While pneumonia is not a new disease, it's certainly an evolving one—and new guidelines are trying to keep up.
Before the antibiotic era began around 1945, Streptococcus pneumoniae caused more than 90% of cases of community-acquired pneumonia (CAP) in adults, according to a review article published in the November 2017 Clinical Infectious Diseases. Now, these organisms account for 30% or fewer of adult CAP cases, according to the CDC. In patients requiring hospitalization, the percentage may be even lower.
Only about 5% of 2,259 adults hospitalized with CAP had pneumococcal pneumonia in the CDC's EPIC study, published in July 2015 by the New England Journal of Medicine. A whopping 62% of patients had no pathogen at all detected on polymerase chain reaction, and 23% had only viral pathogens detected. In other words, this is not your grandmother's pneumonia.
Guidelines have evolved along with the disease, albeit slowly. Most recently, in October 2019, the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) updated their joint guideline on diagnosing and treating adults with CAP from 2007.
While the new guideline shares many similarities with previous recommendations, there are several major differences. Among them, say goodbye to health care-associated pneumonia (HCAP), and be on the lookout for Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). A new era of CAP management has arrived.
The biggest changes
Following the lead of the same societies' joint 2016 guideline on hospital-acquired and ventilator-associated pneumonia (HAP/VAP), the new CAP guideline recommends abandoning use of the HCAP category to guide therapy.
In the 2005 ATS/IDSA guideline on HAP, VAP, and HCAP, risk factors for multidrug-resistant pathogens causing HCAP included prior hospitalization for two days or more in the past 90 days and residence in a nursing home or extended care facility. The guideline introduced HCAP as a new category of nosocomial pneumonia. “It was not a successful strategy,” said Joshua P. Metlay, MD, PhD, FACP, one of two lead authors of the new CAP guideline. “It would have been hard to see that back then, but you could certainly see it now.”
That's because a substantial portion of pneumonia patients admitted to hospitals met HCAP criteria, said infectious diseases subspecialist Richard T. Ellison III, MD, FACP, a professor at the University of Massachusetts Medical School in Worcester, Mass. In turn, clinicians began to routinely prescribe a very wide spectrum of coverage for P. aeruginosa and MRSA, including the infamous combination of vancomycin and piperacillin/tazobactam, he said.
“Now there's evidence that that combination in particular has more risk of causing nephrotoxicity,” said Dr. Ellison. “So I do think that these new guidelines will have a significant change in how patients are managed in the hospital setting.”
The new guideline narrows the criteria for considering treatment of P. aeruginosa and MRSA. Still, for some patients, covering these pathogens will be lifesaving, Dr. Metlay said. “We really tried to emphasize the importance of getting microbiological tests when you're going to cover for these pathogens, because then at least at 48 hours, if you don't have any culture evidence that those are the pathogens, you can de-escalate and stop the broader therapy.”
The new guideline recommends only covering for P. aeruginosa and MRSA in hospitalized patients based on local epidemiology and validated risk factors. While the prior guideline did not generally recommend the routine use of sputum cultures, the new guideline recommends obtaining them for patients with severe disease and for all inpatients empirically treated for P. aeruginosa or MRSA.
Obtaining cultures can support antibiotic stewardship, said IDSA President Thomas M. File Jr., MD, MSc, MACP. “My take is if a patient is expectorating sputum, even in nonsevere ward patients, to send for culture, as it may assist with pathogen-directed therapy for de-escalation and possibly avoid unnecessary broad-spectrum antibiotics,” he said. “If pan-susceptible pneumococcus is isolated, [you] can go with penicillin or amoxicillin.”
The new criteria for considering P. aeruginosa or MRSA function as a kind of replacement for HCAP, according to Michael S. Niederman, MD, MACP, co-chair of the 2005 nosocomial pneumonia guideline committee that proposed HCAP and clinical director and associate chief of the division of pulmonary and critical care at Weill Cornell Medicine in Roslyn, N.Y. (Dr. File reports research funding from Nabriva and previous consultantships for Melinta and bioMérieux. Dr. Niederman reports consultantships and advisory board service for Merck, Pfizer, Nabriva, and Paratek.)
“I think [the change] was not a bad idea, but I think they may have gone a little far in some areas,” said Dr. Niederman.
