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International Journal of Antimicrobial Agents xxx (2015) xxxxxx

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

journal homepage: http://www.elsevier.com/locate/ijantimicag

Review

Fluoroquinolones or macrolides alone versus combined with

-lactams for adults with community-acquired pneumonia:
Systematic review and meta-analysis
Ayelet Raz-Pasteur a,1 , David Shasha b,,1 , Mical Paul b
a
Division of Infectious Diseases and Internal Medicine A, Rambam Health Care Campus, The Ruth and Bruce Rappaport Faculty of Medicine, TensionIsrael
Institute of Technology, 8 Haalya Hashnya St., Haifa, 33705, Israel
b
Division of Infectious Diseases, Rambam Health Care Campus, 8 Haalya Hashnya St., Haifa, 33705, Israel

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

Article history: Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. This review
Received 5 March 2015 compared two of the main treatment alternatives: quinolone or macrolide monotherapy versus their
Accepted 22 April 2015 combination with -lactams. A systematic review and meta-analysis of randomised controlled trials
(RCTs) including adult inpatients and outpatients with CAP that compared treatment with any res-
Keywords: piratory uoroquinolone or macrolide administered as single agent with combination therapy of a
Community-acquired pneumonia
-lactam plus either a uoroquinolone or a macrolide (four separate comparisons) were conducted.
Macrolides
The primary outcome was all-cause 30-day mortality. Secondary outcomes included clinical and micro-
Quinolones
Systematic
biological failure, treatment discontinuation and adverse events. A comprehensive search was conducted
Review with no date, language or publication status restrictions. Pooled risk ratios (RRs) with 95% condence
Meta-analysis intervals are reported. Sixteen RCTs randomising 4809 patients were included. All but one included
hospitalised patients. Mortality was low, and no differences between groups were observed in all com-
parisons. Quinolone monotherapy resulted in signicantly less clinical failures [RR = 0.72 (0.570.91)],
treatment discontinuations [RR = 0.65 (0.540.78)] and diarrhoea [RR = 0.13 (0.050.34)] compared with
-lactam/macrolide combinations (nine trials). Addition of a -lactam to quinolones did not improve
outcomes (three trials). In all comparisons, treatment discontinuation and diarrhoea were more frequent
in patients receiving combination therapy with a -lactam. Overall, there is no evidence for a benet of
-lactam/macrolide or -lactam/quinolone combination therapies over monotherapy with a respiratory
uoroquinolone. The ecological implications of selecting uoroquinolone or -lactam monotherapy as
the preferred regimen for hospitalised CAP among adults should be further investigated.
2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction
Community-acquired pneumonia (CAP) remains a common
cause of morbidity throughout the world despite the availability
of potent new antimicrobials and effective vaccines. The estimated
yearly incidence of CAP is 12 cases per 1000 population. In the
USA, CAP is the sixth leading cause of death and the number one
cause of death from infectious diseases. CAP is a common reason
for antibiotic prescription in the community and in hospitals, affect-
ing resistance ecology in both settings. Thus, antibiotic treatment
Corresponding author. Tel.: +972 4 777 1758; fax: +972 4 777 1620.
E-mail addresses: drdudidu@gmail.com, d shasha@rambam.health.gov.il
(D. Shasha).
1
These two authors contributed equally to this work.
for CAP should target the most effective and efcient antibiotic
regimens.
The American Thoracic Society/Infectious Diseases Society of
America (ATS/IDSA) guidelines for the management of CAP in
adults recommend primarily a macrolide for healthy outpatients
[1]. A respiratory uoroquinolone or a -lactam combined with a
macrolide are recommended as alternatives for outpatients with
co-morbidities and for inpatients. The combination of a -lactam
and a respiratory uoroquinolone is recommended when Pseu-
domonas aeruginosa is a consideration [1]. The British Thoracic
Society (BTS) guidelines recommend amoxicillin or clarithromycin
for outpatients or inpatients with CURB-65 of 01, amoxicillin plus
clarithromycin or a respiratory uoroquinolone for hospitalised
patients with CURB-65 of 2, and for severe CAP, a penicillin plus
a macrolide, a penicillin plus a quinolone or a cephalosporin plus a
macrolide [2].

