The hospitalist perspective on treatment of community-acquired bacterial pneumonia.

C L I N I C A L F O C U S : C L I N I C A L P ROTO C O L S A N D C A R D I O VA S C U L A R D I S E A S E , E M E R G E N C Y S U R G E R Y, A N D E M E R G E N C Y M E D I C I N E

The Hospitalist Perspective on Treatment of Community-Acquired Bacterial Pneumonia

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DOI: 10.3810/pgm.2014.03.2737

Alpesh N. Amin, MD, MBA 1 Elizabeth A. Cerceo, MD 2 Steven B. Deitelzweig, MD 3 James C. Pile, MD 4 David J. Rosenberg, MD 5 Bradley M. Sherman, MD 6 Department of Medicine, University of California at Irvine, Irvine, CA; 2 Department of Hospital Medicine, Cooper University Health Care, Camden, NJ; 3Ochsner Clinic Foundation, New Orleans, LA; 4 Department of Hospital Medicine, Medicine Institute, Cleveland Clinic, Cleveland, OH; 5Department of Medicine, Hofstra North Shore LIJ School of Medicine, Manhasset, NY; 6 Department of Medicine, Glen Cove Hospital, North Shore LIJ University Health System, Oyster Bay, NY 1

Abstract: Community-acquired bacterial pneumonia (CABP) is an important health care concern in the United States and worldwide, and is associated with significant morbidity, mortality, and health care expenditure. Streptococcus pneumoniae is the most frequent causative pathogen of CABP. Other common pathogens include Staphylococcus aureus, Haemophilus influenzae, Enterobacteriaceae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. However, in clinical practice, the causative pathogen of CABP is most often not identified. Therefore, a common treatment approach for patients hospitalized with CABP is empiric antibiotic therapy with a β-lactam in combination with a macrolide, respiratory fluoroquinolones, or tetracyclines. An increase in the incidence of S. pneumoniae that is resistant to frequently used antibiotics, including β-lactams, macrolides, and tetracyclines, provides a challenge for the physician when selecting empiric antimicrobial therapy. When patients with CABP do not respond to initial therapy, they must be adequately reevaluated with further diagnostic testing, change in antimicrobial regimen, and/or transfer of the patient to a higher level of care. The role of hospital medicine physicians is crucial in treating patients who are hospitalized with CABP. An important focus of hospitalists is to provide care improvement in a way that addresses both patient and hospital needs. It is essential that the hospitalist provides best possible patient care, including adherence to quality measures, optimizing the patient’s hospital length of stay, and arranging adequate post-discharge care in an effort to prevent readmission and provide appropriate ongoing outpatient care. Keywords: community-acquired pneumonia; hospitalist; hospital medicine; antimicrobial therapy

Introduction

Correspondence: Alpesh N. Amin, MD, MBA, Department of Medicine, University of California, Irvine, UCIMC, 101 The City Drive South, Building 26, Room 1005, ZC-4076H, Irvine, CA 92868. Tel: 714-456-3785 Fax: 714-456-7182 E-mail: [email protected]

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Community-acquired bacterial pneumonia (CABP) is an important health concern in the United States and worldwide, and is associated with significant patient morbidity, mortality, and health care expenditure. The incidence of CABP is approximately 5 cases per 1000 person-years in working-age persons (18 to 64 years old).1 In 2007, pneumonia accounted for 610 000 hospitalizations in patients aged $ 65 years.2 Along with influenza, pneumonia is the ninth leading cause of death in the United States and the leading cause of death from an infectious etiology.3 Hospitalists commonly care for a high percentage of patients admitted to the hospital with CABP. In our article, we review causative pathogens, discuss current diagnosis and treatment practices for patients with CABP, assess issues of nonresponding patients, and summarize important aspects of patient care from the perspective of the hospitalist.

Causative Pathogens

Streptococcus pneumoniae is the most common cause of CABP. Multidrug-resistant S. pneumoniae (MDRSP) is of increasing concern in patients presenting with

© Postgraduate Medicine, Volume 126, Issue 2, March 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


