Beta-Lactam Monotherapy in Community-Acquired Pneumonia: Is it Beta or Worse?

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1 Beta-Lactam Monotherapy in Community-Acquired Pneumonia: Is it Beta or Worse? R. Joel Moore, PharmD Master s Pharmacotherapy Resident Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, UT Health San Antonio May 5, 2017 Learning Objectives 1. Describe the current epidemiology and microbiology of community-acquired pneumonia 2. Describe available empiric treatment strategies for community-acquired pneumonia, focusing on the potential advantages and disadvantages of each strategy 3. Evaluate current literature regarding empiric treatment of community-acquired pneumonia in hospitalized adults with beta-lactam/macrolide combination therapy, beta-lactam monotherapy, and fluoroquinolone monotherapy 4. Given a patient case, determine the appropriateness of beta-lactam monotherapy as empiric treatment for community-acquired pneumonia

2 Background & Introduction 1) Pneumonia has been described for thousands of years; however, its causes have only been elucidated recently 1 2) Causes of pneumonia 2,3 a) Bacterial i) Many potential pathogens (Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, etc.) ii) Mycobacterium tuberculosis (1) Acid-fast staining bacillus (2) Incidence much lower in US compared to other countries b) Viral i) Influenza, respiratory syncytial virus, parainfluenza virus, human metapneumovirus, adenovirus, coronavirus, and rhinovirus ii) Viral infections commonly predispose individuals to secondary bacterial infections c) Fungal i) Histoplasma and Coccidioides (1) Histoplasma endemic to Ohio and Mississippi River valleys (2) Coccidioides endemic to southwestern United States d) Undetermined cause in half of those hospitalized for CAP in the US 4 3) Costs of pneumonia 5-7 a) In the U.S., accounts for an estimated 63,000 deaths, 1.2 million hospitalizations, and 2.3 million emergency department visits annually b) Mean cost per stay is $9,500 i) Costs increased by approximately $2,000 per stay in past decade 4) Pneumonia classification 8,9 a) Community-acquired pneumonia (CAP) 10 i) An acute infection of the pulmonary parenchyma contracted from the community ii) May be either bacterial or viral b) Hospital-acquired pneumonia (HAP) 2 i) Develops hours after admission to acute care facility ii) Associated with different causative pathogens than CAP c) Ventilator-associated pneumonia (VAP) 2 i) Pneumonia occurring >48 hours post-endotracheal intubation ii) Associated with pathogens similar to those found in HAP d) Healthcare-associated pneumonia (HCAP) was described previously but has now been removed from current guidelines 9,11 Epidemiology 1) Early literature described Streptococcus pneumoniae as causative pathogen for approximately 95% of cases of pneumonia 4 2) S. pneumoniae currently detected in approximately 10-15% of inpatient cases in the U.S. 4 a) Attributable in part to the implementation of pneumococcal vaccines i) 7-valent pneumococcal conjugate vaccine (PCV7) (1) Introduced into U.S. infant immunization schedule in 2000 (2) Resulted in 168,000 fewer hospitalizations for pneumonia annually ii) 13-valent pneumococcal conjugate vaccine (PCV13) (1) Serotypes corresponding to >60% of disease isolates in children (2) Replaced PCV7 in 2010 Moore Page 2 of 20

3 iii) 23-valent pneumococcal polysaccharide vaccine (PPSV23) (1) Serotypes corresponding to 85-90% of invasive pneumococcal disease (IPD) (2) Lacks the superior immunogenicity of the conjugate vaccine b) Decline also due to decreased rates of cigarette smoking 16 c) Higher proportion in Europe and other countries of S. pneumoniae compared to other pathogens 17 3) Disproportionately affects the young and elderly 6 a) 7% of hospital stays in those aged 1-17 years b) 4% of hospital stays in those aged years c) 6% of hospital stays in those aged >85 years Incidence of Pneumonia-Related Hospitalization by Age Group No. of cases per 10,000 adults per yr yr yr yr 80 yr Age Group Figure 1: Incidence of pneumonia-related hospitalization by age group 18 4) 30-day mortality in elderly patients who are hospitalized for CAP is 10-12% 19 a) Approximately 18% of these patients are readmitted within 30 days 20 Diagnosis & Clinical Manifestations 1) Definitive diagnosis based on presence of select clinical features 4,8 a) Symptoms: cough, fever, sputum production, shortness of breath, leukocytosis, and pleuritic chest pain b) Imaging: newly recognized lung infiltrate on chest imaging i) Difficult to identify in those with chronic lung disease and obese patients ii) Differential diagnosis of an abnormal chest radiograph 21 (1) Congestive heart failure with viral syndrome (2) Aspiration pneumonitis (3) Pulmonary infarction (4) Acute exacerbation of pulmonary fibrosis (5) Pulmonary vasculitis 2) Role of cultures and urine tests 8,22 a) Blood and sputum cultures recommended for moderate- or high-severity CAP b) Pneumococcal and legionella urinary antigen tests should be considered in severe CAP, but are not otherwise recommended Moore Page 3 of 20

