&get_box_var;

ORIGINAL ARTICLE

The Effect of Macrolide Resistance on the Presentation and Outcome

of Patients Hospitalized for Streptococcus pneumoniae Pneumonia
Catia Cilloniz1, Richard K. Albert2,3, Adamanthia Liapikou4, Albert Gabarrus1, Ernesto Rangel5, Salvador Bello6,
Francesc Marco7, Josep Mensa8, and Antoni Torres1
1
Department of Pneumology, Institut Clinic del Torax, Hospital Clinic of BarcelonaInstitut dInvestigacions Biomediques August Pi i
Sunyer, University of Barcelona, Ciber de Enfermedades Respiratorias, Barcelona, Spain; 2Department of Medicine, Denver Health,
Denver, Colorado; 3University of Colorado, Aurora, Colorado; 4Respiratory Department, Sotiria Chest Diseases Hospital, Athens,
Greece; 5Facultad de Medicina, Universidad Autonoma de Nayarit, Tepic Nayarit, Mexico; 6Servicio de Neumologia, Hospital
Universitario Miguel Servet, Zaragoza, Spain; and 7Department of Microbiology and 8Department of Infectious Disease, Hospital Clinic of
Barcelona, Barcelona, Spain

Abstract Patients with macrolide-resistant organisms were less likely to have

Rationale: There are conicting reports describing the effect of
macrolide resistance on the presentation and outcomes of patients
with Streptococcus pneumoniae pneumonia.
Objectives: We aimed to determine the effect of macrolide
resistance on the presentation and outcomes of patients with
pneumococcal pneumonia.
Methods: We conducted a retrospective, observational study in
the Hospital Clinic of Barcelona of all adult patients hospitalized
with pneumonia who had positive cultures for S. pneumoniae from
January 1, 2000 to December 31, 2013. Outcomes examined included
bacteremia, pulmonary complications, acute renal failure, shock,
intensive care unit admission, need for mechanical ventilation, length
of hospital stay, and 30-day mortality.
Measurements and Main Results: Of 643 patients hospitalized
for S. pneumoniae pneumonia, 139 (22%) were macrolide resistant.
bacteremia, pulmonary complications, and shock, and were less likely
to require noninvasive mechanical ventilation. We found no increase
in the incidence of acute renal failure, the frequency of intensive
care unit admission, the need for invasive ventilatory support,
the length of hospital stay, or the 30-day mortality in patients
with (invasive or noninvasive) macrolide-resistant S. pneumoniae
pneumonia, and no effect on outcomes as a function of whether
treatment regimens did or did not comply with current guidelines.
Conclusions: We found no evidence suggesting that patients
hospitalized for macrolide-resistant S. pneumoniae pneumonia were
more severely ill on presentation or had worse clinical outcomes if
they were treated with guideline-compliant versus noncompliant
regimens.
Keywords: community-acquired pneumonia; Streptococcus
pneumoniae resistant to macrolide; pneumonia; pneumococcal
pneumonia

Streptococcus pneumoniae is identied
in 2060% of patients requiring
hospitalization for community-acquired
pneumonia (CAP), making it the leading
cause of CAP (13), and in 5.549%
of patients hospitalized for healthcare-
associated pneumonia (HCAP) (1, 4,
5). The mortality of patients with
S. pneumoniae pneumonia ranges from
6.4% in outpatients and in hospitalized
patients who do not require treatment in
an intensive care unit (ICU) to more than
35% in those requiring treatment in the
ICU (6).
Current Infectious Disease Society of
America/American Thoracic Society
(IDSA/ATS) guidelines recommend
a macrolide antibiotic (azithromycin,

( Received in original form February 2, 2015; accepted in final form March 25, 2015 )
Supported by Ciber de Enfermedades Respiratorias (CibeRes CB06/06/0028), 2009 Support to Research Groups of Catalonia 911, and Institut
dInvestigacions Biomediques August Pi i Sunyer.
Author Contributions: A.T. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data
analysis. Study concept and design, A.T., R.K.A., and C.C. Acquisition of data, C.C., A.L., and E.R. Analysis and interpretation of data, C.C., R.K.A., F.M.,
S.B., J.M., and A.T. Drafting of the manuscript, A.T., R.K.A., and C.C. Critical revision of the manuscript for important intellectual content, A.T., C.C., and
R.K.A. Statistical analysis, A.G. Study supervision, A.T., R.K.A., and C.C.
Correspondence and requests for reprints should be addressed to Antoni Torres, M.D., Ph.D., Department of Pneumology, Hospital Clinic of Barcelona,
Barcelona, Spain. E-mail: atorres@clinic.ub.es
This article has an online supplement, which is accessible from this issues table of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 191, Iss 11, pp 12651272, Jun 1, 2015
Copyright 2015 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201502-0212OC on March 25, 2015
Internet address: www.atsjournals.org

Cilloniz, Albert, Liapikou, et al.: Macrolide-Resistance Streptococcus pneumoniae Pneumonia 1265