Hospitalist Perspective on Treatment of CABP

CABP. Antimicrobial surveillance data show an increase in resistance among S. pneumoniae to common antibiotics, including β-lactams, macrolides, and tetracyclines, from 1998 to 2011.4 In the Assessing Worldwide Resistance Evaluation (AWARE) surveillance program between 2008 and 2010, 30% of S. pneumoniae isolates were multidrugresistant, defined as resistant to $ 2 of the following: penicillin ($ 8 mg/L), ceftriaxone, erythromycin, tetracycline, levofloxacin, and trimethoprim-sulfamethoxazole.5 Risk factors for β-lactam-resistant S. pneumoniae are listed in Table 1.6 The most important patient risk factor for developing MDRSP is previous antibiotic use.7 Other common pathogens include Staphylococcus aureus (identified in 4%–25% of patients with CABP), Haemophilus influenzae (3%–10%), Enterobacteriaceae (3%–10%), Legionella pneumophila (2%–8%), Mycoplasma pneumoniae (1%–6%), and Chlamydophila pneumoniae (4%–6%).6,8–10 Post-influenza bacterial pneumonia occurs in approximately 0.5% to 2.5% of patients with influenza and frequently identified pathogens include S. pneumoniae, H. influenzae, and S. aureus.11 Staphylococcus aureus is another common causative pathogen of CABP, frequently, methicillin-susceptible S. aureus (MSSA); however, methicillin-resistant S. aureus (MRSA) has begun to emerge.12 Though still an infrequent cause of CABP, MRSA-induced CABP is increasing in the United States. Patients with MRSA pneumonia may have a more severe clinical presentation than patients with CABP caused by other organisms.10 In a prospective study of 627 patients with community-acquired pneumonia (CAP), a pathogen was identified in 102 (17%) patients; MSSA was the identified pathogen in 9 (1.5%) patients, and MRSA was the identified pathogen in 14 (2.4%) patients.10 In a separate prospective study of 4543 patients with culture-positive pneumonia, S. aureus was the identified pathogen in 25.5% of patients, and 35% of the cases exhibited methicillin resistance.13 However, the high prevalence of S. aureus identified in the study is inconsistent with other studies of the epidemiology of CABP. The different findings may be due to the methodology of the study, including the retrospective Table 1. Risk Factors for β-lactam-resistant Streptococcus pneumoniae Aged 2 years or 65 years

β-lactam therapy within the previous 3 months Alcoholism Medical comorbidities Immunosuppressive illness or therapy Exposure to a child in a daycare center Data from Mandell LA, Wunderink RG, Anzueto A, et al; Infectious Diseases Society of America.6

nature of the study and the inclusion of only culture-positive cases. Many European countries have a lower rate of MRSA pneumonia compared with the United States. In a study of 1071 patients with CABP, MRSA was the identified pathogen in only 0.6% of patients.14 Although MRSA is an infrequent cause of pneumonia, it remains important because it occurs in younger patients and can result in high mortality if not suspected early.12 Viruses are detected in 15% to 54% of hospitalized adults with CAP.15 Co-infection with bacteria and viruses is relatively common and is detected in 4% to 30% of hospitalized adults with CAP.15 It is challenging to differentiate viral CAP from mixed infection and bacterial CAP. Using biomarkers and viral testing (see Diagnostic Testing section) together holds potential for identifying patients with a viral infection for whom antibiotic exposure can be safely limited. Pathogens will vary based on the patient population. In a prospective study of 3523 patients with CAP, microbial etiology was established for 32% of outpatients, 41% of inpatients treated in non-intensive care unit (ICU) settings, and 53% of patients treated in the ICU.16 In outpatients, atypical pathogens (36%), S. pneumoniae (35%), viruses (9%), and mixed etiologies (9%) were most often identified. For inpatients treated in non-ICU settings, S. pneumoniae (43%) was the most common pathogen, followed by atypical pathogens (16%), mixed etiologies (13%), and viruses (12%). The most often seen pathogen in patients treated in the ICU was S. pneumoniae (42%), followed by mixed etiologies (22%), and atypical pathogens (14%).

Diagnosis Diagnostic Testing

The presence of clinical features, such as cough, fever, sputum production, and pleuritic chest pain can suggest a diagnosis of CABP in patients6; however, no combination of history and physical findings is sufficient without a chest radiograph (CXR) to diagnose pneumonia. Radiographic findings may be concealed by volume depletion.17 Rehydration may facilitate the expression of infiltrates, and for patients with negative chest radiography findings, repeat imaging may be necessary in 24 to 48 hours.6 If CXR is not available and/or not possible, such as in emergency situations, in resource-limited settings, or in pregnant women, a possible alternative is lung ultrasound.18,19 Notably, there are several disease states that may mimic pneumonia in clinical, radiographic, and laboratory findings and represent a challenge to the diagnosing physician (Table 2).20,21 It is important to add that a repeat CXR during treatment is necessary only

© Postgraduate Medicine, Volume 126, Issue 2, March 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 19 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Amin et al

Table 2. Disease States That Mimic CAP


Unusual infectious diseases (eg, tuberculosis, actinomycosis) Pulmonary embolism Cryptogenic organizing pneumonia Pulmonary vasculitis (eg, Wegener’s granulomatosis, Churg-Strauss syndrome) Hypersensitivity pneumonitis Acute or chronic eosinophilic pneumonia Leukemia Neoplasms (eg, bronchogenic carcinoma, lymphoma, bronchoalveolar carcinoma) Bronchocentric granulomatosis Lupus pneumonitis Drug-induced pulmonary infiltrates Acute sickle chest syndrome Radiation pneumonitis Acute alveolar hemorrhage Data from Alves dos Santos JW, Torres A, Michel GT, et al20 and Rome L, Murali G, Lippmann M.21 Abbreviation: CAP, community-acquired pneumonia.

when the patient is deteriorating or not improving. A repeat CXR is recommended in patients aged . 50 years at 7 to 12 weeks posttreatment.22 The CXR is used to document resolution of pneumonia and exclude underlying diseases.22 Generally, additional testing is not warranted. Situations in which more extensive diagnostic testing is required are listed in Table 3. In recent years, the use of microbiologic analyses (eg, blood/sputum cultures, urinary antigen tests [UATs], or polymerase chain reactions [PCRs]) to identify a pathogen in CAP has declined.8 Various factors may be responsible, including difficulty in obtaining a useful sample, limitation of currently available tests to detect pathogens, guidelines in place for timely administration of antibiotics, and similar clinical outcomes regardless of whether a patient is treated empirically or with pathogen-directed therapy.8 Nevertheless, diagnostic testing is evolving and may be useful in providing data to ensure patients receive appropriate therapy.

