By Kathryn Radigan, MD

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: In patients with newly diagnosed community-acquired pneumonia, basing the duration of antibiotic treatment on clinical stability criteria led to a significant reduction in duration of antibiotic treatment without an increased risk of adverse outcomes.

SOURCE: Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: A multicenter randomized clinical trial. JAMA Intern Med 2016;176:1257-1265.

Although the Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines suggest a minimum of five days of treatment in patients with one or more community-acquired pneumonia (CAP)-associated instability criteria and who achieve an afebrile state for 48-72 hours, the optimal length of antibiotic treatment has not been formally investigated. To determine whether the duration of antibiotic treatment based on IDSA/ATS criteria was as effective as conventional treatment, Uranga et al conducted a multicenter, noninferiority, randomized, clinical trial performed at four teaching hospitals in Spain. From Jan. 1, 2012, through Aug. 31, 2013, 312 hospitalized patients diagnosed with CAP were randomized to an intervention or control group on day five of their hospitalization.

Pneumonia was defined as a new pulmonary infiltrate on chest X-ray in addition to at least one symptom compatible with pneumonia, including cough, fever, dyspnea, and/or chest pain. Patients were excluded if they were infected by HIV, exhibited chronic immunosuppression, resided in a nursing home or previously were in an acute care hospital/palliative care unit, ingested antibiotics within the previous 30 days, required a longer course of antibiotics based on identification of bacteria, required a chest tube, or presented with extrapulmonary infection. For patients randomized to the intervention group, treatment with antibiotics continued for a minimum of five days, with cessation of treatment at that time if their body temperature was ≤ 37.8°C for 48 hours and they had ≤ 1 CAP-associated sign of clinical instability. Signs of CAP-associated instability included systolic blood pressure < 90 mmHg, heart rate > 100 beats per minute, respiratory rate > 24 per minute, arterial oxygen saturation < 90%, or PaO2 < 60 mmHg on room air. Physicians determined the length of antibiotics in the control group. In both groups, physicians chose the type of antibiotic based on local guidelines. Main outcomes included clinical success rate at days 10 and 30 from hospital admission and CAP-related symptoms at days five and 10 (measured by the 18-item CAP symptoms questionnaire score, range 0-90).

Of the 312 patients who were enrolled, 150 patients were randomized to the control group and 162 to the intervention group. When comparing groups, there were no significant differences in age or sex distribution. The number of days receiving antibiotics was significantly longer for patients in the control group compared to the intervention group (median 10; interquartile range [IQR], 10-11 vs. median 5; IQR, 5-6.5 days, respectively; P < 0.001). An intention-to-treat analysis comparing patients at day 10 demonstrated clinical success of 48.6% (71 of 150) in the control group and 56.3% (90 of 162) in the intervention group (P = 0.33). There were no differences in clinical success between the control and intervention groups at day 30. At day five and day 10, the mean CAP symptom questionnaire scores were 24.7 (standard deviation [SD], 11.4) vs. 27.2 (SD, 12.5) and 18.6 (SD, 8.5) vs. 17.9 (SD, 7.4), respectively (P = 0.69). For the per-protocol analysis, clinical success was 50.4% (67 of 137) in the control group and 59.7% (86 of 146) in the intervention group at day 10 (P = 0.12). At day 30, clinical success was 92.7% (126 of 137) in the control group and 94.4% (136 of 146) in the intervention group (P = 0.54). At day five and day 10, the mean CAP symptoms questionnaire scores were 24.3 (SD, 11.4) vs. 26.6 (SD, 12.1) and 18.1 (SD, 8.5) vs. 17.6 (SD, 7.4), respectively (P = 0.81). The researchers agreed that basing the duration of antibiotic use on clinical stability criteria can be safely implemented in hospitalized patients presenting with CAP.

COMMENTARY

Even though CAP is one of the leading causes of morbidity and mortality,1 the optimal duration of antibiotic treatment for CAP is unknown. For years, it was standard to treat patients until a clinical response occurred. Typically, this resulted in antibiotic length of therapy less than four days.2 With the growing concern for antibiotic resistance after World War II, doctors increasingly were concerned about relapse of pneumonia and treated for an additional two to three days after resolution of symptoms. Unfortunately, this practice led to the philosophy that treating beyond resolution of symptoms could prevent antibiotic resistance. This mindset translated into common practice until 2007 with the release of the IDSA/ATS guidelines. These guidelines suggested five days of treatment in patients who were afebrile for 48-72 hours and exhibited no signs of clinical instability. Although many entertained these recommendations, they were not widely adopted.

To further investigate the optimal length of antibiotic treatment for CAP and support the IDSA/ATS guidelines, Uranga et al conducted a multicenter, non-inferiority, randomized, clinical trial that included 312 hospitalized patients diagnosed with CAP. At day five, patients were randomized either to an intervention group that limited antibiotics to five days as long as body temperature was ≤ 37.8°C for 48 hours with ≤ 1 CAP-associated sign of clinical instability or to antibiotics per determination of the caring physician. Through these interventions, researchers discovered there was no significant difference in either the clinical success rate or the CAP symptom questionnaire scores. Since this study was a non-inferiority study, its creators did not address specific benefits of shortened length of antibiotic therapy. For instance, the literature says that shortened length of antibiotics leads to lower rates of antibiotic resistance.3 Reduced duration of antibiotics also may lead to improved adherence, decreased incidence and severity of side effects, and cost savings.4,5

Before widely adopting these guidelines, one should be aware of the exclusion criteria that may make this study inapplicable for many patients. These exclusion criteria were extensive and included patients with HIV or chronic immunosuppression (comprising solid organ transplant patients, patients post-splenectomy, taking ≥ 10 mg of prednisone daily or the equivalent for 30 days, on other immunosuppressive agents, demonstrating neutropenia); patients residing in nursing homes; patients discharged from acute care hospitals, onsite subacute care units, or palliative care units within the previous 14 days; and/or patients who had ingested oral antibiotics within 30 days of admission, required longer duration of antibiotics based on cause, required a chest tube, acquired an extrapulmonary infection, or transferred to the ICU prior to randomization. Depending on the site of practice, these exclusion criteria may include the majority of one’s patient population. It also may be important to note that 80% of patients received a fluoroquinolone, and it is unclear if these same results would be appreciated with alternative antibiotic regimens.

The IDSA/ATS recommendations for shorter duration of antibiotic treatment based on clinical stability criteria can be safely implemented in hospitalized patients with CAP. It should be noted that these recommendations must be applied safely, ensuring that the exclusion criteria of this study are respected. Future studies are needed to further delineate the benefits of shorter antibiotic courses.

REFERENCES

  1. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. JAMA 1996;275:134-141.
  2. Ventola CL. The antibiotic resistance crisis: Part 1: Causes and threats. P T 2015;40:277-283.
  3. Lonks JR, Garau J, Gomez L, et al. Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clin Infect Dis 2002;35:556-564.
  4. Thornsberry C, Sahm DF, Kelly LJ, et al. Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: Results from the TRUST Surveillance Program, 1999-2000. Clin Infect Dis 2002;34 Suppl 1:S4-S16.
  5. Gay K, Baughman W, Miller Y, et al. The emergence of Streptococcus pneumoniae resistant to macrolide antimicrobial agents: A 6-year population-based assessment. J Infect Dis 2000;182:1417-1424.