Blood transfusions have been the cornerstone of life support since the introduction of the ABO classification in the 20th century. The physiologic goal is to restore adequate tissue oxygenation when the demand exceeds the offer. Although it can be a life-saving therapy, blood transfusions can lead to serious adverse effects, and it is essential that physicians remain up to date with the current literature and are aware of the pathophysiology, initial management and risks of each type of transfusion reaction. We aim to provide a structured overview of the pathophysiology, clinical presentation, diagnostic approach and management of acute transfusion reactions based on the literature available in 2022. The numbers of blood transfusions, transfusion reactions and the reporting rate of transfusion reactions differ between countries in Europe. The most frequent transfusion reactions in 2020 were alloimmunizations, febrile non-hemolytic transfusion reactions and allergic transfusion reactions. Transfusion-related acute lung injury, transfusion-associated circulatory overload and septic transfusion reactions were less frequent. Furthermore, the COVID-19 pandemic has challenged the healthcare system with decreasing blood donations and blood supplies, as well as rising concerns within the medical community but also in patients about blood safety and transfusion reactions in COVID-19 patients. The best way to prevent transfusion reactions is to avoid unnecessary blood transfusions and maintain a transfusion-restrictive strategy. Any symptom occurring within 24 h of a blood transfusion should be considered a transfusion reaction and referred to the hemovigilance reporting system. The initial management of blood transfusion reactions requires early identification, immediate interruption of the transfusion, early consultation of the hematologic and ICU departments and fluid resuscitation.

Aztreonam/avibactam is one of the last therapeutic options for treating infections caused by NDM-like-producing Enterobacterales. However, PBP3-modified and NDM-producing Escherichia coli strains that co-produce CMY-42 have been shown to be resistant to this drug combination. The aim of our study was to assess the in vitro activity of cefepime/taniborbactam and cefepime/zidebactam against such aztreonam/avibactam-resistant E. coli strains. MIC values of aztreonam, aztreonam/avibactam, cefepime, cefepime/taniborbactam, cefepime/zidebactam and zidebactam alone were determined for 28 clinical aztreonam/avibactam-resistant E. coli isolates. Those isolates produced either NDM-5 (n = 24), NDM-4 (n = 2) or NDM-1 (n = 2), and they all co-produced CMY-42 (n = 28). They all harboured a four amino acid insertion in PBP-3 (Tyr-Arg-Ile-Asn or Tyr-Arg-Ile-Lys). All strains were resistant to aztreonam/avibactam and cefepime, as expected. The resistance rate to cefepime/taniborbactam was 100%, with MIC₅₀ and MIC₉₀ being at 16 mg/L and 64 mg/L, respectively. Conversely, all strains were susceptible to cefepime/zidebactam, with both MIC₅₀ and MIC₉₀ at 0.25 mg/L. Notably, all strains showed low MICs for zidebactam alone, with MIC₅₀ and MIC₉₀ at 0.5 mg/L and 1 mg/L. Our data highlighted the excellent in vitro performance of the newly developed β-lactam/β-lactamase inhibitor combination cefepime/zidebactam against aztreonam/avibactam-resistant E. coli strains, suggesting that this combination could be considered as an efficient therapeutic option in this context. Our study also highlights the cross-resistance between acquired resistance to aztreonam/avibactam and the cefepime/taniborbactam combination.

The design of inhibitors against metallo-β-lactamases (MBLs), the largest family of carbapenemases, has been a strategic goal in designing novel antimicrobial therapies. In this regard, the development of bicyclic boronates, such as taniborbactam (TAN) and xeruborbactam, is a major achievement that may help in overcoming the threat of MBL-producing and carbapenem-resistant Gram-negative pathogens. Of concern, a recent report has shown that New Delhi MBL-9 (NDM-9) escapes the inhibitory action of TAN by a single amino acid substitution with respect to New Delhi MBL-1 (NDM-1), the most widely disseminated MBL. Here, we report a docking and computational analysis that identifies that “escape variants” against TAN can arise by disruption of the electrostatic interaction of negative charges in the active site loops of MBLs with the N-(2-aminoethyl)cyclohexylamine side chain of TAN. These changes result in non-productive binding modes of TAN that preclude reaction with the MBLs, a phenomenon that is not restricted to NDM-9. This analysis demonstrates that single amino acid substitutions in non-essential residues in MBL loops can unexpectedly elicit resistance to TAN.

