Study details optimal combo therapy for drug-resistant bacteremia

Initiating antibiotic treatment quickly, with the right drug, can reduce mortality in patients with drug-resistant bloodstream infections, but combination antibiotic therapy may be necessary only for the most severely ill patients, according to a new study published in The Lancet Infectious Diseases.

The authors of study, who presented their research at this week's European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), say the finding that combination antibiotic therapy may not be necessary for all patients with drug-resistant bloodstream infections could help clinicians avoid unnecessary overuse of crucial, last-resort antibiotics and reduce the risk of side effects associated with those drugs.

"This finding is important for antibiotic stewardship programmes to reduce consumption of some drugs and, potentially, adverse events," the authors write.

Pros, cons of combination therapy

The study is part of the INCREMENT project, an international retrospective study of patients with bloodstream infections caused by carbapenemase-producing Enterobacteriaceae (CPE), which are multidrug-resistant organisms associated with high morbidity and mortality. CPE bloodstream infections tend to strike severely ill patients and have few treatment options.

While the best treatment option for CPE infections remains unclear, some previous studies have shown that combination antibiotic treatment may be the best approach. The idea behind combination therapy, essentially, is to broaden the spectrum of pathogens treated and reduce the risk of inappropriate treatment in patients with life-threatening bloodstream infections.

But the concern is that this wide-net approach could promote the development of antibiotic resistance if the drugs aren't well-targeted, and potentially harm patients by causing adverse events.

To investigate the effects of antibiotic therapy, including combination therapy, on patients with CPE bloodstream infections, an international team of investigators evaluated the outcomes of 437 patients who had been treated for CPE bloodstream infections at hospitals in 10 countries from 2004 through 2013.

They split the patients into those who had received appropriate therapy—defined as treatment that was administered within 5 days of infection and included a drug that was active against the infection—and inappropriate treatment. In some cases, appropriate treatment included combination therapy. The main outcome investigators were concerned with was 30-day all-cause mortality.

Of the 343 patients who received appropriate treatment, 132 (38.5%) died of all causes by day 30, compared with 57 of the 94 patients (60.6%) who received inappropriate treatment—a finding that indicated appropriate antibiotic treatment within 5 days of infection can have a protective effect on patients with CPE bloodstream infections.

When the investigators further analyzed the subset of patients who had received appropriate treatment, they found only a small difference in mortality between the patients who received combination therapy (47 of 135 [35%] died) and those who received monotherapy (85 of 208 [41%] died). But when they dug a little deeper, they found that combination therapy did reduce mortality in one particular group—those who had a high probability of death.

Clinical scoring system

That probability was based on the INCREMENT-CPE mortality score, a clinical scoring system developed by the investigators to predict the likelihood of mortality in patients with CPE bloodstream infections. The model, which had already been validated in this group of patients in a previous study, assigns points to patients based in part on the severity of their illness and underlying conditions.

Patients who receive a score of 0 to 7 are considered at low risk of death, while those who receive a score of 8 to 15 are considered a high risk. Just over half the patients who received appropriate antibiotic treatment were in the low-mortality-score group. 

The authors say these findings suggest combination therapy should be used only for patients who are identified by the INCREMENT-CPE score as having a high risk of death.

"Contrary to present recommendations, combination therapy can be avoided in a substantial proportion of patients with bloodstream infections due to CPE. These patients can be identified using the INCREMENT-CPE score and if they are low risk they can be treated with a single active antimicrobial," lead author Jesus Rodriguez-Bano, PhD, of the University Hospital Virgen Macarena in Sevilla, Spain said in an ECCMID press release.

"We hope that, as a result of these findings, clinicians will be able to evaluate patients better so that only those at high risk will be given combination therapy."

The authors of an accompanying commentary in The Lancet Infectious Diseases say clinical scoring systems like INCREMENT-CPE are a step toward more individualized antibiotic treatment, a necessary component of antibiotic stewardship efforts. "In the area of spreading antimicrobial resistance, we should use antibiotics only as much as needed and as little as possible—this conclusion also means an individualised approach is needed that identifies patients in need of combination therapy," they write.  

See also:

Apr 22 Lancet Infect Dis study

Apr 22 ECCMID press release

Apr 22 Lancet Infect Dis commentary

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