http://dx.doi.org/10.1016/j.ijantimicag.2015.04.010
0924-8579/ 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Please cite this article in press as: Raz-Pasteur A, et al. Fluoroquinolones or macrolides alone versus combined with -
lactams for adults with community-acquired pneumonia: Systematic review and meta-analysis. Int J Antimicrob Agents (2015),
http://dx.doi.org/10.1016/j.ijantimicag.2015.04.010
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Although all of these alternatives are considered equivalent in

efcacy [3], evidence for the comparison of a respiratory uoro-
quinolone or a macrolide administered as single agents compared
with either combined with a -lactam has not been compiled to
date in a meta-analysis. The outcomes of interest in such a com-
parison are mainly effectiveness, but also adverse events (AEs) and
the ecological impact of adopting a certain policy in the community
and in hospitals. Therefore, a systematic review and meta-analysis
of randomised controlled trials (RCTs) comparing quinolone or
macrolide monotherapy versus quinolones or macrolides com-
bined with a -lactam as treatment for CAP was conducted.

2. Methods

RCTs of adults aged >18 years with CAP, treated in the hospital
[intensive care unit (ICU) and non-ICU] or in the community were
included. CAP was dened as a new inltrate on chest radiography
or computed tomography (CT) and at least one positive nding out
of the following: new onset of a cough; purulent tracheobronchial
secretions; fever; and focal respiratory abnormalities on physical
examination [2].
RCTs that compared any respiratory uoroquinolone or any
macrolide administered as single agent with combination ther-
apy consisting of a respiratory uoroquinolone or macrolide plus
a -lactam were included. Analyses were stratied by compari-
son. Trials in which the uoroquinolone or the macrolide in the
combination arm was optional (permitted according to physicians
discretion) were excluded.
The primary outcome was all-cause mortality at 30 days. If
not reported, all-cause mortality at the end-of-study follow-up
was collected and the length of follow-up was documented. Sec-
ondary outcomes included: clinical failure at end of treatment;
the need for treatment discontinuation; microbiological failure;
mean time to defervescence; duration of hospital stay for hos-
pitalised patients; resistance development expressed as rates of
any clinical superinfections and superinfections caused specically
by bacteria resistant to the study antibiotics; and AEs address-
ing specically diarrhoea [including Clostridium difcile-associated
diarrhoea (CDAD)], nausea/vomiting and dermatological reactions.
The study denitions for clinical and microbiological failure were
accepted. Data were extracted preferentially by intention to treat.
A comprehensive search with no date, language or publica-
tion status restrictions was conducted of PubMed, LILACS and
The Cochrane Library until December 2014 as well as conference
proceedings of the European Congress of Clinical Microbiology
and Infectious Diseases (ECCMID) and Interscience Conference of
Antimicrobial Agents and Chemotherapy (ICAAC) 20092014. In
addition, previous systematic reviews of CAP, all references of
included trials and the National Institutes of Health (NIH) trial reg-
istry were searched. The following search strategy was adapted
for each database: [(community AND pneumonia) OR community-
acquired pneumonia OR (Community-Acquired Infections [MeSH]
AND pneumonia [MeSH])] AND (quinolone OR uoroquinolone OR
macrolide OR -lactam OR individual antibiotic names). In PubMed,
the Cochrane sensitivity- and precision-maximising lter for RCTs
was used [4].
The risk of bias was examined using the individual domain
approach, for all domains recommended in The Cochrane Hand-
book [4]. Assessment was based on the methods described in the
publication, trial registry and correspondence with authors if nec-
essary. We planned to examine the effect of risk of bias on results
through sensitivity analyses, but the paucity of trials under each
comparison limited our ability to do this. Three reviewers indepen-
dently applied inclusion/exclusion criteria and extracted all data
from all trials. Differences were resolved by discussion. Authors
Fig. 1. Flow diagram of the selection of studies for inclusion in the meta-analysis.
were contacted for missing data regarding the primary outcome
and risk of bias.
Risk ratios (RRs) were calculated for individual trials, with 95%
condence intervals (CIs), and a meta-analysis was performed
using the xed-effect model. A RR > 1 favours combination ther-
apy. The CIs for mortality in one cluster-randomised trial were
adjusted to clustering using a reported design effect of 1.18 [5], as
recommended in The Cochrane Handbook [4]. Heterogeneity was
examined visually and statistically using the 2 test (P < 0.1) and
the I2 test (I2 > 50% dening signicant inconsistency). To address
heterogeneity, we dened a priori subgroup analyses of pneumo-
coccal CAP, severe CAP (treated in ICU or CURB-65 > 2) and patients
with bacteraemia. However, data allowed only the rst. Analyses
were performed using RevMan 5.3 (The Nordic Cochrane Centre,
Copenhagen, Denmark).
3. Results
The search resulted in 563 publications, of which 530 were non-
randomised. Twelve RCTs were excluded because the macrolide
was optional, and one was excluded because the -lactam agent
was optional. After further excluding duplicate publications (Fig. 1),
16 RCTs fullling the inclusion criteria were included [520] Two
were published only as conference proceedings and contact with
the authors could not be established [6,13].
The trials included a total of 4809 patients with a mean or
median age between 37 and 72 years (Table 1). A single trial
included outpatients that were recruited in the emergency room
[7], and the remainder included inpatients. Hospitalised patients
had moderate-to-severe pneumonia; one study included only
patients with mild pneumonia [19], and in four studies pneumo-
nia severity was not described [6,13,15,20]. Low risk of bias was
described for allocation generation and concealment in four tri-
als [5,11,14,18], and four further trials only addressed allocation

