Change in Vancomycin Absorption after Intraperitoneal Injection and Correlation between Intraperitoneal Vancomycin Absorption and Peritoneal Equilibration Test Score in Mice with Peritoneal Injuries

Abstract

Peritonitis is a serious complication in peritoneal dialysis patients and requires antibiotic administration. Intraperitoneal vancomycin is an empiric therapy for peritonitis caused by Gram-positive cocci; however, there is no way to predict vancomycin absorption after intraperitoneal administration. Therefore, we aimed to evaluate the changes in vancomycin absorption after intraperitoneal injection into mice with chlorhexidine gluconate (CG) induced peritoneal injuries. Additionally, we examined the correlation between intraperitoneal vancomycin absorption and peritoneal equilibration test (PET) score. PET score was determined using glucose concentration in the peritoneal dialysis fluid at each dwell time (D_t) and D₂ (2 h of dwell time)/D₀ (0 h of dwell time) glucose ratio. Vancomycin was injected into the peritoneal cavity of mice, blood was collected after 1–8 h, and peritoneal fluid was recovered. The residual ratio of intraperitoneal vancomycin was significantly decreased in the CG group at all time points compared to that in the vehicle group. CG group significantly exhibited higher serum vancomycin concentrations than the vehicle group, and the maximum serum concentration increased depending on CG concentration, with 0.05 and 0.1% CG groups showing 3.9- and 6.1-times higher vancomycin concentrations, respectively, than the vehicle group. A significant correlation was observed between the D_t/D₀ glucose ratios and residual vancomycin ratios in the peritoneal fluid 2 or 6 h after intraperitoneal injection. A good correlation was observed between the D₂/D₀ glucose and residual vancomycin ratios 6 h after intraperitoneal vancomycin injection. Thus, PET score can predict residual intraperitoneal vancomycin, aiding in dosing decisions.

INTRODUCTION

Patients with end-stage renal disease require dialysis or kidney transplantation as an alternative treatment. However, kidney transplantation is limited by various factors, including the low number of donors. Therefore, dialysis is the major treatment option for patients with end-stage renal disease. Recently, the “PD first” strategy, which involves initial treatment with peritoneal dialysis (PD) and subsequent switching to hemodialysis (HD) after utilizing the residual renal function, has been anticipated to provide a good prognosis for patients. PD is expected to retain the residual renal function because water removal is slower than in HD.¹⁾ Additionally, its cost is lower than that of HD and can be performed at home. However, peritonitis is a serious complication of PD that requires antibiotic treatment.

Vancomycin is an anti-methicillin-resistant Staphylococcus aureus agent that is administered intraperitoneally to treat bacterial peritonitis.²⁾ The absorption rate of vancomycin from the peritoneal cavity to the systemic circulation is approximately 50%, with some variations observed among different patients.³⁾ Moreover, vancomycin is better absorbed by patients with peritonitis than by those without peritonitis.⁴⁾ We previously revealed that the permeability of large-molecular-weight compounds (molecular weight [MW]: 350–70000) is enhanced in peritoneal injuries.⁵⁾ These reports suggest that the absorption of vancomycin, a large-molecular-weight compound (MW: 1485.71), after intraperitoneal administration is affected by the peritoneal membrane function.

Maintaining adequate concentrations of antimicrobial agents in the abdominal cavity is important to ensure full efficacy and to avoid resistance. Nevertheless, no method has been established to predict vancomycin absorption after intraperitoneal administration; therefore, the dose of vancomycin is empirically determined. In this study, we evaluated the changes in the intraperitoneal absorption of vancomycin and peritoneal membrane functions in mice with peritoneal injuries. Peritoneal membrane function was examined using the peritoneal equilibration test (PET), as in clinical practice.⁶⁾ Additionally, we assessed the correlation between the vancomycin residual ratio in the abdominal cavity and the PET score.

MATERIALS AND METHODS

Materials

Vancomycin (vancomycin hydrochloride powder: 0.5 g; MEEK) was obtained from Kobayashi Kako Co., Ltd. (Fukui, Japan). Ciprofloxacin was purchased from Combi Blocks Inc. (San Diego, CA, U.S.A.). Chlorhexidine gluconate (CG) was purchased from Sigma-Aldrich (St. Louis, MO, U.S.A.). Hematoxylin–eosin (H&E) stain was obtained from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). PD fluid (PDF) (Dianeal PD-4 4.25) was obtained from Baxter Ltd. (Tokyo, Japan). All other chemicals were of the highest available purity.

