Introduction
Patients with end-stage renal disease (ESRD) who require intermittent hemodialysis (IHD) are more susceptible to infection, which is the major cause of death in this population. In patients with ESRD who require IHD, the use of additional vascular access devices such as peripherally inserted central catheters to treat such infections should be minimised in order to avoid complications such as infection and thrombosis, as well as to maintain venous patency for hemodialysis access.
Because of their low cost, easy administration, and lengthy clinical usage, vancomycin, cefazolin, and aminoglycosides have traditionally been considered the principal intravenous antimicrobials used with IHD. Despite this, a growing body of work is exploring the use of a broader range of antimicrobials for patients requiring IHD via post-dialysis administration; nevertheless, the existing evidence is mostly restricted to pharmacokinetic studies of infected or uninfected patients.
The aim of this review is to describe and evaluate the available literature on the post-dialytic administration of parenteral antimicrobials in patients with ESRD requiring IHD.
Methods of Literature Review
Publications were assessed for relevancy prior to inclusion, with emphasis on those evaluating high-flux IHD. Studies utilizing low-flux IHD were only included in select clinical contexts lacking data on high-flux IHD. Studies assessing antimicrobial dosing in the settings of continuous renal replacement therapy (CRRT), peritoneal dialysis, home dialysis, and extended IHD were excluded. Antimicrobials included in this review were limited exclusively to those currently commercially available and with supporting literature evaluating thrice-weekly intra-dialytic or post-dialytic dosing with IHD.
Results
Vancomycin
Vancomycin is a glycopeptide antibiotic with a spectrum of activity limited to Gram-positive bacteria, including MRSA, that has been in clinical use since the late 1950s. Vancomycin is primarily cleared renally, with renal clearance accounting for ~ 70% of total clearance in patients with normal renal function and as high as 95% of total clearance in patients with ESRD. Owing to its high degree of renal clearance, low cost, clinical longevity, feasibility of therapeutic drug monitoring (TDM), and the increased incidence of MRSA infections among patients with ESRD requiring IHD, there is a wide breadth of experience with administering vancomycin with or following IHD. Vancomycin dosing in the setting of high-flux IHD is well described. Therefore, it is recommended to monitor serum vancomycin levels prior to IHD.
Telavancin
Telavancin’s enhanced potency against S. aureus relative to vancomycin has supported its role as an alternative agent for difficult-to-treat Gram-positive infections, which constitute a significant burden for many patients with ESRD receiving IHD. However, in recent years several studies have sought to describe potential dosing strategies for this patient population and provide preliminary support for the use of telavancin in thrice-weekly post-IHD dosing.
A study of 44 uninfected adults was performed to determine PK parameters of telavancin in the setting of varying degrees of renal dysfunction. Subjects were divided into three groups, consisting of normal renal function (creatinine clearance [CrCl] > 80 mL/min, n = 15), severe renal impairment (CrCl < 30 mL/min, n = 15), and ESRD on IHD (n = 14). A separate compilation of two phase I PK studies evaluated medically stable adults with varying degrees of renal function, from normal (CrCl > 80 mL/min) to ESRD (requiring IHD).
Based on the exposure profile of telavancin in ESRD, the available PK data appear to support the feasibility of thrice-weekly post-IHD telavancin dosing. However, clinical data are extremely limited and dialyzer types were either low-flux or unreported .The optimal dosing of telavancin following high-flux IHD remains unknown and the safety profile of telavancin dosing with IHD is poorly characterized. In addition, it must be noted that patients with pre-existing moderate–severe renal dysfunction experienced lower rates of treatment success in a subgroup analysis of phase III trials evaluating telavancin for cSSSI, and also experienced increased mortality in phase III trials evaluating telavancin for HABP/VABP. Nonetheless, a careful risk/benefit assessment should be conducted prior to considering telavancin in this setting.
Daptomycin
Daptomycin is a cyclic lipopeptide antibiotic with broad spectrum of activity against Gram-positive bacteria, including MRSA and vancomycin-resistant enterococci (VRE). The FDA-approved dosing strategy is 4 or 6 mg/kg every 48 h, regardless of the dialysis schedule. The proportion of daptomycin removed by high-flux HD (HFHD) was found to be 39%. The mean total drug steady-state Cmin at 72 h, drawn prior to IHD, was 15.3 µg/mL. A Monte Carlo analysis sought to determine an optimal post-dialysis dosing scheme.
Daptomycin PK following IHD were further elucidated in a separate 5000-subject Monte Carlo PK/PD analysis. Authors suggest considering more frequent CPK monitoring in this patient population. This strategy is expected to achieve adequate antibiotic exposure throughout the dosing interval while maintaining a very low probability of trough concentrations exceeding the suggested threshold. Multiple PK studies have proposed daptomycin dosing strategies following IHD. Antibiotics may be administered during the last hour of a dialysis session in the community. Intradialytic dosing has been described, but is less preferable to post-IHD dosing.