For example, although the guideline proposes that clinicians should obtain local data on whether P. aeruginosa or MRSA is prevalent in their patients with CAP, Dr. Niederman said that is not likely to happen. While the intention of antibiotic stewardship is good, he said, “I'm concerned that there are patients who epidemiologically would be at risk and might benefit but won't get that therapy [for P. aeruginosa or MRSA] because nobody has a knowledge of local risk factors, as recommended in the guideline.”
However, the new emphasis on obtaining sputum assessments should enable hospitals to use those objective data to ascertain their local epidemiology, said Dr. Ellison, who is also hospital epidemiologist at UMass Memorial Medical Center. “I think there has been less of a push for trying to get sputum samples in the last decade, and this is really going to reinforce the need for us to actually obtain culture data,” he said.
Still, there are many false-negative sputum cultures, with varying causes, and in some chronically ill patients, a sputum culture may reflect colonizing and not infecting organisms, Dr. Niederman said. For instance, the patient may have already been started on antibiotics, or the sample could be poor, which can be a problem in nonintubated patients especially, he said. “If you're dealing with someone who is elderly and weak … it can be quite difficult to obtain them,” agreed Dr. Ellison, adding that it is ideal to have a nurse or other staff member coach the patient to provide a good specimen, rather than simply place a collection cup beside the bed.
With regard to empiric therapy for inpatients with CAP, not much has changed since the previous guideline.
“The empirical treatment recommendations for inpatients are quite similar to what they've been,” said Dr. Metlay, who is chief of the division of general internal medicine at Massachusetts General Hospital in Boston. “Although very recently, we've had some new antimicrobial agents into the market … there wasn't a lot of data that would suggest that the old drugs shouldn't continue to be used.”
For hospitalized adults with nonsevere CAP who do not have risk factors for P. aeruginosa or MRSA, the guideline recommends empiric treatment with a beta-lactam plus a macrolide or with a respiratory fluoroquinolone. For patients who have documented allergies or contraindications to both macrolides and fluoroquinolones, a third option is combination therapy with a beta-lactam and doxycycline.
In the ICU, patients should not receive monotherapy. “That's not new, but it's a really important point that hospitalists need to be aware of,” Dr. Niederman said. For those with severe CAP without risk factors for P. aeruginosa or MRSA, the guideline recommends a standard regimen of combination therapy with a beta-lactam and macrolide or a beta-lactam and a respiratory fluoroquinolone, with stronger evidence in favor of the former.
“I would agree. My thinking is a macrolide's a better choice,” Dr. Niederman said. “There's more data on it as the second drug, and … there's been a lot of concerns about side effects of quinolones. However, if Legionella is likely or proven, a quinolone may be a better option as the second drug.”
Fluoroquinolones have stood the test of time in terms of effectiveness, but there are increasing questions about their safety. Since 2008, the antibiotic class has been fraught with FDA warnings about several risks, including tendinopathy, hypoglycemic coma, and mental health side effects.
Some critics have questioned whether the guideline pushes hard enough to steward fluoroquinolones. Infectious diseases subspecialist Brad Spellberg, MD, FACP, maintained that the drugs should not have been included as first-line options to treat CAP. “Using an oral agent that's active against P. aeruginosa to treat pneumococcal and Mycoplasma pneumonia is unwise. … They need to be reserved and preserved for patients who need oral gram-negative therapy,” he said.
The respiratory fluoroquinolones (e.g., moxifloxacin and levofloxacin), however, are not as effective against P. aeruginosa as, say, ciprofloxacin, and they are active against Legionella species, Chlamydia species, and Mycoplasma, Dr. Ellison noted. “Those three pathogens are not as well covered by doxycycline or certainly the penicillins, so that's the reason” fluoroquinolones are recommended by the guideline. He acknowledged that macrolides also provide coverage for that group of bugs.
When developing the guideline, Dr. Metlay and colleagues found evidence that treatment with fluoroquinolones is still very effective for patients with CAP, he said. “There's no data that would suggest that outcomes are worse—perhaps better in some settings—so it would be hard to remove those drugs as part of our recommended standard therapy for inpatients with pneumonia.”
It's true that fluoroquinolones are safe and effective for CAP, Dr. Spellberg agreed. “Is that the point? No.” The issue is how the results of trials are applied in the real world, where antibiotic resistance is a major concern. “They have to be interpreted in the context of proper clinical practice,” he said.