At a Glance Commentary
Scientic Knowledge on the
Subject: There are conicting reports
describing the effect of macrolide
resistance on the presentation
and outcomes of patients with
Streptococcus pneumoniae pneumonia.
What This Study Adds to the
Field: Although the prevalence
of in vitro resistance to macrolide
antibiotics is increasing, we found
no evidence this resistance worsened
outcomes in patients hospitalized for
S. pneumoniae pneumonia.
clarithromycin, or erythromycin) as
rst-line therapy for previously healthy
patients who have no risk factors for
drug-resistant S. pneumoniae infection
(strong recommendation; level I
evidence) and a combination of
a macrolide and a b-lactam for patients
who require hospitalization but not in
the ICU. In patients with CAP who
require ICU admission the guideline
recommends using a combination
of a b-lactam plus macrolide or
a uoroquinolone (5).
The prevalence of macrolide
resistance in S. pneumoniae is increasing
with recent rates ranging from 18 to 35%
(711). Although some studies link
macrolide resistance with treatment
failure in community-acquired
respiratory tract infections (1214), the
effect of having macrolide-resistant
S. pneumoniae on clinical outcomes of
patients with pneumonia has not been
clearly established. We performed
a retrospective observational study of
prospectively collected data to examine
the effect of macrolide resistance on
the outcomes of patients who were
hospitalized for pneumonia caused by
S. pneumoniae.
Methods
Ethics Statement
The study was approved by the Ethics
Committee of the Hospital Clinic of
Barcelona (Barcelona, Spain; Register: 2009/
5451). Written informed consent was waived
because of the noninterventional design.
1266 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 | June 1 2015
Study Design and Patients
This was a retrospective observational
study of data that were prospectively
collected in the Hospital Clinic of
Barcelona. Subjects included all adults
admitted with S. pneumoniae pneumonia
from January 1, 2000 to December 31,
2013, including those coming from
nursing homes.
Pneumonia was dened as the
presence of a new inltrate on a chest
radiograph together with clinical
symptoms that were suggestive of lower
respiratory tract infection (e.g., fever,
cough, sputum production, pleuritic chest
pain). We excluded patients who were
receiving an immunosuppressant, those
taking more than 10 mg/day of prednisone,
or cytotoxic therapy, and all patients
known to have human immunodeciency
virus infection.
Data Collection and Evaluation
At the time of hospital admission we
recorded the patients age, sex, smoking
history, alcohol use, illicit drug
consumption, comorbidities, antibiotic
treatment in the previous 30 days before
hospital admission, whether they
were receiving inhaled or systemic
corticosteroids, clinical symptoms and
signs, arterial blood gases, chest
radiograph ndings, a variety of
laboratory tests, the results of diagnostic
procedures (see later), the pneumonia
severity index and CURB-65 score
(consciousness, urea, respiratory rate,
blood pressure, 65 year old) (15, 16), and
the initial antibiotic therapy.
Over the course of their
hospitalization we recorded the length of
hospital stay and the 30-day in-hospital
mortality, and whether the patients
required noninvasive and/or invasive
ventilatory support, had any pulmonary
complications, dened as multilobar
inltration, pleural effusions, or
meeting criteria for the acute respiratory
distress syndrome (17), or developed
septic shock or acute renal failure.
Microbiologic Evaluation and
Diagnostic Criteria
All patients had microbiologic
examination of expectorated sputum,
urine, two samples of blood, and
nasopharyngeal swabs. Those who
underwent a thoracentesis, intubation,
or bronchoscopy also had microbiologic
ORIGINAL ARTICLE
examination of the pleural uid,
tracheobronchial aspirates, and/or
bronchoalveolar lavage. Sputum and
blood samples were obtained in the
emergency department for bacterial
culture before starting antibiotic therapy.
Nasopharyngeal swabs were processed for
respiratory virus detection. Urine was
sent for S. pneumoniae and Legionella
pneumophila antigen assessment within
24 hours after hospital admission.
Sputum testing included Gram and
Ziehl-Neelsen staining and culturing for
bacterial, fungal, and mycobacterial
pathogens. Blood samples for serology
of atypical pathogens and respiratory
viruses were collected at admission
and between the third and sixth week
thereafter.
For the purpose of this study patients
were considered to have S. pneumoniae
pneumonia if S. pneumoniae was
cultured from the blood, pleural uid,
tracheobronchial aspirates (at >105 CFU/
ml) or bronchoalveolar lavage (at >104
CFU/ml), or from sputum using standard
microbiologic methods.
Strains were initially screened for
antimicrobial susceptibility by Sensititre
(Trek Diagnostic Systems Ltd., West Sussex,
UK). Penicillin and other antibiotic
susceptibility were dened according to the
2012 break points by the Clinical Laboratory
Standards Institute. For S. pneumoniae
isolates, minimum inhibitory
concentrations (MICs) were determined
using the Sensititre for penicillin,
cefotaxime, ceftriaxone, cefepime,
imipenem, meropenem, erythromycin,
clindamycin, levooxacin, and vancomycin.
