Acute pyelonephritis - Emerging treatments

Meropenem/vaborbactam

Meropenem/vaborbactam is a combination of the carbapenem antibiotic meropenem with the beta-lactamase inhibitor vaborbactam.[74][75] It is approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of adults with complicated urinary tract infection, including pyelonephritis, caused by susceptible gram-negative microorganisms (Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae complex). In the TANGO I randomized controlled trial (RCT) study, meropenem/vaborbactam was shown to be noninferior to piperacillin/tazobactam for complete resolution along with microbial eradication in complicated urinary tract infections (UTIs) in adults, including acute pyelonephritis.[75]

Plazomicin

Plazomicin is a next-generation aminoglycoside designed to evade all clinically relevant aminoglycoside-modifying enzymes, the main mechanism of aminoglycoside resistance.[76] It is not a first-line agent, but it has been approved by the FDA for the treatment of adults with complicated UTIs, including pyelonephritis, caused by susceptible gram-negative microorganisms (E coli, K pneumoniae, Proteus mirabilis, and E cloacae complex) in patients who have limited or no alternative treatment options. It is not approved by the EMA for this or any other indication. One study has shown plazomicin to be noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains.[77]

Cefepime/enmetazobactam

Cefepime/enmetazobactam is a combination of the fourth-generation cephalosporin cefepime with the beta-lactamase inhibitor enmetazobactam. The FDA and EMA have approved cefepime/enmetazobactam for the treatment of adults with complicated UTIs, including pyelonephritis, caused by susceptible gram-negative microorganisms (E coli, K pneumoniae, Pseudomonas aeruginosa, P mirabilis, and E cloacae complex). One RCT showed cefepime/enmetazobactam to be noninferior to, and even superior to, piperacillin/tazobactam for clinical cure and microbiologic eradication in cases of complex UTI and acute pyelonephritis.[78]

Cefepime/taniborbactam

Cefepime/taniborbactam is an investigational combination of the fourth-generation cefepime with the beta-lactamase inhibitor taniborbactam. Studies have demonstrated activity against Enterobacterales species and P aeruginosa. In one recent phase 3 RCT, cefepime/taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem.[79]

Tebipenem

Tebipenem is an orally bioavailable investigational carbapenem antibiotic with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. In one recent phase 3 trial, tebipenem was noninferior to intravenous ertapenem in the treatment of complicated UTI and acute pyelonephritis.[80] The FDA has granted the drug fast-track designation but states further clinical trials are needed.

Antioxidant/anti-inflammatory therapies

Some factors of E coli (e.g., adhesins, siderophores, toxins, polysaccharide coatings) in the future may provide effective targets for anti-UTI interventions.[22] In animal models of pyelonephritis, treatment with the free radical scavengers catalase and dimethylsulfoxide was able to prevent renal scarring.[81] 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.[82]

Vaccine therapy

Specific-antigen vaccines are being studied due to advances in protein purification and the development of recombinant DNA technology.[83] Immunizing 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.[84]