A randomized non-inferiority study comparing imipenem/cilastatin/relebactam with standard-of-care Gram-negative coverage in cancer patients with febrile neutropenia.

BACKGROUND: Antibiotic overuse leads to the emergence of antibiotic resistance that threatens immunocompromised cancer patients. Infections caused by MDR Gram-negative pathogens are difficult to treat and associated with high mortality. Hence, empirical therapy with standard-of-care (SOC) antibiotics could be suboptimal in these vulnerable patients. New antibiotics covering potential resistant pathogens may be considered. METHODS: We conducted a randomized non-inferiority study comparing safety and efficacy of imipenem/cilastatin/relebactam (IPM/REL), a ß-lactam/ß-lactamase inhibitor combination, with SOC antibiotics (cefepime, piperacillin/tazobactam or meropenem) in cancer patients with febrile neutropenia. Patients received at least 48 h of IV antibiotics and were assessed at end-of-IV (EOIV) therapy, test of cure (TOC; Days 21-28), and late follow-up (LFU; Days 35-42). RESULTS: A total of 100 patients were enrolled (49 IPM/REL and 50 SOC). Demographics and rates of documented microbiological infections were similar in both groups. In the SOC arm, 86% of antibiotics consisted of cefepime. Patients on IPM/REL had a higher favourable clinical response at EOIV than those on SOC (90% versus 74%; P = 0.042); however, responses were similar at TOC and LFU. Microbiological eradication was comparable at all three timepoints. Study drug-related adverse events and adverse events leading to drug discontinuation were similar in both groups, with no study drug-related mortality. CONCLUSIONS: Our results suggest that compared with SOC antibiotics, predominantly cefepime, IPM/REL for empirical coverage of febrile neutropenia in cancer patients is generally safe and could be associated with a better clinical outcome at EOIV. The current SOC consisting mainly of agents that do not cover for ESBL-producing and carbapenem-resistant Enterobacterales bacteria should be reconsidered.

Procalcitonin Level Monitoring in Antibiotic De-Escalation and Stewardship Program for Patients with Cancer and Febrile Neutropenia.

OBJECTIVE: Serial procalcitonin (PCT) monitoring has been adopted to supplement clinical judgement and help guide antibiotic therapy as part of antimicrobial stewardship programs. PCT levels peak 24 to 48 h after infection onset and decline with infection resolution. We explored the role of PCT as an infection biomarker for guiding antibiotic therapy in cancer patients hospitalized for febrile neutropenia. DESIGN: Prospective randomized study. METHODS: Patients were enrolled between October 2021 and August 2023 and received empiric intravenous broad-spectrum antibiotics (IVBSA) for at least 48 h. PCT was measured at baseline and 48-72 h after IVBSA initiation. PCT drop 48-72 h after IVBSA initiation was defined as a reduction of 30% from baseline or a PCT level < 0.25 ng/mL. De-escalation was defined as a switch from IVBSA to oral or simplified once-daily IV therapy. RESULTS: Of the 89 patients with available PCT levels, 53 (60%) had a PCT drop, most of whom (79%) underwent IVBSA de-escalation. Compared with patients without a PCT drop, patients with a PCT drop had a higher de-escalation rate at 72 h (71% vs. 45%; p = 0.003) and a shorter median antibiotic duration (55 h vs. 98 h; p = 0.004). Patients with bacteremia had a significantly higher median PCT level than those without bacteremia (2.35 ng/mL vs. 0.370 ng/mL, p = 0.013). CONCLUSIONS: In patients with cancer and febrile neutropenia, a PCT drop was associated with earlier therapy de-escalation and shorter antibiotic duration. PCT monitoring may be useful in antimicrobial stewardship initiatives in this patient population. CLINICAL TRIALS IDENTIFIER: NCT04983901.

Procalcitonin for antimicrobial stewardship among cancer patients admitted with COVID-19.

Background: Procalcitonin (PCT) has been used to guide antibiotic therapy in bacterial infections. We aimed to determine the role of PCT in decreasing the duration of empiric antibiotic therapy among cancer patients admitted with COVID-19. Methods: This retrospective study included cancer patients admitted to our institution for COVID-19 between March 1, 2020, and June 28, 2021, with a PCT test done within 72 hr after admission. Patients were divided into two groups: PCT <0.25 ng/ml and PCT ≥0.25 ng/ml. We assessed pertinent cultures, antibacterial use, and duration of empiric antibacterial therapy. Results: The study included 530 patients (median age, 62 years [range, 13-91]). All the patients had ≥1 culture test within 7 days following admission. Patients with PCT <0.25 ng/ml were less likely to have a positive culture than were those with PCT ≥0.25 ng/ml (6% [20/358] vs. 17% [30/172]; p<0.0001). PCT <0.25 ng/ml had a high negative predictive value for bacteremia and 30 day mortality. Patients with PCT <0.25 ng/ml were less likely to receive intravenous (IV) antibiotics for >72 hr than were patients with PCT ≥0.25 ng/ml (45% [162/358] vs. 69% [119/172]; p<0.0001). Among patients with PCT <0.25 ng/ml and negative cultures, 30 day mortality was similar between those who received IV antibiotics for ≥72 hr and those who received IV antibiotics for shorter durations (2% [2/111] vs. 3% [5/176], p=0.71). Conclusions: Among cancer patients with COVID-19, PCT level <0.25 ng/ml is associated with lower likelihood of bacterial co-infection and greater likelihood of a shorter antibiotic course. In patients with PCT level <0.25 ng/ml and negative cultures, an antibiotic course of >72 hr may not be necessary. PCT could be useful in enhancing antimicrobial stewardship in cancer patients with COVID-19. Funding: This research was supported by the National Institutes of Health/National Cancer Institute under award number P30CA016672, which supports MD Anderson Cancer Center's Clinical Trials Office.