The Effect of Macrolide Resistance on the Presentation and Outcome of Patients Hospitalized for Streptococcus pneumoniae Pneumonia

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1 &get_box_var; ORIGINAL ARTICLE The Effect of Macrolide Resistance on the Presentation and Outcome of Patients Hospitalized for Streptococcus pneumoniae Pneumonia Catia Cilloniz 1, Richard K. Albert 2,3, Adamanthia Liapikou 4, Albert Gabarrus 1, Ernesto Rangel 5, Salvador Bello 6, Francesc Marco 7, Josep Mensa 8, and Antoni Torres 1 1 Department of Pneumology, Institut Clinic del Tórax, Hospital Clinic of Barcelona Institut d Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Ciber de Enfermedades Respiratorias, Barcelona, Spain; 2 Department of Medicine, Denver Health, Denver, Colorado; 3 University of Colorado, Aurora, Colorado; 4 Respiratory Department, Sotiria Chest Diseases Hospital, Athens, Greece; 5 Facultad de Medicina, Universidad Autonoma de Nayarit, Tepic Nayarit, Mexico; 6 Servicio de Neumologia, Hospital Universitario Miguel Servet, Zaragoza, Spain; and 7 Department of Microbiology and 8 Department of Infectious Disease, Hospital Clinic of Barcelona, Barcelona, Spain Abstract Rationale: There are conflicting 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, 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. Patients with macrolide-resistant organisms were less likely to have 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 identified in 20 60% of patients requiring hospitalization for community-acquired pneumonia (CAP), making it the leading cause of CAP (1 3), and in % of patients hospitalized for healthcareassociated 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 d Investigacions Biomèdiques 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. atorres@clinic.ub.es This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Med Vol 191, Iss 11, pp , Jun 1, 2015 Copyright 2015 by the American Thoracic Society Originally Published in Press as DOI: /rccm OC on March 25, 2015 Internet address: Cilloniz, Albert, Liapikou, et al.: Macrolide-Resistance Streptococcus pneumoniae Pneumonia 1265

2 At a Glance Commentary Scientific Knowledge on the Subject: There are conflicting 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 first-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 fluoroquinolone (5). Theprevalenceofmacrolide resistance in S. pneumoniae is increasing with recent rates ranging from 18 to 35% (7 11). Although some studies link macrolide resistance with treatment failure in community-acquired respiratory tract infections (12 14), 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. Study Design and Patients This was a retrospective observational studyofdatathatwereprospectively 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 defined as the presence of a new infiltrate 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 immunodeficiency 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 findings, 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, defined as multilobar infiltration, 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 examination of the pleural fluid, 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 fluid, tracheobronchial aspirates (at >10 5 CFU/ ml) or bronchoalveolar lavage (at >10 4 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 defined 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, levofloxacin, 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 defined as an isolate with an erythromycin MIC less than or equal to 0.5 mg/l, intermediate resistance was defined as an erythromycin MIC of 1 mg/l, and resistance erythromycin was defined as an erythromycin MIC greater than or equal to 2 mg/l. S. pneumoniae was considered to be macrolide resistant when MICs were 1266 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 June

3 Macrolide-sensitive S. pneumoniae 504 patients (78.4%) 331 (65.6%) invasive cases (empyema + bacteremia) 5878 screened patients with CAP 643 patients analyzed 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 defined 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 (first quartile third 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 Specimen Isolates (n = 643) adjusted for multiple comparisons. A P value less than 0.05 was considered significant. 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 Sensitive (n = 504; 78%) Excluded (n=5235): Microbiological culture negative for antibiogram Macrolide-resistant S. pneumoniae 139 (21.6%) 67 (48.2%) invasive cases (empyema + bacteremia) Figure 1. Flow diagram of the selected population. CAP = community-acquired pneumonia. Macrolide Resistant (n = 139; 22%) Blood, n (%) 356 (55) 294 (58) 62 (45) Sputum, n (%) 264 (41) 197 (39) 67 (48) TBAS or BAL, n (%) 51 (8) 38 (8) 13 (9) Pleural fluid, n (%) 34 (5) 26 (5) 8 (6) Definition of abbreviations: BAL = bronchoalveolar lavage; TBAS = tracheobronchial aspirate. 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 macrolideresistant 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 first 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 findings of this study are that we could find no evidence of more severe Cilloniz, Albert, Liapikou, et al.: Macrolide-Resistance Streptococcus pneumoniae Pneumonia 1267

