An engineered prodrug selectively suppresses ß-lactam resistant bacteria in a mixed microbial setting.

The rise of ß-lactam resistance necessitates new strategies to combat bacterial infections. We purposefully engineered the ß-lactam prodrug AcephPT to exploit ß-lactamase activity to selectively suppress resistant bacteria producing extended-spectrum-ß-lactamases (ESBLs). Selective targeting of resistant bacteria requires avoiding interaction with penicillin-binding proteins, the conventional targets of ß-lactam antibiotics, while maintaining recognition by ESBLs to activate AcephPT only in resistant cells. Computational approaches provide a rationale for structural modifications to the prodrug to achieve this biased activity. We show AcephPT selectively suppresses gram-negative ESBL-producing bacteria in clonal populations and in mixed microbial cultures, with effective selectivity for both lab strains and clinical isolates expressing ESBLs. Time-course NMR experiments confirm hydrolytic activation of AcephPT exclusively by ESBL-producing bacteria. In mixed microbial cultures, AcephPT suppresses proliferation of ESBL-producing strains while sustaining growth of ß-lactamase-non-producing bacteria, highlighting its potential to combat ß-lactam resistance while promoting antimicrobial stewardship.

Clinical Outcomes Associated With Diltiazem Use in Heart Failure With Reduced Ejection Fraction After Implementation of a Clinical Support System.

BACKGROUND: Despite atrial fibrillation guideline recommendations, many patients with heart failure with reduced ejection fraction (EF) continue to receive IV diltiazem for acute rate control. OBJECTIVE: Our institution recently implemented a clinical decision support system (CDSS)-based tool that recommends against the use of diltiazem in patients with an EF ≤ 40%. The objective of this study was to evaluate outcomes of adherence to the aforementioned CDSS-based tool. METHODS: This multi-hospital, retrospective study assessed patients who triggered the CDSS alert and compared those who did and did not discontinue diltiazem. The primary outcome was the occurrence of clinical deterioration. The primary endpoint was compared utilizing a Fisher's Exact Test, and a multivariate logistic regression model was developed to confirm the results of the primary analysis. RESULTS: A total of 246 patients were included in this study with 146 patients in the nonadherent group (received diltiazem) and 100 patients in the adherent group (did not receive diltiazem). There was a higher proportion of patients experiencing clinical deterioration in the alert nonadherence group (33% vs 21%, P = 0.044), including increased utilization of inotropes and vasopressors, and higher rate of transfer to ICU. CONCLUSION AND RELEVANCE: In patients with heart failure with reduced EF, diltiazem use after nonadherence to a CDSS alert resulted in an increased risk of clinical deterioration. This study highlights the need for improved provider adherence to diltiazem clinical decision support systems.

A Cephalosporin Prochelator Inhibits New Delhi Metallo-ß-lactamase 1 without Removing Zinc.

Antibacterial drug resistance is a rapidly growing clinical threat, partially due to expression of ß-lactamase enzymes, which confer resistance to bacteria by hydrolyzing and inactivating ß-lactam antibiotics. The increasing prevalence of metallo-ß-lactamases poses a unique challenge, as currently available ß-lactamase inhibitors target the active site of serine ß-lactamases but are ineffective against the zinc-containing active sites of metallo-ß-lactamases. There is an urgent need for metallo-ß-lactamase inhibitors and antibiotics that circumvent resistance mediated by metallo-ß-lactamases in order to extend the utility of existing ß-lactam antibiotics for treating infection. Here we investigated the antibacterial chelator-releasing prodrug PcephPT (2-((((6R,7R)-2-carboxy-8-oxo-7-(2-phenylacetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)thio) pyridine 1-oxide) as an inhibitor of New Delhi metallo-ß-lactamase 1 (NDM-1). PcephPT is an experimental compound that we have previously shown inhibits growth of ß-lactamase-expressing E. coli using a mechanism that is dependent on both copper availability and ß-lactamase expression. Here, we found that PcephPT, in addition to being a copper-dependent antibacterial compound, inhibits hydrolysis activity of purified NDM-1with an IC50 of 7.6 µM without removing zinc from the active site and restores activity of the carbapenem antibiotic meropenem against NDM-1-producing E. coli. This work demonstrates that targeting a metal-binding pharmacophore to ß-lactamase-producing bacteria is a promising strategy for inhibition of both bacterial growth and metallo-ß-lactamases.