beta-lactam monotherapy in community-acquired...

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 pneumonia2. Describe available empiric treatment strategies for community-acquired pneumonia, focusing on the

potential advantages and disadvantages of each strategy3. Evaluate current literature regarding empiric treatment of community-acquired pneumonia in hospitalized

adults with beta-lactam/macrolide combination therapy, beta-lactam monotherapy, and fluoroquinolonemonotherapy

4. Given a patient case, determine the appropriateness of beta-lactam monotherapy as empiric treatment forcommunity-acquired pneumonia

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Background & Introduction 1) Pneumonia has been described for thousands of years; however, its causes have only been elucidated recently1

2) Causes of pneumonia2,3

a) Bacteriali) 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) Virali) Influenza, respiratory syncytial virus, parainfluenza virus, human metapneumovirus, adenovirus,

coronavirus, and rhinovirusii) Viral infections commonly predispose individuals to secondary bacterial infections

c) Fungali) 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 US4

3) Costs of pneumonia5-7

a) In the U.S., accounts for an estimated 63,000 deaths, 1.2 million hospitalizations, and 2.3 millionemergency department visits annually

b) Mean cost per stay is $9,500i) Costs increased by approximately $2,000 per stay in past decade

4) Pneumonia classification8,9

a) Community-acquired pneumonia (CAP)10

i) An acute infection of the pulmonary parenchyma contracted from the communityii) May be either bacterial or viral

b) Hospital-acquired pneumonia (HAP)2

i) Develops 48-72 hours after admission to acute care facilityii) Associated with different causative pathogens than CAP

c) Ventilator-associated pneumonia (VAP)2

i) Pneumonia occurring >48 hours post-endotracheal intubationii) Associated with pathogens similar to those found in HAP

d) Healthcare-associated pneumonia (HCAP) was described previously but has now been removed fromcurrent guidelines9,11

Epidemiology 1) Early literature described Streptococcus pneumoniae as causative pathogen for approximately 95% of cases of

pneumonia4

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 vaccines12-15

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

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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 smoking16 c) Higher proportion in Europe and other countries of S. pneumoniae compared to other pathogens17

3) Disproportionately affects the young and elderly6 a) 7% of hospital stays in those aged 1-17 years b) 4% of hospital stays in those aged 65-84 years c) 6% of hospital stays in those aged >85 years

Figure 1: Incidence of pneumonia-related hospitalization by age group18 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 days20

Diagnosis & Clinical Manifestations 1) Definitive diagnosis based on presence of select clinical features4,8

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 radiograph21

(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 tests8,22 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

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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 secretions4,23

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 protein24

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-6526

i) Five variables with a single point awarded for each

Figure 2: Severity assessment in a hospital setting: the CURB-65 score.26

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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 – 0.1-0.7% 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 risk28 Microbiology 1) Typical pathogens

a) Streptococcus pneumoniae i) Most commonly isolated bacterial cause of CAP18 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

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3) Community-acquired pneumonia requiring hospitalization among U.S. adults (EPIC-CAP) study18 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, 2010–2012.18

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 group18

Pathogen detected 18-49 years (n=681)

50-64 years (n=773)

65-79 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%

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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 admission18 Pathogen detected PSI I-III

(n=1475) PSI IV-V (n=784)

P-value* Non-ICU (n=1777)

ICU (n=482)

P-value§

S. pneumoniae 4% 7% 0.02 4% 8% <0.001 M. pneumoniae 3% 1% 0.001 2% 1% 0.06 S. aureus 1% 3% 0.001 1% 5% <0.001 L. pneumophila 2% 1% 0.06 2% 1% 0.43 Enterobacteriaceae 1% 2% 0.002 1% 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 Options29-32 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

(0.06-0.5) 0.12 (0.06-0.25)

1 (0.13-1)

0.03-0.06 0.12-0.3 0.06 0.06-1

Levofloxacin 1 (1-2) 0.25 (0.25-0.5)

0.5 (0.03->8)

0.015-0.5 0.5-2.5 0.016-0.03 0.5-1

Macrolides Erythromycin 1.0a >128 - 8 ≤0.015 0.5 0.25 Azithromycin 1.0a - - 2 0.015 0.5 0.25 Clarithromycin 0.25a >128 - 16 ≤0.015 0.046 0.03 2nd Generation Cephalosporins Cefuroxime 0.25 2 16 2 - - - 3rd Generation Cephalosporins Cefotaxime 0.06 2 0.25 0.015 - - - Ceftriaxone 0.06 4 0.25 0.015 - - - Aminopenicillins Ampicillin, Amoxicillin

