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.

Specifics of Antibiotic Dose Adjustment in CRRT

Drugs with a large volume of distribution, which do not rely on renal clearance

  • Ceftriaxone
  • Moxifloxacin
  • Clindamycin
  • Linezolid
  • Quinupristin
    /dalfopristin
  • Voriconazole
  • Clavulanate

Theoretically, these drugs should not need any changes to their dosing.

The amount of free drug dissolved in body water is normally so laughably small that renal (or renal-like) mechanisms can never play an important role in their clearance.

Drugs with a large volume of distribution, which do rely on renal clearance

  • Levofloxacin
  • Ciprofloxacin
  • Colistin
  • Amphotericin (liposomal)

These drugs should be given with an increased dosing interval.

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.

For some reason, Pea and Furlanut give only levofloxacin as an example of a drug affected in this way. Levofloxacin is excreted partially by tubular secretion, which may explain this sort of pharmacokinetics. Ciprofloxacin could probably also be included in this category, but its elimination is variably reliant on non-renal elimination routes (eg. faecal and biliary). The function of these elimination pathways is going to be wildly erratic in the critically ill population, so its uncertain how any given dose of ciprofloxacin is going to behave during CRRT.

Lastly, colistin seems to be a renally cleared drug with a massive volume of distribution, and its clearance by CRRT is poor in comparison to renal clearance. However, the issue is complicated by the fact that it avidly adsorbs onto the haemofilter membrane.

Drugs with a small volume of distribution, which do not rely on renal clearance

  • Ceftriaxone
  • Moxifloxacin
  • Clindamycin
  • Linezolid
  • Quinupristin
    /dalfopristin

This is a largely theoretical category.

Theoretically, these drugs would not need any adjustment to their dosing in CRRT, in comparison to a renally "normal" individual. Their small volume of distribution makes them easily available for renal (or dialytic) clearance, but the normal mechanisms they rely on for clearance remain unimpaired in renal failure.

Practically speaking, most drugs which have a small volume of distribution are also easily cleared renally, in part because they end up being filtered freely by the glomerulus, and not reabsorbed. Thus, this category really only applies to those drugs like adenosine, which are degraded rapidly by plasma enzymes, never even making it to the glomerulus. A discussion of their CRRT excretion is therefore completely meaningless.

Drugs with a small volume of distribution, which do rely on renal clearance

  • β-lactams
  • Carbapenems
  • Aminoglycosides
  • Most cephalosporins
  • Glycopeptides
  • Fluconazole

Theoretically, these drugs should not need any changes to their dosing.

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.

In fact, for some of these 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.