Clinical Microbiology and Infection 24 (2018) 1171e1176

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Clinical Microbiology and Infection

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Original article

Are third-generation cephalosporins associated with a better

prognosis than amoxicillineclavulanate in patients hospitalized in the
medical ward for community-onset pneumonia?*
E. Batard 1, 2, *, F. Javaudin 1, 2, E. Kervagoret 1, E. Caruana 2, Q. Le Bastard 1, 2,
G. Chapelet 1, 3, N. Goffinet 2, E. Montassier 1, 2
1)
Universit

e de Nantes, Microbiotas Hosts Antibiotics Bacterial Resistances (MiHAR), Institut de Recherche en Sant

e 2, Nantes, France
2)
CHU Nantes, Emergency Department, Nantes, France
3)
CHU Nantes, Clinical Gerontology Department, Nantes, France

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: We aimed to assess whether treatment with ceftriaxone/cefotaxime is associated with lower
Received 13 February 2018 in-hospital mortality than amoxicillineclavulanate in pati0ents hospitalized in medical wards for
Received in revised form community-onset pneumonia.
14 June 2018
Methods: We conducted a retrospective and multicentre study of patients hospitalized in French medical
Accepted 18 June 2018
Available online 28 June 2018
wards for community-onset pneumonia between 2002 and 2015. Treatments with ceftriaxone/cefo-
taxime or amoxicillineclavulanate were defined by their start in the emergency department for a
Editor: M. Paul duration of 5 days or more with no other b-lactam. A logistic regression analysis was performed on the
overall population, and a propensity score analysis was restricted to patients treated with either cef-
Keywords: triaxone/cefotaxime or amoxicillineclavulanate.
Amoxicillineclavulanate Results: 1698 patients (median age, 80 y) were included, of which 716 and 198 were treated with amoxi-
Cefotaxime cillineclavulanate and ceftriaxone/cefotaxime, respectively. In-hospital mortality was 10% (9e12%). In
Ceftriaxone multivariate analysis, factors associated with in-hospital mortality were treatment with ceftriaxone/cefo-
Community-onset pneumonia
taxime (aOR 2.9; (1.4e5.7)), pneumonia severity index class 4 or 5 (aOR 7.8 (4.3e15.7)), do-not-resuscitate
Mortality
order (aOR 8.7 (5.2e14.6)) and fluid therapy (aOR 6.3 (2.5e15.1)). The propensity score analysis was per-
formed on 178 patients treated with ceftriaxone/cefotaxime matched with 178 patients treated with
amoxicillineclavulanate; no significant association between treatment with ceftriaxone/cefotaxime and in-
hospital mortality was found (OR 1.5 (0.7e3.0)).
Conclusion: In the largest study aiming to compare amoxicillineclavulanate and ceftriaxone/cefotaxime
in community-onset pneumonia, ceftriaxone/cefotaxime was not associated with lower in-hospital
mortality than amoxicillineclavulanate. Our results suggest that ceftriaxone/cefotaxime should not be
preferred over amoxicillineclavulanate for patients hospitalized in medical wards with community-
onset pneumonia. E. Batard, Clin Microbiol Infect 2018;24:1171
© 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction treatment of patients with comorbidities and/or age of
65 years

Ceftriaxone, cefotaxime, and amoxicillineclavulanate are
equally recommended by French and European guidelines for the
*
This study has been presented as an oral flash presentation (O1035) at the
ECCMID 2018 in Madrid, Spain.
* Corresponding author. E. Batard, MiHAR Lab (Microbiotas Hosts Antibiotics and

IRS2, 22 Boulevard Benoni-
Bacterial Resistance), Institut de Recherche en Sante
Goullin, 44200 Nantes, France.
E-mail address: eric.batard@univ-nantes.fr (E. Batard).
who are hospitalized in the medical ward for a community-
acquired pneumonia [1,2]. These antibiotics are frequently used
for this condition [3e5]. It has long been suggested that narrow-
spectrum b-lactams be preferred over third-generation cephalo-
sporins (3GCs) to treat community-acquired pneumonia and to
preserve the microbial ecology of hospitals [6]. Resistance to 3GCs
in the Enterobacteriaceae is associated with exposure to antibiotics
in general and to cephalosporins and fluoroquinolones in particular
[7e12]. Conversely, most studies have found no relationship be-
tween amoxicillineclavulanate use and resistance mediated by