Please cite this article in press as: Raz-Pasteur A, et al. Fluoroquinolones or macrolides alone versus combined with -
lactams for adults with community-acquired pneumonia: Systematic review and meta-analysis. Int J Antimicrob Agents (2015),
http://dx.doi.org/10.1016/j.ijantimicag.2015.04.010
 ANTAGE-4589; No. of Pages 7
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http://dx.doi.org/10.1016/j.ijantimicag.2015.04.010
lactams for adults with community-acquired pneumonia: Systematic review and meta-analysis. Int J Antimicrob Agents (2015),
Please cite this article in press as: Raz-Pasteur A, et al. Fluoroquinolones or macrolides alone versus combined with -

Table 1
Study characteristics.

Study Monotherapy Combination therapy Blinding Allocation No. randomised Age (years) (mean S.D.) Location Study year
generation/ [monother- [monother- end
concealmenta apy/combination] apy/combination]

Etemadi et al. (2011) [6] i.v. azithromycin i.v. ceftriaxone 2 g b.i.d. + p.o. Probably B/B 32/31 NS Iran NS
500 mg OD clarithromycin 500 mg b.i.d. open
Fogarty et al. (2004) [18] i.v. levooxacin i.v./i.m. ceftriaxone 12 g Open A/A 134/135 61.6 16.59/59.8 18.1 USA 2000
500 mg OD OD + i.v. erythromycin
5001000 mg QID
Frank et al. (2002) [7] i.v./p.o. i.v. ceftriaxone 1 g OD + i.v. Open A/B 115/121 67.8 13.11/67.3 13.17 USA 1999

A. Raz-Pasteur et al. / International Journal of Antimicrobial Agents xxx (2015) xxxxxx

levooxacin azithromycin 500 mg OD
500 mg OD
Lee et al. (2012) [8] i.v. levooxacin i.v. ceftriaxone 2 g OD + p.o. Open A/B 20/20 54.0 20.0/53.0 16.0 South Korea 2011
750 mg OD azithromycin 500 mg OD

