Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems

Abstract

Uncomplicated urinary tract infection is one of the most common indications for antibiotic use in the community. However, the Gram-negative organisms that can cause the infection are becoming more resistant to antibiotics. Many multidrug resistant organisms retain susceptibility to two old antibiotics, nitrofurantoin and fosfomycin. Advantages over newer drugs include their high urinary concentrations and minimal toxicity. Fosfomycin is a potential treatment option for patients with uncomplicated urinary tract infection due to resistant organisms. Nitrofurantoin may be more effective and can be used for urinary infections in pregnant women. Nitrofurantoin Nitrofurantoin has been available since 1953, and in Australia since the 1970s. Its exact mechanism of action is not well understood and presumably multifactorial. Nitrofurantoin requires reduction by bacterial enzymes producing 'highly reactive electrophilic' metabolites. These then inhibit protein synthesis by interfering with bacterial ribosomal proteins. 11 Nitrofurantoin has 80% oral bioavailability, and approximately 25% is excreted unchanged in the urine, with only a small portion reaching the colon. 12 Like fosfomycin, therapeutic concentrations are only reached in the urinary tract, 13 so the clinical use of nitrofurantoin is limited to the treatment of uncomplicated urinary tract infection in women. Administration with food results in higher urinary concentrations and fewer gastrointestinal adverse effects. Antimicrobial activity Nitrofurantoin is active against common causes of urinary tract infection including E. coli, Citrobacter and Enterococcus. Klebsiella and Enterobacter are less reliably susceptible. Serratia, Acinetobacter, Morganella, Proteus and Pseudomonas are usually resistant. 14 Overall, resistance to nitrofurantoin is uncommon and many multidrug resistant organisms retain susceptibility. 15-17 Australian data are limited, but studies suggest resistance rates in E. coli of 1-2%. 4,6

Revival of older antibiotics for the therapy of urinary tract infections: old, but gold Part 1: Antimicrobial susceptibility of extended-spectrum β-lactamase-producing and AmpC β-lactamase-producing Escherichia coli isolates

“…[9][10][11][12]21,37]. Fosfomycin and nitrofurantoin both have unique chemical structures and mechanisms of action, therefore, these is no need to expect cross-resistance with other antibacterial drugs [9][10][11][12]21,38]. The utility of trimethoprim/sulfamethoxazole in the therapy of ESBL-positive and carbapenemasepositive Gram-negative isolates has been reported previously, both in UTIs and invasive infections [39]; nevertheless, this was not highlighted in our study.…”

Multidrug Resistant Acinetobacter Isolates Release Resistance Determinants Through Contact-Dependent Killing and Bacteriophage Lysis

“…(Giske, 2015). This could be mediated by point mutations in nsfA or nsfB, which metabolize nitrofurantoin into the reactive intermediates that interfere with ribosomal subunits, or by oxqAB in some Acinetobacter spp., but the LH6 sequenced strain does not possess these efflux genes (Sekyere, 2018;Gardiner et al, 2019). Previously, a high incidence of fluoroquinolone resistance was also found among the Listeria spp., while aminoglycoside resistance was found in E. coli and Salmonella spp.…”

Comprehensive genomic analysis reveals virulence factors and antibiotic resistance genes inPantoea agglomeransKM1, a potential opportunistic pathogen

“…Previously published clinical reports demonstrated that P. agglomerans can be responsible for a wide range of infections encompassing pneumonia, bladder and wound/skin infections, septicemia and meningitis [71]. While bacitracin is an antibiotic prescribed against skin infections, fosfomycin is an effective drug against bladder infections [72][73][74]. Vancomycin is used to treat meningitis, and rifampicin exerts antimicrobial activity against Mycobacterium species, as such being the antibiotic of choice prescribed against tuberculosis [75,76].…”