Vancomycin in peritoneal dialysis: Clinical pharmacology considerations in therapy

Abstract

Intraperitoneal vancomycin is the first-line therapy in the management of peritoneal dialysis (PD)-related peritonitis.

However, due to the paucity of data, vancomycin dosing for peritonitis in patients on automated peritoneal dialysis (APD) is empiric and based on clinical experience rather than evidence. Studies in continuous ambulatory peritoneal dialysis (CAPD) patients have been used to provide guidelines for dosing and are often extrapolated for APD use, but it is unclear whether this is appropriate. This review summarizes the available pharmacokinetic data used to inform optimal dosing in patients on CAPD or APD. The determinants of vancomycin disposition and pharmacodynamic effects are critically summarized, knowledge gaps explored, and a vancomycin dosing algorithm in PD patients is proposed.

Introduction

Vancomycin is often selected as empiric first-line therapy for suspected gram-positive organisms in peritoneal dialysis (PD)-related peritonitis. However, data on vancomycin dosing in various PD modalities are limited, especially for automated peritoneal dialysis (APD). The paucity of well- designed pharmacokinetic studies has led to vancomycin dosing guidelines for PD patients that are based on limited information resulting in the possibility of achieving sub- or supra-therapeutic trough concentrations in this special patient population.¹ population.^2,1.3 Metabolism is negligible and elimination occurs primarily through glomerular filtration, such that advanced renal dis- ease substantially reduces the clearance of vancomycin resulting in an elimination half-life of about 7.5 days com- pared to 4–6 h in normal patients. This means that in patients with kidney failure, the dosing of vancomycin must be adjusted.^4,5

Principles of vancomycin therapy

Vancomycin is a tricyclic glycopeptide antibiotic with broad spectrum activity against gram-positive bacteria. It is effective for the treatment of gram-positive infections including peritonitis and is the drug of choice for methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is poorly absorbed following oral administration. Therefore, it is commonly administered as an intravenous infusion, except in PD where the route is preferentially intraperitoneal. Approximately 50% of vancomycin is protein bound in plasma with a variable volume of distribution ranging between 0.4 L/kg and 1 L/kg in the non-PD

The Clinical and Laboratory Standards Institute (CLSI) has established the vancomycin break point for susceptible S. aureus isolates with minimal inhibitor concentration (MIC) values of ≤ 2 mg/L and intermediate or resistant for MIC values greater than 2 mg/L.⁶ Despite the CLSI defined break points, treatment failure for patients infected with aureus and vancomycin MICs between 1 mg/L and 2 mg/L have been reported compared to those with lower reported MICs.^7,8 This may be due to inappropriate selection of doses that are sufficiently high to maintain plasma concentrations that exceed the MIC. To optimize the vancomycin exposure–response relationship for efficacy during S. aureus infections, one must examine the ratio of the area under the concentration–time curve and the MIC (AUC/MIC). Vancomycin trough concentrations between 15 mg/L and 20 mg/L for MIC break points ≤ 1 mg/L ensure a ratio of 2' 400 and have been an advocated target for clinical effectiveness.^3,9 It should be noted that goal trough values recommended by consensus guidelines for efficacy may lead to nephrotoxicity, which might be a consideration for patients on PD with residual kidney function (RKF).¹⁰ This, however, is not well studied. In practice, clinical judgment together with therapeutic drug monitoring (TDM) of steady-state vancomycin plasma concentrations is a common approach in the treatment of peritonitis in PD.

Pharmacokinetic/pharmacodynamic modeling and simulation

Pharmacokinetic/pharmacodynamic modeling and simula- tion is an innovative approach that can help inform crucial decisions, such as predicting clinical end points of new doses and dosing regimens or optimization of drug regi- mens. By understanding what the body does to the drug (pharmacokinetics) and what the drug does to the body (pharmacodynamics), dosing regimens can be tailored to the PD population to avoid nephrotoxicity, retaining anti- microbial eradication and suppressing the emergence of resistance. Regulatory authorities mandate the submission of pharmacokinetic/pharmacodynamic evaluations for drug application, which include dose evaluation in special popu- lations. However, despite the evaluation of the need for dose adjustments in patients with end-stage renal disease (ESRD)—such as those on hemodialysis—the process is not well established for old drugs. Even in those cases when dose adjustments are proposed for patients with ESRD, there is minimal attention in patients on PD.