Results were interpreted according to the
2012 Clinical and Laboratory Standards
Institute criteria (performance standards
for antimicrobial susceptibility testing,
22nd informational supplement, M100-S22;
Clinical and Laboratory Standards Institute,
Wayne, PA). All isolates were tested
for antimicrobial susceptibilities using
Clinical and Laboratory Standards
Institute microdilution methods.
Macrolide-susceptible S. pneumoniae was
dened as an isolate with an erythromycin
MIC less than or equal to 0.5 mg/L,
intermediate resistance was dened as an
erythromycin MIC of 1 mg/L, and
resistance erythromycin was dened as an
erythromycin MIC greater than or equal to
2 mg/L. S. pneumoniae was considered to
be macrolide resistant when MICs were
ORIGINAL ARTICLE
5878 screened patients with CAP
643 patients analyzed
Macrolide-sensitive S. pneumoniae
504 patients (78.4%)
331 (65.6%) invasive cases
(empyema + bacteremia)
Figure 1. Flow diagram of the selected population. CAP = community-acquired pneumonia.
greater than or equal to 1 mg/L
(i.e., intermediate resistance or resistant).
Data on macrolide-resistant specimens
include those that showed resistance and
those showing intermediate resistance.
Appropriateness of empiric antibiotic
treatment was dened according to IDSA/
ATS guidelines for management of CAP and
HCAP (5, 18).
Statistical Analysis
We report the mean and SD for continuous
variables with normal distribution and
the median (rst quartilethird quartile)
for those with nonnormal distribution
and compared them using the t test or
the nonparametric Mann-Whitney test,
respectively. Categorical variables are
presented as number of patients
(percentage) and were compared using the
chi-square test or Fisher exact test. All
reported P values are two sided and not
Table 1. Results of Microbiologic Testing
Macrolide Sensitive
Specimen Isolates (n = 643)
Blood, n (%) 356 (55)
Sputum, n (%) 264 (41)
TBAS or BAL, n (%) 51 (8)
Pleural uid, n (%) 34 (5)
Definition of abbreviations: BAL = bronchoalveolar lavage; TBAS = tracheobronchial aspirate.
Cilloniz, Albert, Liapikou, et al.: Macrolide-Resistance Streptococcus pneumoniae Pneumonia
Excluded (n=5235):
Microbiological culture
negative for antibiogram
Macrolide-resistant S. pneumoniae
139 (21.6%)
67 (48.2%) invasive cases
(empyema + bacteremia)
adjusted for multiple comparisons. A
P value less than 0.05 was considered
signicant. All analyses were performed
with IBM SPSS Statistics for Windows,
Version 20.0 (IBM Corp., Armonk, NY).
Results
Demographic and Clinical Variables
on Presentation
During the study period 5,878 patients
were hospitalized with a diagnosis of
CAP. Of these, 643 had one or more
microbiologic studies that were positive for
S. pneumoniae and 139 (22%) of these
were macrolide resistant (Figure 1,
Table 1). Their demographics and clinical
characteristics are presented in Table 2.
Because only 12 (1.8%) patients had
intermediate resistance to macrolides their
results were pooled with the 127 who had
high level of resistance.
Macrolide Resistant
(n = 504; 78%) (n = 139; 22%)
294 (58) 62 (45)
197 (39) 67 (48)
38 (8) 13 (9)
26 (5) 8 (6)
Outcomes
By univariate analysis patients with
macrolide-resistant S. pneumoniae
pneumonia were more likely to have received
antibiotics within the previous 30 days and
more likely to have chronic obstructive
pulmonary disease. Patients with macrolide-
resistant disease were less likely to have fever,
bacteremia, pulmonary complications, or
shock (Table 3) and were also less likely to
require noninvasive ventilation (although the
number of patients receiving noninvasive
ventilation was too small for a meaningful
comparison). We found no suggestion
that patients with macrolide-resistant
S. pneumoniae pneumonia presented with
more severe disease or had worse clinical
outcomes regardless of whether we did or did
not exclude patients who died within the rst
3 days of admission (Table 4) or if we restricted
the analysis exclusively to patients with invasive
disease (i.e., bacteremia and/or empyema)
(see Table E1 in the online supplement).
Outcomes Related to Antibiotic
Treatment
Surprisingly, 129 patients (20%) were
treated with a single antibiotic, a regimen
that would be inconsistent with IDSA/ATS
guidelines for treating hospitalized patients
with either CAP or HCAP (Table 5).
Despite this, we found no suggestion that
patients receiving treatment that was
inconsistent with these guidelines had
worse clinical outcomes (Table 6).
Outcomes of Patients with Macrolide-
Resistant S. pneumoniae Pneumonia
Who Received Combination Therapy
That Did or Did Not Include
a Macrolide
Of the 104 patients with macrolide-resistant
S. pneumoniae pneumonia, 71 (68%)
received a dual antibiotic regimen that
included a macrolide and 33 (32%) did not.
Despite their regimen containing only one
antibiotic to which their organism was
resistant, we found no difference in the
outcomes of patients with macrolide-resistant
versus macrolide-sensitive S. pneumoniae
pneumonia (Table 7), with the exception that
the frequency of ICU admission was higher in
patients receiving dual therapy that did not
include a macrolide.
Discussion
The important ndings of this study are that
we could nd no evidence of more severe
1267
 ORIGINAL ARTICLE