https://doi.org/10.1016/j.cmi.2018.06.021
1198-743X/© 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
1172 E. Batard et al. / Clinical Microbiology and Infection 24 (2018) 1171e1176
extended-spectrum b-lactamase (ESBL) or resistance to 3GCs in the
Enterobacteriaceae [13e18]. A panel of French experts recently
listed b-lactams by increasing order of spectrum width and
resistance-promoting potential [19]. In this six-rank classification,
amoxicillineclavulanate (rank #2) had a narrower spectrum and
lower resistance-promoting potential than 3GCs (rank #3). Hence,
from an ecological point of view, it may be preferable to treat
community-onset pneumonia with amoxicillineclavulanate rather
than 3GCs, although this point remains to be demonstrated.
However, 3GCs have been increasingly used to treat this condition,
although ceftriaxone has never been shown to be superior to other
b-lactamsdespecially amoxicillineclavulanatedin community-
onset pneumonia [20].
Here, we aim to assess whether treatment with ceftriaxone/
cefotaxime is associated with a better prognosis than
amoxicillineclavulanate in patients hospitalized in the medical
ward for community-onset pneumonia.
Methods
Study design, setting and participants
This study was retrospectively conducted in two populations of
patients treated for community-onset pneumonia. The first study
population originated from a French academic centre (Centre
Hospitalier Universitaire de Nantes, Nantes, France), the study
period ranging from January 2002 to December 2015. Patients who
were hospitalized between 2002 and 2013 have been described
previously [5,20]. The second study population originated from a
previously reported multicentre study in seven other French hos-
pitals, including two academic centres [5]. Local hospital guidance
limited the use of 3GCs for community-onset pneumonia in two of
the eight hospitals [5]. Eligible patients were selected from the
institution's databases using the following criteria: age of
18
years, admission through the emergency department (ED), transfer
from the ED to any acute medical ward (except for intensive- and
intermediate-care units), and a main diagnosis of pneumonia
according to the 10th International Classification of Diseases at
hospital discharge. In order to cover both community-acquired and
healthcare-associated pneumonia and to exclude hospital-acquired
pneumonia, patients transferred from another acute-care hospital
to the ED were not eligible. Among eligible patients, we randomly
selected 100 cases per year (except for 168 cases in 2013) using a
computer-generated random number list [5,20]. Among these
randomly selected cases, inclusion and exclusion criteria were
subsequently applied. Patients were included if the diagnosis of
pneumonia was mentioned on the ED chart's conclusion and if an
antibacterial agent was administered in the ED. Patients were
excluded if any other acute infectious disease was diagnosed or
suspected in the ED chart's conclusion.
Outcome, exposure variables and data sources
The primary outcome was in-hospital mortality. The exposure
was a three-level variable: (a) treatment with a 3GC, defined as a
treatment with ceftriaxone or cefotaxime started in the ED and
administered for at least 5 days without any other b-lactam; (b)
treatment with amoxicillineclavulanate, started in the ED and
administered for at least 5 days without any other b-lactam; (c)
other treatment. This classification was based on the b-lactam
exposure, and patients in each class could have received non-b-
lactam antibiotics (e.g., a macrolide or a fluoroquinolone). In
addition, exposures to a 3GC and to amoxicillineclavulanate were
alternatively defined as a treatment with a 3GC (or amox-
