Effective Treatments of UTI—Is Intravesical Therapy the Future?

Abstract

Urinary tract infection (UTI) afflicts millions of patients globally each year. While the majority of UTIs are successfully treated with orally administered antibiotics, the impact of oral antibiotics on the host microbiota is under close research scrutiny and the potential for dysbiosis is a cause for concern. Optimal treatment of UTI relies upon the selection of an agent which displays appropriate pharmacokinetic-pharmacodynamic (PK-PD) properties that will deliver appropriately high concentrations in the urinary tract after oral administration. Alternatively, high local concentrations of antibiotic at the urothelial surface can be achieved by direct instillation into the urinary tract. For antibiotics with the appropriate physicochemical properties, this can be of critical importance in cases for which an intracellular urothelial bacterial reservoir is suspected. In this review, we summarise the underpinning biopharmaceutical barriers to effective treatment of UTI and provide an overview of the evidence for the deployment of the intravesical administration route for antibiotics.

SWOT and Root Cause Analyses of Antimicrobial Resistance to Oral Antimicrobial Treatment of Cystitis

“…(1) Cystitis treatment failures and AMR result from a bladder milieu that allows adaptable microbes [8] to shelter under a biofilm [91] to evade antimicrobials [38], and membrane pumps [121] allow them to expel OAT; (2) Interchangeable use of the term UTI and cystitis. While absorbed OAT can reach pathogens in upper urinary tracts via perfused blood, the uropathogens causing cystitis can only be eliminated by the urinary fraction of absorbed OAT (Figure 2), because the circulating levels [126,127,130] of the drug are less likely to reach the planktonic microbes and those attaching to the apical side of umbrella cells (Figure 1); (3) The battle between OAT and the uropathogens provoking cystitis is heavily influenced by the physiology of urine flow [20,25,113] and drug physiochemistry [107,132]; (4) The principle of the five Ds-drug, dose, duration, drug route, and de-escalation-for AMS [44] advocates for obtaining the right drug concentration in urine above the MIC (Figures 2-5) [124,154]. The principle of the five "Ds" can be best illustrated by an intravesical gentamicin dose of 80 mg [155][156][157][158][159] (Figure 5B), delivering a bactericidal concentration with a 90% elimination of live bacteria within 3 h of administration, with a comparative lower incidence of AMR [140] and recurrence [37] than those reported with OAT [38,123].…”

“…As opposed to the urine and plasma plots of OAT shown in Figure 2B, the plot in Figure 5B is projected from a recent study on post-operative prophylaxis by intravesical gentamicin [160]. As depicted by the low plasma levels (red curve in Figure 5B), the limited bioavailability of drugs from the bladder can allow the local administration of a drug concentration (yellow curve in Figure 5B) that would be in a toxic range if administered systemically by oral or intravenous route [154]. Accordingly, IAT gains an asymmetric advantage in combating adaptable uropathogens by delivering a concentration 4-1000-fold higher than the MIC [122], even biofilm-inhibitory and eradication concentrations [91], upon its first contact with microbes and thereby lowers the likelihood of AMR development [123], whereas OAT exposes the bladder urothelium to a higher concentration [23,106] in a gradual fashion, allowing uropathogens to adapt and survive with AMR [39,150].…”

New Insights into the Pathogenesis and Treatment of Urinary Tract Infections

“…In complex cases of UTI, to avoid the emergence of AMR, alongside the development of new non-antibiotic alternatives, there is a growing need to better target antibiotic therapies [3]. A recent review by Morris and colleagues [4] emphasizes the fact that the optimal treatment of UTI involves not only determining the antibiotic susceptibility profile of the pathogen, but also assessing the pharmacokineticpharmacodynamic (PK-PD) properties of the chosen agent, i.e., the likelihood that the chosen antibiotic can be present in the target tissue in sufficient concentrations and for sufficient time to resolve the infection. The authors therefore review the evidence for the use of direct instillation of antibiotics in the urinary tract [4].…”

“…A recent review by Morris and colleagues [4] emphasizes the fact that the optimal treatment of UTI involves not only determining the antibiotic susceptibility profile of the pathogen, but also assessing the pharmacokineticpharmacodynamic (PK-PD) properties of the chosen agent, i.e., the likelihood that the chosen antibiotic can be present in the target tissue in sufficient concentrations and for sufficient time to resolve the infection. The authors therefore review the evidence for the use of direct instillation of antibiotics in the urinary tract [4]. The development of an intravesical antibiotic delivery route would not only avoid AMR, but also, by virtue of the negligible urothelial permeability of the drugs, safeguard non-urothelial microbial communities, including those residing in the gut that are critical to overall health.…”

“…The development of an intravesical antibiotic delivery route would not only avoid AMR, but also, by virtue of the negligible urothelial permeability of the drugs, safeguard non-urothelial microbial communities, including those residing in the gut that are critical to overall health. In their review, Morris et al also highlight the fact that while an intravesical approach to drug delivery is promising and has attracted the interest of clinicians, a better delivery system needs to be developed, as drug delivery through standard drainage catheters carries a high risk of infection [4]. While several groups have investigated the use of functionalized antimicrobial particles suitable for intravesical treatment of UTI, and some have attempted to improve antibiotic instillation using nano-sized delivery platforms, none of these approaches have been approved for this use [5][6][7].…”