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2014 American Medical Association. All rights reserved.

SupplementaryOnlineContent

Garin N, Genn D, Carballo S, et al. -Lactam monotherapy vs -lactammacrolidecombination treatment in moderately severe community-acquired pneumonia: a

randomized noninferiority trial.JAMA Internal Medicine.Published online October 6,2014. doi:10.1001/jamainternmed.2014.4887.

eMethods

eFigure 1.Time to Clinical Stability Stratified by Severity of the Pneumonia

eTable 1.Diagnostic Tests and Microbiological Documentation of Pneumonia

eTable 2.Reason for Changing Antibiotic Treatment

eTable 3.Time to Stabilization of the Different Vital Signs

eTable 4.Cause of Readmission Within 30 Days After Discharge

eTable 5.Secondary Outcomes in Patients Infected With Atypical Pathogens

This supplementary material has been provided by the authors to gi ve readers additional information abou t theirwork.

wnloaded From: http://archinte.jamanetwork.com/ on 03/30/2016

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eMethods

Design and patients

Open design:

We chose a pragmatic design to compare two treatment strategies reflecting clinical practice in whichphysicians switch to another treatment in case poor clinical response. Clinical deterioration or failure toimprove is expected in around 20% of patients with pneumonia and a blinded design would have required

unblinding for all those patients. This would result in potential inhomogeneity in the process of care

between blinded and non-blinded patients and any imbalance in the number of unblinded patients betweenthe two groups would have been difficult to deal with. Therefore, we preferred an open design. However, to

control for the information bias inherent to the open nature of the trial, we chose an objective primary

endpoint, and outcome assessors blinded to treatment allocation.

Inclusion criteria:

age 18 years or older

at least two clinical findings suggestive of pneumonia among fever or hypothermia, new orincreasing cough, sputum production, pleuritic chest pain, tachypnea, dyspnea or focal signs on

chest examination

presence of a new infiltrate on chest X-ray unexplained by another disease. All X-rays werereviewed by one of the investigators.

Need for hospitalization as decided by the emergency physician in charge of the patient.

Exclusion criteria:

receipt of solid organ or bone marrow transplant

chronic use of glucocorticoids (> 10 mg / day of prednisone or equivalent for > 14 days)

active use of immunosuppressive therapy for the treatment of auto-immune or inflammatorydisease

known HIV infection

recent hospitalization (

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combination therapy arm:either cefuroxime 1.5 g three times a day intravenously followed bycefuroxime 500 mg twice a day orally or amoxicillin/clavulanic acid 1.2 g intravenously fourtimes a day followed by amoxicillin /clavulanic acid 625 mg three times a day orally

plus

clarithromycin 500 mg twice a day, either intravenously or orally

Recommended duration of treatment: 5-10 daysMinimal duration of intravenous treatment with the beta-lactam drug: 48 hours

Timing of oral switch and dosage adaptation in case of renal impairment were at the discretion of thephysician in charge of the patient.

Adherence to the allocated treatment was assessed during hospitalization by daily visit of one of the study

nurses or investigators. After discharge, it was based on prescriptions filled and patients declarations.

Diagnostic criteria

An etiologic diagnosis for pneumonia was accepted as follows:

isolation of a known pathogen in blood cultures or pleural fluid

detection ofL.pneumophilaor S.pneumoniaeantigen in the urine

positive PCR forM.pneumoniaeor C.pneumoniae;

growth of a pathogen typical for pneumonia in a good quality (as assessed by microscopy) sputumsample


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eFigure 1. Time to Clinical Stability Stratified by Severity of the Pneumonia

a. PSI category I-III

b. PSI category IV

Combination therapy: +++++

Monotherapy: +++++


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c. CURB-65 category 0-1

d. CURB-65 category 2 or more

Combination therapy: +++++

Monotherapy: +++++


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eTable 1. Diagnostic Tests and Microbiological Documentation of Pneumonia

Monotherapy(n=291)

