Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials

Elizabeth L Alexander; Jeffery Loutit; Mario Tumbarello; Richard Wunderink; Tim Felton; George Daikos; Karen Fusaro; Dan White; Shu Zhang; Michael N Dudley

doi:10.1093/ofid/ofx063

Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials

Open Forum Infect Dis. 2017 Jun 1;4(2):ofx063. doi: 10.1093/ofid/ofx063. eCollection 2017 Spring.

Authors

Affiliations

¹ Infectious Diseases Care Global Innovation Group, The Medicines Company, Parsippany, New Jersey.
² Infectious Diseases Care Global Innovation Group, Rempex Pharmaceuticals (a wholly-owned subsidiary of The Medicines Company), San Diego, California.
³ Institute of Infectious Diseases, Catholic University of the Sacred Heart, A. Gemelli Hospital, Rome, Italy.
⁴ Pulmonary and Critical Care Medicine, Northwestern University-Feinberg School of Medicine, Chicago, Illinois.
⁵ Centre for Respiratory Medicine and Allergy, University of Manchester, United Kingdom; and.
⁶ First Department of Propedeutic Medicine, University of Athens, Medical School, Greece.

Abstract

Background: The increasing incidence of multidrug-resistant Gram negatives, such as carbapenem-resistant Enterobacteriaceae (CRE), has resulted in a critical need for new antimicrobials. Most studies of new antimicrobials have been performed in patients with nondrug-resistant pathogens. We performed a retrospective analysis of patients with CRE infections to inform the design of phase 3 clinical trials.

Methods: This was a retrospective study at 22 centers in 4 countries. Baseline data, treatment, and outcomes were collected in patients with complicated urinary tract infection (cUTI)/acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bacteremia due to CRE.

Results: Two hundred fifty-six cases of CRE infection were identified: 75 cUTI/AP, 21 HABP, 20 VABP, and 140 bacteremia. The patient population had significant comorbidities: 32.8% had chronic renal insufficiency, and 26.2% were immunocompromised. Illness severity at presentation was high: 29.3% presented with septic shock. Treatment regimens varied widely; however, a majority of patients received combination therapy. Outcomes were universally poor (28-day mortality was 28.1%) across all sites of infection, particularly in dialysis patients and those with sepsis.

Conclusions: The CRE infections occured in patients with substantial comorbidities and were associated with high mortality and low rates of clinical cure with available antibiotics. Patients with these comorbidities are often excluded from enrollment in clinical trials for registration of new drugs. These results led to changes in the inclusion/exclusion criteria of a phase 3 trial to better represent the patient population with CRE infections and enable enrollment. Observational studies may become increasingly important to guide clinical trial design, inform on the existing standard of care, and provide an external control for subsequent trials.

Keywords: antibiotics; carbapenem-resistant Enterobacteriaceae; clinical trials; mortality..