Community-acquired pneumonia: a US perspective on the guideline gap

Abstract

Community-acquired pneumonia continues to be one of the most common causes of morbidity and mortality due to infectious disease. The aetiologies, clinical presentations, diagnostic modalities and therapeutic options are changing and outpacing the creation of management guidelines. This educational article summarizes a roundtable activity sponsored by an unrestricted educational grant by Paratek that included US experts discussing these changes and identifying gaps in the current guidelines.

New trends in the epidemiology of community-acquired pneumonia (CAP)

CAP continues to be one of the most common causes of morbidity and mortality due to infectious disease in all patients. Despite the COVID-19 pandemic, it continues to be a neglected, but common infection. Interestingly, there is a lack of urgency and disease awareness when one discusses CAP, perhaps because of its commonly used term ‘walking pneumonia’, not realizing that the mortality associated with CAP remains between 10% and 20%.¹ According to the American Thoracic Society (ATS)/IDSA guidelines from 2019, CAP continues to be a growing health problem globally, with an annual global burden of approximately 350 million cases in 2016.² In the USA, there are over 1 million hospitalizations due to CAP per year, not including those associated with SARS-CoV-2.³

Recent changes in the microbial aetiology of CAP

There are several challenges that remain when discussing the evolving epidemiology of CAP in the USA. The most important of these is being the increase in the number of pathogens that are now routinely diagnosed in patients with CAP. This is especially true for the viral causes of pneumonia such as SARS-CoV-2, respiratory syncytial virus and human metapneumovirus. In addition, certain fungal infections such as Histoplasma capsulatum and Coccidioides immitis are also increasing in frequency as causes of non-bacterial CAP in endemic areas. Finally, it is important to point out that in the past 12–24 months there has been an increase in Mycobacterium tuberculosis, especially in the southwest part of the USA. This is possibly due to the large migration of individuals.⁴

Overall, bacterial and viral organisms constitute the most common causes of CAP. Pathogens such as Streptococcus pneumoniae and Haemophilus influenzae continue to be the most common bacterial pathogens recovered from sputum and occasionally, the bloodstream. However, more recently we are seeing an increase in CAP due to Staphylococcus aureus and Klebsiella pneumoniae. In addition, the intracellular pathogens or ‘atypical pneumonias’ frequently constitute up to 30% of causative organisms in large clinical trials. Among these, Mycoplasma pneumoniae and Chlamydophila pneumoniae continue to be the most common.^1,4,5 Among the viral pathogens, influenza virus, rhinovirus and SARS-CoV-2 are the most common organisms detected in the USA.⁴

It is also important to point out that despite all of the advances that have been made in diagnostics over the past decade, only 30%–40% of patients who are admitted with CAP have a microbiological diagnosis. This leads to empirical treatment of CAP in the majority of situations.

Risk factors and clinical presentation

Established risk factors for CAP include older age, chronic comorbidities, viral infection, impaired airway protection (i.e. increased risk for microaspiration), smoking and environmental exposure (water, animal, toxin exposures).^4,6 Over the years, novel risk factors for CAP have emerged, and these mainly involve the use of immunosuppressive therapies in the treatment of chronic diseases. For example, anti-TNF antibodies, ibrutinib and B-cell depleting agents increase the risk for infections due to non-tuberculous mycobacteria, Aspergillus spp. and respiratory viruses, respectively.^7–9 Globalization and immigration play a considerable role in the transmission of respiratory infections. In the last 3 years, we have witnessed a novel virus (SARS-CoV-2) emerging, and certain host factors predispose to severe disease, such as older age, high BMI, socioeconomic background, race, and sex.

The clinical presentation of CAP can range from mild disease characterized by fever, cough and dyspnoea to severe disease characterized by sepsis and respiratory failure. Symptom severity highly depends on pathogen virulence, the burden of exposure, and the host’s immune response. Signs and symptoms of pneumonia may be subtle among patients with advanced age and/or impaired immune systems. Notably, chest radiographs may be poorly sensitive and not able to detect evidence of pneumonia in individuals with impaired immunity. Hence, other radiographical modalities, such as CT scan of the chest, may have improved sensitivity in demonstrating abnormal lung findings. It is essential to highlight that with COVID-19, atypical presentations such as anosmia, dysgeusia, dermatological findings (maculopapular rash, vesicular eruptions, reddish nodules), conjunctivitis, gastrointestinal symptoms and thromboembolic complications have been reported.

CAP versus healthcare-associated pneumonia: a blurring distinction and term in disuse

Per the definition in the 2005 ATS/IDSA guideline, healthcare-associated pneumonia (HCAP) is a pneumonia in non-hospitalized patients with significant healthcare system experience that predisposes an individual to increased risk for MDR organism (MDRO) infection.¹⁰ These risk factors include prior hospitalization for at least 2 days in the preceding 90 days, residence in a nursing home or extended-care facility, interventions such as home infusion therapy, chronic dialysis, home wound care and exposure to family members with MDRO infection. The landmark study of Kollef et al.¹¹ that defined HCAP involved a large US inpatient database demonstrating higher rates of MDRO (mainly MRSA, Pseudomonas and Enterobacter) amongst patients meeting the HCAP criteria of the study and was associated with increased mortality. However, since then, several studies have evaluated the validity of that report. The study by Chalmers et al.¹² found increased mortality among patients meeting the criteria for HCAP but associated it with the patient’s comorbidities rather than the presence of an MDRO. A meta-analysis and systematic review,¹³ which included 24 prospective and retrospective studies, found that guideline-defined HCAP did not accurately identify resistant pathogens, nor did it determine mortality risk with the presence of an MDRO. The accompanying editorial commented that HCAP criteria may not accurately identify risk for MDROs due to the diversity of pathogens across the healthcare system and the different antibiotic policies from country to country.¹⁴ Finally, a Veterans Affairs (VA)-based study also reported that guideline-concordant therapy in non-severe HCAP patients did not improve overall survival.¹⁵

