Community-acquired pneumonia (CAP) is one of the most common and serious infections managed in both the outpatient and inpatient settings. Optimal management of CAP has been the subject of numerous professional society guidelines over the years. In the United States, the American Thoracic Society and Infectious Diseases Society of America each produced widely disseminated guidelines and combined efforts to produce a joint adult CAP guideline published in 2007 .
In 2013, both societies initiated a revision to the CAP guideline for adults and we were asked to co-chair the guideline committee. Several key changes were implemented in the guideline process that significantly impacted the process.
First, the professional societies adopted stricter conflict of interest (COI) rules that identified a range of interactions with industry that would exclude someone from participating on the committee or, at a minimum, exclude someone from voting on specific recommendations within the guideline. The COI policies did prevent several experts in the field from participating on the guideline committee but we recognized the important experience and knowledge they bring to the field and relied on the review process to solicit their feedback. Overall, we support the stricter COI policies though also recognize that COI is about more than just industry interactions and, ultimately, guidelines should reflect the full input of experts in the field.
Second, the professional societies endorsed the more rigorous Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach towards evidence review and guideline generation . The process is arduous and clearly contributed to the multiyear process required to complete the guideline. Unfortunately, numerous key questions addressed by the guideline were not supported by the highest level evidence emphasized by GRADE. As a result, review of lower quality evidence and expert opinion were necessary to address the core guideline questions. Thus, whether the rigorous steps required by GRADE truly resulted in a different set of guideline recommendations is unclear. What is clear is that the multiyear process is difficult to sustain and, given the pace of new research, a faster paced process is required to update the guideline as new information is available. Indeed, even as the guideline was being finalized, new antibiotics were approved for use in CAP and ongoing experience with these agents should be incorporated into updates to the guideline.
In this article, we summarize five key areas of focus of the guideline, representing important changes from the past guideline and/or emerging areas of research that are likely to continue to evolve in the next several years [3▪▪]. We maintain the conventions of the published adult CAP guideline. Specifically, we focus on adults (>18 years) without immunosuppressing conditions who have radiographic confirmation of pneumonia. We recognize that many physicians will diagnose and manage adults with CAP without requiring chest radiography but substantial evidence highlights the inaccuracy of clinical examination to diagnose pneumonia , and the guideline was not developed to manage patients with biomarker evidence of bacterial infection and respiratory complaints, but no definitive evidence of a lung infection.
In this article, we provide a high-level summary of some of the recommendations from the guideline. For a full discussion of the evidence with relevant citations, readers should review the online version of the guideline or the recently published executive summary [3▪▪].
Diagnostic test utilization including microbiological tests and biomarkers
CAP is caused by a range of infectious agents, including both common bacteria and viruses. Like many other infectious illnesses, it would be helpful to be able to accurately and rapidly identify the causal organism to choose appropriate antiinfective therapy. Historically, the two main microbiological tests available to identify an etiological agent in CAP are sputum and blood cultures. In addition, urine antigen tests for Streptococcus pneumoniae and Legionella pneumophila are available and have high level of specificity in adults. More recently, there has been an expansion of molecular assays using respiratory samples to test for a range of viral and bacterial pathogens. Yet, even with the availability of these extensive diagnostic testing strategies, the causal pathogen remains undetected in the majority of adults with CAP . Moreover, high-level evidence does not exist that testing strategies result in improved outcomes for adults with CAP compared with empiric treatment strategies without testing.
We do acknowledge that there is a strong desire to limit antibiotic use, or at least utilize the narrowest spectrum possible, based on sound antibiotic stewardship principles as discussed below. However, there is also no evidence that existing diagnostic tests achieve this outcome and some evidence clearly showing that they do not.
Thus, the adult CAP guideline does not endorse routine use of any current diagnostic testing strategies in the majority of adults with CAP. However, we did identify two major exceptions when testing is recommended. First, adults with severe CAP [defined as 1 major or 3 minor ATS/IDSA criteria (see Table 1)], are the most likely to benefit from microbiological testing as they are more likely to have drug-resistant pathogens and may need expanded therapy beyond the standard empiric recommendations. Second, adults with suspected drug-resistant pathogens, especially methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa, should have testing to either identify the pathogen and target therapy accordingly or de-escalate therapy if cultures do not reveal these pathogens.
We recognize that newer molecular diagnostic platforms are creating the possibility of rapid, accurate pathogen identification including both bacterial and viral pathogens. We strongly encourage evaluation of these testing strategies to determine if the routine use of such tests improves antimicrobial drug selection, and, especially, patient outcomes.