icillineclavulanate) for
1 day, irrespective of other antibacterial
therapies. Exposures to macrolides (including telithromycin and
synergistins) and to fluoroquinolones were defined as a treatment
for
1 day. Exposure to macrolides and fluoroquinolones was
defined alternatively by a treatment duration of 5 days or more.
Medical data from the entire duration of the hospitalization were
collected by trained and supervised abstractors into an electronic
database.
Statistical analysis
Descriptive statistics were expressed as median (25the75th
percentiles) and proportions (95%CI). First, we tested in the overall
population the association between in-hospital mortality and
treatment, using logistic regression. All variables with a P
value < 0.2 on univariate analysis were included in the multivariate
analysis and were selected using an automated backward proced-
ure. Interactions were added when necessary. Subgroup analyses
were performed on pneumonia severity index (PSI) class 5 patients,
and on patients who had no DNR order in the ED. A sensitivity
analysis was performed on patients treated in centres where the
mortality rate was not significantly different from the others.
Second, as the empirical selection of antibiotic might be influ-
enced by the presence of underlying comorbidities and illness
severity, we simulated the experimental comparison of ceftriaxone/
cefotaxime and amoxicillineclavulanate with a propensity score
analysis. This analysis was restricted to the subgroup of patients
treated with either amoxicillineclavulanate or cefotaxime/ceftri-
axone, as defined earlier. The propensity score (PS) was defined as
the individual probability of being treated with ceftriaxone or
cefotaxime. Cases and controls were 1:1 matched without
replacement and with a calliper set at 0.2. The balance in the dis-
tribution of baseline covariates was checked using the standardized
mean difference (SMD) [21]. All statistical tests were two-tailed,
and p 0.05 was considered statistically significant. Statistical an-
alyses were performed using R software 3.2.3 (2015-12-10, http://
CRAN.R-project.org) with MASS, tableone and Matching libraries.
Ethical issues
This study was approved by the ethics committee of Centre
Hospitalier Universitaire de Nantes (Number 2014-04-01). Ac-
cording to French law, no consent was required from patients in
this retrospective study.
Results
After case selection (Supplementary file, Fig. S1), 1698 patients
were included. Among these, 956 originated partly from a previ-
ously described and ongoing monocentric population (from
2002e2015), and 742 originated from seven other hospitals (2013).
Patient characteristics are reported in Table 1. Blood culture was
sampled in the ED for 1161 patients, and was sterile, truly positive
and contaminated in 1071 (92.2% (90.5e93.7%)), 73 (6.3%
(5.0e7.9%)) and 17 (1.5% (0.9e2.4%)) cases, respectively. Blood
cultures drawn outside the ED (i.e. in the medical ward) were truly
positive in five additional cases, and were contaminated in three
additional cases (Supplementary file, Table S1). Only 869 patients
(51%) received one unique antibacterial agent during their hospital
stay, and 484 (29%), 242 (14%) and 103 (6%) received two, three and
four or more antibiotics; 198 patients were treated in the ED with
ceftriaxone/cefotaxime for at least 5 days without any other b-
lactam, and 716 received amoxicillineclavulanate in the ED
without any other b-lactam for at least 5 days (Table 1). Among the
784 patients of the ‘other treatment’ group, 393 (50%) and 480
(61%) were treated for at least 1 day with ceftriaxone/cefotaxime
 E. Batard et al. / Clinical Microbiology and Infection 24 (2018) 1171e1176 1173