4 Table 2. Demographics and Clinical Characteristics on Admission Macrolide Sensitive (n = 504) Macrolide Resistant (n = 139) P Value Age, yr, mean 6 SD Male, sex, n (%) 330 (66) 87 (63) 0.51 Current smoker, n (%) 179 (36) 38 (28) 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) Influenza 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) Previous systemic steroids, n (%) 19 (5) 6 (6) 0.72 Comorbidities, n (%) COPD 110 (22) 44 (32) 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) Chronic renal disease 29 (6) 7 (5) 0.72 Chronic liver disease 39 (8) 12 (9) 0.75 Clinical symptoms, n (%) Fever, >388C 429 (86) 108 (78) Cough 418 (84) 123 (89) 0.17 Sputum production 341 (71) 108 (79) 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 (90 120) 100 (88 113) Respiratory rate, breaths/min 28 (23 32) 28 (24 32) 0.64 Systolic blood pressure, mm Hg 128 ( ) 128 ( ) 0.47 Diastolic blood pressure, mm Hg 70 (62 80) 70 (60 80) 0.79 Laboratory tests, median (IQR) Creatinine, mg/ml 1.1 ( ) 1.1 ( ) 0.29 C-reactive protein, mg/dl 24 (13 32) 22 (11 30) 0.16 White blood cell count, 10 9 /L 15.4 ( ) 13.8 ( ) 0.13 Pa O2 /FI O2, mm Hg 271 ( ) 252 ( ) 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 (%) (18) 22 (16) (34) 37 (27) (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. 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 conflicting. Twenty years ago Moreno and colleagues (19) found no difference in hospital mortality in patients with macrolidesensitive versus -resistant S. pneumoniae (14% vs. 18% in those with macrolidesensitive and -resistant infections, respectively; P = 0.8). Two subsequent studies found trends toward an increased mortality in patients with macrolideresistant pneumococcal disease that were not statistically significant (20, 21) but Song and colleagues (22) did not (P = 0.6 or 0.9 for patients with pneumonia severity index 1 5 and 4 or 5, respectively) American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 June

5 Table 3. Outcomes According to Macrolide Sensitivity Macrolide Sensitive (n = 504) Macrolide Resistant (n = 139) P Value Bacteremia, n (%) 299 (60) 65 (47) Days of hospital stay, median (IQR) 8 (5 12) 8 (4 14) d in-hospital mortality, n (%) 40 (8) 13 (9) 0.59 ICU admission, n (%) 145 (29) 35 (25) 0.40 Mechanical ventilation,* n (%) None 387 (84) 106 (84) 0.96 Noninvasive 22 (5) 1 (1) Invasive 50 (11) 19 (15) 0.20 Pulmonary complications, n (%) 218 (44) 45 (32) Multilobar infiltration 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) Definition of abbreviations: ARDS = acute respiratory distress syndrome; ICU = intensive care unit; IQR = interquartile range. *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% confidence interval, ; 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%confidence interval, ; P = 0.03). Other observational studies also find that mortality is lower in inpatients with CAP and pneumococcal bacteremia who are treated with macrolides (21, 24, 25) but no benefit 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 infiltration, acute respiratory distress syndrome, and acute renal failure(table6). 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 (27 29). 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 finding opens again the question of the potential antiinflammatory 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) Days of hospital stay, median (IQR) 8 (5 12) 8 (5 14) 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) Invasive 47 (10) 16 (13) 0.39 Pulmonary complications, n (%) 211 (43) 42 (31) Multilobar infiltration 143 (29) 29 (21) Pleural effusion 96 (20) 18 (13) ARDS 24 (5) 4 (3) 0.34 Acute renal failure, n (%) 147 (30) 37 (28) 0.61 Shock, n (%) 63 (13) 7 (5) Definition of abbreviations: ARDS = acute respiratory distress syndrome; ICU = intensive care unit; IQR = interquartile range. *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