4 i) Both have good specificity, but sensitivity approximately 70-80% ii) Only L. pneumophila serogroup 1 (accounts for ~80% of community-acquired cases of L. pneumophila) identifiable via urinary antigen 3) Microscopic evaluation of pulmonary secretions 4,23 a) Gram staining and sputum culture are positive in 80% of cases of pneumococcal pneumonia i) Good-quality specimen required (>10 inflammatory cells per epithelial cell) ii) Should be obtained before, or within 6-12 hours after, initiation of antibiotics 4) Role of biomarkers a) C-reactive protein 24 i) Protein of the acute phase, synthesized by hepatocytes ii) Production stimulated by IL-6, IL-1β, and TNFα in response to infection or tissue inflammation iii) Insufficient evidence to support its routine use in diagnosing CAP or assessing its likely etiology b) Procalcitonin (PCT) 25 i) Precursor to calcitonin, a hormone, and is a component of the innate pro-inflammatory response ii) Released within 4 hours of inoculation with bacteria or bacterial endotoxin iii) PCT threshold 0.1 ng/ml (1) 80.9% sensitive and 51.6% specific in detecting any bacterial CAP vs. viral CAP (2) 87.6% sensitive and 49.3% specific in detecting typical bacterial CAP vs. viral and atypical CAP iv) PCT values for patients with atypical bacteria more similar to those with viruses than typical bacteria (except for Legionella) 5) Several tools available to stratify patients by severity and for resource allocation a) CURB i) Five variables with a single point awarded for each Figure 2: Severity assessment in a hospital setting: the CURB-65 score. 26 Moore Page 4 of 20

5 i) 0 or 1: low risk of death (<3%) ii) 2: intermediate risk (3-15%) iii) 3 to 5: high risk (>15%) b) Pneumonia Severity Index (PSI) (Appendix A) 27 i) Composed of 20 items and classifies patients into five categories (1) Class I-II % 30-day mortality (2) Classes III-IV 1-9% 30-day mortality (3) Class V 27% 30-day mortality ii) Age and comorbidities highly weighted and may underestimate severity of pneumonia in young patients and those without previous diseases c) Comparisons between PSI and CURB-65 are mixed i) Recent meta-analysis concluded that PSI is superior at identifying low risk patients and CURB-65 is superior to PSI for identifying patients at the highest risk 28 Microbiology 1) Typical pathogens a) Streptococcus pneumoniae i) Most commonly isolated bacterial cause of CAP 18 ii) Gram-positive diplococci iii) Lancet shaped or arranged in chains iv) Normal upper respiratory tract flora in 5-40% of humans b) Haemophilus influenzae i) Small, gram-negative, pleomorphic bacteria ii) Found on mucous membranes of the upper respiratory tract in humans iii) Up to 25% produce beta-lactamase c) Staphylococcus aureus i) Gram-positive, coagulase-positive spherical cells arranged in grapelike irregular clusters ii) Nasal carriage occurs in 20-50% of humans d) Enterobacteriaceae (e.g., Klebsiella pneumoniae) i) Gram-negative rods ii) Present in respiratory tract and feces of ~5% of normal individuals 2) Atypical pathogens a) Mycoplasma pneumoniae i) Atypical due to their small size and growth on complex but cell-free media ii) Incubation period varies from 1-3 weeks with an insidious onset iii) Initially associated with a nonproductive cough, but is occasionally paroxysmal b) Legionella pneumophila i) Fastidious, aerobic gram-negative bacteria ii) Gram stain unreliable as stains poorly iii) Ubiquitous in warm, moist environments iv) Antigens can be detected in the patient s urine by immunologic methods c) Chlamydophila pneumoniae i) Gram-negative bacteria ii) Obligate intracellular parasites Moore Page 5 of 20

6 3) Community-acquired pneumonia requiring hospitalization among U.S. adults (EPIC-CAP) study 18 a) Active population-based surveillance for CAP requiring hospitalization i) Age 18 years ii) Five hospitals in Chicago and Nashville b) 2,488 adults enrolled from January 2010 through June 2012 Figure 3: Pathogen Detection among U.S. Adults with Community-Acquired Pneumonia Requiring Hospitalization, c) Of those in whom a pathogen was detected, bacteria were implicated in only 37% of cases i) S. pneumoniae was the most commonly detected bacterium (1) Five times greater incidence in those 65 years compared to younger adults ii) Atypical pathogens (M. pneumoniae, L. pneumophila, and C. pneumoniae combined) detected in 4% of adults Table 1. Bacterial pathogen detection among hospitalized adults with CAP by age group 18 Pathogen detected years (n=681) years (n=773) years (n=506) 80 years (n=299) All ages (n=2259) S. pneumoniae 5% 5% 7% 3% 5% M. pneumoniae 4% 1% 1% 1% 2% S. aureus 1% 2% 1% 1% 2% L. pneumophila 1% 2% 1% 1% 1% Enterobacteriaceae 1% 1% 2% 2% 1% Moore Page 6 of 20

