Acute pyelonephritis - Emerging treatments

Antioxidant/anti-inflammatory therapies

Some factors of Escherichia coli (e.g., adhesins, siderophores, toxins, polysaccharide coatings) in the future may provide effective targets for anti-urinary tract infection interventions.[15] In animal models of pyelonephritis, treatment with the free radical scavengers catalase and dimethylsulfoxide was able to prevent renal scarring.[60] Similarly, in mice with kidneys inoculated with E coli, lipoprotein saccharide demonstrated less renal scarring 6 weeks after inoculation if the mice received a cox-2 inhibitor.[61]

Vaccine therapy

Specific-antigen vaccines are being studied due to advances in protein purification and the development of recombinant DNA technology.[62] Immunising mice with an E coli capsular antigen linked to diphtheria toxoid has been shown to improve immunogenicity of the vaccine and increase cell-mediated immune activity in response to subsequent E coli exposure.[63]

Meropenem/vaborbactam

Vaborbactam is a novel beta-lactamase inhibitor. Its combination with meropenem is being developed as a new agent to treat serious gram-negative infections (e.g., complicated urinary tract infection), including infections caused by bacteria resistant to currently available carbapenems.[64][65] The European Medicines Agency (EMA) has approved meropenem/vaborbactam for the treatment of adults with complicated urinary tract infections (including pyelonephritis).

Plazomicin

Plazomicin is a next-generation aminoglycoside designed to evade all clinically relevant aminoglycoside-modifying enzymes, the main mechanism of aminoglycoside resistance.[66] It has been approved by the US Food and Drug Administration (FDA) for the treatment of patients 18 years of age or older with complicated urinary tract infections, including pyelonephritis, and bloodstream infections due to certain Enterobacteriaceae in patients who have limited or no alternative treatment options. One study has shown plazomicin to be non-inferior to meropenem for the treatment of complicated urinary tract infections and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains.[67] The marketing application to the EMA for plazomicin was withdrawn in 2020.[68]

Cefiderocol

Cefiderocol is a novel siderophore cephalosporin that has broad activity against Enterobacteriaceae and non-fermenting bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii, including carbapenem-resistant strains. It has been approved by the EMA for treating gram-negative bacterial infections.[69] It has been approved by the FDA for the treatment of adults with complicated urinary tract infections including kidney infections caused by susceptible gram-negative micro-organisms who have limited or no alternative options. A phase 2 double-blind, non-inferiority trial (n=448) found that treatment with cefiderocol was non-inferior compared with imipenem/cilastatin for the treatment of complicated urinary tract infection in people with multidrug-resistant gram-negative infections.[70]

Imipenem/cilastatin/relebactam

This three-drug combination includes relebactam, a beta-lactamase inhibitor, together with the previously approved carbapenem antibiotic imipenem/cilastatin. Relebactam can restore imipenem activity against many imipenem-resistant strains of Enterobacteriaceae and P aeruginosa. The new combination has been approved by the EMA for treatment of gram-negative bacterial infections and by the FDA for the treatment of adults with complicated urinary tract infections who have limited or no alternative options.[71] The National Institute for Health and Care Excellence advises that the new combination may be used when there are limited treatment options, particularly when other antimicrobial treatments have failed.[72] A prospective, randomised, double-blind, phase 2 dose-ranging study (n=298) compared the efficacy and safety of imipenem/cilastatin/relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. Imipenem/cilastatin/relebactam was shown to be as effective as imipenem/cilastatin alone, was well tolerated, and may cover highly resistant pathogens.[73]