Cefazolin
Cefazolin is used to treat many infections associated with Gram-positive organisms, including methicillin-susceptible Staphylococcus aureus (MSSA) and some highly susceptible Enterobacterales. It is widely distributed into most body tissues with high protein binding (80%) and up to 80% is cleared unchanged through the kidneys. Cefazolin 1 g (~ 15 mg/kg) post-dialysis is well-tolerated and effective against susceptible isolates in anuric patients with chronic ESRD requiring IHD. No toxic effects of cefrazolin were observed among study patients. A study by Marx et al. evaluated the PK of cefazolin in patients undergoing IHD with high-efficiency HD (HEHD, n = 15) or HFHD (n = 10) with a focus on dialytic clearance.
Patients in both groups achieved predialysis total serum concentrations of 3- to 18-fold the MIC for susceptible organisms. The authors suggest thrice-weekly 20 mg/kg dosing of cefazolin is adequate for patients undergoing chronic IHD. No adverse reactions were reported with this dosing strategy. The study was conducted over 84 months in patients infected with MSSA bacteremia and undergoing chronic high-flux hemodialysis.
Ceftazidime
Ceftazidime is an inexpensive and oft-utilized third-generation cephalosporin with potent bactericidal activity against a wide range of Gram-negative pathogens. It displays protein binding of approximately 20% and a Vd of 0.23 L/kg. Using low-flux filters, a 6- to 8-h IHD session removed approximately 88% from the plasma in one study. Ceftazidime elimination half-life of 0.5–2 g every 36–48 h, adjusted by indication, would constitute appropriate dosing in patients with creatinine clearance < 15 mL/min.
Based on the delineated dose adjustment factors, ceftazide could be downtitrated to 0.4 g daily for patients with ESRD who would normally receive a daily dose of 6 g. Recommendations for the administration of ceftazidime following IHD are scarce. Recently, a case of P. aeruginosa infective endocarditis with previous treatment failure in an anuric patient with ESRD requiring high-flux IHD was presented.
The authors noticed a dip in pre-IHD concentrations below 8 µg/mL at 70 h using a ceftazidime dosing strategy. This regimen, combined with oral ciprofloxacin, was used for a total of 6 weeks and was well-tolerated.
Cefepime
Cefepime is primarily eliminated by the kidney in unchanged form (85%) with a half-life of approximately 2 h. Multiple PK studies have evaluated cefepime PK/PD in patients with ESRD requiring IHD. The authors concluded that thrice-weekly dosing after each IHD achieved drug levels well above the MIC90 of 8 µg/mL for most target pathogens.
Cefepime-induced neurotoxicity using higher doses in the setting of ESRD has been previously reported. A study of patients with febrile neutropenia and mildly impaired renal function reported that the probability of neurological toxicity, manifested as altered mental status, or myoclonia, increased with trough plasma levels exceeding 22 µg/mL. Most recently, a PK study of nine patients undergoing high-flux thrice-weekly IHD evaluated cefepime dosing using TDM. Initial dose utilized was 15 mg/kg (ranging from 750–1500 mg) and subsequent doses were based on trough serum levels.
The authors concluded that a thrice-weekly 1g/1.5g cefepime dosing strategy may be well-tolerated in patients with highly-susceptible pathogens such as P. aeruginosa.
Ertapenem
Ertapenem is a long-acting, once daily parenteral carbapenem with a broad spectrum of activity against Gram-negative bacteria. It has a relatively low Vd (Vd at steady state = 0.12 L/kg in adults) and 80% is eliminated via the kidneys. The FDA-approved dosing strategy is 500 mg daily, compared with standard dosing of 1 g daily. The AUC∞ for ESRD patients was increased by 192% versus healthy controls. 30% of ertapenem was removed via a 4-h low-flux hemodialysis session.
Neurotoxicity may manifest in varying degrees, including seizures, hallucinations, and cognitive dysfunction. It is possible that the prolonged half-life and decreased renal clearance may result in drug accumulation. Alternate ertapenem dosing strategies in the setting of IHD have been suggested. A single dose of 1 g ertapenem was administered to seven non-infected patients undergoing high-flux hemodialysis.
Plasma concentrations at 48 h, two-thirds of the 72-h dosing interval, were maintained above the MIC for targeted pathogens.
Aminoglycosides
Aminoglycosides are bactericidal antibiotics that have been in clinical use since the 1940s. Their place in therapy is generally reserved to MDR aerobic Gram-negative bacilli and synergistic therapy for Gram-positive infectious endocarditis. There is wealth of clinical experience with dialysis-based dosing of aminoglycoside. Aminoglycoside PK characteristics were. elucidated in a prospective observational study of 167 patients treated with 216 total courses of aminoglycosides.