7 d) 65% of the study population was PSI class I-III, 26% class IV, and 9% class V i) Median PSI score was 76 Table 2. Bacterial pathogen detection among hospitalized adults with CAP by PSI and ICU admission 18 Pathogen detected PSI I-III PSI IV-V P-value* Non-ICU ICU P-value (n=1475) (n=784) (n=1777) (n=482) S. pneumoniae 4% 7% % 8% <0.001 M. pneumoniae 3% 1% % 1% 0.06 S. aureus 1% 3% % 5% <0.001 L. pneumophila 2% 1% % 1% 0.43 Enterobacteriaceae 1% 2% % 3% <0.001 *P value comparing proportion of each detection between PSI I-III and PSI IV-V P value comparing proportion of each detection between non-icu and ICU admission Treatment Options Table 3. Representative MICs (range) (mcg/ml) of selected antimicrobials against CAP organisms Antimicrobial S. pneumo. MSSA K. pneumo. H. influenzae M. pneumo. L. pneumo. C. pneumo. Respiratory Fluoroquinolones Moxifloxacin ( ( ) 0.25) (0.13-1) Levofloxacin 1 (1-2) 0.25 ( ) (0.03->8) Macrolides Erythromycin 1.0 a > Azithromycin 1.0 a Clarithromycin 0.25 a > nd Generation Cephalosporins Cefuroxime rd Generation Cephalosporins Cefotaxime Ceftriaxone Aminopenicillins Ampicillin, Amoxicillin 0.03 a Aminopenicillin/Beta-Lactamase Inhibitor Amoxicillin a Clavulanate Ampicillin-Sulbactam 0.03 a C. pneumo. = Chlamydophila pneumoniae; H. influenzae = Haemophilus influenzae; K. pneumo. = Klebsiella pneumoniae; L. pneumo. = Legionella pneumoniae; M. pneumo. = Mycoplasma pneumoniae; MSSA = methicillin-sensitive Staphylococcus aureus; S. pneumo. = Streptococcus pneumoniae a Penicillin-susceptible S. pneumoniae (MIC 0.06 mcg/ml) Moore Page 7 of 20

8 Guideline Recommendations 1) Guidelines generally recommend coverage for both typical and atypical pathogens commonly found in CAP; however, atypical coverage is controversial Table 4. Empiric antibiotics suggested for community-acquired pneumonia American (IDSA/ATS) 8 British (NICE/BTS) 33,34 European (ESCMID/ERS) 22 Inpatient not in ICU; moderate severity Preferred Alternative Preferred Alternative Preferred Alternative Betalactam a + macrolide Respiratory fluoroquinolone Amoxicillin + macrolide Respiratory fluoroquinolone b Aminopenicillin ± macrolide Respiratory fluoroquinolone ATS = American Thoracic Society; BTS = British Thoracic Society; IDSA = Infectious Diseases Society of America; ESCMID = European Society for Clinical Microbiology and Infectious Diseases; ERS = European Respiratory Society; NICE = National Institute for Health and Care Excellence a Preferred beta-lactam drugs include cefotaxime (third generation), ceftriaxone (third generation), and ampicillin b Respiratory fluoroquinolone limited to situations in which other options cannot be prescribed or are ineffective (e.g., hepatotoxicity, skin reactions, cardiac arrhythmias, and tendon rupture). a) Recommendations for fluoroquinolone monotherapy or beta-lactam/macrolide dual therapy largely based on retrospective studies (Appendix, Tables 5 and 6) b) Mycoplasma and Chlamydophila infections are often self-limited and associated with low mortality risk 35 c) A 2012 Cochrane review and meta-analysis assessed treatment failure with regimens containing atypical antibiotic coverage compared to typical coverage only 36 i) 28 trials and 5,939 patients ii) Primary outcome: clinical failure in all studies iii) Non-significant trend toward an advantage in the atypical arm (RR 0.93; 95% CI 0.84 to 1.04) iv) Authors concluded no benefit with empirical atypical coverage in hospitalized patients with CAP d) Fluoroquinolone treatment considerations i) May be more strongly associated with Clostridium difficile-associated diarrhea (CDAD) than other antibiotics 37,38 ii) Monotherapy may result in better adherence to guideline-concordant therapy iii) More readily switch to PO 39 e) Macrolide treatment considerations i) Development of resistance of S. pneumoniae against multiple antibiotic classes ii) Possible increased risk of cardiac events 44,45 iii) Might favorably affect the host inflammatory response through nonantibiotic effects 46 Clinical Question Is empiric therapy with a beta-lactam noninferior in treating CAP in non-icu, hospitalized patients compared to beta-lactam-macrolide combination therapy or fluoroquinolone therapy? Moore Page 8 of 20

