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. It is the second most common reason for admission to the hospital and the most common infectious cause of death. It accounts for over 4.5 million outpatient and emergency room visits annually. ^{[1, 2]}

CAP is defined as pneumonia acquired outside a hospital or long-term care facility. It may be diagnosed within 48 hours of hospital admission. The designation "healthcare-associated pneumonia"  (HCAP) is no longer included in the pneumonia guidelines. ^{[1, 2, 3]}

A number of pathogens can give rise to CAP, generally categorized into typical and atypical pathogens. A third category seen are respiratory viruses. Overall, the most common causes are Streptococcus pneumoniae and respiratory viruses. However, in a large portion of the population, around 62%, no pathogen is detected despite extensive microbiologic evaluation. ^[1]

Typical bacterial pathogens that cause CAP include Streptococcus pneumoniae (penicillin-sensitive/resistant strains), Haemophilus influenzae (ampicillin-sensitive/resistant strains), Moraxella catarrhalis (all strains penicillin-resistant), Staphylococcus aureus, Group A streptococci, aerobic gram-negative bacteria (eg, Enterobacteriaceae such as Klebsiella spp or Escherichia coli) and microaerophilic bacteria and anaerobes. 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 typically caused by polymicrobic infection (eg, aerobic/anaerobic oral organisms). 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 bacteria are defined as bacteria with intrinsic resistance to beta-lactams and their inability to be visualized on Gram stain or cultured using traditional techniques. They 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. ^[1]

Respiratory viruses include: Influenza A and B viruses, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), other coronaviruses (eg, Middle East respiratory syndrome CoV, severe acute respiratory syndrome CoV, CoV-229E, CoV-NL63, CoV-OC43, CoV-HKU1), rhinoviruses, parainfluenza viruses, adenoviruses, respiratory syncytial virus, human metapneumovirus and human bocaviruses. ^[1]

For all suspected CAP patients with the exception of COVID-19, 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. ^[4]

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. ^[4]

Outpatient

In this setting, empiric regimens are designed to target S pneumoniae, the most common, and atypical, pathogens. Coverage is expanded for outpatients with comorbidities, smoking, and recent antibiotic use to include or better treat beta-lactamase-producing H influenzae, M catarrhalis, and methicillin-susceptible S aureus. For those with structural lung disease, such as cystic fibrosis, coverage is further expanded to include Enterobacteriaceae, such as E coli and Klebsiella spp.

No comorbidities/previously healthy; age < 65 years; no recent antibiotic use; no risk factors for MRSA or Pseudomonas aeruginosa (macrolides should only be used if local pneumococcal resistance is less than 25%):

• Amoxicillin 1 g tid  or
• Azithromycin 500 mg PO one dose, then 250 mg PO daily  or
• Clarithromycin 500 mg PO bid or extended-release 1000 mg PO daily  or
• Doxycycline 100 mg PO bid

Comorbidities present (eg, alcoholism, chronic heartlung/liver/renal diseases, malignancy, asplenia, diabetes mellitus) and who have used antibiotics in the last 3 months:

• Preferred: Combination of a beta-lactam ( amoxicillin-clavulanate 500 mg/125 mg PO tid or  amoxicillin-clavulanate 875 mg/125 mg  PO BID or  amoxicillin-clavulanate 2000 mg/125 mg)  plus  a macrolide (azithromycin  or clarithromycin) or doxycycline (100 mg PO bid)
• Alternatives to the above regimen:
• If cephalosporins can be taken, 

  • Cefpodoxime 200 mg PO bid or  cefuroxime 500 mg or cefditoren 400 mg PO bid plus  a macrolide (azithromycin or clarithromycin) or doxycycline (100 mg PO bid)
• If beta- lactams cannot be taken:

  • Levofloxacin 750 mg PO q24h or
  • Moxifloxacin 400 mg PO q24h or
  • Lefamulin 600 mg PO BID in the absence of hepatic impairment or drug interactions

Duration of therapy: minimum of 5 days, should be afebrile for at least 48 hours, clinically improving (based on symptoms and vital signs). Patients with documented MRSA or Pseudomonas aeruginosa should receive a minimum of 7 days treatment. Pneumonia complicated by meningitis, endocarditis or other deep-seated infection will require longer courses of therapy.

Inpatient, non-ICU (Non-severe inpatient pneumonia)

In this setting, empiric antibiotic regimens are designed to treat S aureus, gram-negative enteric bacilli (eg, Klebsiella pneumoniae) as well as typical pathogens (eg, S pneumoniae, H influenzae, and M catarrhalis) and atypical pathogens (eg, Legionella pneumophilia, M pneumoniae, and C pneumoniae). Therapy is started as soon as CAP is suspected as the diagnosis and ideally within 4 hours of presentation.