The 2019 guideline did comment on possibly ‘moving away’ from the HCAP definition and its management as it has caused the overuse of broad-spectrum antibiotics.² Therefore the term HCAP is broadly now in disuse and the preferred approach is individualized risk for MDROs based on local epidemiology. An effort to perform an appropriate collection of respiratory cultures (and/or blood cultures) at the time of diagnosis of pneumonia (i.e. within 48–72 h) will improve the yield of cultures. Newer studies involving multiplex PCR can expedite diagnosis. Appropriate modification of antibiotics based on microbiological data can help reduce prolonged broad-spectrum antibiotic exposure.

Novel therapeutics for CAP

Adjuvant therapy has been generally relegated to supportive therapy, but a recent breakthrough study found that adding hydrocortisone to antibiotics in the setting of severe CAP was associated with decreased risk of mortality by Day 28, therefore this intervention is likely to become standard of care.¹⁶

Omadacycline is a tetracycline antibiotic and was approved in 2018 for treatment of bacterial CAP (CABP). It overcomes the resistance by tetracycline efflux and ribosomal protection mechanisms and has activity against Legionella pneumophila, M. pneumoniae and C. pneumoniae. Thus, it can be used as a single agent to treat CABP as an alternative to the empirical combination of a β-lactam and a macrolide. The efficacy and safety of omadacycline were tested on a Phase III randomized control trial (OPTIC) comparing omadacycline in 388 patients with moxifloxacin in 386 patients with CABP followed by oral omadacycline or moxifloxacin. The early clinical response was 81.1% in the omadacycline group compared with 82.7% in the comparator group. In the post-treatment evaluation, clinical response rate was 87.6% in the omadacycline arm compared with 85.1% in the moxifloxacin arm. The rate of adverse events leading to treatment discontinuation was 5.5% with omadacycline compared with 7% with moxifloxacin.^17,18

Lefamulin is a novel pleuromutilin antibiotic and was approved in August 2019 by the US FDA for use in CABP. Lefamulin inhibits protein synthesis by inhibition of the 50S bacterial ribosome. It has activity against S. pneumoniae, MRSA, VRE, MDR Neisseria gonorrhoeae, C. pneumoniae, L. pneumophila, M. pneumoniae and H. influenzae. Lefamulin exhibits time-dependent killing, with higher concentrations in epithelial lining fluid than in plasma. Lefamulin was non-inferior to moxifloxacin in 551 adults with CABP in a Phase III (LEAP-1) clinical trial. Early clinical response was 87.3% versus 90.2%. The rate of drug discontinuation was 2.9% in the lefamulin arm and 4.4% in the moxifloxacin arm. In the second Phase III clinical trial (LEAP-2), oral lefamulin was compared with moxifloxacin in 738 patients with CABP Lefamulin was non-inferior to moxifloxacin for CABP (90.8% versus 90.8%), clinical response (87.5% versus 89.1%) and clinically evaluable population (89.7% versus 93.6%).^17,18

Cefiderocol is the first in a class of siderophore cephalosporins with activity against ESBL- and carbapenemase-producing Gram-negative bacteria (carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii), MDR Stenotrophomonas maltophilia and Burkholderia cepacia. Potential indications include complicated urinary tract infection, healthcare-associated pneumonia/ventilator-associated pneumonia, bloodstream infection and sepsis caused by MDR Gram-negative isolates. It is a potent broad-spectrum agent that is not routinely recommended for first-line CAP treatment unless there is clinical failure to first-line therapy, in addition to risk factors for MDROs.^17,18

Solithromycin is a novel, fourth-generation macrolide, known as a fluoroketolide, which inhibits protein synthesis by binding to the bacterial ribosome.¹⁹ It has activity against macrolide-resistant S. pneumoniae, H. influenzae and atypical pathogens, with potential indication for use in CABP. Oral solithromycin was non-inferior to oral moxifloxacin in 860 adults with CABP in a Phase III trial (SOLITAIRE-ORAL). Early clinical response was 78.2% versus 77.9%. Elevation of ALT was observed in 5.4% of the solithromycin group compared with 3.3% in the moxifloxacin group, and AST was elevated in 2.5% of the solithromycin group compared with 1.9% in the comparator group. Solithromycin (IV to oral) was non-inferior to moxifloxacin (IV to oral) in 863 adults with CABP in a Phase III clinical trial (SOLITAIRE-IV). The early clinical response in ITT was 79.3% in the solithromycin arm compared with 79.7% in the moxifloxacin arm, with a higher rate of adverse drug reactions in the solithromycin arm. This agent exhibits activity against macrolide-resistant strains of S. pneumoniae; however, it is not FDA approved for this use.

The video is playable in the HTML version at https://doi.org/10.1093/jac/dkae050.

Funding

This Virtual Roundtable was supported by an unrestricted educational grant from Paratek Pharmaceuticals, Inc.

Transparency declarations

Relevant to this manuscript: M.M. reports nothing to declare; L.A. reports consulting for ViiV, Shionogi, Ferring, La Jolla Pharmaceuticals, bioMérieux, Pfizer, and being of the board of director for the Infectious Diseases Society of America; J.A.V. reports consulting for Cidara, Melinta, AbbVie, Insmed and Vedanta, and speaking for AbbVie and Melinta; L.O.-Z. reports consulting for GSK, Melinta, Pfizer, Gilead and Viracor.