This review aims to summarize the available evidence on vancomycin pharmacokinetic and pharmacodynamic PD-related studies, to address the physicochemical and PD modality-specific considerations—with attention on APD— and to highlight areas where research is needed on dosing vancomycin for PD-related peritonitis.

Vancomycin physicochemical properties and drug transport across the peritoneum Movement of vancomycin from the peritoneum cavity to plasma is based on Fick’s law (Figure 1). Middle- molecular-weight solutes such as vancomycin (1486 g/mol) are dependent on dwell time during PD for absorption into the plasma. Vancomycin is compatible with glucose-based and icodextrin dialysate fluids. The drug is stable in various PD solutions for up to 24 h at 37°C with the stability increased for up to 14 days in icodextrin if stored under refrigerated conditions. Based upon a single-dose study of six noninfected subjects on PD, vancomycin has a lower dialysate to plasma ratio than urea and creatinine at 2 h.¹³ There is no correlation between vancomycin PD clearance and dialysis adequacy (Kt/V) following an intravenous dose in patients on APD.¹⁴

Figure 1. Illustration of vancomycin absorption, distribution, and elimination following an intraperitoneal dose.

Increasing the dwell time enhances vancomycin bioavailability. Peritoneum and dialysate properties should be considered as both these affect the rate and the extent of absorption following an intraperitoneal dose. Following dosing and an appreciable dwell time, vancomycin is eliminated by PD, renal, and nonrenal sources. These processes make up the total body clearance of vancomycin. This illustration is a derivative of “Simple squamous epithelium,” “Arteries,” “Arterial circulation,” and “Bubble” by Servier Medical Art (https://smart.servier.com/) distributed under the Creative Commons License (CC BY 3.0). PD: peritoneal dialysis.

Teicoplanin, a glycopeptide antibiotic with a similar molecular structure (1564 g/mol) and spectrum of activity to vancomycin, was studied in noninfected adults on con- tinuous ambulatory peritoneal dialysis (CAPD).¹⁵ The absolute bioavailability (F_IP) was calculated using dialysate drug concentration (corrected for amount remaining in the cavity) and drug amount sampled, which was then plotted against a total dwell time of 5 h. Teicoplanin sys- temic bioavailability, reflecting transfer from the peritoneal space, was directly related to dwell time. Furthermore, the consistency in absorption increased with time suggesting that complete and less variable bioavailability with teico- planin can be achieved with longer dwell times.

The rate at which vancomycin is absorbed is dependent on the permeability of the peritoneal membrane. Vancomy-cin intraperitoneal to systemic transfer rate increases in patients with inflammatory peritonitis.¹⁶

Vancomycin bioavailability during CAPD

Vancomycin pharmacokinetics has primarily been studied in patients on CAPD. Bioavailability studies conducted in these patients typically employ a 6-h dwell time. The FIP, or the amount of vancomycin reaching systemic circulation from the peritoneal space relative to an intravenous dose, is approximately 50%.¹⁷ Supporting the hypothesis of a leaky peritoneum due to membrane inflammation, patients on CAPD with peritonitis have an F_IP of 70–91%.^16,18 Bioa- vailability changes can also be observed with different age cohorts. For example, in a pediatric study in children aged 5–17 years, the bioavailability was reported to be as high as about 70% in the absence of peritonitis.¹⁹

A summary of the absorption parameters from studies conducted in infected and noninfected patients on CAPD is presented in Table 1. The equilibration half-life describes the time allowed for drug transfer between the peritoneal space to the systemic circulation following an intraperitoneal dose of vancomycin. Following intraperito- neal dosing, vancomycin equilibration half-life in patients on CAPD without peritonitis was 2.9 h and those with peritonitis 1.6–2.9 h.^22,24,25 Assuming no differences between perito- neum transport in those with or without peritonitis and five half-lives, steady-state equilibrium between the dialytic compartment and the systemic circulation would be achieved following a 10–15 h dwell.