Table 2. Demographics and Clinical Characteristics on Admission

Macrolide Sensitive (n = 504) Macrolide Resistant (n = 139) P Value

Age, yr, mean 6 SD 63 6 18 67 6 18 0.005

Male, sex, n (%) 330 (66) 87 (63) 0.51
Current smoker, n (%) 179 (36) 38 (28) 0.071
Current alcohol user, n (%) 107 (21) 25 (19) 0.46
Nursing home resident, n (%) 15 (3) 7 (5) 0.25
Previous antibiotics, n (%) 51 (11) 26 (19) 0.008
Inuenza vaccine, n (%) 107 (34) 32 (40) 0.29
Pneumococcal vaccine, n (%) 52 (10) 10 (7) 0.27
Previous inhaled steroids, n (%) 95 (19) 35 (26) 0.096
Previous systemic steroids, n (%) 19 (5) 6 (6) 0.72
Comorbidities, n (%)
COPD 110 (22) 44 (32) 0.015
Other chronic respiratory disease 121 (24) 41 (29) 0.18
Chronic cardiovascular disease 61 (12) 23 (17) 0.18
Diabetes mellitus 90 (18) 24 (17) 0.81
Chronic neurologic disease 53 (11) 23 (17) 0.063
Chronic renal disease 29 (6) 7 (5) 0.72
Chronic liver disease 39 (8) 12 (9) 0.75
Clinical symptoms, n (%)
Fever, >388 C 429 (86) 108 (78) 0.013
Cough 418 (84) 123 (89) 0.17
Sputum production 341 (71) 108 (79) 0.057
Pleuritic chest pain 269 (55) 75 (55) .0.99
Dyspnea 359 (73) 109 (78) 0.17
Confusion 98 (20) 26 (19) 0.82
Vital signs, median (IQR)
Heart rate, beats/min 104 (90120) 100 (88113) 0.069
Respiratory rate, breaths/min 28 (2332) 28 (2432) 0.64
Systolic blood pressure, mm Hg 128 (110145) 128 (112145) 0.47
Diastolic blood pressure, mm Hg 70 (6280) 70 (6080) 0.79
Laboratory tests, median (IQR)
Creatinine, mg/ml 1.1 (0.91.5) 1.1 (0.91.4) 0.29
C-reactive protein, mg/dl 24 (1332) 22 (1130) 0.16
White blood cell count, 109/L 15.4 (10.120.4) 13.8 (9.918.6) 0.13
PaO2/FIO2, mm Hg 271 (229310) 252 (219305) 0.057
PSI risk score, n (%) 0.10
I 4 (1) 0 (0)
II 131 (26) 25 (18)
III 105 (21) 26 (19)
IV 174 (35) 63 (45)
V 90 (18) 25 (18)
CURB-65 risk class, n (%) 0.13
0 90 (18) 22 (16)
1 164 (34) 37 (27)
2 131 (27) 47 (35)
3 74 (15) 21 (15)
4 27 (6) 6 (4)
5 2 (0.4) 3 (2)

Definition of abbreviations: COPD = chronic obstructive pulmonary disease; CURB-65 = consciousness, urea, respiratory rate, blood pressure,
65 year old; IQR = interquartile range; PSI = pneumonia severity index.
Percentages are calculated on nonmissing data. Bold values indicate statistical significance.

presentations or worse clinical outcomes
in patients who were admitted to the
hospital with roentgenographically proven
pneumonia caused by S. pneumoniae
pneumonia as a function of whether the
organisms cultured were sensitive or
resistant to macrolide antibiotics or if
the patients had invasive or noninvasive
disease. We also found no evidence of
worse clinical outcomes in patients who
were treated with regimens that were
consistent versus inconsistent with current
guidelines for treating CAP or HCAP.
Literature on the effect of macrolide
resistance on outcomes of patients with
S. pneumoniae infections is conicting.
Twenty years ago Moreno and colleagues
(19) found no difference in hospital
mortality in patients with macrolide-
sensitive versus -resistant S. pneumoniae
(14% vs. 18% in those with macrolide-
sensitive and -resistant infections,
respectively; P = 0.8). Two subsequent
studies found trends toward an increased
mortality in patients with macrolide-
resistant pneumococcal disease that were
not statistically signicant (20, 21) but Song
and colleagues (22) did not (P = 0.6 or 0.9
for patients with pneumonia severity index
15 and 4 or 5, respectively).

1268 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 | June 1 2015
ORIGINAL ARTICLE

Table 3. Outcomes According to Macrolide Sensitivity

Macrolide Sensitive Macrolide Resistant

(n = 504) (n = 139) P Value

Bacteremia, n (%) 299 (60) 65 (47) 0.009

Days of hospital stay, median (IQR) 8 (512) 8 (414) 0.96
30-d in-hospital mortality, n (%) 40 (8) 13 (9) 0.59
ICU admission, n (%) 145 (29) 35 (25) 0.40
Mechanical ventilation,* n (%) 0.064
None 387 (84) 106 (84) 0.96
Noninvasive 22 (5) 1 (1) 0.041
Invasive 50 (11) 19 (15) 0.20
Pulmonary complications, n (%) 218 (44) 45 (32) 0.017
Multilobar inltration 149 (30) 32 (23) 0.13
Pleural effusion 98 (20) 20 (14) 0.16
ARDS 28 (6) 6 (5) 0.55
Acute renal failure, n (%) 153 (31) 41 (30) 0.84
Shock, n (%) 67 (14) 10 (7) 0.050

Definition of abbreviations: ARDS = acute respiratory distress syndrome; ICU = intensive care unit; IQR = interquartile range.
Percentages are calculated on nonmissing data. Bold values indicate statistical significance.
*Patients who received initially noninvasive ventilation but needed subsequent intubation were included in the invasive mechanical ventilation group.

