicated Community-Acquired Pneumonia Requiring Hospitalization in the United States. Clin Infect Dis. 2018 Apr 17;66(9):1333-1341.
- Klompas M, Ochoa A, Ji W, McKenna C, Clark R, Shenoy ES, Hooper D, Rhee C; CDC Prevention Epicenters Program. Prevalence of Clinical Signs Within Reference Ranges Among Hospitalized Patients Prescribed Antibiotics for Pneumonia. JAMA Netw Open. 2020 Jul 1;3(7):e2010700.
- Eliakim-Raz N, Robenshtok E, Shefet D, Gafter-Gvili A, Vidal L, Paul M, Leibovici L. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults. Cochrane Database Syst Rev. 2012 Sep 12;2012(9):CD004418.