9 Literature Review Rodrigo C, McKeever TM, Woodhead M, et al. Single versus combination antibiotic therapy in adults hospitalised with community acquired pneumonia. Thorax 2013;68: Purpose Determine variation in use of single vs. combination antibiotic therapy in CAP and whether observed differences are related to clinical outcomes by pneumonia severity Design Population Intervention Endpoints Retrospective cohort study conducted in the United Kingdom Inclusion: Age > 16 years New infiltrates on CXR consistent with CAP Symptoms suggestive of lower respiratory tract infection Treatment given as for CAP Exclusion: Discharged from hospital within 10 days prior to current admission Receipt of fluoroquinolone antibiotics Single-agent therapy with beta-lactam antibiotic: any penicillin or cephalosporin Combination therapy with beta-lactam and macrolide: erythromycin, clarithromycin, azithromycin Primary: 30-day inpatient death rate Secondary: Length of stay ICU admission Need for mechanical ventilation (MV) Need for inotropic support (INS) Time of death 30-day readmission Methods All trusts across England and Wales invited to participate in BTS adult CAP national audit Sites asked to include consecutive immunocompetent adults hospitalized with CAP during the periods December 1, 2009 January 31, 2010 and December 1, 2010 January 31, 2011 Statistical Analyses Pearson s χ 2 used to compare categorical variables, perform univariate analyses and generation of ORs and 95% CIs Mann-Whitney U test used to compare non-parametric continuous variables Association between combination antibiotic therapy and 30-day IP death rate examined using a logistic regression model o Adjusted for age, sex, binary variables within CURB65 score (excluding age), comorbidities, IV antibiotic use, nursing home residency and ICU admission Subgroup analysis based on CURB65 score performed following adjustment for sex, comorbidities, IV antibiotic use and nursing home residency Statistical significance defined as P value < 0.05 Results expressed as OR with 95% CI Moore Page 9 of 20

10 Results 6312 patients in national audit dataset o 1072 (17%) received antibiotic other than a beta-lactam or a beta-lactam/macrolide combination à 5240 for analysis o Single-agent therapy: 2001 patients (38.2%) Amoxicillin-clavulanate (42.7%), amoxicillin (23.3%), benzylpenicillin (17.6%), piperacillin-tazobactam (12.8%), cephalosporins (3.6%) o Combination therapy: 3239 patients (61.8%) Clarithromycin (96.1%), erythromycin (3.7%), azithromycin (0.2%) o Approximately 50% CURB score 2 Significant differences at baseline o Combination therapy patients were younger (73 years vs. 76 years, p=0.001), had less coexisting stroke, renal disease, active malignancy o ICU support (OR 0.66, p<0.001) and IV ABX use (8.7% vs. 6.8%, p=0.009) were more common in the combination therapy group Authors Conclusion Critique Reviewer s Assessment Multivariate analyses of the association between antibiotic therapy and clinical outcomes Outcome measures Total (n=5240) Adj. OR (95% CI) Betalactam/macrolide combination therapy (n=3239) Beta-lactam therapy (n=2001) P- Value 30 day IP death (23.0) 536 (26.8) 0.72 (0.60 to <0.001 rate (24.4) 0.85) ICU admission 419 (8) 282 (8.7) 136 (6.8) 0.94 (0.72 to ) Need for MV 151 (2.9) 93 (2.9) 58 (2.9) 0.99 (0.71 to 1.38) day IP death rate stratified by PNA severity Low severity 201/ /1339 (7.9) 95/908 (10.5) 0.80 (0.56 to (CURB65=0-1) (8.9) 1.16) Moderate severity 370/ /919 (21.7) 171/561 (30.5) 0.54 (0.41 to <0.001 (CURB65=2) (25) 0.72) High severity (CURB65 3) 710/1513 (46.9) 440/981 (44.9) 270/532 (50.8) 0.76 (0.60 to 0.96) Combination therapy was associated with a significantly lower death rate after adjustment for demographic factors, PNA severity and treatment factors in patients with moderate- and high-severity CAP Strengths: Large number of patients Multivariate analysis used to adjust for confounders Limitations: High death rate (24%) related to severity Absence of additional details related to ABX therapy Absence of information about other aspects of care Treatment with fluoroquinolones excluded Despite the use of robust post hoc analyses, the retrospective design, the inherent biases of this study, and differences in antimicrobials used limit its generalizability to treating hospitalized patients empirically for CAP