can detect 17 respiratory viruses and 3 bacterial pathogens (Bordetella pertussis, C. pneumoniae, and M. pneumoniae).24 Most recently, the FDA cleared a loop-mediated isothermal DNA amplification (LAMP) to detect M. pneumoniae infections.25 Use of PCR testing is usually employed to identify viral pathogens. Most effective use of the bacterial PCR tests has not been defined. They may be more helpful than the UAT listed in Table 3, or in patients who fail to respond to therapy. Bacterial PCR tests have the potential to allow focused antibiotic therapy early in the course of patient treatment, but will have to undergo additional study before they are widely used.

Inflammatory Markers Procalcitonin is an inflammatory biologic marker that can be beneficial in distinguishing between bacterial and nonbacterial causes of pneumonia.23,26 In a randomized controlled trial, use of a procalcitonin algorithm helped decrease duration of antimicrobial therapy and lowered antibiotic-related adverseeffect rates.27 Procalcitonin appears to be most useful in ruling out CABP and thus identifying patients who do not need antibacterial therapy.23 C-reactive protein (CRP) is another marker of inflammation, however, CRP has limited diagnostic value for pneumonia.28 Use of CRP has only been shown to be informative in ruling out pneumonia initially in the outpatient setting. In a diagnostic study of outpatients, signs and symptoms correctly identified diagnostic risk in 26% of patients.28 In the 74% of patients in whom diagnostic doubt remained, measurement of CRP concentration helped to correctly exclude pneumonia. All study patients had acute respiratory illness but were at generally low risk for pneumonia, so that CRP added modestly to clinical impression in the ability to rule out CAP without a CXR. Further research is necessary to determine the performance of CRP in other settings.

Polymerase Chain Reaction Testing Use of PCR, an innovative molecular test, can quickly and efficiently detect specific pathogens.23 Advantages compared with conventional diagnostic techniques include the opportunity to identify drug resistance, ability to recognize specific clones for epidemiologic assessment, possibility of testing for several pathogens at a time, ability to detect organisms that are unable to be cultured, and the fact that PCR is less affected by prior antimicrobial therapy.23 Polymerase chain reactions may be a very useful tool in the detection of respiratory viruses, and for many respiratory viruses, PCR is now the most sensitive diagnostic approach.23 Currently, US Food and Drug Administration (FDA)-cleared PCR 20

Urinary Antigen Testing Urinary antigen testing detects soluble pneumococcal antigen or Legionella antigen in urine. A positive pneumococcal or Legionella UAT is useful in confirming the respective infection23; however, a negative result in the respective test does not adequately rule out a pneumococcal or Legionella infection. Disadvantages of the pneumococcal UAT are that it is affected by hydration status and does not isolate an organism for in vitro susceptibility testing.23 Nevertheless, the pneumococcal UAT may be more cost-effective in ICU patients.29 The Legionella UAT can detect only Legionella pneumophila serogroup 1, which accounts for approximately



Table 3. Clinical Indications for More Extensive Diagnostic Testing Indication

Blood Culture

Sputum Culture

Legionella UAT

Pneumococcal UAT

Other

Intensive care unit admission Failure of outpatient antibiotic therapy Cavitary infiltrates Leukopenia Active alcohol abuse Chronic severe liver disease Severe obstructive/structural lung disease Asplenia (anatomic or functional) Recent travel (within past 2 weeks) Positive Legionella UAT result Positive pneumococcal UAT result Pleural effusion

X

X X X

X X

X X

Xa

X

X X X

X X X X

Xb

X X

X

X X

X X X X

d

X NA X

Xc NA X

Xe

Endotracheal aspirate if intubated, possibly bronchoscopy or nonbronchoscopic bronchoalveolar lavage. Fungal and tuberculosis cultures. c Hotel or cruise ship stay in previous 2 weeks, suspect Legionella species; travel to or residence in southwestern United States, suspect Coccidioides species or Hantavirus; travel to or residence in Southeast and East Asia, suspect Burkholderia pseudomallei, avian influenza, severe acute respiratory syndrome. d Special media for Legionella. e Thoracentesis and pleural fluid cultures. From Mandell LA, Wunderink RG, Anzueto A, et al; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72.6 © 2007; by permission of Infectious Diseases Society of America. Abbreviations: NA, not applicable; UAT, urinary antigen test.


a

b

85% of community-acquired isolates in the United States and Europe.23 The low cost and rapid performance make the test a favored option in the detection of Legionella.8,23 Use of these tests should be focused on the patient populations with the indications listed in Table 3.

