The global burden of antimicrobial resistance – urinary tract infections

Abstract

Antimicrobial resistance (AMR) emerged as a significant global healthcare problem. Antibiotic use has accelerated the physiologic process of AMR, particularly in Gram-negative pathogens. Urinary tract infections (UTI) are predominantly of Gram-negative nature. Uropathogens are evolutionarily highly adapted and selected strains with specific virulence factors, suggesting common mechanisms how bacterial cells acquire virulence and AMR factors. The simultaneous increase in resistance and virulence is a complex and context-dependent phenomenon. Amongst known AMR mechanisms, the plenitude of different β-lactamases is especially prominent. The risk for AMR in UTI varies in different patient populations. History of antibiotic consumption and physiology of urinary flow are major factors that shape AMR prevalence. The urinary tract is in close crosstalk with the microbiome of other compartments, such as the gut or the genital tracts. In addition, pharmacokinetic properties and the physiochemical composition of urinary compartments can contribute to emergence of AMR. Alternatives to antibiotic treatment and a broader approach to address bacterial infections are needed. Among the various alternatives studied, antimicrobial peptides (AMPs) and bacteriophage treatment appear to be highly promising approaches. We here summarize the present knowledge of clinical and microbiological AMR in UTI and discuss innovative approaches, namely new risk prediction tools and the use of non-antibiotic approaches to defend against uropathogenic microbes.

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

“…The WHO now recognizes AMR as one of the greatest threats to global healthcare. The warning triggered by the WHO [20,39,42] within the clinical and scientific communities is captured in 249,067 results generated by a recent PubMed search on "Antimicrobial resistance". The efforts to contain AMR have led to the rise in AMS within clinical governance oversight of prescriber practices as a contemporary feature within hospital services [4,43].…”

“…The self-medication of OAT also does not burden doctors or nurses as is the case with the parenteral administration of antimicrobials. The primary weaknesses of OAT are inter-individual variability in the clinical outcomes and AMR owing to inter-individual variability in pharmacokinetics [25,29,30,[96][97][98] and hepatobiliary vs. renal clearance [20] delaying the achievement of the minimum inhibitory concentration (MIC) in urine [23,87]. The oral bioavailability of OAT differs with race [32,99], food intake [97], inter-individual variability in the gastric emptying time [100], posture (supine or ambulatory) [101,102], and the general health status of the patient [103].…”

“…It is noteworthy that the antimicrobial effect of OAT on cystitis takes effect only after the absorbed dose fraction runs the gauntlet of pharmacokinetics to be filtered from the plasma by the kidneys into urine (Figure 2) [20,23,26,30,32,35,87,105]. The variability in the pharmacokinetics of OAT stems from variable absorption of drug from the gut [23,106], first pass metabolism of drug in the liver before its systemic distribution and renal excretion (Figure 2) for an intermittent ureteric delivery of OAT into urine.…”

“…Many groups have suggested that the biochemical mechanisms driving the adaptability of uropathogens in the variable pH and osmolality of urine [17,18] are as dogged as the signaling pathways driving the gain of virulence [19][20][21] and antimicrobial resistance (AMR) [22]. From a clinical perspective, AMR refers to a microbial phenotype capable of surviving the exposure to a drug treatment course at a concentration anticipated to prevent its survival [20]. While the efficacy of antimicrobials for treating systemic infections (bacteriemia) can be reliably indexed by the plasma levels of antimicrobials above the minimum inhibitory concentration (MIC), the killing of the uropathogens causing cystitis is determined by urine levels above the MIC [23][24][25][26].…”

“…Uropathogens exposed to below-MIC levels in urine bestow The infection of the urothelium can only occur after uropathogens successfully compete for available nutrients with the commensal microbiome [13] by employing mechanisms of commensalism [14], mutualism, and parasitism [15,16]. Many groups have suggested that the biochemical mechanisms driving the adaptability of uropathogens in the variable pH and osmolality of urine [17,18] are as dogged as the signaling pathways driving the gain of virulence [19][20][21] and antimicrobial resistance (AMR) [22]. From a clinical perspective, AMR refers to a microbial phenotype capable of surviving the exposure to a drug treatment course at a concentration anticipated to prevent its survival [20].…”