Empiric treatment recommendations
As with past versions of the adult CAP guideline, empiric treatment recommendations were based on severity of illness and site of care. As noted above, while we would prefer to be able to make pathogen-directed treatment recommendations, the reality is that pathogen identification is too uncommon and empiric treatment strategies are needed. We also recognized that the microbial pathogenesis of CAP is changing. In particular, the introduction of the pneumococcal conjugate vaccine in the early 2000s has resulted in a significant decline in the frequency of Strep. pneumoniae as a respiratory pathogen in both children and adults . Indeed, it is likely that an increasing proportion of adult cases of CAP are because of viral pathogens alone, eliminating the need for any antibacterial therapy. Unfortunately, we did not identify any high-level studies that supported a strategy of withholding antibiotic therapy at the time of CAP diagnosis. We acknowledge that the combination of positive findings with rapid viral testing and negative findings with a biomarker, such as procalcitonin that predicts bacterial infection could ultimately support, such a nonantibiotic treatment strategy for adults with CAP; however, there is currently insufficient data to currently support such an approach.
Thus, recommendations for empiric antibiotic therapy focus on the typical bacterial pathogens identified in CAP patients, with broader coverage recommended for outpatients with co-morbidities or inpatients, especially those with severe CAP. Some key changes in the current guideline included:
- (1) Recommending monotherapy with beta-lactams (e.g. amoxicillin) for uncomplicated outpatients, largely based on the results of inpatient trials.
- (2) Reducing the strength of recommendation for monotherapy with macrolides for uncomplicated outpatients, largely based on the continued emergence of macrolide resistance among clinical isolates of Strep. pneumoniae.
- (3) Acknowledging the rising number of reports of adverse drug events associated with certain classes of antibiotics, especially fluoroquinolones (vascular injury, tendinopathy, Clostridium difficile infection) and emphasizing that when multiple treatment options are presented, the final choice should reflect a risk--benefit assessment for each individual patient.
Notably, although newer antimicrobial agents were recently approved for CAP (omadacycline, lefamulin), experience with these agents was too limited to have them listed as first-line agents in the current adult CAP guideline. Still, we believe that ongoing monitoring and evaluation is critical and could support updates to these empiric treatment recommendations in the next few years.
Accounting for drug-resistant pathogens
One of the major strategies endorsed as part of the last adult CAP guideline was the recognition of healthcare-associated pneumonia (HCAP) as a distinct entity that would warrant broader spectrum empiric antibiotic treatment to cover for drug-resistant pathogens, especially MRSA and P. aeruginosa. HCAP risk factors included nursing home or long-term care residence, recent hospitalization, and hemodialysis. Unfortunately, the HCAP strategy failed for several reasons: HCAP poorly predicted the presence of these drug-resistant pathogens in most settings, HCAP criteria were widely prevalent and led to extensive and inappropriate use of broader agents (e.g. vancomycin, piperacillin--tazobactam, carbapenems) for CAP patients, and outcomes for patients meeting HCAP criteria were worse when they received broader treatment compared with standard guideline recommended treatment [7,8,9▪].
Therefore, the guideline committee recommended that clinicians abandon the use of HCAP as a strategy for prescribing broader spectrum antibiotic therapy. The challenge, however, was identifying an alternative strategy, as we also recognized that a small proportion of adults with CAP are infected with these drug-resistant pathogens and are likely to suffer worse outcomes if treatment does not cover for them. Although a few clinical prediction rules have been developed and likely outperform HCAP as tools to identify CAP patients at higher risk of drug-resistant pathogens, none of these rules has been tested in clinical settings and demonstrated to lead to improved patient outcomes. In addition, we recognize that the risk of drug-resistant pathogens varies enormously by clinical site and as the ultimate performance of any prediction rule relates to the baseline prevalence of the different pathogens, it is critically important for sites to measure their own local rates of these pathogens. Thus, some sites may adopt more aggressive strategies for the use of broader spectrum empiric treatments, especially in patients with severe CAP, whereas other sites may be able to withhold such therapies even in the face of known risk factors. Therefore, although the guideline committee was very sympathetic to the desire for a simple rule guiding the use of anti-MRSA and anti-P. aeruginosa therapy, the reality is that there is no substitute for clinicians having knowledge of their local etiological data to determine if these are needed.
In part to help support such local data gathering, as noted above, the committee recommended routinely obtaining sputum and blood culture data whenever drug-resistant pathogens are suspected, especially when broader spectrum empiric therapy is initiated. In addition, routinely collecting such diagnostic tests when broader spectrum empiric therapy is initiated would allow for de-escalation of therapy at 24–48 h if culture results do not indicate the presence of drug-resistant pathogens requiring the broader therapy.