Patients could have more than one pulmonary complication.

In an observational study Asadi and
colleagues (23) found that outpatients with
CAP had a lower mortality if they were treated
with regimens that were consistent with
published guidelines compared with those
whose regimens were not (6% vs. 1%,
respectively; odds ratio, 0.23; 95% condence
interval, 0.090.59; P = 0.002). Within the
group receiving treatment that was concordant
with guidelines, those receiving macrolides
were less likely to die within 30 days (64% vs.
0.2%; odds ratio, 2.3; 95% condence interval,
0.090.86; P = 0.03). Other observational
studies also nd that mortality is lower in
inpatients with CAP and pneumococcal
bacteremia who are treated with macrolides
(21, 24, 25) but no benet was seen if data are
restricted to randomized controlled trials (24).
Baddour and colleagues (26) found no
difference in the mortality of patients treated
with combination antibiotic therapy versus
monotherapy unless the patients were critically
ill. We found that patients hospitalized with
S. pneumoniae pneumonia who were treated
with guideline-compliant regimens had lengths
of hospital stay than those treated with
regimens that were noncompliant but the
patients treated with guideline-consistent
regimens were more likely to have bacteremia
on admission, multilobar inltration, acute
respiratory distress syndrome, and acute renal
failure (Table 6).
Several observational studies and a recent
randomized controlled trial have found
improved outcomes in patients with CAP if
their treatment regimens included a macrolide
antibiotic (2729). We found no difference in
outcomes in patients whose regimens did or
did not include a macrolide (Table 7), except
that patients with S. pneumoniae resistant to
macrolide had less need for ICU admission.
This nding opens again the question of the
potential antiinammatory effect of macrolide
(30, 31).
Our study has a number of limitations.
First, because the data were collected from
a single academic teaching hospital in Spain
the results might not generalize to other

Table 4. Outcomes According to Macrolide Sensitivity Excluding Patients Who Died within the First 3 Days of Admission

Macrolide Sensitive (n = 493) Macrolide Resistant (n = 133) P Value

Bacteremia, n (%) 295 (60) 62 (47) 0.006

Days of hospital stay, median (IQR) 8 (512) 8 (514) .0.99
30-d in-hospital mortality, n (%) 32 (6) 9 (7) 0.93
ICU admission, n (%) 140 (28) 32 (24) 0.29
Mechanical ventilation,* n (%) 0.13
None 385 (85) 105 (86) 0.81
Noninvasive 20 (4) 1 (1) 0.060
Invasive 47 (10) 16 (13) 0.39
Pulmonary complications, n (%) 211 (43) 42 (31) 0.013
Multilobar inltration 143 (29) 29 (21) 0.089
Pleural effusion 96 (20) 18 (13) 0.097
ARDS 24 (5) 4 (3) 0.34
Acute renal failure, n (%) 147 (30) 37 (28) 0.61
Shock, n (%) 63 (13) 7 (5) 0.014

Definition of abbreviations: ARDS = acute respiratory distress syndrome; ICU = intensive care unit; IQR = interquartile range.
Percentages are calculated on nonmissing data. Bold values indicate statistical significance.
*Patients who received initially noninvasive ventilation but needed subsequent intubation were included in the invasive mechanical ventilation group.

Patients could have more than one pulmonary complication.

Cilloniz, Albert, Liapikou, et al.: Macrolide-Resistance Streptococcus pneumoniae Pneumonia 1269

 ORIGINAL ARTICLE

Table 5. Antibiotic Regimens for multiple comparisons. Fifth, because

we only encountered three patients with
Macrolide Sensitive Macrolide Resistant
macrolide-resistant disease who were
(n = 504) (n = 139) treated with macrolide monotherapy
we cannot comment on the use of
Monotherapy, n (%) 95 (19) 34 (25) this regimen in this setting, although
Quinolone 53 (11) 22 (16) macrolide monotherapy would not be
b-Lactam 35 (7) 7 (5) an appropriate choice for treating
Macrolide 4 (1) 3 (2) hospitalized patients.
Other 3 (1) 2 (1)
Combination, n (%) 405 (81) 104 (75)
b-Lactam 1 macrolide 229 (46) 69 (50) Conclusions
b-Lactam 1 quinolone 114 (23) 22 (16) We found no evidence suggesting that
Macrolide 1 quinolone 8 (2) 1 (1) patients hospitalized with culture- and
Other 54 (11) 12 (9) roentgenographically proven, invasive or
Guideline-consistent regimens, n (%) 346 (69) 91 (66)
Guideline-inconsistent regimens, n (%) 154 (31) 47 (34) noninvasive S. pneumoniae pneumonia
were more severely ill at presentation or
Percentages are calculated on nonmissing data. had worse outcomes if their organism was
resistant versus sensitive to macrolide
antibiotics and/or if they were treated with
patients admitted to other types of isolates to determine their specic guideline-compliant versus noncompliant
hospitals in other countries. Second, mechanism of macrolide resistance and regimens. Although the prevalence of
although we found no difference in the our failure to nd any differences in in vitro resistance to macrolide antibiotics
outcomes in patients with macrolide- outcomes could have resulted from is increasing, we found no evidence that
resistant versus -sensitive organisms, we a high fraction of the macrolide-resistant this resistance worsened outcomes in
could only analyze 139 patients with organisms having the ermB gene. A patients hospitalized for S. pneumoniae
macrolide-resistant organisms and this Spanish study found that 89.9% of pneumonia. n
sample size may result in a large type II macrolide-resistant pneumococci carried
error. Our sample size, however, is larger the ermB gene (35) but Daneman Author disclosures are available with the text
of this article at www.atsjournals.org.
than many previous studies of macrolide- and colleagues (36) found equal
resistant S. pneumoniae reported in the representation of the mefA and ermB Acknowledgment: The authors are indebted
literature (14, 19, 20, 22, 3234). Third, genes in their series of macrolide failures. to all medical and nursing colleagues for their
we did not genotype the S. pneumoniae Fourth, there were no adjustments made assistance and cooperation in this study.