Table I.

Vancomycin absorption parameters in adult and pediatric noninfected and PD-related peritonitis patients on PD.

					Plasma concentration
Infection status	Dose	Dwell time (h)	Bioavailability (%)a	Dosing	(mg/L)	Time of sampling (h)	Reference
Adults
Negative	30 mg/kg	6	49b	Single	24.9	6	17
	10 mg/kg	4	65	Single	6.3	5	20
PD—Peritonitis	30 mg/kg	6	91	Single	40	4	16
	2 g	6	70	Single	39.7	6	18
	500 mg	6	83	Multiple	10.2	6	21
	15 mg/kg	4	66	Single	16.1	6	22
	30 mg/kg	10–12	N/A	Multiple	33.8	12	23
Pediatric
Negative	550 mg/m2	6	70	Single	23.3	6	19

A_D(t): amount of drug recovered in dialysis fluid at the end of dwell; AUC_IP: area under the plasma concentration–time curve following an intraperitoneal dose; AUC_IV: area under the plasma concentration–time curve following an intravenous dose; D_IP: amount of drug administered in the dialysis fluid; F_IP: fraction of drug absorbed following intraperitoneal administration; N/A: not reported; PD: peritoneal dialysis; IP: intraperitoneal.

^aUnless noted, bioavailability was calculated based on the amount of drug recovered in the dialysate following IP administration using the equation F_IP = D_IP − A_D(t)/D_IP.

^bCalculated absolute bioavailability using the equation F_IP = AUC_IP × D_IV/AUC_IV × D_IP.

Vancomycin bioavailability during APD

Vancomycin possesses the desired physiochemical proper- ties as a drug candidate for intraperitoneal administration in APD patients. In addition, with its well-established stability in PD fluids, bioavailability is adequate as long as sufficient dwelling time is allowed for drug absorption. However, the appropriate duration of the dwell time has not been well studied. Hence, it is crucial to monitor van- comycin levels frequently to adjust dosing to get therapeutic concentrations in each individual patient.

Vancomycin clearance during PD

Vancomycin elimination following an intraperitoneal dose is governed by its total body clearance. Total body clearance is the sum of clearances contributed from elimination organs, mainly kidneys, in the case of vancomycin, and is defined as the volume of plasma cleared of vancomycin per time unit. Elimination processes in PD patients include those originating from RKF, other nonrenal sources plus the drug cleared through PD. Total body clearance is especially important as it controls the overall exposure of vancomycin for the given bioavailability achieved from a dwell. Dialytic clearance is defined as the volume of plasma that has been cleared of vancomycin (i.e. removed from systemic circulation into the peritoneal space) by PD per unit time. Figure 1 describes the various clearance processes involved in vancomycin elimination following an intraperitoneal dose. Moreover, a summary of vancomycin pharmacokinetic systemic parameters is provided in Table 2. Vancomycin clearance in patients on PD differs among studies due to several factors including the presence or absence of peritonitis, presence and extent of RKF, dwell times, dialysate volume, effect of antibiotic-free PD exchanges, and age.³⁰

Table 2.

Vancomycin distribution and clearance parameters in adult and pediatric noninfected and PD-related peritonitis patients on CAPD or APD.