Table 1
Patient characteristics.

Description All patients Amoxicillineclavulanate 3GC p

Number 1698 716 (42%) 198 (12%) e

Age (years), median (IQR) 80 (67e87) 82 (73e88) 80 (69e86) 0.08
Male, n (%) 930 (55%) 395 (55%) 111 (56%) 0.89
Nursing home resident, n (%) 430 (1659) (25%) 179 (704) (25%) 62 (191) (31%) 0.09
Neoplastic disease, n (%) 260 (15%) 105 (15%) 41 (21%) 0.052
Liver disease, n (%) 44 (3%) 17 (2%) 8 (4%) 0.30
Congestive heart failure, n (%) 282 (17%) 137 (19%) 35 (18%) 0.72
Cerebrovascular disease, n (%) 251 (15%) 120 (17%) 36 (18%) 0.72
Renal disease, n (%) 144 (8%) 70 (10%) 21 (11%) 0.83
History of pneumonia, n (%) 248 (15%) 100 (14%) 35 (18%) 0.23
Immunocompromised, n (%) 192 (11%) 56 (8%) 39 (20%) <0.001
Altered mental status, n (%) 393 (1545) (23%) 169 (669) (24%) 49 (161) (25%) 0.81
Respiratory rate
30/min, n (%) 426 (1426) (25%) 164 (598) (23%) 55 (168) (28%) 0.18
Systolic blood pressure <90 mmHg, n (%) 70 (1689) (4%) 26 (713) (4%) 10 (197) (5%) 0.48
Temperature <35 C or
40 C, n (%) 66 (1682) (4%) 20 (709) (3%) 17 (196) (9%) <0.001
Pulse
125 bpm, n (%) 145 (1690) (9%) 49 (713) (7%) 18 (197) (9%) 0.36
Arterial pH < 7.35, n (%) 80 (734) (5%) 27 (283) (4%) 16 (103) (8%) 0.019
Blood urea nitrogen
11 mmol/L, n (%) 454 (1628) (27%) 192 (692) (27%) 66 (185) (33%) 0.086
Sodium <130 mmol/L, n (%) 85 (1676) (5%) 36 (711) (5%) 8 (194) (4%) 0.70
Glucose
14 mmol/L, n (%) 63 (1576) (4%) 25 (673) (3%) 10 (173) (5%) 0.42
Haematocrit <30%, n (%) 109 (1680) (6%) 45 (711) (6%) 15 (195) (8%) 0.63
Partial pressure of arterial oxygen <8 kPA or oxygen 394 (1672) (23%) 162 (701) (23%) 59 (196) (30%) 0.046
saturation <90%, n (%)
Pleural effusion, n (%) 97 (6%) 45 (6%) 6 (3%) 0.11
PSI class 1, n (%) 103 (6%) 17 (2%) 11 (6%)
PSI class 2, n (%) 180 (11%) 47 (7%) 14 (7%)
PSI class 3, n (%) 308 (18%) 151 (21%) 25 (13%)
PSI class 4, n (%) 699 (41%) 341 (48%) 86 (43%)
PSI class 5, n (%) 408 (24%) 160 (22%) 62 (31%) 0.002
Antibacterial treatment in the preceding 3 months, n (%) 174 (10%) 47 (7%) 35 (18%) <0.001
Antibacterial therapy before the arrival in the ED, n (%) 331 (19%) 89 (12%) 60 (30%) <0.001
Fluid therapy, n (%) 198 (12%) 47 (7%) 43 (22%) <0.001
Non-invasive ventilation, n (%) 15 (1%) 3 (0%) 4 (2%) 0.068
DNR order, n (%) 134 (8%) 31 (4%) 20 (10%) 0.003
Fluoroquinolone, n (%) 349 (21%) 77 (11%) 46 (23%) <0.001
Macrolide, streptogramin or ketolide, n (%) 290 (17%) 48 (7%) 59 (30%) <0.001
Bacteraemia, n (%) 78 (5%) 11 (2%) 6 (3%) 0.28
Centre 1, n (%) 109 (6%) 41 (6%) 6 (3%) <0.001
Centre 2, n (%) 102 (6%) 47 (7%) 10 (5%)
Centre 3, n (%) 93 (5%) 38 (5%) 16 (8%)
Centre 4, n (%) 138 (8%) 44 (6%) 34 (17%)
Centre 5, n (%) 89 (5%) 25 (3%) 24 (12%)
Centre 6, n (%) 956 (56%) 441 (62%) 70 (35%)
Centre 7, n (%) 114 (7%) 40 (6%) 25 (13%)
Centre 8, n (%) 97 (6%) 40 (6%) 13 (7%)
Academic status, n (%) 1179 (69%) 522 (73%) 101 (51%) <0.001

3GC, third-generation cephalosporin (ceftriaxone or cefotaxime); DNR, do not resuscitate; ED, emergency department; PSI, pneumonia severity index.
Treatment groups were defined as follows: 3GC, treatment with a 3GC started in the ED and 3GC was administered for at least 5 days without another b-lactam; amox-
icillineclavulanate, treatment with amoxicillineclavulanate started in the ED and administered for at least 5 days without another b-lactam. P values, comparison of 3GC and
amoxicillineclavulanate. As percentages have been rounded, their sum may not reach 100%. Numbers of patients with available data are reported in brackets when necessary.