Table 6. Outcomes according to Appropriateness of Treatment and Macrolide Sensitivity

Guideline-Consistent Regimens (n = 437) Guideline-Inconsistent Regimens (n = 201)

Macrolide Macrolide Macrolide Macrolide
Sensitive Resistant Total Sensitive Resistant Total
(n = 346) (n = 91) (n = 437) P Value (n = 154) (n = 47) (n = 201) P Value P Value* P Value P Value

Bacteremia, n (%) 217 (63) 46 (51) 263 (61) 0.039 81 (53) 19 (41) 100 (51) 0.15 0.040 0.28 0.017
Days of hospital stay, 8 (512) 9 (514) 8 (513) 0.81 6.5 (411) 6 (413) 6 (412) 0.74 0.005 0.10 0.001
median (IQR)
30-d in-hospital 27 (8) 6 (7) 33 (8) 0.70 13 (8) 6 (13) 19 (9) 0.38 0.81 0.22 0.42
mortality, n (%)
ICU admission, n (%) 109 (32) 23 (25) 132 (30) 0.25 36 (24) 11 (23) 47 (24) 0.99 0.071 0.81 0.081
Mechanical 0.046 0.58 0.040
ventilation,x n (%)
None 265 (83) 71 (87) 336 (84) 0.48 119 (86) 35 (81) 154 (85) 0.44 0.44 0.44 0.74
Noninvasive 21 (7) 0 (0) 21 (5) 0.017 1 (1) 1 (2) 2 (1) 0.38 0.007 0.17 0.018
Invasive 32 (10) 11 (13) 43 (11) 0.38 18 (13) 7 (16) 25 (14) 0.59 0.35 0.66 0.29
Pulmonary 166 (49) 28 (31) 194 (45) 0.002 50 (32) 16 (34) 66 (33) 0.84 0.001 0.70 0.004
complications,jj n (%)
Multilobar inltration 116 (34) 19 (21) 135 (31) 0.020 32 (21) 12 (26) 44 (22) 0.49 0.040 0.54 0.019
Pleural effusion 69 (20) 13 (14) 82 (19) 0.20 28 (18) 7 (15) 35 (18) 0.59 0.63 0.92 0.67
ARDS 24 (7) 5 (6) 29 (7) 0.58 4 (3) 1 (2) 5 (3) 0.88 0.052 0.40 0.033
Acute renal failure, n (%) 119 (35) 33 (37) 152 (36) 0.80 34 (22) 7 (15) 41 (21) 0.31 0.004 0.009 <0.001
Shock, n (%) 47 (14) 6 (7) 53 (12) 0.061 20 (13) 3 (7) 23 (12) 0.24 0.79 0.99 0.78

Definition of abbreviations: ARDS = acute respiratory distress syndrome; ICU = intensive care unit; IQR = interquartile range.
Percentages are calculated on nonmissing data. Bold values indicate statistical significance.
*P values are for the comparison of guideline consistent/macrolide sensitive with guideline inconsistent/macrolide sensitive.

P values are for the comparison of guideline consistent/macrolide resistant with guideline inconsistent/macrolide resistant.

P values are for the comparison of guideline consistent/total with guideline inconsistent/total.
x
Patients who received initially noninvasive ventilation but needed subsequent intubation were included in the invasive mechanical ventilation group.
jj
Patients could have more than one pulmonary complication.

1270 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 | June 1 2015
ORIGINAL ARTICLE

Table 7. Outcomes of Patients with Macrolide-Resistant Streptococcus pneumoniae Pneumonia Treated with Dual Antibiotic
Regimens That Did or Did Not Contain a Macrolide

Dual Therapy, Not Including Dual Therapy Including

a Macrolide (n = 33) a Macrolide (n = 71) P Value

Bacteremia, n (%) 17 (52) 36 (51) 0.99

Days of hospital stay, median (IQR) 11 (618) 8 (413) 0.12
30-d in-hospital mortality, n (%) 4 (12) 4 (6) 0.25
ICU admission, n (%) 14 (42) 15 (21) 0.024
Mechanical ventilation,* n (%) 0.28
None 22 (81) 57 (86) 0.55
Noninvasive 1 (4) 0 (0) 0.29
Invasive 4 (15) 9 (14) 0.88
Pulmonary complications, n (%) 14 (42) 18 (25) 0.079
Multilobar inltration 11 (33) 11 (15) 0.038
Pleural effusion 7 (21) 9 (13) 0.26
ARDS 2 (7) 3 (4) 0.61
Acute renal failure, n (%) 11 (33) 25 (36) 0.81
Shock, n (%) 2 (6) 6 (8) 0.67