					Clearance (mL/min)
Modality	Infection status	Route	Vd (L/kg)	Plasma half-life (h)	Totale	Dialyticf	Renalh	Reference
Adults
CAPD	Negative	IP	0.56	111	5	1.2	N/A	17
		IV	0.73	92	6.4	1.4	0.65	26
	PD—peritonitis	IP	0.61	N/A	N/A	15.7	N/A	22
		IP	0.87	N/A	8.5	12.2	N/A	23
		IV	0.55	104	4.1	3.8g	N/A	27
		IV	1.1	115	7.2	1.4	N/A	28
APD	Negative	IV	0.4	11.6b/62.8c	7.4	2.1	1.7	14
HVPD	Multiplea	IV	0.7	71.2d	N/A	8.1g	N/A	29
Pediatric
CAPD	Negative	IP	0.48	25	10.7	2.5	1.4	19
APD					14.9	3.1

A_d(t₁ to t₂): total amount of drug collected in the dialysate between the sampling interval; APD: automated peritoneal dialysis; AUC: area under the plasma concentration–time curve; AUC(t₁ to t₂): area under the plasma concentration–time curve between the sampling interval; C_d: drug concentration in dialysis fluid at the end of the exchange; CAPD: continuous ambulatory peritoneal dialysis; CL_D: dialytic clearance; C_p: plasma drug concentration at the midpoint of the dialysate collection; HVPD: high-volume peritoneal dialysis; N/A: not reported; t: duration of the exchange; V_D: volume of dialysis fluid at the end of the exchange; V_d: volume of distribution; PD: peritoneal dialysis; IP: intraperitoneal; IV: intravenous.

^aPatients in the study had varying systemic infections.

^bHalf-life determined after 8 h of sampling during the APD portion of the study.

^cHalf-life determined after 16 h of sampling during the ambulatory CAPD portion of the study.

^dHalf-life determined after 24 h of sampling.

^eTotal plasma clearance was calculated using the equation CL_total = Dose/AUC.

^fUnless noted, calculations used the time-average method to calculate dialytic clearance using CL_D = A_d(t₁ to t₂)/AUC(t₁ to t₂).

^gTime-specific method was used to calculate dialytic clearance using CL_D = C_d × V_D/C_p × t.

^hUrinary clearance was calculated using the equation CL_R = A_u/AUC(t₁ to t₂).

Continuous ambulatory peritoneal dialysis

CAPD typically employs dwell times between 4 h and 6 h, which may not be sufficient to reach equilibration between the dialysate and the plasma. Studies in noninfected adult CAPD patients report dialytic clearances ranging between 1.2 mL/min and 2.4 mL/min, which account for 20–25% of the total plasma clearance.^17,26,31 In patients with peritonitis, vancomycin dialytic clearance increases to 3.8 mL/min following a less than 5-h exchange.27 Clearances of up to 8.5 mL/min after the first 4 h of exchange have also been reported.18 Vancomycin clearance through elimination from the drained peritoneal dialysate contributes to 20– 70% of the total plasma clearance.^18,27 As a consequence, vancomycin elimination half-life in the systemic circulation ranges between 66 h and 115 h in patients on CAPD.^20,26-28 One major reason in the reported variability in the plasma half-life could be the difference in the sampling times which may not completely capture the decline of the plasma concentrations during the terminal elimination phase. Table 2 also includes a summary of above para- meters in these patients.

Automated peritoneal dialysis

Studies conducted in the APD population are only reserved to the parenteral administration of antibiotics in patients without peritonitis, yet vancomycin is primarily used to treat peritonitis and is mostly administered intraperitoneally.^32,33 With rapid cycling (i.e. multiple short dwell times), the dialytic clearance of vancomycin may be increased. Therefore, if doses and dwell times used for those on the cycler are similar to those in CAPD, the result may be subtherapeutic levels due to frequent exchanges.