and amoxicillineclavulanate, respectively. Overall, the numbers of
patients treated for at least 1 day with amoxicillineclavulanate and
cefotaxime/ceftriaxone were 1196 and 591, respectively. The
median length of antibacterial therapy was 11 (8e13) days. The
median length of treatment with ceftriaxone/cefotaxime and
amoxicillineclavulanate was 7 (3e10) and 9 (5e11) days,
respectively.
Predictors of mortality in the overall population
Among 1698 patients, 178 died, an in-hospital mortality of 10%
(9e12%). Mortality among patients treated with amox-
icillineclavulanate, patients treated with ceftriaxone/cefotaxime,
and other patients was 35 out of 716 (5% (3e7%)), 24 out of 198 (12%
(8e18%)) and 119 out of 784 (15% (13e18%)), respectively. Odd ra-
tios (ORs) are reported in Table 2. In comparison with patients
treated with amoxicillineclavulanate, patients treated with a 3GC
and patients treated with other antibacterial regimens had higher
mortality: ORs 2.7 (1.5e4.6) and 3.5 (2.4e5.2), respectively. There
was no significant association between death and treatment with a
macrolide or with a fluoroquinolone. Fluid therapy in the ED, DNR
order in the ED, and PSI classes 4 and 5 were also significantly
associated with mortality. In-hospital mortality was low in centre
#3 (2%, 95%CI 0e8%), whereas it ranged from 7% (95%CI 3e15%) to
15% (95% CI 10e23%) in the other centres. Hence, centres were
dichotomized between this low-mortality centre (coded G2 in the
centre variable, 93 patients) and other centres (coded G1 in the
centre variable, 1605 patients).
Seven explanatory variables were entered in the multivariate
model: the three-level treatment group, PSI class 4 or 5, fluid
therapy in the ED, DNR order in the ED, centre G2, antibacterial
treatment in the preceding 3 months, and treatment with a fluo-
roquinolone. In the final model, treatment with a 3GC was signif-
icantly associated with in-hospital mortality (adjusted OR 2.9
(1.4e5.7)) (Table 3). The Hosmer and Lemeshow goodness-of-fit
test showed no significant difference between observed and
1174 E. Batard et al. / Clinical Microbiology and Infection 24 (2018) 1171e1176

Table 2
Risk factors for mortality in community-onset pneumonia: univariate analysis.