Dr. Metlay added that when there are multiple treatment options, the guideline does not endorse one over another. “You have to make an individualized decision, and that decision includes weighing some of these risks as well as the benefits,” he said.
Guidance where there was none
The new guideline addresses four key issues that were not brought up in previous guidelines: procalcitonin, corticosteroids, rapid molecular tests, and new antibiotics.
In 2017, the FDA approved an expanded indication for the first procalcitonin test to assist clinicians in making the decision to stop antibiotic treatment in patients with lower respiratory tract infections. The higher the level of the infection biomarker in the blood, the higher the likelihood of bacterial infection.
“The data are fairly convincing across numerous clinical trials that if you use procalcitonin to allow early de-escalation or cessation of therapy, you will decrease antibiotic use by around 25%, with no change in clinical cure or death,” said Dr. Spellberg, who is chief medical officer at the Los Angeles County-University of Southern California Medical Center.
Despite the promise of procalcitonin, the guideline does not generally recommend its use to assist in determining the duration of therapy. This is because the biomarker has been shown to be effective in settings where the average duration of therapy exceeds the recommended five to seven days, the guideline said. “We thought that in general, if you're going to agree with that and give five days as your standard duration, then there really is no role for measuring procalcitonin as well, because there's no evidence that you can reduce it further than that using procalcitonin,” Dr. Metlay said.
Dr. File, however, said he has found the test useful, particularly when a patient tests positive for a virus and has a very low procalcitonin level, suggesting a very low likelihood of concomitant bacterial infection. “This likely represents monoinfection with a virus, giving us confidence to stop the antibiotics well before five days,” he said.
Although the guideline didn't address this, procalcitonin can also be a valuable tool to help decide which patients to put in the ICU, Dr. Niederman noted. In one study, published in the October 2016 CHEST, hospitalized patients who had a high procalcitonin level and met three minor criteria for severe CAP ended up in the ICU 36% of the time, compared to 13% for those who met three minor criteria but had a low procalcitonin level. “To me, procalcitonin added a lot of value in figuring out who to put in the ICU,” he said.
Another new area of guidance is corticosteroids, which have been much discussed for patients with severe CAP. The guideline recommends against using them generally, and especially not for influenza-related CAP, although they may be considered in patients with refractory septic shock. Most experts agreed with this recommendation.
However, Dr. Niederman pointed to a randomized trial published in February 2015 by JAMA, which showed that steroids decreased treatment failure in patients with severe pneumonia plus a high inflammatory response (e.g., elevated C-reactive protein level). “I think it's a little bit too simple to say no [patients with] severe pneumonia should get steroids,” he said. “I believe that [those with] severe pneumonia with a high level of inflammation should.”
The guideline also offers limited support for the new nucleic acid amplification tests. It mentions that several of those available can identify the cause of pneumonia, but they “require rigorous testing to assess the impact” on treatment decisions and clinical outcomes.
“Personally, we have found these tests very useful but agree more studies are needed to assess the impact,” said Dr. File, who is also professor of internal medicine, master teacher, and chair of the infectious disease section at Northeast Ohio Medical University in Rootstown, Ohio. “We are in a revolution of development of these new rapid tests, and I suspect within the near future, we will have these studies.”
Finally, the guideline said that newer antibiotics approved to treat CAP by the FDA require further research. These drugs include omadacycline (a tetracycline agent), lefamulin (a pleuromutilin agent/novel mechanism of action), and delafloxacin (a new fluoroquinolone). There is no mention of how or when to consider these new agents, Dr. File noted. “This is likely in part due to the fact that these were all just recently approved.” In fact, delafloxacin was approved in October 2019, just after publication of the guideline.
By necessity, the new drugs were designed to be equal to existing antibiotics, Dr. Niederman noted. “They haven't shown a specific reason that we have to use them,” he said. “Nonetheless, I think, since some people are beta-lactam allergic and since some people don't want to take quinolones, it's good to have non-beta-lactam, non-fluoroquinolone alternatives.” Dr. Ellison added that their cost will likely be much higher than other currently available drugs.
“Each of these provide some advantages regarding spectrum,” Dr. File said of the new antibiotics. “I hope there can be a follow-up to the guidelines with some additional guidance regarding these agents.”