To date, there has only been two studies exploring intravenous vancomycin disposition in subjects on rapid- cycling modalities.^14,29 In a pharmacokinetic study con- ducted in noninfected patients on APD, participants received a 15-mg/kg intravenous administration of vanco- mycin, followed by three cycle treatments over the course of 8 h.¹⁴ Two 8-h off-cycler dwells were given after the on- cycle treatments for a total of 24 h for the study. A 2-L 2.5% dextrose dialysate prescription was used during and off-cycler dwell. The plasma half-life was 11.6 h following an on-cycler exchange consisting of three 2 h dwells. When the same patients were removed from the cycler and allowed to dwell for 7–8 h, the plasma half-life increased to 62.8 h. Although vancomycin was not dosed intraperitoneally in this study, rapid decline in the plasma half-life supports the contribution of APD in the removal of drug. Clearance values did not largely differ from those on CAPD. Approximately 30% of vancomycin was removed by APD relative to the total plasma clearance, which is close to the proportion reported in patients on CAPD. For patients receiving high-volume peritoneal dialysis (HVPD), the pharmacokinetic parameters did not largely differ from those on APD.²⁹ Patients received continuous rapid cycling during HVPD with an average of 35 L over the course of 24 h. Following an average intravenous dose of 18 mg/kg, serial blood sampling was obtained for up to 24 h to estimate the pharmacokinetic parameters. A large portion of the patients were treated for systemic infections with a majority being anuric. Despite differences in the dialytic clearance estimated during rapid cycling with multiple high-volume exchanges, the plasma half-life of vancomycin did not largely differ compared to previous reports in APD and CAPD.

It is important to note the sampling strategies of the previous investigators when estimating the plasma half-life of vancomycin in patients on rapid-cycling modalities. Both studies obtained blood samples for up to 24 h following intravenous drug administration. As vancomycin continues to decline with time following the first 24 h, it is difficult to estimate the true plasma elimination half-life as a significant portion of the elimination profile has not been captured.

Although intraperitoneal vancomycin administration is recommended by guidelines in patients with PD peritonitis, both intravenous administration studies provide a valuable insight toward drug clearance during APD.³⁴ It should be noted that intravenous administration of vancomycin may not be adequate to achieve effective antibacterial concentrations in the peritoneum.

The current International Society for Peritoneal Dialysis (ISPD) guideline recommends supplemental dosing in order to achieve plasma vancomycin troughs above 15 mg/L when administered intermittently. Alternatively, temporarily switching to CAPD is another option for APD patients who develop peritonitis but is not always feasible. In patients on APD, leveraging the long dwell to appreciate optimal vancomycin transfer is appropriate to ensure adequate time to achieve and sustain therapeutic levels.

Impact of RKF and treatment outcome RKF in PD patients will have a profound effect for hydrophilic drugs removed exclusively through renal filtration. Enhanced drug clearance from RKF may have implications to treatment outcomes in patients with PD-related peritonitis. Therefore, patients with greater RKF may require higher or more frequent antibiotic dosing.

The importance of RKF on the outcome of PD-related peritonitis in patients treated with antibiotics has been dis- cussed for more than 10 years, but the data describing this relationship are still scarce and controversial. The ISPD 2010 update on PD-related infections has previously recommended a 25% increase in antibiotic dose in patients with a daily urine output of over 100 mL.³⁶ This recommendation has been removed in the updated 2016 guide- line, which reflects the lack of evidence to support this empiric recommendation.³⁴ In a retrospective study examining the impact of RKF on vancomycin concentrations, the influence of RKF was found to not have a significant impact.³⁷ Vancomycin concentrations appeared lower in patients who were non-anuric across both modalities even though a 25% higher dose was administered to those with RKF. This, however, was concluded to not be statistically significant. Similar results have been published showing no difference in treatment outcomes in non-anuric and anuric patients treated with cefazolin and gentamicin.³⁸

In contrast, a recent study investigating the relationship between RKF- and PD-related peritonitis treatment out- comes was able to explain treatment failures related to the remaining degree of renal function.³⁹ Treatment failure in those with gram-positive and culture-negative peritonitis were found to be significantly higher for patients with a urinary creatinine clearance greater than 0–5 mL/min com- pared to those who were anuric. Significantly higher relapse and recurrence were observed in those patients with gram- positive or culture-negative infections and creatinine clearances greater than 5 mL/min. Cefazolin and vancomycin were the main antibiotics used in the study. These observations may be useful when attempting to understand the impact of RKF on treatment outcomes and raise the ques- tion as to whether patients with RKF greater than 5 mL/min were under-dosed with antibiotic in previous studies.

