SupplementaryOnlineContent

Garin N, Genn D, Carballo S, et al. -Lactam monotherapy vs -lactammacrolide

combination 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 give readers additional information about their
work.

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eMethods
Design and patients
Open design:
We chose a pragmatic design to compare two treatment strategies reflecting clinical practice in which
physicians switch to another treatment in case poor clinical response. Clinical deterioration or failure to
improve 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 between
the 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 or
increasing 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 were
reviewed 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 inflammatory
disease
known HIV infection
recent hospitalization (<14 days)
residency in a nursing home
planned admission to the intensive care unit
three or more minor criteria or one major criteria on the ATS/IDSA 2007 score
Pneumonia Severity Index category V
previous administration of an intravenous antibiotic
administration of oral antibiotics for more than 24 hours during the 14 days before inclusion
known bronchiectasis
colonization with resistant pathogens, defined as isolation in earlier admissions of one pathogen
intrinsically resistant to the prescribed treatment (P.aeruginosa, methicillin-resistant
Staphylococcus aureus, S.maltophilia)
long term oxygen or non-invasive ventilation
previously included in the study

Intervention
Initial treatment:
monotherapy arm: either cefuroxime 1.5 g three times a day intravenously followed by
cefuroxime 500 mg twice a day orally or amoxicillin/clavulanic acid 1.2 g intravenously four
times a day followed by amoxicillin /clavulanic acid 625 mg three times a day orally

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

Minimal 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 the
physician 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 of L.pneumophila or S.pneumoniae antigen in the urine
positive PCR for M.pneumoniae or C.pneumoniae;
growth of a pathogen typical for pneumonia in a good quality (as assessed by microscopy) sputum
sample

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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

Blood cultures (n, %)

Sputum cultures (n, %)
Oropharyngeal swab for M.pneumoniae
and C. pneumoniae (n, %)
L. pneumophila urinary antigen
S. pneumoniae urinary antigen
Streptococcus pneumoniae# (n, %)
Legionella pneumophila (n, %)
Mycoplasma pneumoniae (n, %)
Others (n, %)

Monotherapy
(n=291)
259 (89.0)
143(49.1)
281 (96.6)

Combination therapy
(n=289)
262 (90.7)
128 (44.3)
283 (97.9)

270 (92.8)
226 (77.7)
43 (148)
12 (41)
6 (21)
34 (117)

275 (95.2)
233 (80.6)
45 (156)
4 (14)
9 (31)
27 (93)

20 Gram-negative Enterobacteriacae, 12 Haemophilus influenzae, 7 Pseudomonas aeruginosa, 6 Streptococcus sp, 6

Staphylococcus 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 penicillin
None of the S.aureus isolates was methicillin-resistant

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eTable 2. Reason for Changing Antibiotic Treatment

Monotherapy (n=39)
Non specified or decision of the physician in
charge
Pathogen resistant to the prescribed
treatment
Fever persisting for more than 72 hours
Admission to the intensive care or
intermediate care unit
Empyema or lung abscess
Additional, non-pulmonary infection
Allergy
Suspected liver toxicity
Interstitial nephritis with acute renal failure

Combination therapy
(n=46)
19

4#

8
5

4
5

3
4
3
1
0

6
2
3
2
1

clarithromycin 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 Signsa

Heart rate < 100
bpm days, mean
(95% CI)
Temperature < 38.0
C days, mean (95%
CI)
Respiratory rate <
24 / days, mean
(95% CI)
SaO2 > 90 % on
room air days, mean
(95% CI)
Time to clinical
stability days, mean
(95% CI)
a

Monotherapy
(n=291)
5.9 (4.3-7.5)

Combination therapy
(n=289)
4.5 (3.0-6.0)

P value (logrank)
0.14

4.5 (3.0-6.0)

4.1 (2.7-5.5)

0.57

6.8 (6.6-9.4)

6.1 (4.6-7.6)

0.54

8.0 (6.6-9.4)

7.1 (5.7-8.4)

0.51

9.5 (8.1-10.9)

8.5 (7.2-9.8)

0.44

Time 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 Discharge

New episode of pneumonia
Heart failure, acute coronary syndrome
Other respiratory diagnosis
Other cause

Monotherapy
(n=23)

Combination
therapy (n=9)

P value

7 (304)
2 (87)
6 (261)
8 (348)

0
2 (222)
2 (222)
5 (556)

006
030
082
028

Hemoptysis, pulmonary embolism, acute exacerbation of a chronic obstructive pulmonary disease, asthma

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eTable 5. Secondary Outcomes in Patients Infected With Atypical

Pathogens
In-hospital death (n, %)
Intensive care unit admission (n, %)
Complicated pleural effusion (n, %)
Length of stay in days (median, IQR)
30-days death (n, %)
30-days readmission (n, %)
90-days death (n, %)
90-days readmission (n, %)
New pneumonia within 30 days (n, %)

Monotherapy
(n=18)

Combination
therapy(n=13)

0
3 (167)
1 (56)
85 (68-113)
2 (111)
0
3 (167)
1 (56)
0

0
0
0
80 (60-90)
0
1 (77)
0
1 (77)
0

P value
012
039
038
021
023
012
081

need for thoracic drainage or surgery

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