Antibiotic-prescribing decisions have both individual and societal consequences. Appropriately, increasing attention is being paid to the unintended harms that are caused by these prescriptions. At the individual level, these harms include dose-dependent and idiosyncratic adverse events as well as an increased individual risk of subsequent antibiotic-resistant infections. At the societal level, studies have demonstrated a clear link between per capita or per patient utilization of antibiotic classes and resistance to those classes in the community or hospital, respectively. Thus, as highlighted earlier, every antibiotic prescription decision must be framed as a risk-benefit decision.
The guideline committee spent considerable time discussing how best to incorporate these concerns over individual and community-level risk associated with antibiotic prescribing. Ultimately, the adult CAP guideline emphasized evidence demonstrating equivalence of different antibiotic treatment strategies as we did not feel that adverse events reported for individual classes of drugs should invalidate existing data that demonstrated therapeutic equivalence across drug classes. For example, while increasing reports highlight individual risks of fluoroquinolones and fluoroquinolone drug resistance among multiple pathogens (especially Gram-negative pathogens) is a rising problem, such evidence did not change the available randomized trial evidence demonstrating therapeutic equivalence of respiratory fluoroquinolones to other empiric treatment regimens. However, the continued inclusion of these different treatment options does not mean that they should be treated equally in all situations. Moreover, local infection control strategies may particularly influence the relative favoring of one strategy over another.
Similarly, the guideline committee endorsed the goal of limiting antibacterial drug exposure to those patients who have susceptible bacterial infections. We strongly endorsed de-escalation strategies that narrow or perhaps even stop all antibacterial drugs depending on the available laboratory and clinical evidence. Moreover, we called for future studies to test empiric strategies that withhold antibiotics in selected groups of patients with CAP.
However, it is worth highlighting that relative to the total amount of antibiotic prescribing, especially in the outpatient setting, the amount prescribed to treat adult patients with CAP is relatively small and is likely not the major driver of the drug toxicities and resistance patterns that are being reported. Thus, although antimicrobial stewardship is an important perspective to consider in developing CAP treatment guidelines, it is also important to highlight that the major efforts to reduce inappropriate and unnecessary antibiotic-prescribing patterns should focus on other patient populations, especially those with acute bronchitis and upper respiratory tract infections that are not responsive to antibiotic therapies.
Role of corticosteroids
One of the major new therapeutic drug classes to be evaluated since the release of the last CAP guideline was corticosteroids. Several randomized trials have now been published and meta-analyses have summarized these data [10,11]. Although some of these analyses have highlighted the potential for clinical benefit in the use of corticosteroids in patients with severe CAP, the guideline committee did not endorse routine use of corticosteroids in patients with CAP, including severe CAP. This decision reflected several considerations including: important weaknesses in some of the trials that drove the positive results of the meta-analyses, appreciation of risks associated with widespread use of corticosteroids in patients with CAP, and knowledge of ongoing major trials designed to provide more definitive evidence on the use of steroids for adults with CAP, including one strongly negative randomized controlled trial published after the guidelines had been finalized and accepted for publication [12▪]. Notably, we did emphasize settings in which corticosteroid use is recommended and could co-exist in adults with CAP, including reactive airway diseases, other steroid-dependent chronic conditions, and sepsis with refractory shock.
Appropriate management of patients with pneumonia has been the focus of debate for over 100 years. Indeed, despite the discovery and wide-spread use of antibiotics and vaccines, pneumonia remains a major source of morbidity and mortality worldwide. In the United States, acute cough illness is one of the leading causes of urgent and emergency care visits and although pneumonia is the underlying diagnosis in only a minority of these patients, it drives much of the management strategy for this patient population. Given the magnitude of the problem, it is disappointing that the development of new and effective preventive, diagnostic and therapeutic strategies has been relatively slow. Notable exceptions include the introduction of the pneumococcal conjugate vaccine, improved universal uptake of influenza vaccination, and the relatively recent introduction of new antimicrobial drug options. Moreover, emerging molecular diagnostic assays hold the potential to support rapid, point-of-care testing strategies that could transform treatment strategies from purely empiric to more pathogen-directed. However, for such strategies to be recommended in future iterations of the adult CAP guideline will require evidence that such strategies improve patient outcomes. As new evidence becomes available, we support a process that will allow more frequent updates to the adult CAP guideline.
The authors are indebted to the outstanding other members of the ATS/IDSA Adult CAP guideline committee: Ann C. Long, Antonio Anzueto, Jan Brozek, Kristina Crothers, Laura A. Cooley, Nathan C. Dean, Michael J. Fine, Scott A. Flanders, Marie R. Griffin, Mark L. Metersky, Daniel M. Musher, Marcos I. Restrepo, and Cynthia G. Whitney.
Financial support and sponsorship
Administrative support for the guideline committee was provided by the American Thoracic Society.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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