I Kidney Not: Antibiotic Dosing Strategies in Intermittent Hemodialysis

Outpatient intravenous (IV) antimicrobial therapy can prove challenging. For those with end-stage renal disease, administering IV antibiotics post-intermittent hemodialysis (post-IHD) improves convenience, reduces the risk of infectious and thrombotic complications, as well as healthcare costs associated with placement of an additional central venous access.¹ Generally, patients can receive the same dose post-IHD, although dosing may need to be increased with residual renal function, if antibiotics are infused during dialysis rather than after, or during longer intra-dialytic periods.

Cefazolin
A post-IHD regimen of 2g/2g/3g is commonly used based on a prospective study of patients with MSSA bacteremia comparing vancomycin and cefazolin. The authors concluded this regimen is well tolerated and effective.² A subsequent study found 3g thrice-weekly leads to excessive serum levels and increased toxicity risk.³ Pharmacokinetic studies have shown that the MSSA MIC of 8 µg/mL is exceeded 2-3-fold when dosed at 2g in thrice-weekly HD,^4,5 suggesting 2g/2g/2g is adequate for most infections. 2g/2g/3g may be considered for deep-seated infections to improve attainment of trough concentrations above the MIC.

Cefepime
One pharmacokinetic study concluded that 2g post-IHD achieved levels above the MIC90 of 8 µg/mL for most pathogens, including Pseudomonas aeurginosa.⁶ A recent study suggested that 1g/1g/1.5g post-IHD may be adequate. However, this regimen did not achieve levels above the MIC90 for P. aeruginosa, and these patients were anuric, suggesting higher doses may be needed in patients with residual renal function.

Ceftriaxone
A study of 1g/1g/1g post-IHD dosing suggested that supplemental doses were not necessary.⁷ Another study noted that this regimen may achieve concentrations below the MIC of common pathogens, particularly during the 3-day interdialytic interval, favoring 2g/2g/2g post-IHD instead.⁸

Daptomycin
In the package insert, recommended dosing for IHD is 4 or 6 mg/kg every 48 hours, which does not align with thrice-weekly IHD.⁹ Some studies suggest increasing the dose by 50% during the 72-hour interdialytic period.^10,11 However, this is based on a dose of 6 mg/kg (i.e., 6/6/9) and it is not clear if this is necessary with higher doses. A post-IHD dose of 10 mg/kg was more likely than 6 mg/kg q48h to achieve an adequate Cmax/MIC and AUC/MIC, and doses as high as 14.5 mg/kg post-IHD have been reported without a significant increase in adverse events.^12,13

Ertapenem
A pharmacokinetic study of 500mg post-IHD thrice-weekly found that it maintained concentrations above a theoretical MIC90 of 2 mcg/mL for the entire interdialytic period, although serum trough concentrations were significantly lower than with 500mg daily.¹⁴ Interestingly, two pilot studies of 1g post-IHD had trough concentrations lower than predicted by the pharmacokinetic study, but still maintained adequate time above the MIC with 80-87.5% clinical success rates.^15,16

Meropenem
A retrospective study found that post-IHD was comparable in clinical efficacy to daily dosing.¹⁷ However, there was much variation between the regimens employed (2g/2g/3g, 2g/2g/2g, 1g/1g/1g and 1g/1g/2g). Another study showed that 1-2g post-IHD may be effective in achieving concentrations at 4-5 times the MIC in severe infections.¹⁸

Table 1. Proposed post-dialytic antibiotic dosing regimens following intermittent, thrice weekly hemodialysis.

M. Gabriela Cabanilla, PharmD, PhC is an assistant professor at the University of New Mexico College of Pharmacy and an inpatient infectious diseases pharmacist clinician at the University of New Mexico Hospital in Albuquerque, NM. Cabanilla's clinical interests include immunocompromised infectious diseases and optimizing antimicrobial dosing in the critically ill, particularly in ECMO.

Brandon Dionne, PharmD, BCPS-AQ ID, BCIDP, AAHIVP is an associate clinical professor at Northeastern University School of Pharmacy and Pharmaceutical Sciences and an infectious diseases clinical pharmacist at Brigham and Women’s Hospital in Boston, MA. Dionne’s clinical interests include Bayesian modeling of antimicrobial pharmacokinetics/pharmacodynamics as well as implementation science as it relates to antimicrobial stewardship.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.