Characteristic Description Survivors Non-survivors OR (95%CI) p

Cases Number 1520 (90%) 178 (10%) e e

Demographic Age (years), median (IQR) 79 (65e86) 85 (79e90) 1.05 (1.03e1.06) <0.001
Male, n (%) 827 (54%) 103 (58%) 1.2 (0.8e1.6) 0.38
Nursing-home resident, n (%) 348 (1485) (23%) 82 (174) (46%) 2.9 (2.1e4.0) <0.001
Comorbid conditions Neoplastic disease, n (%) 220 (14%) 40 (22%) 1.7 (1.2e2.5) 0.005
Liver disease, n (%) 40 (3%) 4 (2%) 0.9 (0.3e2.1) 0.76
Congestive heart failure, n (%) 249 (16%) 33 (19%) 1.2 (0.8e1.7) 0.46
Cerebrovascular disease, n (%) 213 (14%) 38 (21%) 1.7 (1.1e2.4) 0.01
Renal disease, n (%) 125 (8%) 19 (11%) 1.3 (0.8e2.2) 0.27
History of pneumonia, n (%) 221 (15%) 27 (15%) 1.1 (0.7e1.6) 0.82
Immunocompromised, n (%) 170 (11%) 22 (12%) 1.1 (0.7e1.8) 0.64
Physical examination findings Altered mental status, n (%) 308 (1390) (20%) 85 (155) (48%) 3.6 (2.6e5.0) <0.001
Respiratory rate
30/min, n (%) 352 (1266) (23%) 74 (160) (42%) 2.4 (1.7e3.2) <0.001
Systolic blood pressure <90 mmHg, n (%) 55 (1513) (4%) 15 (176) (8%) 2.5 (1.3e4.3) 0.003
Temperature <35 C or
40 C, n (%) 60 (1508) (4%) 6 (174) (3%) 0.8 (0.3e1.8) 0.71
Pulse
125 bpm, n (%) 115 (1514) (8%) 30 (176) (17%) 2.5 (1.6e3.8) <0.001
Laboratory and radiographic Arterial pH <7.35, n (%) 54 (644) (4%) 26 (90) (15%) 4.6 (2.8e7.6) <0.001
findings Blood urea nitrogen
11 mmol/L, n (%) 367 (1462) (24%) 87 (166) (49%) 3.0 (2.2e4.1) <0.001
Sodium <130 mmol/L, n (%) 73 (1501) (5%) 12 (175) (7%) 1.4 (0.7e2.6) 0.26
Glucose
14 mmol/L, n (%) 51 (1408) (3%) 12 (168) (7%) 2.1 (1.0e3.9) 0.027
Haematocrit <30%, n (%) 95 (1506) (6%) 14 (174) (8%) 1.3 (0.7e2.2) 0.41
Partial pressure of arterial oxygen <8 kPA or oxygen 343 (1495) (23%) 51 (177) (29%) 1.4 (1.0e1.9) 0.07
saturation <90%, n (%)
Pleural effusion, n (%) 84 (6%) 13 (7%) 1.3 (0.7e2.4) 0.34
Pneumonia severity index (PSI) Class 1e3, n (%) 580 (38%) 11 (6%) e e
Class 4e5, n (%) 940 (62%) 167 (94%) 9.4 (5.3e18.5) <0.001
Antibiotic before admission Antibacterial treatment in the preceding 3 months, n (%) 150 (10%) 24 (13%) 1.4 (0.9e2.2) 0.13
Antibacterial therapy before arrival in the ED, n (%) 297 (20%) 34 (19%) 1.0 (0.6e1.4) 0.89
Treatment in the ED Fluid therapy, n (%) 149 (10%) 49 (28%) 3.5 (2.4e5.0) <0.001
DNR order, n (%) 70 (5%) 64 (36%) 11.6 (7.9e17.2) <0.001
In-hospital antibacterial therapy Amoxicillineclavulanatea, n (%) 681 (45%) 35 (20%) 0.3 (0.2e0.4)e <0.001
3GCb, n (%) 174 (11%) 24 (13%) 1.2 (0.7e1.9)e 0.42
Other treatmentc, n (%) 665 (44%) 119 (67%) 1.2 (0.7e1.9)e 0.42
Fluoroquinolone, n (%) 305 (20%) 44 (25%) 1.3 (0.9e1.9) 0.15
Macrolide, n (%) 262 (17%) 28 (16%) 0.9 (0.6e1.4) 0.61
Amoxicillineclavulanatea with neither macrolide or 574 (38%) 26 (15%) 0.3 (0.2e0.4) <0.001
fluoroquinolone, n (%)
Amoxicillineclavulanatea with macrolided, n (%) 48 (3%) 0 (0%) e e
Amoxicillineclavulanatea with fluoroquinoloned, n (%) 68 (4%) 9 (5%) 1.1 (0.5e2.2) 0.72
3GCb with neither macrolide nor fluoroquinolone, n (%) 87 (6%) 12 (7%) 1.2 (0.6e2.1) 0.58
3GCb with macrolided, n (%) 54 (4%) 5 (3%) 0.8 (0.3e1.8) 0.61
3GCb with fluoroquinoloned, n (%) 39 (3%) 7 (4%) 1.6 (0.6e3.3) 0.29
Macrolide alone, n (%) 22 (1%) 0 (0%) e e
Fluoroquinolone alone, n (%) 40 (3%) 0 (0%) e e
Blood culture Bacteraemia, n (%) 68 (4%) 10 (6%) 1.3 (0.6e2.4) 0.49
Centre Centre 1, n (%) 99 (7%) 10 (6%) 0.9 (0.4e1.6) 0.65
Centre 2, n (%) 93 (6%) 9 (5%) 0.8 (0.4e1.6) 0.57
Centre 3, n (%) 91 (6%) 2 (1%) 0.2 (0.0e0.6) 0.017
Centre 4, n (%) 117 (8%) 21 (12%) 1.6 (1.0e2.6) 0.06
Centre 5, n (%) 78 (5%) 11 (6%) 1.2 (0.6e2.2) 0.55
Centre 6, n (%) 850 (56%) 106 (60%) 1.2 (0.8e1.6) 0.36
Centre 7, n (%) 102 (7%) 12 (7%) 1.0 (0.5e1.8) 0.99
Centre 8, n (%) 90 (6%) 7 (4%) 0.7 (0.3e1.3) 0.28
Academic status, n (%) 1051 (69%) 128 (72%) 1.1 (0.8e1.6) 0.45