11 Garin N, Genne D, Carballo S, et al. Beta-lactam monotherapy vs beta-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial. JAMA Intern Med. 2014;174(12): Purpose To test the noninferiority of a beta-lactam alone compared with a beta-lactam and macrolide combination in moderately severe CAP Design Open-label, multicenter, noninferiority, randomized trial conducted in Switzerland Population Inclusion: Age 18 years Presence of at least 2 clinical findings suggestive of pneumonia Presence of a new infiltrate on chest radiograph Exclusion: Severe immunosuppression Recent hospitalization (<14 days) Residency in a nursing home Severe pneumonia (PSI category V) Administration of any antibiotic for more than 24 hours before inclusion Intervention Randomized to initial treatment with a beta-lactam alone or a beta-lactam and a macrolide o Beta-lactam: cefuroxime 1.5 g IV three times daily followed by 500 mg twice daily PO or amoxicillin-clavulanic acid 1.2 g IV four times daily followed by 625 mg three times daily PO o Macrolide: clarithromycin 500 mg IV/PO twice daily Urine samples tested for L. pneumophila antigen Change in treatment only allowed if clinical deterioration o Admission to ICU o Lack of resolution of fever after 72 hours o Isolation of a resistant pathogen Endpoints Primary: Proportion of patients who did not reach clinical stability at day 7 o HR < 100/minute o SBP > 90 mmhg o Tympanic temperature < 38.0 C o RR < 24/minute o O 2 saturation > 90% on room air Secondary: 30- and 90-day mortality, transfer to ICU, length of stay, readmission, recurrence of pneumonia, subsequent introduction of any new antibiotic, complicated pleural effusion requiring chest tube insertion or thoracic surgery Methods Two pairs of blood cultures obtained before initiation of ABX Urine sample collected for detection of L. pneumophila antigen S. pneumoniae urine antigen detection left to discretion of provider Pharyngeal swab obtained on first day of the study Statistical Analyses o Processed for detection of C. pneumoniae and M. pneumoniae by PCR 8% noninferiority margin 280 patients per arm to have 90% power with a one-sided alpha of 0.10 Continuous variables reported as mean (SD) or median (IQR) Proportion of unstable patients at 7 days measured by Kaplan-Meier method o Unstable patients who were discharged were censored o Patients who died were considered unstable Subgroup analyses o Pathogen identified (atypical or typical) o Patient age (< 65 or 65 years) o PSI (category IV vs. I-III) Post hoc analysis conducted by the CURB-65 score ( 2 vs. < 2) Moore Page 11 of 20

12 Results January 13, 2009 January 31, patients included, 22 patients excluded after randomization o 291 in the monotherapy arm o 289 in the combination arm Median age of 76 years (21-101) and 251 (60.5%) had 1 or more comorbidities o Mean PSI score was 84 Pathogen Detected Monotherapy Arm Combination Arm S. pneumoniae 14.8% 15.6% L. pneumophila 4.1% 1.4% M. pneumoniae 2.1% 3.1% Amoxicillin-clavulanate used in 224 patients (77.0%) in the monotherapy arm and 215 patients (74.4%) in the combination arm o Remaining 141 patients treated with cefuroxime Median time to administration of clarithromycin was 47 hrs in patients with L. pneumophila infection in the monotherapy arm Endpoint Monotherapy (n=291) Combination Therapy (n=289) P-Value Primary endpoint Patients not reaching clinical 120 (41.2) 97 (33.6) 0.07 stability at day 7 Secondary endpoints ICU admission 12 (4.1) 14 (4.8) 0.68 LOS, median (IQR), d 8 (6-13) 8 (6-12) 0.65 Any change in initial ABX 39 (13.4) 46 (15.8) 0.39 treatment 30-day death 14 (4.8) 10 (3.4) day death 24 (8.2) 20 (6.9) day readmission 23 (7.9) 9 (3.1) day readmission 47 (16.2) 37 (12.7) 0.25 New PNA within 30 days 10 (3.4) 6 (2.1) 0.31 Authors Conclusion Critique Reviewer s Assessment In subgroup analyses, the effect of the treatment arm differed for patients with identification of an atypical pathogen (HR of reaching stability, 0.33; 95% CI, ) and those without (HR, 0.99; 95% CI, ) No significant interaction when stratified based on PSI or CURB65 categories, or age Noninferiority of initial empirical treatment with beta-lactam monotherapy in hospitalized patients with moderately severe CAP could not be determined Strength: Randomized, prospective, noninferiority design Limitations: Lack of blinding Inclusion of patients in PSI categories I and II Clinical stability as primary endpoint More Legionella in the monotherapy arm While this study did not demonstrate noninferiority of beta-lactam monotherapy in hospitalized individuals with CAP, the higher prevalence of Legionella in the monotherapy arm and inclusion of PSI categories I and II make these results less applicable to patients with more severe CAP (e.g., PSI categories III and IV)

