The college examiners love to ask questions about antibiotic dosing. These typically take the template shape of "how does [ICU problem] influence antibiotic dosing?", where [ICU problem] has historically been critical illness, renal failure and CVVHDF. The SAQ most relevant to this chapter is Question 4 from the second paper of 2018, which asked the trainees to discuss the "principles involved in determining the loading dose and dosing frequency of antimicrobials in patients undergoing continuous veno-venous haemodiafiltration (CVVHDF)"

An excellent resource exists, which has more information on this topic. One can also pay eighty quid to publishers of the Renal Drug Database. The information below relates more to patients requiring regular or continuous renal replacement therapy, rather than those who have merely have impaired renal clearance(that is a topic for another chapter).

The question of "how to adjust my antibiotic dose in CRRT" depends on one's reliance on renal clearance for that particular drug, and the volume of distribution. Broadly, the peculiarities of pharmacokinetics in dialysis are explored in the Required Reading section for the renal failure and dialysis SAQs. In general the question "how to adjust the dose of Drug X" is a question of how closely the CRRT circuit models the normal renal excretion mechanisms of Drug X. For the resource-poor exam candidate, I would recommend an excellent article by Trotman et al. while it is still available for free from the Russian distribution of the Gambro site.

General Principles of Antibiotic Dose Adjustment in CRRT

  • Antibiotics with time-dependent killing:
    • if the drug is rapidly cleared by CRRT, the dosing interval should be decreased (i.e. the doses need to be given more frequently)
  • Antibiotics with concentration-dependent killing:
    • if the drug is rapidly cleared by CRRT, the actual dose should be increased, and dosing interval should remain more or less the same.
  • If the RRT is intermittent (eg. SLED):
    • the antibiotics should be given after the end of each session.

Antibiotic Dosing Adjustment for CRRT
Drugs Explanations 
Drugs which require no dose adjustment during CRRT
  • Moxifloxacin
  • Voriconazole
  • Itraconazole
  • Clindamycin
  • Liposomal amphotericin
High volume of distribution: The amount of free drug dissolved in body water is normally so laughably small that clearance by CRRT can never play an important role in their clearance. Their dosing in patients on CRRT should be the same as their dosing for patients with anuric renal failure.
  • Ceftriaxone
  • Colistin
  • Vancomycin
Highly protein or lipid bound: these drugs are not very susceptible to removal by dialysis, again because the free water-soluble fraction available is so small. 
  • Linezolid
  • Ceftriaxone
Predominantly hepatic clearance:  these drugs do not usually rely on renal clearance mechanisms, and in the presence of renal failure and CRRT their clearance will not be
  • β-lactams
  • Carbapenems
  • Aminoglycosides
  • Most cephalosporins
  • Fluconazole
  • Aciclovir

Excellent clearance by CRRT: These drugs should be cleared easily by CRRT, because normally they are cleared by glomerular filtration (with a little help from tubular secretion). The glomerular filtration is a renal excretion mechanism which should be well modelled by the CRRT circuit.

Drugs which require an increased dosing interval during CRRT
  • Vancomycin
  • Levofloxacin
  • Daptomycin
  • Ciprofloxacin?
Actively transported drugs: The renal clearance of these drugs is usually reliant on some sort of exchange pump or active transport mechanism in the tubule. The CRRT filter is of course a dumb porous membrane without any sort of fancy pumps, and it will only filter the free fraction, of which there may not be much. Ciprofloxacin could probably also be included in this category, but its elimination is variably reliant on non-renal elimination routes (eg. faecal and biliary).
Drugs with require a dose increase during CRRT
  • Fluconazole

For some drugs the CRRT clearance is better than the normal renal clearance, and an increased dose/frequency may be required. Fluconazole is a classic example of a drug which requires an up-adjustment of daily dose if the CRRT dose exceeds 2L/hr.

References

McKenzie, Cathrine. "Antibiotic dosing in critical illness." Journal of antimicrobial chemotherapy 66.suppl 2 (2011): ii25-ii31.

Ulldemolins, Marta, et al. "Antibiotic dosing in multiple organ dysfunction syndrome." CHEST Journal 139.5 (2011): 1210-1220.

Chertow, Glenn M., et al. "Guided medication dosing for inpatients with renal insufficiency." Jama 286.22 (2001): 2839-2844.

Linton, A. L., and D. H. Lawson. "Antibiotic therapy in renal failure."Proceedings of the European Dialysis and Transplant Association. Vol. 1. 1970.

Trotman, Robin L., et al. "Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy." Clinical infectious diseases 41.8 (2005): 1159-1166.