Factors to determine the antibiotic regimen depend on the likelihood that MRSA or Pseudomonas is present. Risk factors for MRSA or Pseudomonas infection are known colonization or prior infection with these organisms, particularly from a respiratory tract specimen, and recent hospitalization within the past 3 months, with usage of intravenous (IV) antibiotics

Without suspicion for MRSA or Pseudomonas

• Combination of a beta-lactam (ampicillin-sulbactam 1.5-3 g IV q6h or  ceftriaxone 1-2 g IV q24h  or   cefotaxime 1-2 g IV q8h  or  ceftaroline 600 mg IV q12h)  plus  azithromycin 500 mg IV/PO q24h  or  doxycycline 100 mg PO BID  or
• Levofloxacin 750 mg IV or PO q24h or
• Moxifloxacin 400 mg IV or PO q24h or

With known colonization or prior infection with Pseudomonas, recent hospitalization with IV antibiotic use, or other strong suspicion for pseudomonal infection

• Combination therapy with both an antipseudomonal beta-lactam (pipericillin- tazobactam 4.5 g IV q6h or cefepime 2 g IV q8h or ceftazidime 2 g IV q8h or meropenem 1 g IV q8h  or imipenem 500 mg IV q6h) plus an antipseudomonal fluoroquinolone (ciprofloxacin 400 mg IV q8h or Levofloxacin 750 mg IV q24h)

With known colonization or prior infection with MRSA or other strong suspicion for MRSA infection

• Add vancomycin 15 to 20 mg/kg/dose IV every 8 to 12 hours initially and adjust to therapeutic monitoring  or linezolid 600 mg IV every 12 hours

Contradictions to macrolides and fluroquinolones

• Combination of a beta-lactam (ampicillin-sulbactam 1.5-3 g IV q6h  or  ceftriaxone 1-2 g IV q24h  or   cefotaxime 1-2 g IV q8h  or  ceftaroline 600 mg IV q12h)  and doxycycline 100 mg BID

Inpatient, ICU (Severe inpatient pneumonia)

In this setting, empiric regimens are designed to target S pneumoniae, the most common, and atypical, pathogens. Coverage is expanded for inpatients with comorbidities, smoking, and recent antibiotic use to include or better treat beta-lactamase-producing H influenzae, M catarrhalis, and methicillin-susceptible S aureus. For those with structural lung disease, such as cystic fibrosis, coverage is further expanded to include Enterobacteriaceae, such as E coli and Klebsiella spp.

No comorbidities/previously healthy; age < 65 years; no recent antibiotic use; no risk factors for MRSA or Pseudomonas aeruginosa (macrolides should only be used if local pneumococcal resistance is less than 25%):

• Amoxicillin 1 g tid  or
• Azithromycin 500 mg PO one dose, then 250 mg PO daily  or
• Clarithromycin 500 mg PO bid or extended-release 1000 mg PO daily  or
• Doxycycline 100 mg PO bid

Comorbidities present (eg, alcoholism, chronic heartlung/liver/renal diseases, malignancy, asplenia, diabetes mellitus) and who have used antibiotics in the last 3 months:

• Preferred: Combination of a beta-lactam ( amoxicillin-clavulanate 500 mg/125 mg PO tid or  amoxicillin-clavulanate 875 mg/125 mg  PO BID or  amoxicillin-clavulanate 2000 mg/125 mg)  plus  a macrolide (azithromycin  or clarithromycin) or doxycycline (100 mg PO bid)
• Alternatives to the above regimen:
• If cephalosporins can be taken, 

  • Cefpodoxime 200 mg PO bid or  cefuroxime 500 mg or cefditoren 400 mg PO bid plus  a macrolide (azithromycin or clarithromycin) or doxycycline (100 mg PO bid)
• If beta- lactams cannot be taken:

  • Levofloxacin 750 mg PO q24h or
  • Moxifloxacin 400 mg PO q24h or
  • Lefamulin 600 mg PO BID in the absence of hepatic impairment or drug interactions

Updated guidelines

Updated guidelines recommend the following:

• No indication in adding anaerobic coverage for suspected aspiration pneumonia beyond the standard regimens indicated above except lung abscess or empyema is suspected

• No indication routinely using corticosteroids in adults with nonsevere CAP

• No indication to use corticosteroids routinely in adults with severe CAP

• No indication for routinely using corticosteroids in adults with severe influenza pneumonia

•  Surviving Sepsis Campaign recommendations  are indicated for the use of corticosteroids in patients with CAP and refractory septic shock 

• Standard antibacterial treatment be initially prescribed for adults with clinical and radiographic evidence of CAP who test positive for influenza in the inpatient and outpatient settings (strong recommendation, low quality of evidence)

• Duration of antibiotic therapy should be guided by a validated measure of clinical stability (resolution of vital sign abnormalities [heart rate, respiratory rate, blood pressure, oxygen saturation, and temperature], ability to eat, and normal mentation), and antibiotic therapy should be continued until the patient achieves stability and for no less than a total of 5 days

New antimicrobials in CAP

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. ^[5]

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. ^[6]

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. ^[7]

Dosing for tigecycline is as follows:

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

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. ^[8]

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. ^[9]

Dosing for lefamulin is as follows:

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

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. ^{[10, 11]}

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