In patients treated with vancomycin, RKF may account for 10–23% of the total body clearance in PD.^14,26 Studies examining the impact of RKF on vancomycin clearance, exposure, and treatment outcomes in PD-related peritonitis are limited. Interestingly, for the subset of patients with a glomerular filtration rate greater than 5 mL/min, RKF accounted for 39–84% of the total vancomycin clearance.¹⁴ It would appear that the impact from RKF has a substantial effect on the total clearance of vancomycin. Thus, the recent 2016 ISPD recommendation of removing the 25% dosage increase to account for RKF is unclear as most of the studies cited accounted for a dosage increase for those who were non-anuric.^37,40 In the absence of additional studies, dosage adjustments to account for RKF may still be appropriate as there is a substantial contribution observed on the total vancomycin clearance. For now, we can only speculate that the resulting impact in treatment failure for gram-positive peritonitis may be associated with higher drug clearance values in patients with creatinine clearances greater than 5 mL/min.

TDM and pharmacodynamic response

Vancomycin TDM is critical for patients with peritonitis and is routinely performed because (1) the concentration plays the key component for the effect and (2) the initial antibiotic dose is needed to target the maximum effect in order to allow proper eradication and prevention of resistance. Moreover, the treatment window time frame is crucial for patients. Hence, appropriate plasma sampling during this time frame is important, but may be difficult as the turnaround time for assay results is a rate-limiting factor in achieving desired therapeutic drug levels. Further- more, not only is it important to ensure that the initial dose is sufficient, but also if that initial dose is able to maintain therapeutic effect throughout treatment. Indeed, plasma trough monitoring is important to guide vancomycin dosing. Blood sampled during or immediately following an exchange will not be reflective of the true vancomycin concentration due to the acute decline in plasma during or after a PD exchange. This decline will eventually equilibrate, as the drug will redistribute from the tissues back into plasma. In the case for APD, blood sampling should occur following the series of exchanges and short dwells.

The traditional role of plasma trough concentration monitoring has been conflicting in the PD population. Unlike the established optimal plasma trough levels of 10–15 mg/L for uncomplicated infections or 15–20 mg/L for complicated infections, there is substantial interpatient variability for those patients on PD. Higher rates of PD-related peritonitis relapse have been associated with a cumulative 4-week plasma trough below 12 mg/L when compared to those maintained above that threshold.⁴¹ In this study, vancomycin was given intravenously where plasma levels were maintained above 12 mg/L rather than the current 15 mg/L recommendation by the ISPD the type of modality did not differ among the outcome groups; however, vancomycin clearance and RKF information were not reported which may have contributed to variabil- ity in the plasma concentration. On the other hand, data from a single-center study involving 34 PD patients experi- encing PD-related peritonitis showed no relationship between plasma vancomycin levels measured during the first week and PD-related peritonitis outcomes.⁴² Here, CAPD was reportedly the most frequent modality (80%) used with an average residual creatinine clearance of 2.8 mL/min/1.73 m2. Vancomycin was dosed based on ISPD recommendations and plasma levels were maintained above 15 mg/L. Of these 34 PD patients with confirmed gram-positive infections, 43% of cases were associated with coagulase-negative Staphylococcus ssp., while only 11% of cases were due to MRSA. Although the frequency and level of vancomycin measurement were not associated with adverse clinical events during the first week of treatment, the number of patients studied may be too small to draw a firm conclusion. Furthermore, studies conducted only correlate clinical outcomes to plasma vancomycin levels without attention to drug concentration in the dialy- sate. Limited data suggest that the vancomycin dialysate:- plasma ratio can vary from 1:3 to 1:5.^37,43,44 Should plasma concentration levels be maintained greater than 15 mg/L, the concentration in the dialysate would range from 3 mg/L to 5 mg/L, which may theoretically be adequate in peritonitis. Further investigation correlating dialysate concentrations and clinical outcomes would be warranted to explore the possibility of vancomycin monitoring in the dialysate rather than in plasma.