Severity-of-Illness Scores

Several scoring systems currently exist for assessing pneumonia severity.30 The most well-known systems include the pneumonia severity index (PSI) and CURB−65. Both the PSI and CURB-65 are valuable tools for deciding whether or not to admit a patient to the hospital. Advantages, limitations, and mortality risk categories of the 2 scoring systems are listed in Table 4.30–34 The PSI stratifies patients into 5 mortality risk classes based on age, gender, comorbid conditions, physical exam, and laboratory assessments.32 Use of the PSI is a complex risk-calculation strategy, which limits its practicality in clinical practice. The CURB-65 system, which is easier to use, identifies 5 factors associated with increased mortality.34 One point is assigned for each of the following risk factors: confusion, urea . 7 mmol/L (blood urea nitrogen [BUN] . 20 mg/ dL), respiratory rate $ 30 breaths/min, systolic blood pressure (SBP) , 90 mm Hg or diastolic (DBP) # 60 mm Hg, and age $ 65 years.34 The CURB-65 investigators suggested that individuals with a score $ 2 should be treated as inpatients, although, patients with a score of 0–1 may often require hospitalization and clinical judgment should always be used when assessing the need for hospital admission.35

Treatment of CABP Empiric Antimicrobial Therapy

Selection of an initial antimicrobial regimen for empiric therapy is based on consideration of the most likely underlying pathogens and knowledge of local susceptibility patterns.6 In the United States, current guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) recommend β-lactams, macrolides, respiratory fluoroquinolones, and tetracyclines.6 For non-ICU patients treated for CABP in the hospital, a respiratory fluoroquinolone or a β-lactam plus a macrolide are recommended. Several other regimens are often used in other countries. Betalactam antibiotics that are effective against S. pneumoniae and other common, non-atypical CABP pathogens, which are not overly broad are preferred. Third-generation cephalosporins are usually used in combination with a macrolide for non-ICU inpatient therapy. Third-generation cephalosporin monotherapy has been associated with increased patient mortality.6 In a retrospective study, 6.3% of patients with CAP died following treatment with ceftriaxone monotherapy, compared with 2.8% of patients treated with ceftriaxone plus a macrolide (P , 0.001).36 Length of stay (LOS) and total charges were also increased in patients treated with ceftriaxone monotherapy compared with a combination with a macrolide (P , 0.001 for both comparisons). Macrolides have activity against S. pneumoniae and atypical pathogens. Clinical failure can often occur due to resistant isolates, which limits the use of macrolide monotherapy.6 Doxycycline can be used as a cost-effective a lternative to a macrolide for


Amin et al

Table 4. Risk Assessment With PSI and CURB-65 Severity Score

Advantages

Limitations

Mortality

PSI

Well validated Improves outcome Good performance in low-mortality-risk patients

Complex to calculate Overemphasis on age and comorbidities Excludes risk factors such as COPD and DM Less useful for decision to admit to ICU or decision to use ventilator or vasopressor support Limited use outside hospital setting

Score

Predicted,32 %

Observed in meta-analysis,33 %

I-II

0.3

0.75

I-III

0.4

1.6

IV

9.3

8.9

V Score

27 Predicted,34 %

28.2 Observed in meta-analysis,33 %

0–1

1.2

2.0

2

9

8.3

3–5

22.6

22.3


CURB-65

Well validated Simple to calculate

Underestimates severity in young patients Does not take into account comorbidities Less useful for decision to admit to ICU or decision to use ventilator or vasopressor support Limited use outside hospital setting

Adapted from Pereira JM, Paiva JA, Rello J. Assessing severity of patients with community-acquired pneumonia. Semin Respir Crit Care Med. 2012;33(3):272–283.31 © 2012, Thieme Publishing Group. Used with permission. Abbreviations: COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ICU, intensive care unit; PSI, pneumonia severity index.

macrolide-resistant S. pneumoniae.6 Fluoroquinolones should be reserved for treating patients with comorbid conditions, risk factors for drug-resistant S. pneumoniae, or those with recent antimicrobial use.6 Fluoroquinolones may often be used in inappropriate patient populations, such as in patients who were previously healthy and have no risk factors for drug-resistant S. pneumoniae infection. Inappropriate use can accelerate emergence of resistance.6 With increasing resistance rates of S. pneumoniae to several antimicrobials, empiric therapy for CABP may evolve.4 In patients with postinfluenza pneumonia, there are theoretic reasons to believe that the late use of a neuraminidase inhibitor can be useful in the management of patients with combined viral and bacterial pneumonia. In addition, a protein-synthesis inhibitor antibacterial (eg, macrolide, aminoglycoside, tetracycline) may be beneficial as part of an antimicrobial combination therapy; however, limited data are available and further clinical study is necessary to support routine clinical use.11

