Community-Acquired Pneumonia Empiric Therapy 

Community-acquired pneumonia (CAP) is one the most common infectious diseases addressed by clinicians. It is a major health problem in the United States and is an important cause of mortality and morbidity worldwide.[1, 2]

CAP is defined as pneumonia acquired outside a hospital or long-term care facility. It occurs within 48 hours of hospital admission or in a patient presenting with pneumonia who does not have any of the characteristics of healthcare-associated pneumonia (ie, hospitalized in an acute care hospital for 2 or more days within 90 days of infection; resided in a nursing home or long-term care facility; received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days of the current infection; or attend a hospital or hemodialysis clinic).[1, 2]

A number of pathogens can give rise to CAP, generally categorized into typical and atypical pathogens.

Typical bacterial pathogens that cause CAP include Streptococcus pneumonia (penicillin-sensitive/resistant strains), Haemophilus influenza (ampicillin-sensitive/resistant strains), and Moraxella catarrhalis (all strains penicillin-resistant) and account for approximately 85% of CAP cases. CAP is usually acquired via inhalation or aspiration of a pulmonary pathogen into a lung segment or lobe. Less commonly, CAP results from secondary bacteremia from a distant source, such as Escherichiacoli urinary tract infection and/or bacteremia. Aspiration pneumonia is the only form of CAP caused by multiple pathogens (eg, aerobic/anaerobic oral organisms). Klebsiella pneumonia CAP occurs primarily in persons with chronic alcoholism and Staphylococcalaureus may cause CAP in patients with influenza. Pseudomonas aeruginosa is a cause of CAP in patients with bronchiectasis or cystic fibrosis.[1]

Atypical pathogen CAP manifests a variety of pulmonary and extrapulmonary findings (eg, CAP plus diarrhea). Atypical CAP can be divided into those caused by either zoonotic or nonzoonotic atypical pathogens. Zoonotic atypical CAP pathogens include Chlamydophila (Chlamydia) psittaci (psittacosis), Coxiella burnetii (Q fever), and Francisella tularensis (tularemia). Nonzoonotic atypical CAP pathogens include Mycoplasma pneumoniae, Legionella species, and Chlamydia pneumoniae. These organisms account for approximately 15% of all CAP cases.[1]

For all suspected CAP patients, in light of better outcomes with the earliest possible interventions the Infectious Diseases Society of America (IDSA) recommends initial empiric antimicrobial therapy until laboratory results can be obtained to guide more specific therapy.[2]

Empiric therapeutic regimens for CAP are outlined below, including those for outpatients with or without comorbidities, intensive care unit (ICU) and non-ICU patients, and penicillin-allergic patients.[2]

Outpatient

No comorbidities/previously healthy; no risk factors for drug-resistant S pneumoniae:

• Azithromycin 500 mg PO one dose, then 250 mg PO daily for 4 d or extended-release 2 g PO as a single dose or
• Clarithromycin 500 mg PO bid or extended-release 1000 mg PO q24h or
• Doxycycline 100 mg PO bid

If received prior antibiotic within 3 months:

• Azithromycin or clarithromycin plus  amoxicillin 1 g PO q8h or  amoxicillin-clavulanate 2 g PO q12h or
• Respiratory fluoroquinolone (eg, levofloxacin 750 mg PO daily or moxifloxacin 400 mg PO daily)

Comorbidities present (eg, alcoholism, bronchiectasis/cystic fibrosis, COPD, IV drug user, post influenza, asplenia, diabetes mellitus, lung/liver/renal diseases):

• Levofloxacin 750 mg PO q24h or
• Moxifloxacin 400 mg PO q24h or
• Combination of a beta-lactam ( amoxicillin 1 g PO q8h or  amoxicillin-clavulanate 2 g PO q12h or  ceftriaxone 1g IV/IM q24h or  cefuroxime 500 mg PO BID) plus  a macrolide (azithromycin or clarithromycin)

Duration of therapy: minimum of 5 days, should be afebrile for 48-72 hours, or until afebrile for 3 days; longer duration of therapy may be needed if initial therapy was not active against the identified pathogen or if it was complicated by extrapulmonary infections

Inpatient, non-ICU

See the list below:

• Levofloxacin 750 mg IV or PO q24h or
• Moxifloxacin 400 mg IV or PO q24h or
• Combination of a beta-lactam (ceftriaxone 1 g IV q24h or  cefotaxime 1 g IV q8h or  ceftaroline 600 mg IV q12h) plus azithromycin 500 mg IV q24h

Duration of therapy: minimum of 5 days, should be afebrile for 48-72 hours, stable blood pressure, adequate oral intake, and room air oxygen saturation of greater than 90%; longer duration may be needed in some cases

Inpatient, ICU

See the list below:

• Combination of a beta-lactam (ceftriaxone 1 g IV q24h or  cefotaxime 1 g IV q8h or  ceftaroline 600 mg IV q12h) plus
• Azithromycin 500 mg IV q24h or
• Levofloxacin 750 mg IV or PO q24h or
• Moxifloxacin 400 mg IV or PO q24h or

If gram-negative rod pneumonia (Pseudomonas) suspected, due to alcoholism with necrotizing pneumoniae, chronic bronchiectasis/tracheobronchitis due to cystic fibrosis, mechanical ventilation, febrile neutropenia with pulmonary infiltrate, septic shock with organ failure:

• Piperacillin-tazobactam 4.5 g IV q6h or 3.375 g IV q4h or  4-h infusion of 3.375 g q8h or
• Cefepime 2 g IV q12h or
• Imipenem/cilastatin 500 mg IV q6h or  meropenem 1 g IV q8h plus
• Levofloxacin 750 mg IV q24h or
• Moxifloxacin 400 mg IV or PO q24h or
• Azithromycin 500 mg IV q24h

Aminoglycoside (gentamicin 7 mg/kg/day IV ortobramycin 7 mg/kg/day IV) was included in older guidelines but is not included in newer guidelines for empiric therapy

Duration of therapy: 10-14 days

If concomitant with or post influenza, add:

• Vancomycin 15 mg/kg IV q12h or
• Linezolid 600 mg IV bid

Risk of aspiration pneumonia/anaerobic lung infection/lung abscess:

See the list below:

• Ampicillin-sulbactam 3 g IV q6h or
• Ceftriaxone 1 g IV q24h plus  metronidazole 500 mg IV q6h or
• Moxifloxacin 400 mg IV or PO q24h or
• Piperacillin-tazobactam 3.375 g IV q6h
• If methicillin-resistant S aureus (MRSA) is suspected, add vancomycin 15 mg/kg IV q12h or  linezolid 600 mg IV/PO q12h
• If influenza is suspected, add oseltamivir 75 mg IV or PO q12h for 5 d

New antimicrobials in CAP

Since the publication of the 2007 IDSA/American Thoracic Society (ATS) guidelines for the management of CAP in adults, 2 intravenous antimicrobials have been approved by the US Food and Drug Administration (FDA) for the treatment of CAP: tigecycline and ceftaroline fosamil.

Use of tigecycline in CAP

Tigecycline was approved by the FDA in 2009 for adults with CAP caused by S pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, H influenza (beta-lactamase-negative isolates), and Legionella pneumophila. In a study conducted to evaluate the efficacy of tigecycline versus levofloxacin in hospitalized patients with CAP, tigecycline achieved cure rates similar to those of levofloxacin in hospitalized patients with CAP. For patients with risk factors, tigecycline provided generally favorable clinical outcomes.[3]

Data from various sources, including PubMed, the European Medicines Agency (EMEA), and the FDA were appraised. Tigecycline was found to be noninferior compared with levofloxacin for the treatment of patients with bacterial CAP requiring hospitalization.[4]

Although tigecycline is indicated for CAP, data from clinical trials suggest a high incidence of adverse events, particularly gastrointestinal adverse effects, which may limit its use.[5]

Dosing for tigecycline is as follows:

• Tigecycline 100 mg IV loading dose, then 50 mg IV q12h for 7-14 d

Use of ceftaroline in CAP

Ceftaroline fosamil is a parenteral cephalosporin antibacterial that was approved by the FDA in 2010 for the treatment of adults with CAP caused by S pneumoniae, including cases with concurrent bacteremia; S aureus (methicillin-susceptible isolates only); H influenza; K pneumonia; Klebsiella oxytoca; and E coli.

Ceftaroline, the active form of ceftaroline fosamil, has broad-spectrum in vitro activity against common causative gram-positive and gram-negative bacteria, including MRSA. However, there are no clinical data supporting the use of ceftaroline fosamil for MRSA pneumonia.[5]

Ceftaroline fosamil is included in Joint Commission pneumonia core measures as one of the recommended beta-lactam antibiotics for CAP in immunocompetent, non-ICU patients.

Dosing for ceftaroline is as follows:

• Ceftaroline 600 mg IV q12h

Use of lefamulin in CAP

Lefamulin (Xenleta) is a first-in-class pleuromutilin antibacterial. It inhibits bacterial protein synthesis through interactions (hydrogen bonds, hydrophobic interactions, and Van der Waals forces) with the A- and P-sites of the peptidyl transferase center (PTC) in domain V of the 23s rRNA of the 50S subunit. It is indicated for the treatment of bacterial CAP due to S pneumoniae, S aureus (methicillin-susceptible isolates), H influenzae, Legionella pneumophila, M pneumoniae, or C pneumoniae in adults. It is administered twice daily as either an intravenous infusion or an oral tablet. Approval was based on LEAP 1 and 2 trials.

In LEAP 1, patients (n=551) were randomized to either lefamulin 150 mg IV q12h or moxifloxacin 400 mg IV q24h. After 6 doses, patients could be switched to oral study drug if prespecified improvement criteria were met. If MRSA was suspected, linezolid or placebo was added to moxifloxacin or lefamulin, respectively. Lefamulin was noninferior to moxifloxacin in terms of early clinical response. Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin.[6]

The LEAP 2 study (n=738) found oral lefamulin 600 mg q12h for 5 days was noninferior to moxifloxacin 400 mg/day for 7 days in the treatment of bacterial CAP.[7]

Dosing for lefamulin is as follows:

Lefamulin 150 mg IV q12hr x 5-7 days OR 600 mg PO q12 hr x 5 days

May switch from IV to oral to complete treatment course

Use of delafloxacin in CAP

Delafloxacin (Baxdela), a fluoroquinolone, gained approval in October 2019 for the treatment of bacterial CAP in adults. Approval was based on a phase 3 randomized, double-blind study (n = 859) that compared delafloxacin to moxifloxacin. Results showed that IV-to-oral delafloxacin was noninferior at 96 hours compared with moxifloxacin.[8, 9]

Dosing for delafloxacin is as follows:

• 300 mg IV q12hr for 5-10 days or
• 300 mg IV q12hr, then switch to a 450-mg tablet PO q12hr for 5-10 days or
• 450 mg PO q12hr for 5-10 days