Study raises questions about broad-spectrum antibiotics for pneumonia

Doctor showing chest x-ray to patient
Doctor showing chest x-ray to patient

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A large study of patients hospitalized for pneumonia suggests that a treatment strategy designed to account for patients with antibiotic-resistant infections should be reconsidered.

The study, published this week in JAMA Internal Medicine, found that pneumonia patients who received empirical broad-spectrum antibiotics had a higher risk of death compared with those who received standard antibiotic therapy. They also had a higher risk of kidney injury, along with Clostridioides difficile and other secondary infections.

The authors of the study say the findings are a good example of how efforts to improve clinical outcomes for patients can sometimes lead clinicians to adopt practices that aren't backed by solid evidence. In the case of pneumonia, concerns about possible infection with resistant organisms like methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa has led to a strategy of early broad-spectrum antibiotics for certain patients.

"The underlying assumption of this approach is that the benefit of more potent antibiotics during the empirical phase exceeds the harms," they write. "Our study questions this assumption."

No benefit, increased risk of harm

The strategy goes back to the 2005 guidelines from the American Thoracic Society and the Infectious Diseases Society of America for treatment of adults who have community-acquired pneumonia (CAP). Those guidelines recommended that pneumonia patients who lived in nursing homes or had been in the hospital in the previous 90 days should be labeled as having healthcare-associated pneumonia (HCAP) and treated empirically with broad-spectrum antibiotics like vancomycin or piperacillin-tazobactam to cover for the possibility that the pneumonia was caused by MRSA or Pseudomonas.

Subsequently, a 2015 study of patients in the Department of Veterans Affairs (VA) healthcare system found that, after those guidelines were published, a substantial shift in treatment of CAP patients occurred, with the proportion of vancomycin prescribing rising from 16% in 2006 to 31% in 2010 and piperacillin-tazobactam prescribing jumping from 16% to 27%. This shift occurred even though less than 5% of patients in the study had resistant bacteria detected.

But it's unclear which patients, and how many, are benefitting from the use of more potent antibiotics.

To get a better sense of how empiric broad-spectrum therapy is affecting clinical outcomes in CAP patients, a team led by investigators from the VA Salt Lake City Health Care System and the University of Utah conducted a retrospective cohort study of all CAP hospitalizations in the VA health care system from 2008 through 2013.

They specifically looked at the 30-day mortality rate associated with three empirical treatment regimens: standard antibiotics alone, standard antibiotics plus anti-MRSA therapy, and anti-MRSA therapy without standard antibiotics. Secondary outcomes included development of kidney injury and secondary infections with C difficile, vancomycin-resistant Enterococcus species, or gram-negative bacteria.

Of the 88,605 CAP patients analyzed in the study, empirical anti-MRSA antibiotics were administered to 33,632 (38%), with 13,528 receiving empirical anti-MRSA therapy with standard antibiotics and 20,104 receiving anti-MRSA therapy without standard antibiotics. The 30-day all-cause mortality rate was 10% (8,929 patients). Only 2% of the patients (2,154) had MRSA detected by clinical culture.

After adjusting for comorbidities and other patient characteristics that might affect treatment regimens and risk of 30-day mortality, the analysis found that empirical anti-MRSA treatment plus standard therapy was significantly associated with greater 30-day mortality compared with standard therapy alone (adjusted risk ratio [aRR], 1.4; 95% confidence interval [CI], 1.3 to 1.5), as was anti-MRSA treatment with non-standard therapy (aRR, 1.5; 95% CI, 1.4 to 1.6).

Analysis of secondary outcomes showed that patients receiving anti-MRSA treatment and standard therapy also had a higher risk of kidney injury (aRR, 1.4; 95% CI, 1.3 to 1.5), secondary C difficile infections (aRR, 1.6; 95% CI, 1.3 to 1.9), vancomycin-resistant Enterococcus spp (aRR, 1.6; 95% CI, 1.0 to 2.3), and secondary gram-negative bacteria detection (aRR, 1.5; 95% CI, 1.2 to 1.8).

In addition, similar associations between anti-MRSA therapy and higher 30-day mortality were found when the researchers looked at sub-groups of patients admitted to the intensive care unit (aRR, 1.3; 95% CI, 1.2 to 1.5), those with a high risk for MRSA (aRR, 1.2; 95% CI, 1.1 to 1.4), and those with MRSA detected on surveillance testing (aRR, 1.6; 95% CI, 1.3 to 1.9). There was no significant difference in risk of 30-day mortality, however, for patients with a MRSA-positive culture (aRR, 1.1; 95% CI, 0.8 to 1.4).

"These findings, which were robust to multiple methods of analysis, contribute to a growing body of evidence that raises questions surrounding widespread empirical use of extended-spectrum antibiotics in patients with community-acquired pneumonia," the authors write.

Rethinking the 'more is better' mantra

For Michael Klompas, MD, MPH, a professor of population medicine at Harvard Medical School and author of an editorial that accompanies the study, the data from this analysis and other studies make a compelling argument that broad-spectrum antibiotics for pneumonia should be avoided until it's clear they are needed.

"The messages are clear: empirical coverage with broad-spectrum agents is not indicated in most patients being treated for pneumonia, and if the diagnosis of pneumonia is uncertain, there is no harm and likely some benefit in taking some time to acquire more diagnostic clarity before treating (such as further imaging, laboratory testing, treating concurrent conditions, and/or observation), so long as the patient is clinically stable," he writes.

Valerie Vaughn, MD, a hospitalist at the University of Michigan's academic medical center who was not involved in the study, says the findings are significant because there's long been a concern among clinicians that CAP patients are being overtreated, given the fact that MRSA is still a very rare cause of pneumonia.

"There was this growing sense that we'd swung the pendulum too far, and were very focused on trying to make sure that we didn't miss any patients with MRSA, so anybody that had a risk for MRSA we treated with vancomycin," Vaughn said. "We really focused on the risk of missing patients that might have MRSA, and less about the potential harms of overtreating what is a much larger number of patients who don't have MRSA pneumonia."

Vaughn hopes that this study, along with revamped CAP guidelines published in October 2019, will spur changes in the how clinicians treat these patients. The new guidelines support abandoning the term HCAP, and recommend that clinicians treat patient empirically for MRSA or Pseudomonas only if locally validated risk factors for either pathogen are present.

"This is definitely something that's been in the front of our minds, the fact that we need to rethink the doctrine that more is better, and that the benefit of catching resistant organisms early in a few patients outweighs the harms of antibiotic side effects in the many who end up not having resistant organisms, or actually may not have pneumonia at all," she said.

Vaughn said the next step for reducing unnecessary antibiotic treatment for pneumonia, which is often overdiagnosed, is development of better diagnostic tools.

"We still don't have a good way of diagnosing pneumonia, or diagnosing pathogens for patients who do have pneumonia," she said. "We need better diagnostics tools, and better ways of using those tools."

See also:

Oct 2, 2019, CIDRAP News story "Guidance on community-acquired pneumonia updated"

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