Newer Antimicrobial Agents for the Treatment of CABP Tigecycline and ceftaroline fosamil are intravenous (IV) antimicrobials that have been approved for the treatment of patients with CABP since the guidelines from IDSA/ATS were published in 2007. Tigecycline is a glycylcycline with in vitro activity against gram-positive, gram-negative, anaerobic, and a typical bacteria. Tigecycline is approved by the FDA for treatment of CAP, complicated intra-abdominal infections, and complicated skin and skin-structure infections, including infections caused by MRSA.37 In 2 phase 3 clinical trials, tigecycline was compared with levofloxacin in patients hospitalized with CAP.38 In a pooled analysis of the trials, cure rates 22

were similar in the clinical modified intent-to-treat (ITT) population, defined as all patients who received $ 1 dose of study drug and who met minimum disease requirements with clinical evidence of CAP (cure rates: 81% in the tigecycline group vs 79.7% in the levofloxacin group; P , 0.001 for noninferiority). Overall, tigecycline-treated patients experienced more adverse events (AEs) that were considered related to the study drug than levofloxacin-treated patients (47.9% vs 37.4%; P , 0.01). Safety concerns have been raised regarding an increased risk of mortality in patients treated with tigecycline.39 Recently, the tigecycline label was revised to reflect the findings of a meta-analysis that demonstrated a 0.6% adjusted risk increase with tigecycline in all-cause mortality in clinical trials of patients with approved indications (95% CI, 0.0–1.2).40,41 The FDA recommends that tigecycline be reserved for situations in which there is no suitable alternative treatment. Ceftaroline, the active form of the prodrug ceftaroline fosamil, is a cephalosporin exhibiting broad-spectrum bactericidal in vitro activity against gram-positive organisms, including multidrug-resistant S. pneumoniae and MRSA, as well as common gram-negative pathogens. Ceftaroline exhibits a high affinity for penicillin-binding proteins (PBPs), including PBP 2a, 2b, and 2x, which correlates with its efficacy against MDRSP and MRSA.42,43 Ceftaroline fosamil is approved by the FDA for the treatment of CABP and acute bacterial skin and skin-structure infections.44 Ceftaroline fosamil was compared with ceftriaxone in 2 phase 3 clinical trials for the treatment of patients with CAP.9,45 In a pooled analysis of the trials, 84.3% of patients treated with ceftaroline fosamil experienced clinical cure compared with 77.7% of patients treated with ceftriaxone (difference, 6.0%; 95% CI, 1.4–10.7) in the modified ITT efficacy population




(defined as any patient who received study drug with a risk class of III or IV based on PSI).46 In response to ongoing efforts to design appropriate clinical trials for the treatment of CABP, the FDA recommended evaluation of clinical response at 72 hours after initiating therapy (day 4).47 At day 4 in the phase 3 clinical trials, clinical response was demonstrated in 69.5% (107/154) of patients in the ceftaroline fosamil-treated group and 59.4% (92/155) of patients in the ceftriaxone-treated group (treatment difference, 10.1%; 95% CI, −0.6–20.6).48 Ceftaroline fosamil was well tolerated in clinical trials and demonstrated a safety profile consistent with the cephalosporin class.49

Switch to Oral Antimicrobial Therapy and Discharge

Patients should be switched to oral therapy when they are hemodynamically stable, improving clinically, able to ingest oral medications, and have a normally functioning gastrointestinal tract.6 Patients should be discharged as soon as they meet the criteria for clinical stability (Table 5),50 have no other active medical problems, and have a safe environment for continued care.6 There is a greater risk of mortality and readmission in patients with . 1 clinical instability marker on discharge. In 1 study, 10.5% of patients with no unstable factors on discharge died or were readmitted compared with 13.7% of patients with 1 instability and 46.2% of patients with $ 2 instabilities (P , 0.003).50 Inpatient observation while first receiving oral therapy is not necessary. A retrospective study of a Medicare database found no significant difference in 14- or 30-day mortality between patients who were “not observed” and patients who were “observed for 1 day.”51

Duration of Therapy

Current guidelines recommend a minimum duration of 5 days of treatment for patients with CABP and therapy should not be stopped until the patient is afebrile for 48 to 72 hours.6,52 Nevertheless, therapy should be kept to the minimum duration that is adequate for the patient. Studies have evaluated Table 5. Criteria for Clinical Stability Temperature # 37.8°C Heart rate # 100 beats/min Respiratory rate # 24 breaths/min Systolic blood pressure $ 90 mm Hg Arterial oxygen saturation $ 90% or PO2 $ 60 mm Hg on room air Ability to maintain oral intake Normal mental status Data from Halm EA, Fine MJ, Kapoor WN, Singer DE, Marrie TJ, Siu AL.50

shorter courses of therapy.53 For instance, levofloxacin 750 mg/day for 5 days was compared with 500 mg/day for 10 days in patients aged $ 65 years with CAP.54 Rates of clinical success were similar between groups (89.0% and 91.9% in the 750- and 500-mg groups, respectively; 95% CI, -7.1–12.7). Additionally, a small study in The Netherlands evaluated adults admitted to the hospital with mild-tomoderate-severe CAP who were treated with amoxicillin for 3 days or 8 days.55 Clinical success rates at day 10 were the same (93%) for both groups (difference 0.1%; 95% CI, −9–10). Likely advantages of shorter-course therapy include reduced resistance, fewer AEs, fewer Clostridium difficile infections, and lower costs.

