Population kinetic–pharmacodynamic analysis of serum potassium in patients receiving sulfamethoxazole/trimethoprim

Abstract

Since trimethoprim (TMP) dose-dependently inhibits the excretion of potassium, a population kinetic-pharmacodynamic analysis was performed to establish an adequate dosing schedule and characterize factors of hyperkalaemia. Dataset was constructed using a retrospective observational cohort of hospitalized patients (>18 years) with oral sulfamethoxazole/trimethoprim formulation. The model integrated a kinetic model for TMP, a urinary TMP concentrationresponse curve and a kinetic model for serum potassium using an indirect response model. The model was a function of body weight, renal function, serum potassium levels and TMP dosing schedule. We evaluated covariates by the stepwise forward and backward selection methods. The Monte Carlo simulation determined the probability of hyperkalaemia (>5.5 or >6.0 meq/L) according to the dosing schedule, renal function and covariates. This study included 317 patients [age 62 (42-72) years] with 4359 serum potassium levels.The significant covariate was non-steroidal anti-inflammatory drugs (NSAIDs), with a 72.3% reduction in 50% inhibitory concentration. Monte Carlo simulation revealed that high-dose TMP (400 mg thrice daily) co-administered with NSAIDs led to mild hyperkalaemia (>10%) and severe hyperkalaemia (approximately 5%), regardless of renal function. In conclusion, clinicians should pay attention to hyperkalaemia with TMP high-dose and co-administered NSAIDs.

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

“…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]. Although IAT (Figure 5) complies with the prescription of the five "Ds", IAT with aminoglycosides or any other broadspectrum antibiotic, to our knowledge, is yet to obtain regulatory approval for therapy or prophylaxis [124].…”

“…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.…”

“…As depicted in the plots (Figure 2B), nitrofurantoin reaches its peak plasma concentration (C max ) in the time range of 2-24 h after oral dosing [23], and only 20-25% of an absorbed dose of nitrofurantoin is ultimately excreted in urine [23], as opposed to the 40-60% excreted for sulfamethoxazole and trimethoprim [87,106]. Even though the peak urine concentration C max of oral nitrofurantoin is twenty-five-fold higher than the plasma C max , the initial delay in reaching the urine MIC leaves a window of opportunity (Figure 3) for the activation of AMR genes to potentially survive subsequent higher concentrations of nitrofurantoin [5][6][7]108,125].…”

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

“…The antimicrobial effect of OAT takes effect only after the absorbed dose fraction gets filtered from plasma by the kidneys into urine (Figure 2). The variability in the pharmacokinetics of OAT stem from the variable absorption from the gut [69,70], first pass metabolism in liver, and systemic distribution followed by renal excretion (Figure 2) for an intermittent ureteric delivery of OAT into urine. Since the bladder [71] receives only 10% of the cardiac output delivered by the renal arteries to kidneys [72,73], the exposure of bladder mucosa to circulating drug levels [74] is minimal compared to the exposure of the luminal side to the urine drug levels(Figure 2).…”

“…As depicted in the plots (Figure 2 B), even though the peak urine concentration Cmax of oral nitrofurantoin is twenty-five-fold higher than in plasma Cmax, the initial delay in reaching urine MIC leaves a window of opportunity (Figure 3) for the activation of AMR genes to survive subsequent higher concentration of nitrofurantoin. Nitrofurantoin reaches its peak serum concentration (Cmax) in the time range of 2-24 hours (Tmax ) after oral dosing [69] and only 20-25% of an absorbed dose of nitrofurantoin is ultimately excreted in urine [69] as opposed to 40-60% for sulfamethoxazole and trimethoprim [63,70]. The figure above vividly illustrates with a mirage graph that OAT being dripped into urine of variable volumes at variable pH from kidneys to bladder may sufficiently facilitate the evasive actions of microbes to gain AMR.…”