New Antimicrobials for Gram-Positive Sustained Infections: A Comprehensive Guide for Clinicians.

Antibiotic resistance is a public health problem with increasingly alarming data being reported. Gram-positive bacteria are among the protagonists of severe nosocomial and community infections. The objective of this review is to conduct an extensive examination of emerging treatments for Gram-positive infections including ceftobiprole, ceftaroline, dalbavancin, oritavancin, omadacycline, tedizolid, and delafloxacin. From a methodological standpoint, a comprehensive analysis on clinical trials, molecular structure, mechanism of action, microbiological targeting, clinical use, pharmacokinetic/pharmacodynamic features, and potential for therapeutic drug monitoring will be addressed. Each antibiotic paragraph is divided into specialized microbiological, clinical, and pharmacological sections, including detailed and appropriate tables. A better understanding of the latest promising advances in the field of therapeutic options could lead to the development of a better approach in managing antimicrobial therapy for multidrug-resistant Gram-positive pathogens, which increasingly needs to be better stratified and targeted.

Listeria monocytogenes Transmission from Donated Blood to Platelet Transfusion Recipient, Italy.

We report Listeria monocytogenes infection in a patient in Italy who was transfused with pooled platelet concentrate. Genomic analysis revealed that L. monocytogenes isolates from the donor blood unit, the transfused platelets, and the patient's blood culture were genetically closely related, confirming transfusion transmission. Additional surveillance and secondary bacterial screening could improve transfusion safety.

Deciphering variable resistance to novel carbapenem-based ß-lactamase inhibitor combinations in a multi-clonal outbreak caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae resistant to ceftazidime/avibactam.

OBJECTIVES: Carbapenemase-producing Enterobacterales represent a major cause of difficult-to-treat infections world-wide. Novel ß-lactam/ß-lactamase inhibitor combinations, including ceftazidime/avibactam (CZA), meropenem/vaborbactam (MVB), and imipenem/relebactam (IMR), represented a break-through in the treatment of some carbapenemase-producing Enterobacterales infections. However, acquired resistance to these agents has been reported in Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Herein, we reported an outbreak caused by CZA-resistant, KPC-producing Klebsiella pneumoniae (KPC-Kp), which was also variably resistant to carbapenem-based ß-lactam/ß-lactamase inhibitor combinations. METHODS: Bacterial isolates were subjected to antimicrobial susceptibility testing, whole-genome sequencing, determination of blaKPC gene dosage, and analysis of carbapenemase activity. RESULTS: Overall, 15 KPC-Kp, nine CZA-resistant (CZAR), and six CZA-susceptible isolates were collected from an outbreak involving six patients in a neurorehabilitation facility. Of the nine CZAR isolates, seven were also resistant to MVB and one was also resistant to IMR. Whole-genome sequencing revealed that the outbreak was multi-clonal, with CZAR KPC-Kp belonging to the ST101, ST1519, and two ST512 sub-lineages, which were involved in two independent transmission clusters. Resistance to CZA was primarily mediated by overproduction of KPC-3 associated with increased gene dosage, a mechanism accounting for cross-resistance to MVB in most cases, and to IMR in a single KPC-Kp isolate; multiple OmpK36 aletarions were also detected. Mutated KPC (KPC-53) was detected in a single case. Positivity for CZAR KPC-Kp was inconstantly associated with previous CZA exposure. CONCLUSIONS: In this multi-clonal outbreak of KPC-Kp, the overproduction of KPC-3 was the leading mechanism of cross-resistance to CZA and MVB, whereas resistance to IMR appeared less affected. The emergence and dissemination of similar resistance mechanisms may have relevant clinical and diagnostic implications, and their surveillance is warranted.

A Two Amino Acid Duplication, L167E168, in the Ω-Loop Drastically Decreases Carbapenemase Activity of KPC-53, a Natural Class A ß-Lactamase.

KPC-53 enzyme is a natural KPC variant which showed a duplication of L167E168 residues in the Ω-loop structure. The blaKPC-53 gene was cloned both into pBC-SK and pET-24a vectors, and the recombinant plasmids were transferred by transformation in Escherichia coli competent cells to evaluate the antimicrobial susceptibility and to produce the enzyme. Compared to KPC-3, the KPC-53 was less stable and showed a dramatic reduction of kcat and kcat/Km versus several ß-lactams, in particular carbapenems. Indeed, a 2,000-fold reduction was observed in the kcat values of KPC-53 for imipenem and meropenem. Concerning inhibitors, KPC-53 was susceptible to tazobactam and clavulanic acid but maintained resistance to avibactam. The molecular modeling indicates that the L167E168 duplication in KPC-53 modifies the interactions between residues involved in the catalytic pocket, changing the flexibility of the Ω-loop, which is directly coupled with the catalytic properties of the KPC enzymes.

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: ß-Lactam/ß-Lactamase Inhibitors in Combination and Cefiderocol-An All-Inclusive Guide for Clinicians.

Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new ß-lactam/ß-lactamase inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for several compounds. Cefiderocol warrants a separate discussion for its peculiar mechanism of action. Considering the complexity of summarizing and integrating the emerging literature data of clinical outcomes, microbiological mechanisms, and pharmacokinetic/pharmacodynamic properties of the new BL/BLI and cefiderocol, we aimed to provide an overview of data on the following compounds: aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, cefiderocol, ceftaroline/avibactam, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam, meropenem/nacubactam and meropenem/vaborbactam. Each compound is described in a dedicated section by experts in infectious diseases, microbiology, and pharmacology, with tables providing at-a-glance information.