ARTICLE IN PRESS
Leroy et al. (2005) [9] i.v. levooxacin i.v. cefotaxime 1 g t.i.d. + i.v. Open B/B 196/202 59.8 17.4/59.5 16.2 France, Tunisia, 2002
500 mg b.i.d. ooxacin 200 mg b.i.d. South Africa
Lin et al. (2007) [10] i.v. levooxacin i.v. amoxicillin/clavulanic acid Open A/B 26/24 65.3 13.2/71.0 11.4 Taiwan 2006
750 mg OD 500/1000 mg OD + p.o.
clarithromycin 500 mg b.i.d.
Portier et al., 1996 [12] p.o. sparoxacin p.o. amoxicillin 1 g DB B/B 110/103 60.0 2.0 France 1993
400 mg OD t.i.d. + ooxacin 200 mg b.i.d.
Portier et al. (2005) [11] p.o. moxioxacin p.o. amoxicillin/clavulanic acid Open A/A 174/175 59.3 17.9/62.4 18.0 France 2002
400 mg OD 1000/125 mg t.i.d. + p.o.
roxithromycin 150 mg b.i.d.
Postma et al. (2015) [5] i.v. moxioxacin i.v. penicillin, amoxicillin, Open A/A 888/739 Median (IQR): 71 The 2013
400 mg OD or amoxicillin/clavulanic acid or a (5979)/70 (5980) Netherlands
levooxacin third-generation
500 mg OD cephalosporin + p.o.
azithromycin, i.v. erythromycin
or p.o. clarithromycin
Ramirez and File (2003) [13] i.v. levooxacin i.v. ceftriaxone + p.o. Probably B/B 37/36 NS NS NS
clarithromycin DBb
Rovira et al. (1999) [19] p.o. clarithromycin p.o. cefuroxime 500 mg Open B/B 45/45 37.0 14.0/38.0 15.0 Spain 1997
500 mg OD b.i.d. + p.o. clarithromycin
500 mg OD
Torres et al. (2008) [14] i.v. moxioxacin i.v. ceftriaxone 2 g OD + i.v. DB A/A 271/367 66.0 16.2/64.8 16.7 Europe, Latin 2005
400 mg OD levooxacin 500 mg OD America, South
Africa
Vetter et al. (1997) [20] i.v. clarithromycin i.v. cefuroxime 1.5 g t.i.d. + i.v. Open B/B 118/117 60.0 2.0 Europe, Canada NS
500 mg OD erythromycin 1 g t.i.d.
Vergis et al. (2000) [15] i.v. azithromycin i.v. cefuroxime 750 mg Open A/B 83/86 NS USA 1996
500 mg OD t.i.d. + i.v./p.o. erythromycin
5001000 mg q.i.d.
Xu et al. (2006) [16] i.v. moxioxacin i.v. cefoperazone 2 g OD + p.o. Open B/B 20/20 NS China NS
400 mg OD azithromycin 500 mg OD
Zevros et al. (2004) [17] i.v. levooxacin i.v. ceftriaxone 1 g OD + p.o. Open B/B 107/112 72.84/70.73
USA, Europe, 2002
500 mg OD azithromycin 500 mg OD Canada

S.D., standard deviation; i.v., intravenous; OD, once daily; b.i.d., twice daily; p.o., oral; NS, not specied; t.i.d., three times daily; DB, double-blind; IQR, interquartile range; q.i.d., four times daily.
a
A = adequate; B = not specied.
b
Placebo mentioned with no further description of blinding methods.

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Table 2
Meta-analysis results.

No. of trials No. of patients RR (95% CI)a Inconsistency (I2 ) (%)

Quinolones versus -lactam/macrolide

All-cause mortalityb 5 2683 0.99 (0.701.40) 0
Clinical failureb 9 2441 0.72 (0.570.91) 0
Clinical failuresubgroup pneumococcal pneumonia 7 145 2.03 (0.944.38) 22
Treatment discontinuationb 6 2179 0.65 (0.540.78) 0
Microbiological failure 7 359 0.93 (0.631.38) 0
Any adverse eventsb 7 2727 0.90 (0.811.00) 0
Diarrhoea 3 617 0.13 (0.050.34) 52

Quinolones versus -lactam/quinolone

All-cause mortality 2 1116 1.00 (0.691.45) 42
Clinical failure 3 1252 1.11 (0.891.38) 23
Clinical failuresubgroup pneumococcal pneumonia 3 261 0.92 (0.531.59) 0
Treatment discontinuation Not reported
Microbiological failure 3 255 1.15 (0.711.86) 0
Any adverse events 3 1339 1.02 (0.91.14) 60
Diarrhoea 1 733 2.05 (1.133.73) Not relevant