13 Postma DF, van Werkhoven CH, van Elden LJ, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372(14): Purpose To test the noninferiority of beta-lactam monotherapy to the beta-lactam-macrolide and fluoroquinolone strategies with respect to 90-day mortality Design Cluster-randomized, crossover trial Population Inclusion: Age 18 years Clinically suspected CAP Required antibiotic treatment and hospitalization Exclusion: Patients with cystic fibrosis Intervention Beta-lactam (BL) monotherapy, beta-lactam with a macrolide (BLM), or fluoroquinolone (FQ) monotherapy Endpoints Antibiotics allowed were based on the 2005 Dutch guideline (Appendix C) Primary: All-cause mortality within 90 days after admission Secondary: Time to starting oral treatment, length of hospital stay, occurrence of minor or major complications during the hospital stay Methods Randomized into blocks of six o Each with a sequence of three antibiotic strategies Adherence to the strategy defined as initial treatment with the assigned antibiotic, irrespective of subsequent switches Statistical Analysis Intention-to-treat (ITT) population used in analyses Noninferiority assessed in a one-sided test at a significance level of 0.05 (2-sided 90% confidence intervals) Sensitivity analyses performed o Only patients with radiologically confirmed CAP o 30-day mortality Missing data imputed by multiple imputation (except respiratory rate, heart rate, and confusion at admission) Results 3325 patients eligible for inclusion à 2283 (69%) gave consent Median age 70 years (IQR, 59-79), baseline characteristics of included patients were similar among strategy periods o PSI score 85 across groups and median CURB-65 score was 1 (IQR, 1-2) o o o Microbial causes of CAP were similar in the three groups 15.9% S. pneumoniae 6.8% H. influenzae 2.1% atypical pathogens 27% of patients in BL monotherapy group received an antibiotic regimen covering atypical pathogens as initial therapy 38.7% of patients receiving BL monotherapy received atypical coverage during hospitalization (Table S3, Supplementary Appendix) Average of 4.5 days of treatment o Resistance to the initiated antibiotic treatment was highest in the beta-lactam strategy Primary Outcome o Absolute difference in adjusted risk of death between BL strategy and the BLM strategy was 1.9% (90% CI, -0.6 to 4.4) in favor of the BL strategy o -0.6% (90% CI, -2.8 to 1.9) difference between BL strategy and FQ strategy in favor of the FQ strategy o Do not include 3% margin, thus demonstrating noninferiority Secondary Outcomes o Median length of hospital stay was 6 days o Median duration of IV treatment was 3 days for the FQ strategy and 4 days during the other two periods o Proportions of patients started on oral antibiotics 27% during the FQ strategy periods Moore Page 13 of 20

14 Authors Conclusion Critique Reviewer s Assessment 13% during the BL periods 10% during the BLM periods o No significant difference in occurrence of major or minor complications Beta-lactam monotherapy was noninferior to beta-lactam-macrolide combination therapy and with fluoroquinolone monotherapy Strengths: Primary endpoint was 90-day all-cause mortality Pragmatic design modeling clinical behavior Limitations: Selection bias (inherent to cluster-randomized studies) More than a third of patients in the BL monotherapy group received atypical coverage Noninferiority margin changed from 2% to 3% 7 months after the study began The large percentage of patients in the beta-lactam monotherapy group who received atypical coverage make the results of this study difficult to apply. The beta-lactam monotherapy treatment strategy was noninferior through multiple analyses (including antibiotic-adherent, strategy-adherent, and ITT); however, this study provides inadequate evidence to recommend beta-lactam monotherapy in hospitalized patients with CAP. Conclusion & Recommendations 1) Guideline recommendations for empiric antibiotics for CAP largely based on retrospective studies a) More severe CAP (PSI IV-V and CURB 2) b) Confounding variables likely contributed to perceived mortality benefit of beta-lactam/macrolide combination therapy or fluoroquinolone monotherapy 2) Newer prospective, randomized trial data suggest that coverage of atypical pathogens may be unnecessary in certain groups a) Data insufficient to recommend beta-lactam monotherapy in hospitalized patients with CAP 3) In patients hospitalized with CAP, beta-lactam-macrolide combination or fluoroquinolone therapy should be used a) A cephalosporin plus a macrolide is a reasonable combination for empiric treatment, depending on susceptibilities b) A respiratory fluoroquinolone could be considered in penicillin-allergic patients or those at increased risk of a cardiac event 4) Future trials should only include patients with CURB score 2 and/or PSI categories III, IV, and V a) Stratify and treat patients according to PCT b) Primary outcome: 30-day mortality c) No allowance for atypical coverage in beta-lactam monotherapy group unless evidence of atypical infection i) Legionella urinary antigen positive ii) C. pneumonia or M. pneumonia nasal swab PCR positive Moore Page 14 of 20

