Antimicrobial-associated harm in critical care: a narrative review

Abstract

The belief that, for the individual patient, the benefit of prompt and continued use of antimicrobials outweighs any potential harm is a significant barrier to improved stewardship of these vital agents. Antimicrobial stewardship may be perceived as utilitarian rationing, seeking to preserve the availability of effective antimicrobials by limiting the development of resistance in a manner which could conflict with the immediate treatment of the patient in need. This view does not account for the growing evidence of antimicrobial-associated harm to individual patients. This review sets out the evidence for antimicrobial-associated harm and how this should be balanced with the need for prompt and appropriate therapy in infection. It describes the mechanisms by which antimicrobials may harm patients including: mitochondrial toxicity; immune cell toxicity; adverse drug reactions; selection of resistant organisms within a given patient; and disruption of the microbiome. Finally, the article indicates how the harms of antimicrobials may be mitigated and identifies areas for research and development in this field.

Keywords: Antibiotics; Antifungals; Critical care; Drug-related side effects and adverse reactions.

Fig. 1

Summary of the mechanisms by which antimicrobials may harm patients

Fig. 2

Antibiotics affect mitochondrial function by multiple mechanisms. Summary of findings from ex-vivo investigation. i Direct inhibition of mitochondrial complex (CI–CIV) activity results in the inability to maintain an electrochemical gradient. ii—iii The loss of mitochondrial membrane potential decreases the ability of the cell to generate ATP. Impaired Complex I and Complex III function result in leak of electrons from the ETC into the matrix, which then allows reaction with oxygen to form the superoxide free radical (O₂⁻). iv Inability of Complex I to form ROS impairs NLRP3 activation; whereas excessive mitochondrial ROS enhances NLRP3 inflammasome activity. In health, superoxide is reduced to hydrogen peroxide (H₂O₂) by superoxide dismutase (SOD). The hydrogen peroxide is further reduced to water (H₂O) by catalase. v If excessive superoxide is produced, the anti-oxidant system is overwhelmed resulting in DNA oxidation and damage. vi Consequently, the ability of the cell to generate new mitochondria (mitochondrial biogenesis) is impaired. vii Additionally, ciprofloxacin is able to inhibit DNA topoisomerase, thereby interfering with mitochondrial DNA replication. viii Beta-lactams fit carriers for mitochondrial substrate uptake, causing reduced succinate uptake. Succinate is converted to fumarate which itself has potent antibacterial effects. C I Complex I, C II Complex II, C III Complex III, C IV Complex IV, C V Complex V/ ATP synthase, Cyt C Cytochrome C, FAD Flavin adenine dinucleotide, FAD Flavin adenine dinucleotide, H₂O₂ hydrogen peroxide, Q Co-enzyme Q, NAD nicotinamide adenine dinucleotide, SOD superoxide dismutase, Ψ mitochondrial membrane potential

Fig. 3

Analysis of relative abundance changes prior to (sample A) and following broad spectrum antimicrobials (sample B), demonstrating an increase in Ascomycota, all of which identified as C. albicans, using One Codex (https://onecodex.com/) [92]