Pharmacokinetic sources of variability can be explained in part due to varying exchanges provided by the patient’s PD modality, impact from RKF, and peritoneum physiology affecting drug absorption. In addition, the pharmacodynamics—or bacterial susceptibility measured by its MIC—contributes to the variability in clinical response, which may not be explained due to vancomycin pharmacokinetics alone. Taken together, vancomycin shows substantial interindividual variability in clinical response for patients treated for PD-related peritonitis. Table 3 gives an overview of the pharmacokinetic/pharmacodynamic factors to be considered at the time of TDM of vancomycin in patients on both CAPD and APD regimens.

Table 3.

Pharmacokinetic/pharmacodynamic factors for TDM consideration between CAPD and APD vancomycin regimens.

Pharmacokinetic/pharmacodynamics	PD components	CAPD	APD
Absorption	Dwell time	↓ Bioavailability	↑ Bioavailabilitya
	Dosing route (IP vs. IV)	Same—no absorption occurs following IV administration
Distribution	Permeability (peritonitis vs. non-peritonitis)	Same
	Diffusion
	Protein binding
	Surface area
	Vascularity
Elimination	Dosing route (IP vs. IV)	RKF—Drives variation in systemic circulation
	Body size and dialysate volume	Same—Patient dependent
	Dwell time	↑ Clearance	↓ Clearance
	Number of non-antibiotic exchanges	↓ Clearance	↑ Clearance
Pharmacodynamics	MIC/AUC	Same—susceptibility report

APD: automated peritoneal dialysis; AUC: area under the vancomycin plasma–concentration time curve; CAPD: continuous ambulatory peritoneal dialysis; IP: intraperitoneal; IV; intravenous; MIC: minimal inhibitor concentration; PD: peritoneal dialysis; RKF: residual kidney function.

^aThe bioavailability will increase as a result of drug administered IP during the long-dwell period in APD.

Considerations for intraperitoneal dosing

Maintenance intraperitoneal doses of vancomycin have been proposed as an alternative dosing strategy in order to reduce high systemic exposures while keeping drug concentrations local at the site of infection.^14,45 However, there are no data that correlate the effectiveness of this strategy, feasibility in patient administration of pre-prepared drug— dialysate fluid, clinical laboratory validation of vancomycin detection in dialysate fluid, and the stability of the drug in the dialysate in fluctuating conditions. Clinicians should consider dwell times that achieve sub- stantial equilibrium between the peritoneum compartment and the systemic circulation. The reported bioavailabilities in the literature are dwell time specific and may not be appli- cable in all patient-specific situations. Therefore, considering the transfer half-life between the dialytic compartment and the systemic circulation can be useful to understand the time that it takes to reach equilibrium (i.e. steady state). This may take up to 15 h considering a transfer half-life of 3 h.²² In this situation, dosing during the long-dwell interval may provide adequate drug absorption to achieve therapeutic concentrations in plasma in patients on APD.

The bioavailability of vancomycin significantly increases during PD-related peritonitis. Plasma concentrations as high as 40 mg/L have been reported following a 6-h dwell using recommended intraperitoneal doses of vancomycin in PD-related peritonitis.^16,18 Alternatively, plasma concentrations as low as 10 mg/L have been reported following a 6-h dwell using a 500-mg intraperitoneal dose in PD-related peritonitis.²¹ Regardless of the PD modality, the time to absorption does not largely change between CAPD and APD based on the equilibration half-lives reported.^14,22,25

In patients with PD peritonitis on APD, doses of 15–20 mg/kg for up to 2 g of vancomycin using actual body weight, administered in a dwell of 10–15 h, are a common approach. With higher doses and extended dwell times, peak concentrations of the drug may reach values associated with adverse effects such as ototoxicity (where the concentration exceeds 40 mg/L) or potentially a negative effect on residual renal function if present. However, these adverse effects are often attributable to concomitant nephrotoxic and ototoxic medications used in the course of clinical care.^3,23 TDM should be performed to evaluate therapeutic and toxic concentration fluctuations and to maintain concentrations above 15 mg/L as recommended by the ISPD guidelines; however, its utility in PD requires further investigation.