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16 27. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336(4): Chalmers JD, Singanayagam A, Akram AR, et al. Severity assessment tools for predicting mortality in hospitalised patients with community-acquired pneumonia. Systematic review and meta-analysis. Thorax. 2010;65(10): Doi Y, Chambers HF. Chapter 20. Penicillins and β-lactamase Inhibitors. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Updated Edition. 8 ed. New York, New York: Elsevier Saunders; Craig WA, Andes DR. Chapter 21. Cephalosporins. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Updated Edition. 8 ed. New York, New York: Elsevier Saunders; Sivapalasingam S, Steigbigel NH. Chapter 29. Macrolides, Clindamycin, and Ketolides. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Updated Edition. 8 ed. New York, New York: Elsevier Saunders; Hooper DC, Strahilevitz J. Chapter 34. Quinolones. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Updated Edition. 8 ed. New York, New York: Elsevier Saunders; National Institute for Health and Care Excellence. Pneumonia: 27 Diagnosis and management of community- and hospital-acquired pneumonia in adults. NICE guidelines, (accessed Mar 15, 2017). 34. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management of community acquired pneumonia in adults: update Thorax. 2009;64 Suppl 3:iii File TM, Jr., Marrie TJ. Does empiric therapy for atypical pathogens improve outcomes for patients with CAP? Infect Dis Clin North Am. 2013;27(1): Eliakim-Raz N, Robenshtok E, Shefet D, et al. Empiric antibiotic coverage of atypical pathogens for communityacquired pneumonia in hospitalized adults. Cochrane Database Syst Rev. 2012(9):CD McCusker ME, Harris AD, Perencevich E, Roghmann MC. Fluoroquinolone use and Clostridium difficile-associated diarrhea. Emerg Infect Dis. 2003;9(6): Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372(16): Postma DF, van Werkhoven CH, van Elden LJ, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372(14): Fuller JD, Low DE. A review of Streptococcus pneumoniae infection treatment failures associated with fluoroquinolone resistance. Clin Infect Dis. 2005;41(1): Malhotra-Kumar S, Lammens C, Coenen S, Van Herck K, Goossens H. Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet. 2007;369(9560): Vanderkooi OG, Low DE, Green K, Powis JE, McGeer A, Toronto Invasive Bacterial Disease N. Predicting antimicrobial resistance in invasive pneumococcal infections. Clin Infect Dis. 2005;40(9): Barkai G, Greenberg D, Givon-Lavi N, Dreifuss E, Vardy D, Dagan R. Community prescribing and resistant Streptococcus pneumoniae. Emerg Infect Dis. 2005;11(6): Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20): Schembri S, Williamson PA, Short PM, et al. Cardiovascular events after clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies. BMJ. 2013;346:f Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23(3): Rodrigo C, McKeever TM, Woodhead M, Lim WS, British Thoracic S. Single versus combination antibiotic therapy in adults hospitalised with community acquired pneumonia. Thorax. 2013;68(5): Garin N, Genne D, Carballo S, et al. beta-lactam monotherapy vs beta-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial. JAMA Intern Med. 2014;174(12): Schouten JA, Prins JM, Bonten MJ, et al. Revised SWAB guidelines for antimicrobial therapy of community-acquired pneumonia. Neth J Med. 2005;63(8): Lee JS, Giesler DL, Gellad WF, Fine MJ. Antibiotic Therapy for Adults Hospitalized With Community-Acquired Pneumonia: A Systematic Review. JAMA. 2016;315(6): Gleason PP, Meehan TP, Fine JM, Galusha DH, Fine MJ. Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med. 1999;159(21): Houck PM, MacLehose RF, Niederman MS, Lowery JK. Empiric antibiotic therapy and mortality among medicare pneumonia inpatients in 10 western states : 1993, 1995, and Chest. 2001;119(5): Garcia Vazquez E, Mensa J, Martinez JA, et al. Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone. Eur J Clin Microbiol Infect Dis. 2005;24(3): Moore Page 16 of 20

17 54. Paul M, Nielsen AD, Gafter-Gvili A, et al. The need for macrolides in hospitalised community-acquired pneumonia: propensity analysis. Eur Respir J. 2007;30(3): Bratzler DW, Ma A, Nsa W. Initial antibiotic selection and patient outcomes: observations from the National Pneumonia Project. Clin Infect Dis. 2008;47 Suppl 3:S Blasi F, Iori I, Bulfoni A, Corrao S, Costantino S, Legnani D. Can CAP guideline adherence improve patient outcome in internal medicine departments? Eur Respir J. 2008;32(4): Tessmer A, Welte T, Martus P, Schnoor M, Marre R, Suttorp N. Impact of intravenous {beta}-lactam/macrolide versus {beta}-lactam monotherapy on mortality in hospitalized patients with community-acquired pneumonia. J Antimicrob Chemother. 2009;63(5): Ewig S, Hecker H, Suttorp N, Marre R, Welte T, group Cs. Moxifloxacin monotherapy versus ss-lactam mono- or combination therapy in hospitalized patients with community-acquired pneumonia. J Infect. 2011;62(3): Moore Page 17 of 20