0.03a 0.12 50 0.25 - - -

Aminopenicillin/Beta-Lactamase Inhibitor Amoxicillin-Clavulanate

0.03a 1 2 0.5 - - -

Ampicillin-Sulbactam 0.03a 1 4 0.25 - - - 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 aPenicillin-susceptible S. pneumoniae (MIC ≤ 0.06 mcg/mL)

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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

Preferred Alternative Preferred Alternative Preferred Alternative Inpatient not in ICU; moderate severity

Beta-lactama + macrolide

Respiratory fluoroquinolone

Amoxicillin + macrolide

Respiratory fluoroquinoloneb

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 risk35 c) A 2012 Cochrane review and meta-analysis assessed treatment failure with regimens containing atypical

antibiotic coverage compared to typical coverage only36 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

antibiotics37,38 ii) Monotherapy may result in better adherence to guideline-concordant therapy iii) More readily switch to PO39

e) Macrolide treatment considerations i) Development of resistance of S. pneumoniae against multiple antibiotic classes40-43 ii) Possible increased risk of cardiac events44,45 iii) Might favorably affect the host inflammatory response through nonantibiotic effects46

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?

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Literature Review

Rodrigo C, McKeever TM, Woodhead M, et al. Single versus combination antibiotic therapy in adults hospitalised with community acquired pneumonia. Thorax 2013;68:493-495.47 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 Retrospective cohort study conducted in the United Kingdom Population 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

Intervention Single-agent therapy with beta-lactam antibiotic: any penicillin or cephalosporin Combination therapy with beta-lactam and macrolide: erythromycin, clarithromycin, azithromycin

Endpoints 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 χ2 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

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 Approximately50%CURBscore≥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

Multivariate analyses of the association between antibiotic therapy and clinical outcomes

Outcome measures

Total (n=5240)

Beta-lactam/macrolide combination therapy (n=3239)

Beta-lactam therapy (n=2001)

Adj. OR (95% CI)

P-Value

30 day IP death rate

1281 (24.4)

745 (23.0) 536 (26.8) 0.72 (0.60 to 0.85)

<0.001

ICU admission 419 (8) 282 (8.7) 136 (6.8) 0.94 (0.72 to 1.22)

0.635

Need for MV 151 (2.9) 93 (2.9) 58 (2.9) 0.99 (0.71 to 1.38)

0.508

30 day IP death rate stratified by PNA severity Low severity (CURB65=0-1)

201/2247 (8.9)

106/1339 (7.9) 95/908 (10.5) 0.80 (0.56 to 1.16)

0.238

Moderate severity (CURB65=2)

370/1480 (25)

199/919 (21.7) 171/561 (30.5) 0.54 (0.41 to 0.72)

<0.001

High severity (CURB65≥3)

710/1513 (46.9)

440/981 (44.9) 270/532 (50.8) 0.76 (0.60 to 0.96)

0.025

Authors’ Conclusion

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

Critique 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

Reviewer’s Assessment

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

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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):1894-1901.48 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 O2 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

o Processed for detection of C. pneumoniae and M. pneumoniae by PCR Statistical Analyses

• 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)

Results • January 13, 2009 – January 31, 2013 • 602 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 stability at day 7

120 (41.2) 97 (33.6) 0.07

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 treatment

39 (13.4) 46 (15.8) 0.39

30-day death 14 (4.8) 10 (3.4) 0.42 90-day death 24 (8.2) 20 (6.9) 0.54 30-day readmission 23 (7.9) 9 (3.1) 0.01 90-day readmission 47 (16.2) 37 (12.7) 0.25 New PNA within 30 days 10 (3.4) 6 (2.1) 0.31 • 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, 0.13-0.85) and those without (HR, 0.99; 95% CI, 0.80-1.22)

• No significant interaction when stratified based on PSI or CURB65 categories, or age Authors’ Conclusion

Noninferiority of initial empirical treatment with beta-lactam monotherapy in hospitalized patients with moderately severe CAP could not be determined

Critique 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)

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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):1312-1323. 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

• Antibiotics allowed were based on the 2005 Dutch guideline (Appendix C) Endpoints 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 Microbial causes of CAP were similar in the three groups

