At the recent European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Vienna, results from the INCREMENT study demonstrated for the first time that initiation of empiric combination therapy — as opposed to treatment with a single antibiotic — is only beneficial in patients with bloodstream infections (BSIs) caused by carbapenemase-producing Enterobacteriaceae (CPE). This is specifically in those who have a high mortality risk due to the infection. GlobalData anticipates this study will be influential in the adoption of a single antibiotic regimen in the treatment of patients with a low mortality risk. This will subsequently reduce the risk of adverse events (AEs) due to antibiotic combinations, while at the same time reducing the emergence of antibacterial resistance to multiple antibiotics.

While this finding has the potential to directly influence future guidelines on the appropriate use of antibiotics in patients suffering from CPE infections, GlobalData notes that the underlying cause of this observation justifies further research, as it remains unclear if host factors or pathogen responses in patients with a high disease activity are responsible for the improved outcomes with a combination of antibiotics. Researchers participating in the INCREMENT study also showed that carbapenems can be reserved for patients in whom all other antimicrobial treatment against extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) has failed without affecting treatment outcomes. GlobalData anticipates that this finding could decrease the use of carbapenems, thereby reducing the emergence of resistance to this antibiotic of last resort.

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The INCREMENT study is an observational, multinational effort involving 37 hospitals across 11 countries to assess the efficacy of different antimicrobial treatment options for treating BSIs caused by ESBL-E or CPE. All patients enrolled in the INCREMENT study are graded by a mortality scores such as the INCREMENT-CPE and INCREMENT-ESBLE mortality scores, which includes presence of sepsis or septic shock, a Pitt bacteremia score, a Charlson Comorbidity Index score, and BSIs as primary source of infection.

The INCREMENT study enrolled a total of 437 patients of which 343 patients (78 percent) were shown by blood cultures to have received appropriate antibiotic therapy, whereas the remaining 94 patients (22 percent) received ineffective regimens, resulting in an overall lower mortality in the patients receiving appropriate antibiotic therapy (treatment difference 22.1 percent; 95 percent CI, 11.0–33.3 percent; p ≤0.0001).

Of the 343 patients receiving appropriate antibiotic therapy, 135 patients (39 percent) received combination therapy, whereas the remaining 208 patients (61 percent) received monotherapy. The overall 30-day mortality rate was no different between patients receiving either regimen (adjusted hazard risk 1.63 [95 percent CI, 0.67–3.91]; p = 0.28). However, among patients with a high INCREMENT-CPE score (8–15 points), combination therapy was associated with a lower mortality rate compared with those who received monotherapy; 30 out of 63 patients receiving combination therapy died (48 percent), whereas in the monotherapy treatment arm 64 out of 103 patients (62 percent) died (p = 0.02). 

In addition to enrolling patients with BSIs due to CPE, the INCREMENT study recruited 855 patients with BSIs due to ESBL-E treated between 2004 and 2012. The researchers showed that patients receiving broad-spectrum antibiotics such as carbapenems had similar 30-day mortality rates (489 patients, mortality rate 17 percent) compared with patients who received other antibiotics (excluding carbapenems or beta-lactamase inhibitors, 83 patients, mortality rate 19 percent), or patients receiving an inactive antibiotic choice (283 patients, mortality rate 15.5 percent). However, the study showed that patients receiving an inactive antibiotic choice were at a three-fold increased risk of death.

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BSIs, particular those of ESBL/CPE origin, remain a major challenge to infectious diseases specialists. Current guidelines for treating infections caused by carbapenemase-producing bacteria are based on national, observational, retrospective studies and recommend the use of combination antibiotic therapy over antibiotic monotherapy. GlobalData anticipates that the results from the INCREMENT study will help to change the current treatment paradigm and will result in improved patient outcomes, while reducing the risk of antibiotic resistance.