Future research and dosing guidelines in APD

Empiric gram-positive management using vancomycin for PD-related peritonitis in patients on APD is summarized in Figure 2. This algorithm accounts for RKF and suggests a dosage increase of 20% for those who are non-anuric with a creatinine clearance greater than 5 mL/min based on observational outcome studies.³⁹ In addition, monitoring plasma vancomycin concentrations 48 h post-dose would be appropriate based on previous experience. As such, re-dosing would be necessary to maintain the targeted 15 mg/L concentration. During this time, adjustments to antibiotic therapy should be guided by the microbiology or susceptibility report. This should be practiced together with routine TDM at appropriate sampling times to rationally select the effective dose for each patient. Pharmacometric modeling and simulation could help to increase the knowledge on vancomycin dose expo- sure response relationship and propose optimal dosing and TDM strategies in PD patients.

Figure 2. Proposed vancomycin dosing and monitoring algorithm in patients on APD.

Vancomycin dosing in patients on APD with peritonitis should follow the recommended 15–20 mg/kg dose administered intraper- itoneally. For those who are non-anuric with creatinine clearances >5 mL/min, a 20% increase in the calculated dose is suggested. A vancomycin level should be obtained 48 h post-dose. Dosage adjustments and monitoring should be based on clinical response and microbiological susceptibility reports. APD: automated peritoneal dialysis.

As above recommendations are based on limited evidence, dedicated studies are needed to support them. Table 4 highlights the knowledge gaps and proposes future research topics to better tailor vancomycin treatments in PD patients with peritonitis.

Table 4.

Proposal for critical research areas to optimize vancomycin therapy in PD.

Effect of APD on peritoneal and plasma levels during rapid cycles Peak concentration following absorption from the long dwell Optimal trough concentrations associated with improved clinical outcomes and the timing of trough monitoring specific for the PD population Dosing regimen to achieve optimal trough concentrations Effect of RKF on vancomycin disposition and its implications on dosing Factors affecting non-renal and non-dialytic clearance of vancomycin Determining appropriate clinical plasma sampling time points Validation studies for the proposed vancomycin dosing and monitoring algorithm in APD Future studies correlating clinical outcome with dialysate vancomycin level

APD: automated peritoneal dialysis; PD: peritoneal dialysis; RKF: residual kidney function.

Conclusion

Optimal dosing for vancomycin should consider both the pharmacokinetics (concentration in dialysis fluid and plasma), RKF, PD modality, and physicochemical factors (bioavailability, permeability) and pharmacodynamics (MIC and variability to the susceptibilities of the organ- ism). Generally, vancomycin is given intraperitoneally during the long-day dwell for patients on APD; this approach supports adequate equilibration during the absorption phase between the dialysate and the plasma to reach therapeutic levels. In addition, the impact of rapid cycling and RKF on the total body clearance has yet to be fully defined. With this in mind, TDM may be appropriate; however, there is yet to be an established protocol in PD patients with peritonitis. As the option to temporarily switch to CAPD in APD patients who develop peritonitis may not be convenient, the need for future research on the impact of the cycler on vancomycin clearance is imperative. Upcoming studies (NCT03685747) examining the pharmacokinetic of vancomycin will address some of the knowledge gaps associated with vancomycin pharmacokinetic in patients on APD. For the moment, clinicians should consider the bioavailability, dwell time, and institutional microbiological susceptibilities when dosing vancomycin in PD. Dedicated pharmacokinetic studies in adult and pediatric patients are needed to understand vancomycin disposition in PD patients on rapid-cycling modalities. The integrated use of TDM and MICs via dosing algorithms may help improve clinical outcome.