References:

1. Cimino C, Burnett Y, Vyas N, Norris AH. Post-Dialysis Parenteral Antimicrobial Therapy in Patients Receiving Intermittent High-Flux Hemodialysis. Drugs. 2021;81(5):555-574.
2. Stryjewski ME, Szczech LA, Benjamin DK Jr, et al. Use of vancomycin or first-generation cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis. 2007;44(2):190-6.
3. Renaud CJ, Lin X, Subramanian S, Fisher DA. High-dose cefazolin on consecutive hemodialysis in anuric patients with Staphylococcal bacteremia. Hemodial Int. 2011;15(1):63-8.
4. Fogel MA, Nussbaum PB, Feintzeig ID, et al. Cefazolin in chronic hemodialysis patients: A safe, effective alternative to vancomycin. Am J Kidney Dis. 1998;32:401-409.
5. Sowinski KM, Mueller BA, Grabe DW. Cefazolin dialytic clearance by high-efficiency and high-flux hemodialyzers. Am J Kidney Dis. 2001;37:766-776.
6. Descombes E, Martins F, Hemett OM, et al. Three-times-weekly, post-dialysis cefepime therapy in patients on maintenance hemodialysis: a retrospective study. BMC Pharmacol Toxicol. 2016;17:4.
7. Cohen D, Appel GB, Scully B, Neu HC. Pharmacokinetics of ceftriaxone in patients with renal failure and in those undergoing hemodialysis. Antimicrob Agents Chemother. 1983;24(4):529-532.
8. Simon N, Dussol B, Sampol E, et al. Population pharmacokinetics of ceftriaxone and pharmacodynamic considerations in haemodialysed patients. Clin Pharmacokinet. 2006;45(5):493-501.
9. Cubist Pharmaceuticals. Cubicin (daptomycin) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021572s038lbl.pdf. Revised August 2020. Accessed October 11, 2021.
10. Patel N, Cardone K, Grabe DW, et al. Use of pharmacokinetic and pharmacodynamic principles to determine optimal administration of daptomycin in patients receiving standardized thrice-weekly hemodialysis. Antimicrob Agents Chemother. 2011;55(4):1677-1683.
11. Butterfield JM, Mueller BA, Patel N, et al. Daptomycin pharmacokinetics and pharmacodynamics in a pooled sample of patients receiving thrice-weekly hemodialysis. Antimicrob Agents Chemother. 2013;57(2):864-872.
12. Diolez J, Venisse N, Belmouaz S, Bauwens MA, Bridoux F, Beraud G. Pilot pharmacokinetic study of high-dose daptomycin in hemodialysis patients with infected medical devices. Am J Kidney Dis. 2017;70(5):732-734.
13. Mueller BA, Crompton JA, Donovan BJ, Yankalev S, Lamp KC. Safety of daptomycin in patients receiving hemodialysis. Pharmacotherapy. 2011;31(7):665-672.
14. Ueng YF, Wang HJ, Wu SC, Ng YY. A practical thrice weekly ertapenem in hemodialysis patients. Antimicrob Agents Chemother. 2019;63(12):e01427-19.
15. Hsaiky LM, Salinitri FD, Wong J, et al. Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients. Nephrol Dial Transplant. 2019;34(10):1766-1772.
16. Geerlings CJ, de Man P, Rietveld AP, Touw DJ, Cohen Tervaert JW. A practical thrice weekly ertapenem dosage regime for chronic hemodialysis patients. Clin Nephrol. 2013;80(4):312.
17. Ho V, Tay F, Wu JE, Lum L, Tambyah P. The Case for Intermittent Carbapenem Dosing in Stable Haemodialysis Patients. Antibiotics (Basel). 2020;9(11):815.
18. Thalhammer F, Hörl WH. Pharmacokinetics of meropenem in patients with renal failure and patients receiving renal replacement therapy. Clin Pharmacokinet. 2000;39(4):271-9.