Animals

Male ddY mice (5-week-old) were housed in cages in an air-conditioned room, fed a standard laboratory diet (MF; Oriental Yeast Co., Ltd., Tokyo, Japan), and provided water ad libitum. All animal experiments adhered to the Guidelines for Animal Experimentation of Nagasaki University, Japan (approval number: 1505011222-10).

Establishment of Peritoneal Injury Animal Models

Peritoneal injury mouse models were established as previously described.⁷⁾ Briefly, saline containing 0.01–0.1% CG and 15% ethanol was intraperitoneally injected into mice at a volume of 10 mL/kg body weight. To establish controls, saline containing 15% ethanol was intraperitoneally injected in the same fashion. The established model mice were subjected to the following PET or pharmacokinetic study 24 h after CG or saline and 15% ethanol administration.

Peritoneal Equilibration Test

The peritoneal injury was assessed using PET, as previously described.⁸⁾ Briefly, 3 mL of PDF was intraperitoneally injected into mice. Peritoneal fluid was recovered after 0, 1, and 2 h of dwell time (D_t). The samples were centrifuged at 1600 × g at 4 °C for 15 min. Blood was collected from the tail vein after 1 h, left undisturbed for 300 min at room temperature, and centrifuged at 17863 × g at room temperature for 15 min. Then, concentrations of urea nitrogen (UN) and glucose in the obtained samples were determined using the LabAssay Urea Nitrogen B-Test Wako and LabAssay Glucose commercial kits (FUJIFILM Wako Pure Chemical Corporation), respectively. PET scores were calculated using the following equations:

  

$${\mathrm{D}}_{\mathrm{t}}/{\mathrm{D}}_0 \text{Glucose}=\frac{\text{Glucose concentration in PDF at each dwell time}}{\text{Initial glucose concentration in PDF}}$$

  

$${\mathrm{D}}_{\mathrm{t}}/{\mathrm{P}}_1 \text{UN}=\frac{\text{UN concentration in PDF at each dwell time}}{\text{UN concentration in the blood at 1 h after PDF injection}}$$

D₂ (2 h of dwell time)/D₀ (0 h of dwell time) glucose ratio was calculated assuming the value at the time of sampling for PET, and D₆ (6 h of dwell time)/D₀ (0 h of dwell time) assuming the value at the time of exchange PDF.

Evaluation of Vancomycin Pharmacokinetics

Mice with peritoneal injuries were anesthetized with a mixture of three types of anesthetics (0.3 mg/kg of medetomidine, 4.0 mg/kg of midazolam, and 5.0 mg/kg of butorphanol, i.m.).⁹⁾ Briefly, the skin was cut, and the abdominal wall was exposed. Vancomycin (20 mg/kg) dissolved in 3 mL PDF was injected into the peritoneal cavity using a syringe with 21 G × 1 1/2 needle (Nipro Co., Ltd., Osaka, Japan). The needle was removed, and the pinhole in the abdominal wall was closed with a surgical adhesive (Aron Alpha A; Daiichi Sankyo Pharmaceutical Co., Ltd., Tokyo, Japan) to prevent fluid leakage. To determine the serum vancomycin concentration, blood was collected at 1, 2, 4, 6, or 8 h from the inferior vena cava. Blood samples were maintained at room temperature for 300 min and centrifuged at 17863 × g at room temperature for 15 min. To determine the PDF volume and concentration of vancomycin, PDF was recovered at 1, 2, 4, 6, or 8 h, weighed, and centrifuged at 1600 × g at 4 °C for 15 min.

Quantification of Vancomycin

Vancomycin concentration was quantified using HPLC with UV detection.¹⁰⁾ Briefly, serum or PDF was mixed with 100 μg/mL ciprofloxacin (internal standard) and acetonitrile, placed for 10 min at room temperature, and centrifuged at 17863 × g at room temperature for 5 min. The supernatant was evaporated under nitrogen at 50 °C, and the dried sample was dissolved in the mobile phase (methanol:phosphate buffer [25 mM, pH 2.75] = 20 : 80, v/v).

HPLC conditions were as follows: detector, 220 nm; column, 5C₁₈-MS-II (150 × 4.6 mm; Nacalai Tesque Inc., Kyoto, Japan); column temperature, 25 °C; mobile phase, methanol (reservoir A) and phosphate buffer (25 mM, pH 2.75; reservoir B); flow rate, 1 mL/min in gradient elution. The gradient consisted of four phases: (i) 20% (A) and 80% (B) for 0–6 min, (ii) 40% (A) and 60% (B) for 6–11 min, (iii) 80% (A) and 20% (B) for 11–13 min, and (iv) 20% (A) and 80% (B) for 13–20 min.

