Fosfomycin resistance mechanisms in Enterobacterales: an increasing threat

Vittoria Mattioni Marchetti; Jaroslav Hrabak; Ibrahim Bitar

doi:10.3389/fcimb.2023.1178547

Fosfomycin resistance mechanisms in Enterobacterales: an increasing threat

Front Cell Infect Microbiol. 2023 Jul 4:13:1178547. doi: 10.3389/fcimb.2023.1178547. eCollection 2023.

Authors

Vittoria Mattioni Marchetti^{1

2

3}, Jaroslav Hrabak^{1

2}, Ibrahim Bitar^{1

2}

Affiliations

¹ Department of Microbiology, Faculty of Medicine, University Hospital in Pilsen, Charles University, Pilsen, Czechia.
² Biomedical Center, Faculty of Medicine, Charles University, Pilsen, Czechia.
³ Unit of Microbiology and Clinical Microbiology, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.

Abstract

Antimicrobial resistance is well-known to be a global health and development threat. Due to the decrease of effective antimicrobials, re-evaluation in clinical practice of old antibiotics, as fosfomycin (FOS), have been necessary. FOS is a phosphonic acid derivate that regained interest in clinical practice for the treatment of complicated infection by multi-drug resistant (MDR) bacteria. Globally, FOS resistant Gram-negative pathogens are raising, affecting the public health, and compromising the use of the antibiotic. In particular, the increased prevalence of FOS resistance (FOS^R) profiles among Enterobacterales family is concerning. Decrease in FOS effectiveness can be caused by i) alteration of FOS influx inside bacterial cell or ii) acquiring antimicrobial resistance genes. In this review, we investigate the main components implicated in FOS flow and report specific mutations that affect FOS influx inside bacterial cell and, thus, its effectiveness. FosA enzymes were identified in 1980 from Serratia marcescens but only in recent years the scientific community has started studying their spread. We summarize the global epidemiology of FosA/C2/L1-2 enzymes among Enterobacterales family. To date, 11 different variants of FosA have been reported globally. Among acquired mechanisms, FosA3 is the most spread variant in Enterobacterales, followed by FosA7 and FosA5. Based on recently published studies, we clarify and represent the molecular and genetic composition of fosA/C2 genes enviroment, analyzing the mechanisms by which such genes are slowly transmitting in emerging and high-risk clones, such as E. coli ST69 and ST131, and K. pneumoniae ST11. FOS is indicated as first line option against uncomplicated urinary tract infections and shows remarkable qualities in combination with other antibiotics. A rapid and accurate identification of FOS^R type in Enterobacterales is difficult to achieve due to the lack of commercial phenotypic susceptibility tests and of rapid systems for MIC detection.

Keywords: Enterobacterales; epidemiology; fosfomycin; fosfomycin-resistance; fosfomycin-resistant determinant.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology
Drug Resistance, Bacterial / genetics
Escherichia coli / genetics
Escherichia coli Proteins* / genetics
Fosfomycin* / pharmacology
Klebsiella pneumoniae / genetics

Substances

Fosfomycin
Anti-Bacterial Agents
Escherichia coli Proteins

Grants and funding

The study was supported by research project grants NU20J-05-00033 and NU23J-09-00067 provided by the Czech Health Research Council and by the project National Institute of Virology and Bacteriology (Program EXCELES, ID project no. LX22NPO5103), funded by the European Union–Next Generation EU.