6 Table 5. Antibiotic Regimens patients admitted to other types of hospitals in other countries. Second, although we found no difference in the outcomes in patients with macrolideresistant versus -sensitive organisms, we could only analyze 139 patients with macrolide-resistant organisms and this sample size may result in a large type II error. Our sample size, however, is larger than many previous studies of macrolideresistant S. pneumoniae reported in the literature (14, 19, 20, 22, 32 34). Third, we did not genotype the S. pneumoniae Macrolide Sensitive (n = 504) Macrolide Resistant (n = 139) Monotherapy, n (%) 95 (19) 34 (25) Quinolone 53 (11) 22 (16) b-lactam 35 (7) 7 (5) Macrolide 4 (1) 3 (2) Other 3 (1) 2 (1) Combination, n (%) 405 (81) 104 (75) b-lactam 1 macrolide 229 (46) 69 (50) b-lactam 1 quinolone 114 (23) 22 (16) Macrolide 1 quinolone 8 (2) 1 (1) Other 54 (11) 12 (9) Guideline-consistent regimens, n (%) 346 (69) 91 (66) Guideline-inconsistent regimens, n (%) 154 (31) 47 (34) Percentages are calculated on nonmissing data. isolates to determine their specific mechanism of macrolide resistance and our failure to find any differences in outcomes could have resulted from a high fraction of the macrolide-resistant organisms having the ermb gene. A Spanish study found that 89.9% of macrolide-resistant pneumococci carried theermbgene(35)butdaneman and colleagues (36) found equal representation of the mefa and ermb genes in their series of macrolide failures. Fourth, there were no adjustments made for multiple comparisons. Fifth, because we only encountered three patients with macrolide-resistant disease who were treated with macrolide monotherapy we cannot comment on the use of this regimen in this setting, although macrolide monotherapy would not be an appropriate choice for treating hospitalized patients. Conclusions We found no evidence suggesting that patients hospitalized with culture- and roentgenographically proven, invasive or noninvasive S. pneumoniae pneumonia were more severely ill at presentation or had worse outcomes if their organism was resistant versus sensitive to macrolide antibiotics and/or if they were treated with guideline-compliant versus noncompliant regimens. Although the prevalence of in vitro resistance to macrolide antibiotics is increasing, we found no evidence that this resistance worsened outcomes in patients hospitalized for S. pneumoniae pneumonia. n Author disclosures are available with the text of this article at Acknowledgment: The authors are indebted to all medical and nursing colleagues for their 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 Sensitive (n = 346) Macrolide Resistant (n = 91) Total (n = 437) P Value Macrolide Sensitive (n = 154) Macrolide Resistant (n = 47) Total (n = 201) P Value P Value* P Value P Value Bacteremia, n (%) 217 (63) 46 (51) 263 (61) (53) 19 (41) 100 (51) Days of hospital stay, 8(5 12) 9 (5 14) 8 (5 13) (4 11) 6 (4 13) 6 (4 12) median (IQR) 30-d in-hospital 27 (8) 6 (7) 33 (8) (8) 6 (13) 19 (9) mortality, n (%) ICU admission, n (%) 109 (32) 23 (25) 132 (30) (24) 11 (23) 47 (24) Mechanical ventilation, x n(%) None 265 (83) 71 (87) 336 (84) (86) 35 (81) 154 (85) Noninvasive 21 (7) 0 (0) 21 (5) (1) 1 (2) 2 (1) Invasive 32 (10) 11 (13) 43 (11) (13) 7 (16) 25 (14) Pulmonary 166 (49) 28 (31) 194 (45) (32) 16 (34) 66 (33) complications, jj n(%) Multilobar infiltration 116 (34) 19 (21) 135 (31) (21) 12 (26) 44 (22) Pleural effusion 69 (20) 13 (14) 82 (19) (18) 7 (15) 35 (18) ARDS 24 (7) 5 (6) 29 (7) (3) 1 (2) 5 (3) Acute renal failure, n (%) 119 (35) 33 (37) 152 (36) (22) 7 (15) 41 (21) <0.001 Shock, n (%) 47 (14) 6 (7) 53 (12) (13) 3 (7) 23 (12) Definition of abbreviations: ARDS = acute respiratory distress syndrome; ICU = intensive care unit; IQR = interquartile range. *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 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 June

7 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 a Macrolide (n = 33) Dual Therapy Including a Macrolide (n = 71) P Value Bacteremia, n (%) 17 (52) 36 (51) 0.99 Days of hospital stay, median (IQR) 11 (6 18) 8 (4 13) d in-hospital mortality, n (%) 4 (12) 4 (6) 0.25 ICU admission, n (%) 14 (42) 15 (21) 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) Multilobar infiltration 11 (33) 11 (15) 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. *Patients who received initially noninvasive ventilation but needed subsequent intubation were included in the invasive mechanical ventilation group. 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