What are the principles involved in determining the loading dose and dosing frequency of antimicrobials in patients undergoing continuous veno-venous haemodiafiltration (CVVHDF)? 

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College answer

Initial doses of drugs depend on the volume of distribution of the drug. For most antibiotics this is either unchanged or increased in critically ill patients with renal failure, so the initial dose should be a standard dose or higher. 
 
Subsequent dosing depends on clearance and PK-PD relationships. 
 
Clearance will depend on hepatic function (for those drugs that are hepatically metabolized) and residual renal function and clearance by CVVHDF (renally excreted drugs). 
 
Clearance by CVVHDF depends on ultrafiltration rate + dialysis flow rate (=effluent rate) and saturation coefficient. 
 
Saturation coefficient/sieving is predominantly dependent on protein binding and to a lesser extent on membrane material. 
 
Residual renal function can be estimated from measured creatinine clearance, but this will overestimate the clearance of drugs that undergo significant tubular reabsorption (e.g. fluconazole, colistin). 
 
The clearance determines the appropriate infusion rate (or dose and frequency) for time dependent antibiotics, dosing interval for concentration dependent antibiotics. 
 
Information on dosing frequency can be obtained from therapeutic drug monitoring during therapy Give no marks for molecular size (antibiotics are relatively small molecules) or discussions related to choosing antibiotics. 
 

Discussion

In summary,  these are the  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.

In detail:

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.