Macrolides versus -lactam/macrolide

All-cause mortality 3 467 1.00 (0.402.46) 0
Clinical failure 4 557 0.92 (0.671.26) 36
Clinical failuresubgroup pneumococcal pneumonia 2 59 0.49 (0.102.48) 52
Treatment discontinuation 1 235 0.85 (0.531.38) Not relevant
Microbiological failure 2 117 0.88 (0.431.81) 65
Any adverse events 3 470 0.62 (0.50.78) 83
Diarrhoeac 2 325 0.47 (0.221.01) 79

RR, risk ratio; CI, condence interval.

a
RR < 1 favours monotherapy.
b
In the cluster randomised controlled trial, 30-day all-cause mortality rates were obtained from the study authors; clinical failure was derived from antibiotic modications
related to perceived failure; treatment discontinuations were derived from all discontinuations except for pathogen-directed streamlining; and adverse events were computed
from the list of all complications reported in the articles supplement [5].
c
Difference caused by a trial showing a signicantly higher rate of diarrhoea with intravenous cefuroxime and erythromycin compared with clarithromycin monotherapy.

concealment [7,8,10,15]. Three were double-blind [1214]. One
was a cluster-randomised, crossover trial comparing treatment
strategies assigned to hospitals in dened study periods as the unit
of randomisation [5]. Trial methods were not described in the other
trials.
The trials compared quinolone monotherapy versus -lactam/
macrolide combinations (nine trials) [5,7,8,10,11,13,1618],
quinolone monotherapy versus -lactam/quinolone combina-
tions (three trials) [9,12,14] and macrolide monotherapy versus
-lactam/macrolide combinations (four trials) [6,15,19,20]. The
specic antibiotic comparisons are detailed in Table 1. There were
no trials comparing macrolide monotherapy versus -lactam/
quinolones. Antibiotic treatment was given for 714 days and
follow-up ranged between 3 and 6 weeks. The results are provided
in Table 2 and are summarised below.
3.1. Quinolone versus -lactam/macrolide
No difference in mortality was observed, without hetero-
geneity and large CIs (RR = 0.99, 95% CI 0.701.40; ve trials)
[5,7,11,17,18], with an overall mortality in these trials of 5.1%
(137/2683 patients). Clinical failure (RR = 0.72, 95% CI 0.570.91;
nine trials, 2441 patients; Fig. 2) [5,7,8,10,11,13,1618] and treat-
ment discontinuation (RR = 0.65, 95% CI 0.540.78; six trials, 2179
patients) [5,7,8,10,11,18] were signicantly less common with
quinolone monotherapy, without heterogeneity. In the subgroup
of patients with pneumococcal pneumonia, the opposite direc-
tion was observed, with failure rates higher in the quinolone
monotherapy arm without statistical signicance (RR = 2.03, 95%
CI 0.944.38; seven trials, 145 patients) [7,8,10,11,1618]. Treat-
ment discontinuations were in part related to AEs, as these were
less common with quinolones (mainly diarrhoea, RR = 0.13, 95%
CI 0.050.34, reported in three trials using roxithromycin [11] or
azithromycin [7,8] as the macrolide). The microbiological failure
rate was similar.
3.2. Quinolone versus -lactam/quinolone
No signicant differences were observed with regard to all out-
comes, based on a small number of patients. Two trials reported on
mortality (RR = 1.00, 95% 0.691.45) [9,14], with an overall mortal-
ity in these studies of 8.7% (97/1116 patients), and all three reported
on clinical failure (RR = 1.11, 95% CI 0.891.38; 1252 patients;
Fig. 2) [9,12,14]. There was a signicantly higher risk of diarrhoea
with the addition of the -lactam in one trial (RR = 2.05, 95% CI
1.133.73) [14], with no signicant difference in overall discontin-
uations due to AEs (RR = 1.37, 95% CI 0.872.16). No discontinuation
was reported.
3.3. Macrolide versus -lactam/macrolide
Mortality was low in these trials, one of which included out-
patients (overall 18/467 deaths; 3.9%) [19], and there was no
difference between arms with large CIs (RR = 1.00, 95% CI 0.402.46;
three trials) [6,15,20]. No signicant differences were observed
in clinical failure reported in all trials (Fig. 2) or other efcacy
outcomes. In one trial comparing clarithromycin with cefuroxime
and erythromycin [20], diarrhoea, nausea/vomiting, and discon-
tinuations due to AEs were signicantly more common in the
combination arm.
In all trials, data on resistance development were not provided.
Hospitalisation duration was reported in a single trial of inpatients
[17], with another two reporting on ICU stay or length of stay
related to CAP [9,13]. The time to defervescence was not reported.
CDAD was reported in two trials (964 patients), with two events
reported both in the -lactam arm [7,14].
4. Discussion
In the current review, the question was addressed of whether
the use of a respiratory uoroquinolone alone or a macrolide

