Pharmacokinetic Insights into Ciprofloxacin Treatment for Complicated Urinary Tract Infection in Children

Up to 8% of girls and 2% of boys suffer at least one episode of urinary tract infection (UTI) before the age of 8, with the bacterial infection being the most prevalent in childhood.

UTI includes infections of both the bladder mucosa (cystitis) and kidney tissue, called pyelonephritis or febrile UTI. Uncircumcised girls and boys are at increased risk for UTIs, and those with congenital renal and urinary tract anomalies (ACRTU) and bowel-bladder dysfunctions (IVD) are at risk for recurrences. Furthermore, ACRTUs are an important risk factor for complications such as sepsis, pseudohypoaldosteronism, and renal scarring.

Antibiotics are the cornerstone of treatment, preferably orally. Escherichia coli is the most common bacteria cultured in children with UTI and therefore should be covered with any empiric antibiotic regimen for UTI.

Other bacteria, such as Klebsiella and strains of Pseudomonas , tend to be more common in children with abnormal urine flow and ACRTU. Beta-lactam antibiotics, cephalosporins, and trimethoprim-sulfamethoxazole are the common empiric antibiotics for children with UTI, and other classes of antibiotics are used to cover atypical uropathogens.

Ciprofloxacin, a fluoroquinolone, is used in complicated urinary tract infections in children; However, their resistance rates are increasing rapidly, probably at least in part due to inappropriate use.

The action of fluoroquinolones is concentration dependent, and a sufficient amount of drug in urine is essential to exert the antibiotic effect and reduce antimicrobial resistance. There are no reference values ​​for urinary antibiotic concentrations.

Therefore, the ratio of the area under the concentration-time curve (AUC) and the minimum inhibitory concentration (MIC) is usually the pharmacokinetic/pharmacodynamic (PK/PD) parameter that describes the antimicrobial effect of fluoroquinolones.

Its PK in children has not been widely studied, probably due to previous safety concerns, although there is no evidence of irreversible cartilage damage in children treated with ciprofloxacin. In children, HR is influenced by certain diseases, growth, and certain maturational characteristics.

The primary objective of this study was to document the serum and urine pharmacokinetics of ciprofloxacin in a population of children with complicated UTI. Additionally, unbound concentrations and renal markers cystatin C and creatinine were determined in plasma. A population pharmacokinetic model (PFCpob) was applied to investigate the influence of different covariates on ciprofloxacin exposure in this special population.

Results

Participants. A total of 108 serum and 119 urine samples were obtained from 22 children. One child participated in both an oral (PO) and intravenous (IV) course of ciprofloxacin, so data were collected from 23 antibiotic courses.

Most participants had significant urinary tract comorbidities, such as any type of ACRTU (vesicoureteral reflux, double ureter, dysplastic kidneys) or IVD (overactive bladder, underactive bladder, voiding retention).

E. coli was cultured in 10/23 participants, and other bacteria in 9/23. Urine culture remained sterile in the remaining 4 participants, who had received previous courses of antibiotics. There were more girls than boys in group IV.

Model development. A model with an allometric structure based on fat-free mass (FFM) and the influence of renal function (RF) on renal excretion was chosen as the optimal model. FFM was used because of its performance and because two obese patients were included in the study population.

FFM was calculated using age (in years), body weight (in kilograms), and height (in centimeters). RR was obtained by first calculating the estimated glomerular filtration rate (GFR) per normalized body surface area (BSA) (per 1.73 m2) using the Chehade formula, after which it was divided by 120 ml/min (function normal kidney) to obtain a dimensionless parameter. No other significant covariates were detected.

Model evaluation . Observed plasma and urine concentrations were plotted against the population and corresponding individual predictions. A smoother plateau showed slight deviations from the line of unity for the population predictions and not for the individual predictions.

Bootstrap estimates on the fixed and random effects deviated between 13.4% and 6.10% from the model estimates, with an average deviation of 1.43%, indicating good agreement. No significant deviations from the standard normal distribution were detected, although the value was close for plasma (overall adjusted P value, 0.053 for plasma and 0.179 for urine).

Judging by the model diagnostics described above and the individual concentration-time profiles, the model was considered to have a reasonable fit to the data.

FC dosing simulations . The model was subsequently used to simulate the most common dosing regimen. The simulated AUCs were divided by MIC breakpoints according to the European Committee on Antimicrobial Susceptibility Testing tables. An AUC/MIC value of 125 or higher was postulated as the target DF (MIC P. aeruginosa , 0.5 mg/liter; MIC Enterobacteriaceae 0.06 mg/liter; MIC S. aureus 1 mg/liter).