§ 15.9% S. pneumoniae § 6.8% H. influenzae § 2.1% atypical pathogens

o 27% of patients in BL monotherapy group received an antibiotic regimen covering atypical pathogens as initial therapy

o 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

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§ 13% during the BL periods § 10% during the BLM periods

o No significant difference in occurrence of major or minor complications Authors’ Conclusion

Beta-lactam monotherapy was noninferior to beta-lactam-macrolide combination therapy and with fluoroquinolone monotherapy

Critique 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

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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 <7.35 +30 BUN ≥30 mg/dL +20 Sodium <130 mmol/L +20 Glucose ≥250 mg/dL +10 Hematocrit <30% +10 PaO2 <60 mmHg +10 Pleural effusion +10 Sum <70 = Risk Class II Sum 71-90 = Risk Class III Sum 91-130 = Risk Class IV Sum >130 = Risk Class V

B. Procalcitonin as a marker of etiology in adults hospitalized with CAP25

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

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Table 5. Description of Studies Comparing Beta-Lactam Plus Macrolide Combination Therapy vs. Beta-Lactam Monotherapy for Patients Hospitalized with CAP50

Source Study Design Period of Data Collection

No. of Patients

Age, y Illness Severity Class/Score

Outcomes Beta-Lactam plus Macrolide No./Total (%) who Died

Beta-Lactam Monotherapy No./Total (%) who Died

Adjusted OR (95% CI)

Gleason et al, 199951

Retrospective 1994-1995 12,945 79 (mean) PSI IV-V 30-day mortality

2nd gen. cephalosporin + macrolide: 46/544 (8.4) 3rd gen. cephalosporin + macrolide: 104/1139 (9.1)

511/3430 (14.9) 511/3430 (14.9)

0.71 (0.52-0.96) 0.74 (0.60-0.92)

Houck et al, 200152

Retrospective 1993, 1995, 1997

10,069 79 (mean) PSI IV-V 30-day mortality

Cephalosporin or beta-lactam/beta-lactamase inh + macrolide by year: 1993: 26/312 (8.3) 1995: 48/561 (8.6) 1997: 89/870 (10.2)

242/1740 (13.9) 234/1982 (11.8) 244/1758 (13.9)

0.42 (0.25-0.69) 0.93 (0.62-1.41) 0.87 (0.63-1.19)

García Vázquez et al, 200553

Prospective 1996-2001 1188 68 (mean) PSI IV-V In-hospital mortality

63/918 (6.9) 36/270 (13.3) 0.50 (0.31-0.81)

Paul et al, 200754

Prospective 2002-2004 451 67 (mean) PSI IV-V 30-day mortality

21/282 (7.4) 37/169 (21.9) 0.69 (0.32-1.48)

Bratzler et al, 200855

Retrospective 1998-2001 24,780 NR PSI IV-V 30-day mortality

338/5963 (5.7) 376/4463 (8.4) 0.70 (0.60-0.90)

Blasi et al, 200856

Retrospective/ prospective

2002-2004 2,847 79 (mean) PSI IV-V Mortality at end of ABX

19/330 (5.7) 73/452 (16.2) 0.32 (0.19-0.56)

Tessmer et al, 200957

Prospective 2002-2006 1,854 66 (mean) CRB-65 score ≥ 2

30-day mortality

42/946 (4.4) 78/908 (8.6) 1.04 (0.66-1.63)

Table 6. Description of Studies Comparing Respiratory Fluoroquinolone Monotherapy vs. Beta-Lactam Monotherapy for Patients Hospitalized with CAP50

Source Study Design Period of Data Collection

No. of Patients

Age, y Illness Severity Class/Score

Outcomes Fluoroquinolone Monotherapy No./Total (%) who Died

Beta-Lactam Monotherapy No./Total (%) who Died

Adjusted OR (95% CI)

Bratzler et al, 200855

Retrospective 1998-2001 24,780 NR PSI IV-V 30-day mortality

318/5045 (6.3) 376/4463 (8.4) 0.70 (0.60-0.90)

Blasi et al, 200856

Retrospective/ prospective

2002-2004 2,847 79 (mean)

PSI IV-V Mortality at the end of ABX therapy

33/363 (9.1) 73/452 (16.2) 0.59 (0.37-0.94)

Ewig et al, 201158

Prospective 2002-2007 2,068 64 (mean)

CRB-65 ≥ 2 6-month mortality

NR/365 NR/1703 0.57 (0.35-0.92)a

NR, not reported a Hazard ratio not adjusted OR

beta-lactam monotherapy in community-acquired...

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