Consequences of Inappropriate Initial Therapy

Inappropriate initial therapy in non-ICU patients with CAP is associated with longer hospital stays, increased total hospital charges, and higher mortality rates.56 In a large, retrospective study of 32 324 non-ICU patients with CAP, 4695 (14.6%) experienced initial treatment failure.56 Treatment failure was associated with significantly longer hospital stays (mean ± standard deviation [SD]): 10.1 ± 8.1 days vs 4.9 ± 3.3 days; higher total hospital charges (mean ± SD): $37 602 ± $71 876 vs $14 371 ± $21 633; and increased mortality rates, 8.5% vs 3.3% (P , 0.01 for all comparisons). Broad-spectrum guideline-concordant empiric therapy maximizes the like lihood of starting the patient on appropriate antimicrobial therapy in a timely manner.57

Antimicrobial Stewardship

Antimicrobial stewardship programs can help reduce unnecessary use of antibiotics and support the appropriate use of antibiotics. In a prospective study of inpatients with presumed CAP, a 3-step intervention system was implemented, including: 1) a survey of medical staff to assess knowledge and practice prior to educational interventions; 2) an educational lecture presented to medical staff and hospital attending physicians; and 3) a prospective concurrent review of the management of patients with CAP with direct oral feedback regarding suggested changes.58 Unnecessary days of antibiotic therapy were reduced by 61% in this study, and the duration of antibiotic therapy was reduced from a median of 10 days to a median of 7 days. The Centers for Disease Control and Prevention (CDC) and Institute for Healthcare Improvement (IHI) initiated a stewardship program with a goal of developing a conceptual model of significant drivers for reducing inappropriate antibiotic use.59 Several barriers



Amin et al

were identified, including the ability to engage frontline providers, embedding antibiotic review into the process of care, competing priorities and improvement initiatives, and support from information technology.60 The program identified changes that need to be built into the process of care, including utilizing hand-offs, multidisciplinary rounds, checklists, computerized physician order entry (CPOE) solutions, and engaging the team (eg, nursing, pharmacy, physician assistants). Hospitalists are in an optimal position to initiate antimicrobial stewardship strategies. One such strategy recommended by the CDC is an “antibiotic timeout.” When culture results are available, it is suggested that therapy be reevaluated and the necessity and accuracy of current antibiotic therapy be reassessed.61 The utility of integrating a “time-out” into daily hospitalist work is currently being studied in hospitalist groups.60 In a prospective study, an intervention integrating antimicrobial stewardship strategies consisting of automatic stop dates on antibiotic therapy, duration of antibiotic therapy based on CURB-65 score, and pharmacist feedback helped to reduce duration of antibiotic treatment from 8.3 days to 6.8 days (P , 0.001) and the rate of antibiotic-related adverse effects from 31% to 19% (P = 0.03).62

Nonresponding Patient

It has been noted that 6% to 15% of hospitalized patients with CAP do not respond within 72 hours.63,64 Factors that determine rapidity of resolution include comorbidities, age, severity, and infecting pathogen.65,66 There are several risk factors for failure, including initial infection severity, host factors, causative pathogen factors, and treatment-related factors.67 Approaches to a patient with nonresponding pneumonia include an escalation or change in antimicrobial therapy, additional diagnostic testing, and/or transfer of the patient to a higher level of care.6 Empyema is a common cause of treatment failure, thus a chest computed tomography (CT) scan should be used to detect pleural effusion.64 T horacocentesis of pleural fluid should be performed whenever significant pleural fluid is present.6 Additionally, consideration should be given to the possibility of an incorrect diagnosis (eg, that the patient actually has a disease state that mimics pneumonia; Table 2). If a microbiologic cause has not been identified, further diagnostic testing should be performed. Additional diagnostic testing could include stains or cultures for usual as well as unusual bacteria, fungi, and viruses, CT scan, or bronchoscopy.67 Consideration should be given to broadening the antibiotic regimen to cover the spectrum of usual bacteria as 24

well as resistant S. pneumoniae, Pseudomonas aeruginosa, S. aureus, and anaerobic bacteria. Recommended treatment could include an anti-pseudomonal β-lactam and an IV fluoroquinolone or aminoglycoside, plus an agent active against MRSA.67 Some patients may need to be transferred to a higher level of care. Notably, up to 45% of patients who eventually need to be treated in the ICU were initially admitted to a non-ICU setting.6,68

Patient Care Quality Measures

An important focus of hospitalists is to provide care improvement in a way that addresses both patient and hospital needs. The Joint Commission provides 5 evidence-based quality measures for pneumonia (Table 6).69–75 These process measures are simple, transparent, and easier to improve than outcomes measures71,76; however, these measures may not significantly improve 30-day mortality.77 For instance, 1 study evaluated the effect of the addition of pay-forperformance to public reporting compared with public reporting alone on 30-day mortality in . 6 million patients with acute myocardial infarction, congestive heart failure, pneumonia, or in those who had undergone coronary artery bypass grafting between 2002 and 2009.78 Baseline 30-day mortality was similar between the 2 groups (12.33% for pay-for-performance hospitals and 12.40% for non–payfor-performance hospitals; difference of –0.07%, 95% CI, −0.40 to 0.26). After 6 years, mortality rates remained comparable under the pay-for-performance system (11.82% for pay-for-performance hospitals and 11.74% for non–pay-forperformance hospitals; difference of 0.08%, 95% CI, −0.30 to 0.46). The measurement of quality of care in pneumonia needs to continue to develop to harmonize patient safety and value and quality of care.

