VIENNA – A single, well-targeted antibiotic may be enough to effectively combat serous bloodstream infections in patients who have a low baseline mortality risk.

Among these patients, overall mortality was similar among those receiving a single antibiotic and those getting multiple antibiotics (35% vs. 41%). Patients with a high baseline mortality risk, however, did experience a significant 44% survival benefit when treated with a combination regimen, Jesus Rodríguez-Baño, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

The finding is important when considering the ever-increasing imperative of antibiotic stewardship, Dr. Rodríguez-Baño said in an interview.

“In areas where these pathogens are common, particularly in intensive care units, where they can become epidemic and infect many patients, the overuse of combination therapy will be fueling the problem,” said Dr. Rodríguez-Baño, head of infectious diseases and clinical microbiology at the University Hospital Virgin Macarena, Seville, Spain. “This is a way to avoid the overuse of some broad-spectrum antibiotics. Selecting the patients who should not receive combination therapy may significantly reduce the total consumption” on a unit.

The retrospective study, dubbed INCREMENT, was conducted at 37 hospitals in 10 countries. It enrolled patients with bloodstream infections caused by extended-spectrum beta-lactamase- or carbapenemase-producing Enterobacteriaceae. Dr. Rodríguez-Baño reported results for 437 patients whose infections were caused by the carbapenemase-producing strain.

It was simultaneously published in Lancet Infectious Diseases (Lancet Inf Dis 2017; DOI: http://dx.doi.org/10.1016/S1473-3099(17)30228-1).

These patients were a mean of 66 years old; most (60%) were male. The primary infective agent was Klebsiella pneumonia (86%); most infections were nosocomial. The origin of infections varied, but most (80%) arose from places other than the urinary or biliary tract. Sources were vascular catheters, pneumonia, intraabdominal, and skin and soft tissue. About half of the patients were in severe sepsis or septic shock when treated.

The group was first divided into those who received appropriate or inappropriate therapy (78% vs. 22%). Appropriate therapy was considered to be the early administration of a drug that could effectively target the infective organism. Next, those who got appropriate therapy were parsed by whether they received mono- or combination therapy (61%, 39%). Finally, these patients were stratified by a specially designed mortality risk score, the INCREMENT Carbapenemase-Producing Enterobacteriaceae (CPE) Mortality Score (Mayo Clinic Proceedings. doi.org/10.1016/j.mayocp.2016.06.024).

Severe sepsis or shock at presentation (5 points)
Pitt score of 6 or more (4 points)
Charlson comorbidity index of 2 or more (3 points)
Source of bloodstream infection other than urinary or biliary tract (3 points)
Inappropriate empirical therapy and inappropriate early targeted therapy (2 points)

Patients were considered low risk if they had a score of 0-7, and high of they had a score of 8 or more.

The risk assessment took is quick, easy to figure, and extremely important, Dr. Rodríguez-Baño noted. “This is a very easy-to-use tool that can help us make many patient management decisions. All of the information is already available in the patient’s chart, so it doesn’t require any additional assessments. It’s a very good way to individualize treatment.”

In the initial analysis, all-cause mortality at 30 days was 22% lower among patients who received appropriate early therapy than those who did not (38.5% vs. 60.6%). This translated to a 55% decrease in the risk of death (HR 0.45 in the fully adjusted model).

The investigators next turned their attention toward the group that received appropriate therapy. All-cause 30-day mortality was 41% in those who got monotherapy and 34.8% among those who got combination therapy..

Finally, this group was stratified according to the INCREMENT-CPE mortality risk score.

In the low-risk category, combination therapy did not confer a survival advantage over monotherapy. Death occurred in 20% of those getting monotherapy and 24% receiving combination treatment – not a significant difference (HR 1.21).

Combination therapy did, however, confer a significant survival benefit in the high-risk group. Death occurred in 62% of those receiving monotherapy and 48% of those receiving combination therapy – a 44% risk reduction (HR 0.56).

As long as they were appropriately targeted against the infective organism, all drugs used in the high-mortality risk group were similarly effective at reducing the risk of death. Compared to colistin monotherapy, a combination that included tigecycline reduced the risk of death by 55% (HR 0.45); combination with aminoglycosides by 58% (HR 0.42); and combination with carbapenems by 44% (HR 0.56).

A secondary analysis of this group determined that time was a critical factor in survival. Each day delay after day 2 significantly increased the risk of death, Dr. Rodríguez-Baño said. This 48-hour period gives clinicians a chance to wait for the culture and antibiogram to return, and then choose and initiate the best treatment. Before the results come back, empiric antibiotic therapy is appropriate, but changes should be made immediately after the results come back.

“We tend to think we must give the very best antibiotic at the very first moment that we see a patient with a serious infection,” he said. “But what we found is that it’s not critical to give the perfect antibiotic on the first day. It is critical, however, to give the correct one once you know which bacteria is causing the infection. Since it takes 48 hours for those results to come back, this is perfect timing.”

INCREMENT was funded in large part by the Spanish Network for Research in Infectious Diseases. Dr. Rodríguez-Baño has been a scientific advisor for Merck, AstraZeneca, and InfectoPharm.

msullivan@frontlinemedcom.com

On Twitter @Alz_gal

Monotherapy as good as combo for antibiotic-resistant infections in low-risk patients