Antimicrobial Treatment Options for Difficult-to-Treat Resistant Gram-Negative Bacteria Causing Cystitis, Pyelonephritis, and Prostatitis: A Narrative Review

Abstract

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.

Figure 1.

Chemical structures of novel beta-lactams and beta-lactamase.

Figure 2.

Mortality rates of cefiderocol vs. best available therapy. 95% confidence intervals shown. End of study assed at 28 days (plus or minus 3) after the end of treatment. All-cause mortality includes events after the end of study timepoint that were spontaneously reported by the investigators. Figure generated from data contained in CREDIBLE-CR [143].

Figure 3.

Rates of nephrotoxicity in plazomicin studies 002 and 009. Plazomicin nephrotoxicity risk increases based on minimum serum concentration (C_min) levels and baseline creatinine clearance (CLcr). Data from studies 002 and 009 are aggregated. Rates of nephrotoxicity in the comparator group are aggregated across studies 002 and 009; comparators in study 002 and 009 were levofloxacin and meropenem, respectively.