Hospital LOS

There are well-defined potential harms to being hospitalized (eg, exposure to pathogens, medication errors, etc). Admission and ongoing hospitalization must be based on clear needs and benefits to the patient that offset the known harms. Prevention of admission in low-risk patients who can be safely discharged from the emergency department is an important aspect of hospital LOS, and patients should be appropriately hospitalized based on severity-of-illness scores and clinical judgment.79 In the care of patients with pneumonia, multiple studies have demonstrated safe and effective interventions to reduce hospital LOS. Carratalá and colleagues80 completed a prospective, randomized trial of a



Table 6. Joint Commission Quality Measures for Pneumonia Pneumonia National Hospital Inpatient Quality Measures

Supporting Data

PN-3a

Guidelines from IDSA/ATS recommend pretreatment blood samples for culture be obtained from patients hospitalized with pneumonia admitted to the ICU5 Retrospective study of data on 13 043 Medicare patients hospitalized with pneumonia: use of antibiotics before blood cultures was negatively associated with the detection of bacteremia (OR, 0.5; 95% CI, 0.5–0.6)70 Requires atypical coverage for all patients and 2 antibiotics for patients admitted to the ICU71: • Observational study of 225 patients with severe bacteremic pneumococcal pneumonia: mortality with single effective therapy was significantly higher than with double effective therapy (P = 0.02; OR, 3.0 [95% CI, 1.2–7.6])72 • Observational study of 844 patients with bacteremic pneumococcal pneumonia: 14-day mortality of critically ill patients treated with monotherapy significantly higher than with combination therapy (55.3% vs 23.4%; P = 0.0015)73 • Observational study of 12 495 patients with pneumonia: initial treatment with a second-generation cephalosporin plus a macrolide (HR, 0.71; 95% CI, 0.52–0.96), nonpseudomonal, third-generation cephalosporin plus macrolide (HR, 0.74; 95% CI, 0.60–0.92), or fluoroquinolone monotherapy (HR, 0.64; 95% CI, 0.43–0.94) independently associated with lower 30-day mortality74 • Observational study of 409 patients with bacteremic pneumococcal pneumonia: no macrolide included in initial antibiotic regimen was independently associated with death (OR, 3.1; 95% CI, 1.05–9.17; P = 0.04)75


PN-3b

Blood cultures performed within 24 hours prior to or 24 hours after hospital arrival for patients transferred or admitted to ICU within 24 hours of hospital arrival Blood cultures performed in the emergency department prior to initial antibiotic received in hospital

PN-6

Initial antibiotic selection for CAP in immunocompetent patients

PN-6a

Initial antibiotic selection for CAP in immunocompetent patients—ICU patients

PN-6b

Initial antibiotic selection for CAP in immunocompetent patients—Non-ICU patients

© The Joint Commission, 2014. Reprinted with permission.69 Abbreviations: ATS, American Thoracic Society; CAP, community-acquired pneumonia; HR, hazard ratio; ICU, intensive care unit; IDSA, Infectious Diseases Society of America; OR, odds ratio.

3-step critical pathway to reduce duration of IV antibiotics and LOS. The 3 steps were: 1) early mobilization; 2) use of objective criteria for switching to oral antibiotic therapy; and 3) use of objective criteria for deciding on hospital discharge (Table 7). Median LOS in the 3-step group was 3.9 days compared with 6.0 days in the usual-care group. Median duration of IV antibiotics was 2.0 days in the 3-step group compared with 4.0 days in the usual-care group. Fisher and associates81 linked the level of ambulation during the first 48 hours after admission in elderly patients to LOS. Patients who increased their step total by $ 600 steps had a mean difference in LOS of 1.73 days less (95% CI, 0.60–2.85) compared with those who did not. Hospitalists perform an important role in decreasing hospital costs. A retrospective analysis of inpatients with bacterial pneumonia assessed LOS and cost savings when hospitalists were involved compared with nonhospitalists.82 In the moderate illness category, LOS was 4.9 days for those patients treated by hospitalists and 5.2 days for nonhospitalists (P = 0.04). For patients in the major illness category, LOS was 7.4 days for patients treated by hospitalists and

8 days for patients treated by nonhospitalists (P = 0.03). In the major illness category, mean charges per patient were $20 950 for those patients treated by hospitalists and $23 259 by nonhospitalists (P = 0.03). Hospitalists cared for a higher percentage of patients in the major/extreme illness categories than nonhospitalists (41% vs 32%, respectively; P , 0.001).

Readmission and Optimal Transition to Postdischarge Care

An important aspect of hospitalist care is effective discharge and follow-up care planning. In a survey of 908 primary care physicians regarding communication with hospital-based physicians, 77% of primary care physicians were aware that their patient had been hospitalized.83 Of the 1078 patients included, direct communication between primary care physicians and hospital-based physicians took place in 23% of patients, and a discharge summary was available within 2 weeks of discharge for 42% of patients. These data suggest substantial room for improvement in communication at the time of hospital discharge. Adequate follow-up care can potentially prevent patient readmission.