Combination therapy(n=289)

Blood cultures (n, %) 259 (89.0) 262 (90.7)

Sputum cultures (n, %) 143(49.1) 128 (44.3)

Oropharyngeal swab for M.pneumoniaeand C. pneumoniae(n, %)

281 (96.6) 283 (97.9)

L. pneumophilaurinary antigen 270 (92.8) 275 (95.2)

S. pneumoniaeurinary antigen 226 (77.7) 233 (80.6)

Streptococcus pneumoniae#(n, %) 43 (148) 45 (156)

Legionella pneumophila (n, %) 12 (41) 4 (14)

Mycoplasma pneumoniae (n, %) 6 (21) 9 (31)

Others (n, %) 34 (117) 27 (93) 20 Gram-negative Enterobacteriacae, 12 Haemophilus influenzae,7 Pseudomonas aeruginosa, 6 Streptococcus sp, 6Staphylococcus aureus, 2 Moraxella catarrhalis, 2 anaerobes, 6 others#Six (15.4%) of the S.Pneumoniae were resistant to erythromycin and 2 (2.4 %) of intermediate susceptibility to penicillinNone of the S.aureus isolates was methicillin-resistant


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eTable 2. Reason for Changing Antibiotic Treatment Monotherapy (n=39) Combination therapy

(n=46)

Non specified or decision of the physician incharge

7 19

Pathogen resistant to the prescribed

treatment

8 4#

Fever persisting for more than 72 hours 8 4

Admission to the intensive care orintermediate care unit

5 5

Empyema or lung abscess 3 6

Additional, non-pulmonary infection 4 2

Allergy 3 3

Suspected liver toxicity 1 2

Interstitial nephritis with acute renal failure 0 1clarithromycin stopped before end of the treatment in 12 patients 4 Legionella sp, 3 Gram-negative enterobacteria, 1 Pseudomonas sp# 3 Gram-negative enterobacteria, 1 Pseudomonas sp


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eTable 3. Time to Stabilization of the Different Vital Signs aMonotherapy(n=291)

Combination therapy(n=289)

P value (logrank)

Heart rate < 100bpm days, mean(95% CI)

5.9 (4.3-7.5) 4.5 (3.0-6.0) 0.14

Temperature < 38.0C days, mean (95%CI)

4.5 (3.0-6.0) 4.1 (2.7-5.5) 0.57

Respiratory rate 90 % onroom air days, mean(95% CI)

8.0 (6.6-9.4) 7.1 (5.7-8.4) 0.51

Time to clinicalstability days, mean(95% CI)

9.5 (8.1-10.9) 8.5 (7.2-9.8) 0.44

aTime to stabilization of blood pressure is not included, as this parameter was rarely under the cut-off defining instability


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eTable 4. Cause of Readmission Within 30 Days After DischargeMonotherapy(n=23)

Combinationtherapy (n=9)

P value

New episode of pneumonia 7 (304) 0 006

Heart failure, acute coronary syndrome 2 (87) 2 (222) 030

Other respiratory diagnosis 6 (261) 2 (222) 082Other cause 8 (348) 5 (556) 028Hemoptysis, pulmonary embolism, acute exacerbation of a chronic obstructive pulmonary disease, asthma


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eTable 5. Secondary Outcomes in Patients Infected With AtypicalPathogens

Monotherapy(n=18)

Combinationtherapy(n=13)

P value

In-hospital death (n, %) 0 0

Intensive care unit admission (n, %) 3 (167) 0 012

Complicated pleural effusion (n, %) 1 (56) 0 039Length of stay in days (median, IQR) 85 (68-113) 80 (60-90) 038

30-days death (n, %) 2 (111) 0 021

30-days readmission (n, %) 0 1 (77) 023

90-days death (n, %) 3 (167) 0 012

90-days readmission (n, %) 1 (56) 1 (77) 081

New pneumonia within 30 days (n, %) 0 0 need for thoracic drainage or surgery

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