Please cite this article in press as: Raz-Pasteur A, et al. Fluoroquinolones or macrolides alone versus combined with -
lactams for adults with community-acquired pneumonia: Systematic review and meta-analysis. Int J Antimicrob Agents (2015),
http://dx.doi.org/10.1016/j.ijantimicag.2015.04.010
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Fig. 2. Clinical failure for quinolone or macrolide monotherapy versus their combination with a -lactam (BL). A xed-effect MantelHaenszel (MH) meta-analysis is shown
with results presented as risk ratios with 95% condence intervals (CIs).

alone, both providing adequate antimicrobial coverage against
the pathogens causing CAP, are as effective as double-covering
regimens consisting of a -lactam combined with each. Few
trials addressed each comparison (none comparing macrolide
monotherapy versus -lactams/quinolones), and nearly all focused
on hospitalised patients with CAP. Mortality was low in the
trials and no differences were observed for all comparisons.
Quinolone monotherapy resulted in signicantly less treatment
failure (RR = 0.72, 95% CI 0.570.91) than -lactam/macrolide com-
bination regimens. The corresponding numbers needed to treat
(NNT) with a quinolone to prevent one treatment failure was 28
patients (95% CI 1889), with a control event rate (CER) of 12.4%.
Treatment failure was dened most commonly as a composite of
no cure at end of treatment, need for treatment modication due to
clinical failure, or death related to infection. Quinolone monother-
apy also resulted in less need for any treatment discontinuation
(RR = 0.65, 95% CI 0.540.78; NNT = 9, 95% CI 1320; CER = 21.8%)
and less diarrhoea. Addition of a -lactam to either a quinolone or
a macrolide resulted in signicantly higher rates of diarrhoea with
no difference in clinical outcomes, with large CIs due to the paucity
of trials.
Several previous systematic reviews and meta-analyses com-
pared treatment regimens for CAP. Vardakas et al. investigated
whether respiratory quinolone monotherapy was superior to
-lactams, macrolides or -lactam/macrolide combinations, the
latter pooled together (23 trials) [21]. Clinical success rates
were signicantly higher and AEs signicantly fewer with uoro-
quinolone monotherapy, with no signicant difference in mortality.
We previously compared macrolides versus quinolones, both
given either as monotherapy or in combination therapy regimens,
similarly documenting an advantage to quinolones with regard
to clinical failure and gastrointestinal AEs, but no difference in
mortality [22]. In a systematic review including both RCTs and
observational studies (analysis dominated by the observational
data), there was no difference in mortality between respira-
tory uoroquinolone monotherapy versus -lactam/macrolide
combinations (RR = 1.17, 95% CI 0.911.50, with RR > 1 favour-
ing the quinolone arm; 16 studies, 12,624 patients) [23]. The
results are similar to ours showing similar 30-day mortality with
quinolones versus -lactam/macrolide combinations (RR = 0.99,
95% CI 0.701.40; ve trials, 2683 patients) [5,7,11,17,18]. These
analyses point at a potential advantage of respiratory uoro-
quinolones with regard to tolerability and the pace of pneumonia
resolution, but ultimately no difference in mortality.
The main limitation of this analysis and previous analyses
is the paucity of randomised data overall, considering that the
questions addressed are basic in the management of CAP. No
RCTs conducted among adults with CAP in the community were
identied. The main comparisons of interest were addressed in
three (quinolones versus -lactam/quinolones), four (macrolides
versus -lactam/macrolides) and nine (quinolones versus -
lactam/macrolides) RCTs. The paucity of trials and patients did not
allow an analysis of subgroups of interest, mainly patients with
severe pneumonia. Neither individual trials nor their compilation
have ever shown an effect of antibiotic choice on mortality in CAP.
The outcome of clinical success or failure, for which there are differ-
ences between antibiotic regimens, is ill dened in most trials. It is a
composite of different non-validated endpoints and its signicance
for the individual patient is unclear. Trials do not report consistently
on the time to clinical stability, duration of hospital stay, time to