Amin et al

Table 7. Three-Step Critical Pathway Step in Critical Pathway

Description

Early mobilization

Movement out of bed with a change from the horizontal to the upright position for 20 minutes during the first 24 hours of hospitalization, with progressive movement each subsequent day of hospitalization Patients were switched from IV to oral therapy when they experienced clinical improvement and met the following objective criteria: • Ability to maintain oral intake • Stable vital signsa • Absence of exacerbated major comorbidities (eg, heart failure, chronic obstructive pulmonary disease) and/or septic metastases Predefined criteria for hospital discharge were: • Meeting criteria for switching to oral antibiotic • Baseline mental status • Adequate oxygenation on room air (PO2 60 mm Hg or pulse oximetry 90%)b

Objective criteria for switching to oral antibiotic therapy


Objective criteria for deciding on hospital discharge

Considered as temperature 37.8°C, respiratory rate 24 breaths/min, systolic blood pressure 90 mm Hg without vasopressor support for 8 hours. For patients with chronic hypoxemia or receiving chronic oxygen therapy, PO2 or pulse oximetry measurement had to be similar to their baseline values. Data from Carratalà J, Garcia-Vidal C, Ortega L, et al.80 Abbreviation: IV, intravenous. a

b

In a retrospective analysis of the Medicare Current Beneficiary Summary, the association between follow-up visits and readmission within 90 days was assessed.84 Of the 326 patients included, 79% had a physician follow-up visit within 90 days and 28% were readmitted within 90 days. Physician follow-up visits were negatively associated with 90-day readmission (odds ratio [OR], 0.23; 95% CI, 0.13–0.43). In addition, having a follow-up visit was associated with a decrease of approximately $10 000 in annual health care expenditures. Readmission following hospitalization for pneumonia is a significant, costly, and potentially preventable adverse outcome.85 Variables associated with pneumonia-related readmission include treatment failure, absence of a followup appointment scheduled at time of discharge, lack of attendance at the follow-up appointment, and $ 1 factors for patient instability on hospital discharge.84,86,87 Variables associated with pneumonia-unrelated readmission (eg, if the clinical data suggested a reason other than pneumonia for readmission) include patient age $ 65 years, comorbidities, , high school education, and unemployment.86,87 Hospital readmission is seen as an important indicator of quality of care and the Centers for Medicare and Medicaid Services measure 30-day, all-cause, risk-standardized readmission for pneumonia, acute myocardial infarction, and heart failure. A retrospective study of the Medicare database analyzed 1 168 624 pneumonia hospitalizations; 19.9% of patients were readmitted within 30 days following hospital discharge.88 Of readmitted patients, 38.5% of patients were readmitted for respiratory disease and 22.4% of patients had recurrent pneumonia. A retrospective study evaluated 30-day readmission of adults admitted to the hospital with 26

non-nosocomial pneumonia.89 Twenty percent of patients were readmitted, with 7.4% of readmissions for a diagnosis of pneumonia, and 17.4% of all readmissions because of infectious complications. In a separate retrospective study of consecutive discharges from all medical services at a medical center in Boston, Massachusetts, data from 10 731 patients were analyzed and 22.3% of patients were readmitted to the hospital within 30 days.90 Of patients readmitted, 36.7% of the readmissions were identified as potentially avoidable. For instance, patients who are discharged while they are still unstable are more frequently susceptible to morbidity and mortality or readmission.50

Conclusion

Community-acquired bacterial pneumonia remains an important health care concern in the United States because it carries with it significant morbidity, mortality, and health care expenditure, particularly that linked with hospital admission. Hospitalists perform a vital role in the care of patients with CABP, which includes a commitment to quality and process improvements, efficient use of hospital and health care resources, and an interdisciplinary approach to care. Hospital medicine physicians must be skilled in determining appropriate antimicrobial therapy, encompassing adequate empiric therapy, duration of therapy, and timely switch to oral antibiotics. It is also critical that a thoughtful approach is taken to nonresponding patients, including retriage when indicated. Finally, patient care, quality measures, LOS, and readmissions must be adequately addressed through processes designed to improve inhospital care and safe transition of patients to their post-discharge care providers.



Acknowledgment

Scientific Therapeutics Information, Inc. provided editorial assistance on this manuscript. Funding for editorial assistance was provided by Forest Research Institute, Inc.

Conflict of Interest Statement


Alpesh Amin, MD, MBA, serves on the speakers bureau, served as a consultant, and received research/grant funding from Forest. James C. Pile, MD, David J. Rosenberg, MD, Elizabeth A. Cerceo, MD, Steven B. Deitelzweig, MD, and Bradley M. Sherman, MD, served as consultants for Forest.

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The hospitalist perspective on opioid prescribing: A qualitative analysis.

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Update on bacterial pneumonia and pleuropneumonia in the adult horse.

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A perspective on the enhancer dependent bacterial RNA polymerase.

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The effect of hospitalist discontinuity on adverse events.

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Bacterial pneumonia in older people.

Ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia in elderly patients.

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The effect of methylene blue treatment on aspiration pneumonia.

Acute trenant pneumonia of possible bacterial etiology.

Effect of a hospitalist-run postdischarge clinic on outcomes.

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Antimicrobial and biophysical properties of surfactant supplemented with an antimicrobial peptide for treatment of bacterial pneumonia.

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