Antimicrobial pharmacokinetics and preclinicalin vitromodels to support optimized treatment approaches for uncomplicated lower urinary tract infections

Abstract

Introduction: Urinary tract infections (UTIs) are extremely common. Millions of people, particularly healthy women, are affected worldwide every year. One-in-two women will have a recurrence within 12-months of an initial UTI. Inadequate treatment risks worsening infection leading to acute pyelonephritis, bacteremia and sepsis. In an era of increasing antimicrobial resistance, it is critical to provide optimized antimicrobial treatment.Areas covered: Literature was searched using PubMed and Google Scholar (up to 06/2020), examining the etiology, diagnosis and oral antimicrobial therapy for uncomplicated UTIs, with emphasis on urinary antimicrobial pharmacokinetics (PK) and the application of dynamic in vitro models for the pharmacodynamic (PD) profiling of pathogen response.Expert opinion: The majority of antimicrobial agents included in international guidelines were developed decades ago without well-described dose-response relationships. Microbiology laboratories still apply standard diagnostic methodology that has essentially remained unchanged for decades. Furthermore, it is uncertain how relevant standard in vitro susceptibility is for predicting antimicrobial efficacy in urine. In order to optimize UTI treatments, clinicians must exploit the urine-specific PK of antimicrobial agents. Dynamic in vitro models are valuable tools to examine the PK/PD and urodynamic variables associated with UTIs, while informing uropathogen susceptibility reporting, optimized dosing schedules, clinical trials and treatment guidelines.

The Role of PK/PD Analysis in the Development and Evaluation of Antimicrobials

“…Experimental models must take into account dilution of bacteria during bladder filling and loss through voiding. Over the past years, different models have been developed [28]. In a recent study, a new multicompartment infection model applies a continuous elimination into 16 bladder compartments [29].…”

“…However, an important drawback limits the translation to humans. For example, although the urinary bladder contains relatively low oxygen (PO 2 is about 40 mmHg), in vitro models are generally run at normal atmospheric conditions [28].…”

Application of pharmacokinetic/pharmacodynamic concepts to the development of treatment regimens for sporadic canine urinary tract infections: Challenges and paths forward

“…Although FQs may be active against pathogens associated with UTIs, there are individuals who contend that their use should be limited to more serious diseases in order to reduce the potential for resistance development (Shepherd & Pottinger, 2013). Nevertheless, a number of FQs are FDA-approved to treat uncomplicated human UTIs (Novelli & Rosi, 2017) and are considered to be a secondary or tertiary line of therapy for uncomplicated UTIs around the globe (Abbott et al, 2021) The concentration-effect relationship of FQs has been linked…”

“…A difficulty encountered when estimating the PK/PD relationship in urine pertains to the effect of urine on the pathogen and on MICs. Abbott et al (2021) underscored the importance of using urine-based in vitro models to predict drug efficacy against UTIs. This is in contrast to the classical approach of using drug concentrations in the urine and estimating the ability to hit a PK/PD target based upon MIC data generated using standard CLSI methods in cation-adjusted Mueller Hinton Broth (CAMHB).…”

“…Although FQs may be active against pathogens associated with UTIs, there are individuals who contend that their use should be limited to more serious diseases in order to reduce the potential for resistance development (Shepherd & Pottinger, 2013). Nevertheless, a number of FQs are FDA‐approved to treat uncomplicated human UTIs (Novelli & Rosi, 2017) and are considered to be a secondary or tertiary line of therapy for uncomplicated UTIs around the globe (Abbott et al, 2021). Similarly, the treatment of canine UTIs is considered a within‐label use for three approved FQs including enrofloxacin (https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/140-441), orbifloxacin (https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/141-081), and marbofloxacin (https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/141-151).…”