Please cite this article in press as: Raz-Pasteur A, et al. Fluoroquinolones or macrolides alone versus combined with -
lactams for adults with community-acquired pneumonia: Systematic review and meta-analysis. Int J Antimicrob Agents (2015),
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resumption of routine activities, and other patient-relevant data.
Our analyses of AEs are heterogeneous, probably because of the mix
of specic antibiotics in the comparisons and the heterogeneity in
AE denitions in the individual trials.
Given these limitations in the available evidence, we can cau-
tiously conclude from the analysis presented that monotherapy
with respiratory uoroquinolones is as least as effective and safe
as combination therapy and there are no data showing an advan-
tage for combination regimens. An alternative option to quinolone
monotherapy, not examined in the current systematic review, is
that of -lactam monotherapy. Two recent RCTs [5,24] add signif-
icant weight to the evidence previously compiled in a systematic
review showing that -lactams alone may be as effective as respira-
tory uoroquinolones or combination regimens in the management
of CAP [25]. The two RCTs established that all-cause mortality
is similar with -lactam monotherapy and -lactam/macrolide
combination therapy overall. In one trial, patients with atypical
pathogens (mainly Legionella) and those with severe pneumo-
nia had delayed clinical stability with -lactam monotherapy
[24]. Thus, evidence points towards the safety of either -lactam
monotherapy (supplemented by rapid testing and directed treat-
ment for Legionella) or respiratory uoroquinolone monotherapy,
thus avoiding the need for combination treatment regimens. The
ecological impact of the treatment regimens was not assessed in
the RCTs. Widespread use of respiratory quinolones might have a
negative ecological impact both in hospitals and in the commu-
nity, especially in the reality of over-prescription of antibiotics
for viral upper respiratory tract infections [26]. Increasing rates
of quinolone resistance, as well as resistance to other antibiotic
classes, have been observed with the rising use of quinolones
during the last two decades. Studies report signicant reduc-
tions in quinolone resistance after implementation of programmes
to reduce quinolone use [27] and an almost absence of uoro-
quinolone resistance among children in whom quinolone use is
rare. On the other hand, several studies have demonstrated no cor-
relation between increased use of respiratory uoroquinolones (as
opposed to ciprooxacin) and quinolone resistance [28,29], proba-
bly as the result of a better pharmacokinetic and pharmacodynamic
prole that might slow the selection of resistant mutants [29].
Local epidemiological considerations and the availability of rapid
testing for Legionella might direct the decision to select -lactam
monotherapy or respiratory uoroquinolones as the chosen regi-
men for the treatment of hospitalised CAP patients.
In conclusion, we summarise that monotherapy with res-
piratory uoroquinolones is as safe and efcacious as -
lactam/macrolide combination therapy and results in fewer treat-
ment modications. Addition of a -lactam to the uoroquinolone
does not confer further benet in the treatment of hospitalised CAP
among adults. Data are not available to direct the management of
patients with CAP in the community and severe CAP in the ICU. Fur-
ther studies should examine the ecological implications of selecting
a policy of -lactam monotherapy versus that of a respiratory u-
oroquinolone in the management of CAP in hospitals.
Funding
None.
Competing interests
None declared.
Ethical approval
Not required.
Please cite this article in press as: Raz-Pasteur A, et al. Fluoroquinolones or macrolides alone versus combined with -
lactams for adults with community-acquired pneumonia: Systematic review and meta-analysis. Int J Antimicrob Agents (2015),
http://dx.doi.org/10.1016/j.ijantimicag.2015.04.010
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Please cite this article in press as: Raz-Pasteur A, et al. Fluoroquinolones or macrolides alone versus combined with -
lactams for adults with community-acquired pneumonia: Systematic review and meta-analysis. Int J Antimicrob Agents (2015),
http://dx.doi.org/10.1016/j.ijantimicag.2015.04.010