18 Appendices A. Pneumonia Severity Index (PSI) 27 Step 1: Stratify to Risk Class I vs. Risk Classes II-V Step 2: Stratify to Risk Class II vs. III vs. IV vs. V Presence of: Demographics Over 50 years of age Yes/No If Male +Age (yr) Altered mental status Yes/No If Female +Age (yr) - 10 Pulse 125/minute Yes/No Nursing home resident +10 Respiratory rate >30/minute Yes/No Comorbidity Systolic blood pressure <90 mm Hg Yes/No Neoplastic disease +30 Temperature <35 C or 40 C Yes/No Liver disease +20 History of: Congestive heart failure +10 Neoplastic disease Yes/No Cerebrovascular disease +10 Congestive heart failure Yes/No Renal disease +10 Cerebrovascular disease Yes/No Physical Exam Findings Renal disease Yes/No Altered mental status +20 Liver disease Yes/No Pulse 125/minute +10 Respiratory rate >30/minute +20 If any "Yes", then proceed to Step 2 Systolic blood pressure <90 mmhg +20 If all "No" then assign to Risk Class I Temperature <35 C or 40 C +15 Lab and Radiographic Findings Arterial ph < BUN 30 mg/dl +20 Sodium <130 mmol/l +20 Glucose 250 mg/dl +10 Hematocrit <30% +10 PaO 2 <60 mmhg +10 Pleural effusion +10 Sum <70 = Risk Class II Sum = Risk Class III Sum = Risk Class IV Sum >130 = Risk Class V B. Procalcitonin as a marker of etiology in adults hospitalized with CAP 25 Moore Page 18 of 20

19 C. Flowchart of guideline recommendations on antibiotic treatment of CAP (2005 Dutch Guidelines) 49 Moore Page 19 of 20

20 Table 5. Description of Studies Comparing Beta-Lactam Plus Macrolide Combination Therapy vs. Beta-Lactam Monotherapy for Patients Hospitalized with CAP 50 Source Study Design Period of Data Collection No. of Patients Age, y Illness Severity Class/Score Outcomes Adjusted OR (95% CI) Gleason et Retrospective , (mean) PSI IV-V 30-day al, mortality Houck et al, Retrospective 1993, 1995, García Vázquez et al, Paul et al, 10, (mean) PSI IV-V 30-day mortality Prospective (mean) PSI IV-V In-hospital mortality mortality Prospective (mean) PSI IV-V 30-day Bratzler et Retrospective ,780 NR PSI IV-V 30-day al, mortality Blasi et al, Retrospective/ , (mean) PSI IV-V Mortality prospective at end of Tessmer et Prospective , (mean) CRB-65 score al, ABX 30-day mortality Beta-Lactam plus Macrolide No./Total (%) who Died 2 nd gen. cephalosporin + macrolide: 46/544 (8.4) 3 rd gen. cephalosporin + macrolide: 104/1139 (9.1) Cephalosporin or betalactam/beta-lactamase inh + macrolide by year: 1993: 26/312 (8.3) 1995: 48/561 (8.6) 1997: 89/870 (10.2) Beta-Lactam Monotherapy No./Total (%) who Died 511/3430 (14.9) 511/3430 (14.9) 242/1740 (13.9) 234/1982 (11.8) 244/1758 (13.9) 0.71 ( ) 0.74 ( ) 0.42 ( ) 0.93 ( ) 0.87 ( ) 63/918 (6.9) 36/270 (13.3) 0.50 ( ) 21/282 (7.4) 37/169 (21.9) 0.69 ( ) 338/5963 (5.7) 376/4463 (8.4) 0.70 ( ) 19/330 (5.7) 73/452 (16.2) 0.32 ( ) 42/946 (4.4) 78/908 (8.6) 1.04 ( ) Table 6. Description of Studies Comparing Respiratory Fluoroquinolone Monotherapy vs. Beta-Lactam Monotherapy for Patients Hospitalized with CAP 50 Source Study Design Period of No. of Age, y Illness Outcomes Fluoroquinolone Beta-Lactam Monotherapy Adjusted OR (95% CI) Data Collection Patients Severity Class/Score Monotherapy No./Total (%) who Died No./Total (%) who Died Bratzler et al, Retrospective ,780 NR PSI IV-V 30-day 318/5045 (6.3) 376/4463 (8.4) 0.70 ( ) mortality Blasi et al, Retrospective/ prospective , (mean) PSI IV-V Mortality at the end of ABX 33/363 (9.1) 73/452 (16.2) 0.59 ( ) Ewig et al, Prospective , (mean) NR, not reported a Hazard ratio not adjusted OR CRB-65 2 therapy 6-month mortality NR/365 NR/ ( ) a Moore Page 20 of 20