Definition of abbreviations: ARDS = acute respiratory distress syndrome; ICU = intensive care unit; IQR = interquartile range.
Percentages are calculated on nonmissing data. Bold values indicate statistical significance.
*Patients who received initially noninvasive ventilation but needed subsequent intubation were included in the invasive mechanical ventilation group.

Patients could have more than one pulmonary complication.

Reference 12. File TM Jr. Clinical implications and treatment of multiresistant

1. Kollef MH, Shorr A, Tabak YP, Gupta V, Liu LZ, Johannes RS.
Epidemiology and outcomes of health-care-associated pneumonia:
results from a large US database of culture-positive pneumonia. Chest
2005;128:38543862.
2. Micek ST, Kollef KE, Reichley RM, Roubinian N, Kollef MH. Health care-
associated pneumonia and community-acquired pneumonia: a single-
center experience. Antimicrob Agents Chemother 2007;51:35683573.
3. Welte T, Kohnlein T. Global and local epidemiology of community-
acquired pneumonia: the experience of the CAPNETZ Network. Semin
Respir Crit Care Med 2009;30:127135.
4. Carratala J, Mykietiuk A, Fernandez-Sabe N, Suarez C, Dorca J,
Verdaguer R, Manresa F, Gudiol F. Health care-associated pneumonia
requiring hospital admission: epidemiology, antibiotic therapy, and
clinical outcomes. Arch Intern Med 2007;167:13931399.
5. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean
NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, et al.;
Infectious Diseases Society of America; American Thoracic Society.
Infectious Diseases Society of America/American Thoracic Society
consensus guidelines on the management of community-acquired
pneumonia in adults. Clin Infect Dis 2007;44:S27S72.
6. Chalmers JD, Taylor JK, Singanayagam A, Fleming GB, Akram AR,
Mandal P, Choudhury G, Hill AT. Epidemiology, antibiotic therapy, and
clinical outcomes in health care-associated pneumonia: a UK cohort
study. Clin Infect Dis 2011;53:107113.
7. Jenkins SG, Farrell DJ. Increase in pneumococcus macrolide resistance,
United States. Emerg Infect Dis 2009;15:12601264.
8. Van Bambeke F, Reinert RR, Appelbaum PC, Tulkens PM, Peetermans
WE. Multidrug-resistant Streptococcus pneumoniae infections:
current and future therapeutic options. Drugs 2007;67:23552382.
9. Felmingham D, Canton R, Jenkins SG. Regional trends in beta-lactam,
macrolide, uoroquinolone and telithromycin resistance among
Streptococcus pneumoniae isolates 2001-2004. J Infect 2007;55:111118.
10. Farrell DJ, Klugman KP, Pichichero M. Increased antimicrobial
resistance among nonvaccine serotypes of Streptococcus
pneumoniae in the pediatric population after the introduction of 7-
valent pneumococcal vaccine in the United States. Pediatr Infect Dis
J 2007;26:123128.
11. Farrell DJ, Jenkins SG, Brown SD, Patel M, Lavin BS, Klugman KP.
Emergence and spread of Streptococcus pneumoniae with erm(B)
and mef(A) resistance. Emerg Infect Dis 2005;11:851858.
Streptococcus pneumoniae pneumonia. Clin Microbiol Infect 2006;
12:3141.
13. Klugman KP, Lonks JR. Hidden epidemic of macrolide-resistant
pneumococci. Emerg Infect Dis 2005;11:802807.
14. Neuman MI, Kelley M, Harper MB, File TM Jr, Camargo CA Jr; EMNet
Investigators. Factors associated with antimicrobial resistance and
mortality in pneumococcal bacteremia. J Emerg Med 2007;32:
349357.
15. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE,
Coley CM, Marrie TJ, Kapoor WN. A prediction rule to identify low-
risk patients with community-acquired pneumonia. N Engl J Med
1997;336:243250.
16. Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town
GI, Lewis SA, Macfarlane JT. Dening community acquired
pneumonia severity on presentation to hospital: an international
derivation and validation study. Thorax 2003;58:377382.
17. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E,
Camporota L, Slutsky AS; ARDS Denition Task Force. Acute respiratory
distress syndrome: the Berlin Denition. JAMA 2012;307:25262533.
18. American Thoracic Society; Infectious Diseases Society of America.
Guidelines for the management of adults with hospital-acquired,
ventilator-associated, and healthcare-associated pneumonia. Am J
Respir Crit Care Med 2005;171:388416.
19. Moreno S, Garca-Leoni ME, Cercenado E, Diaz MD, Bernaldo de
Quiros JC, Bouza E. Infections caused by erythromycin-resistant
Streptococcus pneumoniae: incidence, risk factors, and response to
therapy in a prospective study. Clin Infect Dis 1995;20:11951200.
20. Aspa J, Rajas O, Rodrguez de Castro F, Blanquer J, Zalacain R, Fenoll
A, de Celis R, Vargas A, Rodrguez Salvanes F, Espaa PP, et al.;
Pneumococcal Pneumonia in Spain Study Group. Drug-resistant
pneumococcal pneumonia: clinical relevance and related factors.
Clin Infect Dis 2004;38:787798.
21. Lujan M, Gallego M, Fontanals D, Mariscal D, Rello J. Prospective
observational study of bacteremic pneumococcal pneumonia: effect
of discordant therapy on mortality. Crit Care Med 2004;32:625631.
22. Song JH, Jung SI, Ki HK, Shin MH, Ko KS, Son JS, Chang HH, Kim SW,
Lee H, Kim YS, et al.; Asian Network for Surveillance of Resistant
Pathogens Study Group. Clinical outcomes of pneumococcal
pneumonia caused by antibiotic-resistant strains in Asian countries:
a study by the Asian Network for Surveillance of Resistant
Pathogens. Clin Infect Dis 2004;38:15701578.

