Urinary tract infections, including cystitis, acute pyelonephritis, and prostatitis, are among the most common diagnoses prompting antibiotic prescribing. The rise in antimicrobial resistance over the past decades has led to the increasing challenge of urinary tract infections because of multidrug-resistant and "difficult-to-treat resistance" among Gram-negative bacteria. Recent advances in pharmacotherapy and medical microbiology are modernizing how these urinary tract infections are treated. Advances in pharmacotherapy have included not only the development and approval of novel antibiotics, such as ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, ceftolozane/tazobactam, cefiderocol, plazomicin, and glycylcyclines, but also the re-examination of the potential role of legacy antibiotics, including older aminoglycosides and tetracyclines. Recent advances in medical microbiology allow phenotypic and molecular mechanism of resistance testing, and thus antibiotic prescribing can be tailored to the mechanism of resistance in the infecting pathogen. Here, we provide a narrative review on the clinical and pre-clinical studies of drugs that can be used for difficult-to-treat resistant Gram-negative bacteria, with a particular focus on data relevant to the urinary tract. We also offer a pragmatic framework for antibiotic selection when encountering urinary tract infections due to difficult-to-treat resistant Gram-negative bacteria based on the organism and its mechanism of resistance.
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