Histological Examination

Histological analysis was performed via H&E staining. After the recovery of the residual solution from the peritoneal cavity, abdominal walls were cut, fixed with 4% paraformaldehyde in phosphate buffer, embedded with the O.C.T. compound frozen at –80 °C, sliced into 10-μm sections using a microtome (Retoratome REM-710; Yamato Kohki Industrial Co., Ltd., Saitama, Japan), and stained with H&E. Stained samples were observed under a microscope with a 10 × objective lens.

Statistical Analyses

Statistical analyses were conducted using the Dunnett’s test, followed by ANOVA or repeated-measures ANOVA. Correlations were tested using Pearson’s product-moment correlation coefficient (r), which is used to quantify the strength of the linear relationship between two continuous variables in a normally distributed population. Statistical significance was set at α = 0.05.

RESULTS

Qualitative Assessment of Peritoneal Function

The recovered volume of peritoneal fluid 2 h after intraperitoneal injection was approximately 3.5 mL in the vehicle group and <3 mL in the 0.05% and 0.1% CG groups (Fig. 1).

Fig. 1. Evaluation of Ultrafiltration Based on the Residual Solution in the Peritoneal Cavity of CG-Treated Mice

Volume of residual solution in the peritoneal cavity 2 h after intraperitoneal injection in mice treated with 15% ethanol or CG for one day. Each bar represents the mean ± S.E. of at least four experiments. *p < 0.05 vs. vehicle. #, injection volume; CG, chlorhexidine gluconate; S.E., standard error.

D_t/D₀ glucose and D_t/P₁ UN ratios 1 and 2 h after PDF injection were calculated as the PET scores (Fig. 2). D_t/D₀ glucose ratios in 0.05 and 0.1% CG-treated mice were significantly lower than those in the vehicle-treated mice at each recovery time point. In contrast, D_t/P₁ UN ratios in CG-treated mice were higher than those in the vehicle-treated mice.

Fig. 2. Evaluation of Peritoneal Function in CG-Treated Mice Performing the PET

(a) D_t/D₀ glucose and (b) D_t/P₁ UN ratios were determined 1 and 2 h after intraperitoneal injection of dialysate in mice treated with 15% ethanol or CG for one day. Each bar represents the mean ± S.E. of at least four experiments. *p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle. N.S., not significant vs. vehicle. PET, peritoneal equilibration test; UN, urea nitrogen; CG, chlorhexidine gluconate; S.E., standard error.

Evaluation of Vancomycin Pharmacokinetics Using the Peritoneal Injury Mouse Models

Figure 3 shows the time course of the residual ratio of vancomycin dissolved in 4.25 PDF (Fig. 3a) and serum concentration–time profile of vancomycin (Fig. 3b) after intraperitoneal administration in mice. The residual ratio of vancomycin 1 h after injection was approximately 70% in the vehicle group and slowly decreased with time. In contrast, the residual ratio of vancomycin was almost 40% 1 h after injection in the 0.05 and 0.1% CG groups. Moreover, vancomycin was barely detected in the 0.05 and 0.1% CG groups 8 h after injection.

Fig. 3. Time Course of the Residual Ratio and Serum Concentration of Vancomycin in CG-Treated Mice

Time course of the (a) residual ratio of intraperitoneal vancomycin and (b) serum concentration of vancomycin 1, 2, 4, 6, and 8 h after intraperitoneal injection in mice treated with 15% ethanol or CG for one day. Each bar represents the mean ± S.E. of at least three experiments. * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle. CG, chlorhexidine gluconate; S.E., standard error.

In the vehicle group, the serum concentration of vancomycin was very low (<5 μg/mL). CG groups exhibited significantly higher serum vancomycin levels than the vehicle-treated group. In this study, maximum serum concentration (Cmax) of vancomycin was observed 1 h after injection. Cmax was increased in the CG groups, being 3.9- and 6.1 times higher in the 0.05 and 0.1% CG groups, respectively, than in the vehicle group.

Correlation between PET Score and Residual Ratio of Vancomycin in the Peritoneal Injury Models

Next, we evaluated peritoneal injury mouse models prepared with various concentrations of CG as poor correlations were observed between CG concentrations and the residual ratios of intraperitoneal and serum concentrations of vancomycin (data not shown).

First, we prepared mouse models with 0.01–0.1% CG and evaluated the recovery volume of peritoneal fluid and PET score (D₂/D₀ glucose ratio). The recovery volume of peritoneal fluid 2 h after intraperitoneal injection in 0.01–0.1% CG-treated mice is shown in Fig. 4a. D₂/D₀ glucose ratio was significantly decreased in mice treated with >0.02% CG (Fig. 4b). Notably, recovery volume and D₂/D₀ glucose ratio gradually decreased as the CG concentration increased.