The mean serum peak concentration for gentamicin and tobramycin was 7.7 µg/mL and the mean serum pre-IHD concentration was 3. The PK parameters for gentamicin using high-flux dialyzers have been characterized. The optimal dosing strategy for the treatment of invasive, life-threatening infections caused by Gram-negative bacilli is unknown. Individualized post-dialytic dosing with TDM is strongly recommended.
Fluconazole
Fluconazole is an azole antifungal with activity against Cryptococcus spp. and several species of Candida. It exhibits great tissue penetration at all studied body sites, including the cerebrospinal fluid. Given its excellent bioavailability of > 90%, it should be administered enterally whenever clinically feasible. Fluconazole’s PK and safety profile support the appropriateness of intravenous dosing thrice-weekly following IHD in patients with ESRD. The full recommended dose for the indication (generally 400–800 mg for invasive infections) should be utilized and administered only after each IHD session.
Conclusion
Despite the availability of published strategies supporting post-IHD dosing of several parenteral antimicrobials, clear limitations to widespread clinical application exist with many of these agents. Therefore, post-dialytic dosing of intravenous antimicrobials may be considered on a patient-by-patient basis after careful consideration of all clinical, microbiological, and logistical factors that may influence the probability of treatment success.
References
1. Gupta V, Yassin MH. Infection and hemodialysis access: an updated review. Infect Disord Drug Targets. 2013;13(3):196–205.
2. Keller F, Borner K, Schwarz A, Offermann G, Lode H. Therapeutic aminoglycoside monitoring in renal failure patients. Ther Drug Monit. 1987;9(2):148–53.
3. Kato S, Chmielewski M, Honda H, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol. 2008;3(5):1526–33.
4. Zacharioudakis IM, Zervou FN, Ziakas PD, Mylonakis E. Meta-analysis of methicillin-resistant Staphylococcus aureus colonization and risk of infection in dialysis patients. J Am Soc Nephrol. 2014;25(9):2131–41.
5. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for 2006 updates: hemodialysis adequacy, peritoneal dialysis adequacy and vascular access. Am J Kidney Dis. 2006;48(Suppl 1):S1–322.
6. El Nekidy WS, Soong D, Kadri A, Tabbara O, Ibrahim A, Ghazi IM. Salvage of hemodialysis catheter in Staphylococcal bacteremia: case series, revisiting the literature, and the role of the pharmacist. Case Rep Nephrol Dial. 2018;8(2):121–9.
7. Thabit AK, Crandon JL, Nicolau DP. Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials. Expert Opin Pharmacother. 2015;16(2):159–77.
8. Gonsalves CF, Eschelman DJ, Sullivan KL, DuBois N, Bonn J. Incidence of central vein stenosis and occlusion following upper extremity PICC and port placement. Cardiovasc Intervent Radiol. 2003;26:123–7.
9. Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermient hemodialysis. Pharmacotherapy. 2009;29(5):562–77.
10. Launay-Vacher V, Izzedine H, Mercadal L, Deray G. Clinical review: use of vancomycin in haemodialysis patients. Crit Care. 2002;6:313–6. Pai AB, Pai MP. Vancomycin dosing in high flux hemodialysis: a limited-sampling algorithm. Am J Health Syst Pharm. 2004;61:1812–6.
11. Haroon S, Davenport A. Choosing a dialyzer: what clinicians need to know. Hemodial Int. 2018;22(S2):S65–74.
12. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2020;77(11):835–64.
13. Klansuwan N, Ratanajamit C, Kasiwong S, Wangsiripaisan A. Clearance of vancomycin during high-effciency hemodialysis. J Med Assoc Thai. 2006;89:986–91.
14. Ariano RE, Fine A, Sitar DS, Rexrode S, Zelenitsky SA. Adequacy of a vancomycin dosing regimen in patients receiving high-flux hemodialysis. Am J Kidney Dis. 2005;46:681–7.
15. Brown M, Polisetty R, Gracely EJ, Cuhaci B, Schlecht HP. Weight-based loading of vancomycin in patients on hemodialysis. Clin Infect Dis. 2011;53(2):164–6.
16. Ghouti-Terki L, Chasseuil E, Rabot N, et al. Vancomycin during the last hour of the hemodialysis session: a pharmacokinetic analysis. Nephron. 2017;135(4):261–7.
17. Nyman HA, Agarwal A, Senekjian HO, Leypoldt JK, Cheung AK. Removal of vancomycin administered during dialysis by a high-flux dialyzer. Hemodial Int. 2018;22(3):383–7.
18. Crew P, Heintz SJ, Heintz BH. Vancomycin dosing and monitoring for patients with end-stage renal disease receiving intermittent hemodialysis. Am J Health Syst Pharm. 2015;72(21):1856–64.
19. Zelenitsky SA, Ariano RE, McCrae ML, Vercaigne LM. Initial vancomycin dosing protocol to achieve therapeutic serum concentrations in patients undergoing hemodialysis. Clin Infect Dis. 2012;55:527–33.