3GC, third-generation cephalosporin (ceftriaxone or cefotaxime); DNR, do not resuscitate; ED, emergency department; OR, odds ratio.
Treatment groups were defined as follows.
a
Amoxicillineclavulanate treatment started in the ED and was administered for at least 5 days without another b-lactam.
b
3GC treatment started in the ED and was administered for at least 5 days without another b-lactam.
c
The ‘other treatment’ group included patients who did not fulfil the classification criteria of the first two groups.
d
Exposure to macrolides and fluoroquinolones was defined by a treatment duration of 1 day or more.
e
OR compared each group to all the other groups. As percentages have been rounded, their sum may not reach 100%. Numbers of patients with available data are reported in
brackets when necessary.

predicted mortality (p 0.99). The area under the ROC curve of the
multivariate model was 0.83 (95%CI 0.80e0.86). Results were un-
changed when treatment with a macrolide or with a fluo-
roquinolone was added to the model. When the exposures to
macrolides and fluoroquinolones were defined by a treatment
duration of 5 days or more, both were retained in the final multi-
variate model (Supplementary file, Table S2). However, the asso-
ciation between treatment with a 3GC and mortality remained
unchanged (adjusted OR 3.2, 1.5e6.5). If the exposure to a 3GC was
defined as a treatment for 1 day or more during the hospital stay, it
remained associated with an increased in-hospital mortality in
multivariate analysis (adjusted OR 1.6 (1.1e2.2)).
Subgroup and sensitivity analyses
Treatment with a 3GC remained associated with a higher in-
hospital mortality when the same model was applied to the PSI
class 5 subgroup of patients (n ¼ 408, aOR 2.5 (1.2e5.4)) or to
 E. Batard et al. / Clinical Microbiology and Infection 24 (2018) 1171e1176 1175

Table 3
Risk factors for mortality in community-onset pneumonia: multivariate analysis.

Characteristic Description Adjusted OR (95%CI) p

Antibacterial therapy Amoxicillineclavulanate e e

i.v. 3GC 2.9 (1.4e5.7) 0.002
Other treatment 4.3 (2.7e7.1) <0.001
Centre Centre G1 e e
Centre G2 0.1 (0.0e0.5) 0.01
Pneumonia severity index (PSI) class Class 1e3 e e
Class 4e5 7.8 (4.3e15.7) <0.001
Treatment in the ED DNR order 8.7 (5.2e14.6) <0.001
Fluid therapy 6.3 (2.5e15.1) <0.001
Interactions Fluid therapy  3GC 0.2 (0.1e0.9) 0.036
Fluid therapy  other treatment 0.3 (0.1e0.9) 0.033
DNR order  fluid therapy 0.4 (0.2e1.0) 0.041

3GC, Third-generation cephalosporin (ceftriaxone or cefotaxime); DNR, do-not-resuscitate; ED, emergency department.
Centres were dichotomized between one low-mortality centre (G2) and the others (G1).
Treatment groups were defined as follows: 3GC, treatment with a 3GC started in the ED and administered for at least 5 days without another b-lactam; amox-
icillineclavulanate, treatment with amoxicillineclavulanate started in the ED and administered for at least 5 days without another b-lactam; the ‘other treatment’ group
included patients who did not fulfil the classification criteria of the first two groups. Hosmer and Lemeshow goodness of fit, p 0.99. Area under the ROC curve, 0.83 (95%CI,
0.80e0.86).