Fig. 4. Evaluation of Peritoneal Function Based on the Ultrafiltration Capacity and D₂/D₀ Glucose Ratio in CG-Treated Mice

(a) Volume of residual solution in the peritoneal cavity and (b) D₂/D₀ glucose ratio were determined 2 h after intraperitoneal injection of dialysate in mice treated with 15% ethanol or various concentrations of CG for one day. Each bar represents the mean ± S.E. of at least three experiments. * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle. #, injection volume. CG, chlorhexidine gluconate; S.E., standard error.

We prepared mouse models with 0.01–0.1% CG and evaluated the residual ratio of vancomycin in the peritoneal fluid and D_t/D₀ glucose ratio. Significant correlations were observed between the D_t/D₀ glucose ratios and residual ratios of vancomycin in the peritoneal fluid 2 and 6 h after intraperitoneal injection (2 h: r = 0.931 and p < 0.05; 6 h: r = 0.871 and p < 0.05; Fig. 5).

Fig. 5. Correlations between D_t/D₀ Glucose Ratio and Residual Ratio of Vancomycin at the Same Time and 2 and 6 h after Intraperitoneal Injection of Vancomycin

D₂/D₀ glucose ratio and residual ratio of vancomycin dissolved in the dialysate in the peritoneal cavity were determined 2 h after intraperitoneal injection of vancomycin in mice treated with 15% ethanol or various concentrations of CG for one day. D₆/D₀ glucose ratio and the residual ratio of vancomycin in the peritoneal cavity were determined 6 h after intraperitoneal injection of vancomycin. CG, chlorhexidine gluconate.

Next, we evaluated the relationship between the D₂/D₀ glucose ratios and residual ratios of vancomycin in the peritoneal fluid 6 h after intraperitoneal injection. The residual ratio of vancomycin in the peritoneal fluid 6 h after intraperitoneal injection was positively correlated with the D₂/D₀ glucose ratio (r = 0.855 and p < 0.05; Fig. 6).

Fig. 6. Correlation between D₂/D₀ Glucose Ratio and Residual Ratio of Vancomycin 6 h after Intraperitoneal Injection of Vancomycin

D₂/D₀ glucose ratio was determined 2 h after intraperitoneal injection of vancomycin dissolved in the dialysate in mice treated with 15% ethanol or various concentrations of CG for one day. The residual ratio of vancomycin in the peritoneal cavity was determined 6 h after intraperitoneal injection of vancomycin.

DISCUSSION

In this study, we evaluated the changes in vancomycin absorption after intraperitoneal injection in peritoneal injury mouse models and the correlation between intraperitoneal vancomycin absorption and PET score. We previously reported that the absorption of intraperitoneally administered low-molecular-weight compounds is enhanced in peritoneal injury mouse models.¹¹⁾ In addition, it has been shown that increased absorption due to peritoneal damage also occurs in high-molecular-weight compounds.⁵⁾ It is thought that vancomycin is hardly absorbed from the peritoneal cavity; however, in our previous study, we expected that absorption would be enhanced during peritoneal injury.

Intraperitoneal administration of methylglyoxal or CG as a surfactant is used to prepare animal models of peritoneal injury.^12,13) In the CG administration method, inflammation occurs due to macrophage phagocytosis induced by the aggregation of CG particles.¹⁴⁾ As this study focused on peritoneal damage due to peritoneal inflammation, a peritoneal injury model was induced with CG administration, which is thought to reflect the pathogenesis of peritonitis.

Functional changes were assessed based on water removal capacity and PET score, which are used to evaluate peritoneal injury in clinical settings.⁶⁾ The amount of residual fluid in the abdominal cavity 2 h after PDF administration was increased in the vehicle group. However, in the CG groups, the recovered volume was lower than the initial dose, suggesting poor water removal due to peritoneal injury (Fig. 1). Additionally, D_t/D₀ glucose ratio was significantly decreased in the CG groups (Fig. 2a). D_t/D₀ glucose ratio is related to glucose absorption from the peritoneal cavity. Osmotic pressure in the abdominal cavity is thought to decrease due to enhanced glucose transport into the blood. Here, the decreased D_t/D₀ glucose ratio in CG groups was consistent with the poor water removal shown in Fig. 1.

