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

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.

Efficacy and Safety of Meropenem–Vaborbactam Versus Best Available Therapy for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in Patients Without Prior Antimicrobial Failure: A Post Hoc Analysis

“…This raises an important point of discussion, that is the need for a correct balance between limiting the use of novel agents to delay emergence of further resistance and, at the same time, guaranteeing the most active early therapy in case of severe infection. This is particularly important for CRE, by considering together the following reasons: (1) CRE infections are endemic in several countries [8], (2) there is a frequent delay of active therapy in patients with CRE infections [8], and (3) there is lower survival of patients with severe infections when active therapy is delayed [1]. …”

“…Antimicrobial resistance is increasing worldwide, and serious infections due to carbapenem-resistant Enterobacteriaceae (CRE) have been associated with increased morbidity and high mortality [1–8]. In the last decade, the treatment of serious CRE infections was frequently based on the combination of last-resort agents associated with nephrotoxicity, possible subtherapeutic concentrations, and/or intermediate in vitro activity due to limited options and resistance to several classes of antimicrobials [1–3, 9].…”

“…In the last decade, the treatment of serious CRE infections was frequently based on the combination of last-resort agents associated with nephrotoxicity, possible subtherapeutic concentrations, and/or intermediate in vitro activity due to limited options and resistance to several classes of antimicrobials [1–3, 9]. …”

Impact of a multicenter stewardship‐targeted carbapenem justification requirement on the use of carbapenems in 23 hospitals

“…The carbapenem class of antibiotics has a broad spectrum of activity and is indicated for life‐threatening infections and multidrug‐resistant (MDR) organisms . Resistance to carbapenems, such as carbapenem‐resistant Enterobacteriaceae (CRE), has been reported in every state in the United States and has been linked to high mortality and low rates of clinical cure . In order to control and reduce antibiotic resistance, previous studies have identified risk factors such as antibiotic use and intensive care unit (ICU) stay .…”

“…3 Resistance to carbapenems, such as carbapenem-resistant Enterobacteriaceae (CRE), has been reported in every state in the United States and has been linked to high mortality and low rates of clinical cure. 4,5 In order to control and reduce antibiotic resistance, previous studies have identified risk factors such as antibiotic use and intensive care unit (ICU) stay. 6 However, we do not know if controlling these risk factors will lead to a decrease in CRE.…”