All sham groups achieved this target FD for Enterobacteriaceae . For P. aeruginosa , on average, 57% met the target for the lowest IV dose, ranging from 36% for young children with elevated renal function to 88% for older children with renal failure.

For the 15 mg/kg IV dose, this overall increased to 93%, ranging from 86% to 100%. On average, 53% of patients achieved the target FD for the 15 mg/kg oral dose, ranging from 20% to 80%, which increased to 66% for the 20 mg/kg oral dose, ranging from 46%. at 86%. For S. aureus , the target FD was reached in only 3% of the simulations, ranging from 0% to 33%.

Discussion

In this prospective multicenter study, the pharmacokinetics of ciprofloxacin was analyzed in a population of children who were treated for complicated UTI. The clearance (Cl) of the population (median Cl, 15.9 liters/h for 70 kg with normal RR) was lower than in previous studies.

This discrepancy could be caused by differences in the estimation of renal clearance, since the mean renal contribution was estimated at 50%, when it is expected to be two-thirds of the total clearance. In previous studies, renal clearance was estimated using creatinine-based methods; In this population, GFR was estimated with the Chehade formula, which combines cystatin C and creatinine.

In children, estimating GFR with any of these substances has drawbacks, since measuring GFR using an exogenous substance such as EDTA (Cr-EDTA) is considered the gold standard. However, this is not feasible in clinical settings nor is it ethical for research purposes.

Despite being a superior marker for drug elimination compared to creatinine, cystatin C is not widely used in clinical practice. The Chehade formula was derived from a cohort of 238 children who had at least stage 1 chronic kidney disease (CKD). This formula was considered optimal as it combines cystatin C and creatinine, and the majority of children in this population had abnormalities. chronic kidney disease.

Compared with previous studies, the volume of distribution (V) was low in this population; This difference could be explained by the inclusion of patients with cystic fibrosis in these previous studies, in whom the volume of distribution usually increases.

As both Cl and V were lower, the half-life of ciprofloxacin in the study population was approximately comparable to previous analyses: 0.13 to 9.03 h vs. 1.84 to 2.35 hours and 1.26 to 9.29 hours. Furthermore, the estimated bioavailability and constant absorption rate were also similar to previous analyses.

In the PK dosing simulations, all simulated groups achieved the target DF for Enterobacteriaceae . However, on average, 53% of all children achieved the target DF for Pseudomonas aeruginosa , when dosed at 15 mg/kg orally. This is concerning, as ciprofloxacin was prescribed as the only oral alternative to treat P. aeruginosa in 7/22 of these patients.

Subtherapeutic concentrations of fluoroquinolones select for resistant Pseudomonas strains . Therefore, higher oral doses may be required. However, even at a high oral dose of 20 mg/kg, only 46% of children with elevated RR achieved the target DF.

On average, 3% of all children achieved the target PD for S. aureus , as expected since ciprofloxacin generally has weak Gram-positive coverage.

Using unbound concentrations, we attempted to differentiate between tubular secretion and glomerular filtration for renal clearance. However, it was not possible to estimate the contribution of active processes to renal clearance, probably due to paucity of data. It could also be possible that renal comorbidities present in the population altered tubular secretion differently than filtration, as these processes occur in other parts of the kidney.

There are some limitations in this work. First, a relatively high proportion of participants had significant urinary tract abnormalities. This is reflected in the fraction of cultured non- E. coli pathogens , which was 60.9% higher than in most other populations of children with UTI.

Therefore, these results may not be extrapolated to other populations of children with UTI. However, to control antimicrobial resistance, ciprofloxacin should not be a first-line agent for uncomplicated UTI. For children in this population, ciprofloxacin was generally prescribed as the only oral alternative available as dictated by antibiograms.

For some children, ciprofloxacin was preferred because of the supposed better penetrance in renal inflammation due to acute pyelonephritis. These children did not respond to the first-line antibiotics considered, and among them there were four children in whom no pathogen was cultured because they had received previous antibiotics.

Second, urine for analyzes was collected with noninvasive methods. Great effort was made to collect all urine during the study periods, but given the high proportion of children with ACRTU, IVD, and neurogenic bladder in this population, it is likely that urine collections do not represent the total urine output during the study periods. study periods.

This could only have been overcome by collecting urine with indwelling catheters. However, this is unethical for the purpose of research without any other clinical reason. Additionally, since most participants had received previous doses of ciprofloxacin, it could have accumulated in urine. Therefore, we chose to model cumulative urine excretion by at least mediating the urine collection error.