Pharmacokinetics of vancomycin in peritoneal injury models were examined with and without CG treatment. The residual ratio of intraperitoneal vancomycin in the CG groups decreased to less than approximately 40% 1 h after administration and was significantly decreased at all time points compared to that in the vehicle group (Fig. 3a). A previous study showed that the residual ratio of dual macromolecular markers (MW 10000/MW 20000) is decreased by approximately 40% in 0.1% CG-treated mice.⁵⁾ These results suggest that the absorption of high-molecular-weight compounds (MW >1000) is enhanced in peritoneal injuries.

In the vehicle group, a gradual increase in the serum concentration of vancomycin was observed. However, in the CG groups, serum concentrations of vancomycin rapidly increased, becoming approximately six times higher than those in the vehicle group 1 h after administration (Fig. 3b). These results suggest that peritoneal injury increases the permeability of intraperitoneally administered vancomycin, which is rapidly absorbed into the blood after administration.

Maintaining adequate concentrations of vancomycin in the abdominal cavity is important for effective treatment without the development of resistance. However, to date, no method to assess vancomycin absorption from the abdominal cavity into the blood has been established. Patients undergoing PD exhibit some residual renal function, and PD is expected to retain the residual renal function.¹⁾ However, renal dysfunction is a typical side effect of vancomycin.^15–17) As vancomycin is intraperitoneally administered, assuming that it is hardly absorbed from the abdominal cavity, its side effects after intraperitoneal administration are not considered. However, the amount of vancomycin transferred into the blood is high in patients with peritoneal injuries; peritonitis treatment may fail owing to decreased vancomycin concentration in the abdominal cavity and there is a risk of decreased residual renal function due to its side effects. The currently recommended area under the curve (AUC) estimated by serum concentration of vancomycin is more than 400 mg × h/L in patients with infection caused by susceptible bacteria.¹⁸⁾ However, the AUC target value of “intraperitoneal concentration” for the treatment of peritonitis is unclear. There is no doubt that the AUC of “serum concentration” should be kept below 600 mg × h/L to reduce nephrotoxicity.¹⁸⁾ There is also a report that the antibacterial activity of vancomycin decreases in peritoneal dialysis fluid.¹⁹⁾ Therefore, we thought that intraperitoneal administration of vancomycin is desirable for peritoneal dialysis patients, which allows for high concentrations at the infection site without systematic excessive exposure. To maintain adequate concentration of vancomycin in the abdominal cavity and minimize its adverse effects on residual renal function, we estimated the amount of vancomycin transferred to the blood in this study.

We induced various degrees of peritoneal injury in mice by varying the CG concentration (Fig. 4). Additionally, we observed strong correlations between PET score and residual ratio of vancomycin in the peritoneal fluid 2 and 6 h after intraperitoneal injection (Fig. 5). We also observed a strong correlation between D₂/D₀ glucose ratio and residual ratio of vancomycin 6 h after intraperitoneal vancomycin injection (Fig. 6). PET is commonly performed to evaluate the peritoneal function in patients undergoing PD and does not require the administration of other drugs.⁶⁾ Therefore, vancomycin absorption can be predicted using the PET score, which will further help in establishing vancomycin dosing strategies with high efficacy and safety.

In this study, the inactivation of transporters was a concern because CG and ethanol may have protein-denaturing effects. However, in renal elimination, the proportion of transporter-mediated elimination is low because vancomycin is thought to be eliminated mostly by glomerular filtration.²⁰⁾ Therefore, we would not consider the contribution of any transporter with the absorption of vancomycin in this study. On the other hand, it has been reported that vancomycin may be taken up via megalin, which is expressed in the apical membranes of the proximal tubules.²¹⁾ However, the expression of megalin in the peritoneal cavity and its contribution to the uptake of vancomycin is unclear. Further study is needed to know the expression of megalin in the peritoneal cavity and its contribution to the uptake of vancomycin. The observed vancomycin concentrations were much higher in the peritoneal cavity than in the blood (more than 100 times) and correlated with the D₂/D₀ glucose ratio, suggesting that vancomycin absorption into the blood was largely due to transport by passive diffusion. If vancomycin is transported by passive diffusion, the rate of absorption is largely affected by the initial intraperitoneal concentration, according to Fick’s law. Therefore, the residual ratio of vancomycin would change in dose dependency. We could not clarify dose dependency in vancomycin absorption in this study; further studies at various doses were considered necessary.

In conclusion, this study showed that the intraperitoneal absorption of vancomycin was enhanced in mice with peritoneal injuries. Notably, the PET score effectively predicted the residual ratio of intraperitoneal vancomycin. Overall, our findings can aid in the more effective and safe intraperitoneal administration of vancomycin to patients undergoing PD.

Acknowledgments

This study was supported by a Grant-in-aid from the Japanese Association of Dialysis Physicians.

Conflict of Interest

The authors declare no conflict of interest.

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