patients who had no DNR order in the ED (n ¼ 1564, aOR 2.3
(1.2e4.5)). Furthermore, results were unchanged when the low-
mortality G2 centre was excluded from analysis (Supplementary
file, Table S3).
Comparison of amoxicillineclavulanate and 3GCs by propensity
score analysis
Eight explanatory variables were included in the model
designed to estimate the probability of being treated with a 3GC:
PSI class 4 or 5 (aOR 1.1 (0.8e1.7)), DNR order in the ED (aOR 1.5
(0.7e2.9)), fluid loading in the ED (aOR 4.3 (2.6-7.0)), antibacterial
therapy in the 3 previous months (aOR 1.8 (1.0-3.1)), antibacterial
therapy started before the arrival in the ED (aOR 3.5 (2.3-5.2)),
immune compromise (aOR 2.9 (1.8-4.7)), non-invasive ventilation
in the ED (aOR 5.7 (1.2-30.7)), and academic status of the centre
(aOR 0.4 (0.3-0.6)). This propensity model allowed matching of 178
patients treated with a 3GC to 178 patients treated with amox-
icillineclavulanate. All of the explanatory variables of the pro-
pensity score model were satisfactorily balanced between the
amoxicillineclavulanate and 3GC groups, as their SMDs ranged
between <0.001 and 0.107. There was no significant relationship
between treatment with cefotaxime/ceftriaxone and in-hospital
mortality in this matched sample of patients (OR 1.5 (0.7e3.0)).
In other words, the risk difference between matched 3GC- and
amoxicillineclavulanate-treated patients was 3.4% (e0.2% to 9.0%).
Discussion
Here, we report the largest series assessing the association be-
tween mortality and treatment with amoxicillineclavulanate or
ceftriaxone/cefotaxime in patients hospitalized in medical wards
for community-onset pneumonia. Our main finding was that the
in-hospital mortality was not lower in patients treated with cef-
triaxone/cefotaxime in comparison with patients treated with
amoxicillineclavulanate, as well in the overall study population as
in the subgroup of most severe patients. Our results are consistent
with those of previous studies that compared ceftriaxone or cefo-
taxime with amoxicillineclavulanate in community-acquired
pneumonia (Supplementary file, Table S4) [22e24].
This study has four limitations. First, this was a retrospective
study. However, there were no missing data for the response var-
iable (i.e., mortality), and few missing data for the explanatory
variables. The latter mainly affected bacteraemiadas blood cultures
were drawn from only 1161 among 1698 patientsdand some
components of the PSI score.
Second, we did not use multiple imputation to complete missing
data. We considered missing data to indicate the absence of
severity, in order to assign a PSI class to each patient. Of note, Fine
and his colleagues, when they derived the PSI score, could not
distinguish missing and normal data [25]. Furthermore, our series
mortality rates (2% for patients of the PSI classes 1e3, and 15% for
patients of the PSI classes 4 and 5) were similar to mortality rates in
the cohort that has been used to derive the PSI score [25]. Hence,
with the exception of the estimated prognostic value of bacter-
aemia, this treatment of missing data probably only slightly biased
our results.
Third, the level of evidence of the observational design is lower
than for an RCT. However, assuming a 10% in-hospital mortality rate
and a 3% non-inferiority margin, a trial aiming to show that
amoxicillineclavulanate is non-inferior to ceftriaxone would
require more than 2000 patients, and is therefore unlikely ever to
be conducted.
Fourth, numerous patients (49%) received at least two antibac-
terial agents during their hospital stay. This may have biased the
comparison of patients treated with 3GC and with amox-
icillineclavulanate. We limited this bias by defining exposures to
3GC and to amoxicillineclavulanate without other b-lactams, and
by adjusting on treatment with a macrolide or a fluoroquinolone.
Hence, there is plausibly no survival benefit with ceftriaxone/
cefotaxime over amoxicillineclavulanate when treating
community-onset pneumonia in medical wards. Ceftriaxone has a
better activity than amoxicillineclavulanate against Gram-negative
bacteria, particularly against Enterobacteriaceae and Haemophilus
influenzae. Conversely, amoxicillineclavulanate may be more
effective in aspiration pneumonia that may be unrecognized in
elderly patients. Further studies are needed, especially conducted
in other cohorts, to compare the clinical efficacy and collateral ef-
fects of ceftriaxone and amoxicillineclavulanate. Of note, our re-
sults were obtained from patients admitted in medical wards, and
should not be extrapolated to patients admitted from the ED to
intensive- and intermediate-care units. Indeed, patients in the
intensive- or intermediate-care unit should be treated with a 3GC
according to European guidelines, although this point has been
debated [1,26].
In conclusion, in a series of 1698 patients hospitalized for
community-onset pneumonia, ceftriaxone/cefotaxime was not
associated with a lower mortality than amoxicillineclavulanate.
1176 E. Batard et al. / Clinical Microbiology and Infection 24 (2018) 1171e1176
Considering that amoxicillineclavulanate may favour resistance to
3GC in Enterobacteriaceae less than 3GCs, it may be advisable to
prefer amoxicillineclavulanate to ceftriaxone/cefotaxime in treat-
ing patients hospitalized in medical wards with community-onset
pneumonia.
Transparency declaration
The authors declare no conflict of interest.
Funding
None.
Acknowledgments
All authors had access to the data. EB and NG are the guarantors
for the data.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.cmi.2018.06.021.
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