To evaluate the in vitro activity of aztreonam in combination with novel β-lactamase inhibitors, namely avibactam, nacubactam, taniborbactam and zidebactam, against MDR MBL-producing Enterobacterales and Pseudomonas aeruginosa clinical isolates. MIC values of aztreonam, aztreonam/β-lactam inhibitor but also cefiderocol as comparator were determined for 64 and 39 clinical Enterobacterales or P. aeruginosa isolates, respectively, producing representative MBLs, i.e. derivatives of NDM (n = 64), VIM (n = 32), IMP (n = 8) and SPM (n = 2). MICs were also determined for Escherichia coli TOP10 and P. aeruginosa PAO1 harbouring recombinant plasmids producing the different β-lactamases under isogenic backgrounds (n = 22 and n = 11, respectively). Fifty percent inhibitory concentrations were additionally determined for the abovementioned β-lactamase inhibitors using β-lactamase crude extracts. The susceptibility rate for aztreonam was 17.1% among MBL-producing Enterobacterales, while it was very high with aztreonam/zidebactam (98.4%), and to a lower extent with aztreonam/nacubactam (84.4%) and aztreonam/taniborbactam (75%), compared with aztreonam/avibactam (70.3%) and cefiderocol (39.1%). Among MBL-producing P. aeruginosa isolates, the susceptibility rates were 53.8% with aztreonam, 66.7% with aztreonam/nacubactam and aztreonam/taniborbactam combinations, and 69.2% with aztreonam/avibactam, aztreonam/zidebactam and cefiderocol. Altogether, these results showed that combinations including aztreonam and novel β-lactamase inhibitors, such as zidebactam, nacubactam or taniborbactam, have a very significant in vitro activity against MDR MBL-producing Enterobacterales clinical isolates, the aztreonam/zidebactam combination being the best option. On the other hand, aztreonam/zidebactam is equivalent to aztreonam/avibactam and cefiderocol among MBL-producing P. aeruginosa isolates.

Taniborbactam (TAN) is a novel broad-spectrum β-lactamase inhibitor with significant activity against subclass B1 metallo-β-lactamases (MBLs). Here, we showed that TAN exhibited an overall excellent activity against B1 MBLs including most NDM- and VIM-like as well as SPM-1, GIM-1, and DIM-1 enzymes, but not against SIM-1. Noteworthy, VIM-1-like enzymes (particularly VIM-83) were less inhibited by TAN than VIM-2-like. Like NDM-9, NDM-30 (also differing from NDM-1 by a single amino acid substitution) was resistant to TAN.

Xeruborbactam is a newly developed β-lactamase inhibitor designed for metallo-β-lactamases (MBLs). This study assessed the relative inhibitory properties of this novel inhibitor in comparison with another MBL inhibitor, namely taniborbactam (TAN), against a wide range of acquired MBL produced either in Escherichia coli or Pseudomonas aeruginosa . As observed with taniborbactam, the combination of xeruborbactam (XER) with β-lactams, namely, ceftazidime, cefepime and meropenem, led to significantly decreased MIC values for a wide range of B1-type MBL-producing E. coli , including most recombinant strains producing NDM, VIM, IMP, GIM-1, and DIM-1 enzymes. Noteworthily, while TAN-based combinations significantly reduced MIC values of β-lactams for MBL-producing P. aeruginosa recombinant strains, those with XER were much less effective. We showed that this latter feature was related to the MexAB-OprM efflux pump significantly impacting MIC values when testing XER-based combinations in P. aeruginosa . The relative inhibitory concentrations (IC ₅₀ values) were similar for XER and TAN against NDM and VIM enzymes. Noteworthily, XER was effective against NDM-9, NDM-30, VIM-83, and most of IMP enzymes, although those latter enzymes were considered resistant to TAN. However, no significant inhibition was observed with XER against IMP-10, SPM-1, and SIM-1 as well as the representative subclass B2 and B3 enzymes, PFM-1 and AIM-1. The determination of the constant inhibition ( K _i ) of XER revealed a much higher value against IMP-10 than against NDM-1, VIM-2, and IMP-1. Hence, IMP-10 that differs from IMP-1 by a single amino-acid substitution (Val67Phe) can, therefore, be considered resistant to XER.