Cilloniz, Albert, Liapikou, et al.: Macrolide-Resistance Streptococcus pneumoniae Pneumonia 1271


23. Asadi L, Eurich DT, Gamble JM, Minhas-Sandhu JK, Marrie TJ,
Majumdar SR. Guideline adherence and macrolides reduced
mortality in outpatients with pneumonia. Respir Med 2012;106:
451458.
24. Asadi L, Sligl WI, Eurich DT, Colmers IN, Tjosvold L, Marrie TJ,
Majumdar SR. Macrolide-based regimens and mortality in
hospitalized patients with community-acquired pneumonia:
a systematic review and meta-analysis. Clin Infect Dis 2012;55:
371380.
25. Metersky ML, Ma A, Houck PM, Bratzler DW. Antibiotics for bacteremic
pneumonia: improved outcomes with macrolides but not
uoroquinolones. Chest 2007;131:466473.
26. Baddour LM, Yu VL, Klugman KP, Feldman C, Ortqvist A,
Rello J, Morris AJ, Luna CM, Snydman DR, Ko WC, et al.;
International Pneumococcal Study Group. Combination
antibiotic therapy lowers mortality among severely ill patients
with pneumococcal bacteremia. Am J Respir Crit Care Med
2004;170:440444.
27. Caballero J, Rello J. Combination antibiotic therapy for community-
acquired pneumonia. Ann Intensive Care 2011;1:48.
28. Sligl WI, Asadi L, Eurich DT, Tjosvold L, Marrie TJ, Majumdar SR.
Macrolides and mortality in critically ill patients with community-
acquired pneumonia: a systematic review and meta-analysis.
Crit Care Med 2014;42:420432.
29. Garin N, Genne D, Carballo S, Chuard C, Eich G, Hugli O, Lamy O,
Nendaz M, Petignat PA, Perneger T, et al. b-Lactam monotherapy vs
b-lactam-macrolide combination treatment in moderately severe
community-acquired pneumonia: a randomized noninferiority trial.
JAMA Intern Med 2014;174:18941901.
1272 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 | June 1 2015
ORIGINAL ARTICLE
30. Giamarellos-Bourboulis EJ. Macrolides beyond the conventional
antimicrobials: a class of potent immunomodulators. Int J Antimicrob
Agents 2008;31:1220.
31. Restrepo MI, Mortensen EM, Waterer GW, Wunderink RG, Coalson JJ,
Anzueto A. Impact of macrolide therapy on mortality for patients with
severe sepsis due to pneumonia. Eur Respir J 2009;33:153159.
32. Shortridge VD, Doern GV, Brueggemann AB, Beyer JM, Flamm RK.
Prevalence of macrolide resistance mechanisms in Streptococcus
pneumoniae isolates from a multicenter antibiotic resistance
surveillance study conducted in the United States in 1994-1995.
Clin Infect Dis 1999;29:11861188.
33. Ewig S, Ruiz M, Torres A, Marco F, Martinez JA, Sanchez M, Mensa J.
Pneumonia acquired in the community through drug-resistant
Streptococcus pneumoniae. Am J Respir Crit Care Med 1999;159:
18351842.
34. Lonks JR, Garau J, Gomez L, Xercavins M, Ochoa de Echaguen A,
Gareen IF, Reiss PT, Medeiros AA. Failure of macrolide antibiotic
treatment in patients with bacteremia due to erythromycin-resistant
Streptococcus pneumoniae. Clin Infect Dis 2002;35:556564.
35. Perez-Trallero E, Garca-de-la-Fuente C, Garca-Rey C, Baquero F,
Aguilar L, Dal-Re R, Garca-de-Lomas J; Spanish Surveillance Group
for Respiratory Pathogens. Geographical and ecological analysis of
resistance, coresistance, and coupled resistance to antimicrobials
in respiratory pathogenic bacteria in Spain. Antimicrob Agents
Chemother 2005;49:19651972.
36. Daneman N, McGeer A, Green K, Low DE; Toronto Invasive Bacterial
Diseases Network. Macrolide resistance in bacteremic
pneumococcal disease: implications for patient management.
Clin Infect Dis 2006;43:432438.