Antibiotic dosing in renal failure

This has come up in Question 15.2 from the second paper of 2013. Question 13 from the first paper of 2010 also mentions it on a tangent. 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 with renal impairment, rather than those who are subjected to regular or continuous dialysis (that is a topic for another chapter).

In brief:

Principles governing the adjustment of antibiotic dose in renal failure

The main issue to keep mindful of is the reliance of the drug on renal excretion. The greatest disadvantage here is not to antimicrobial efficacy, but to the patient - accumulation will result in toxicity.

A peripheral issue is the killing characteristic of that drug; in renal failure the concentration-dependent killers are largely unaffected, whereas the time-dependent killers enjoy a prolonged period of time at a satisfactory concentration over MIC.

Why would you interval-adjust the antibiotic?

• This is most relevant to concentration-dependent killers which have significant toxicity associated with high concentration troughs.
• The classical examples are aminoglycosides and glycopeptides.
• There is a specific effective concentration you must achieve, which is 8-10 times the MIC.
• Irrespective of whether or not the kidneys work, that concentration will be achieved by the usual mg/kg dose calculation.

• The patient, with their impaired renal excretion mechanisms, will have a prolonged time over MIC, but this will not matter because the killing power is dependent on peak concentration only.
• Frequent dosing will therefore only result in increased toxicity, and not in any improved efficacy.

Why would you dose-adjust the antibiotic?

• This is most relevant to time-dependent killers which have significant toxicity associated with high concentration peaks.
• Fluoroquinolones are the classical example.
• The most important objective is to remain above the MIC for the longest possible time.
• With impaired renal clearance mechanisms, the drug virtually does this all by itself.
• All you need to do is give a loading dose, and then ensure that small regular doses are given to maintain the concentration above MIC. This way, the concentration remains adequate, but small regular doses ensure that high peak levels are not achieved (and the QT interval stays normal)

Why does it not matter for some antibiotics?

• This applies to time-dependent killers which are not especially toxic.
• Strictly speaking, β-lactams and carbapenems fall into the category of dose adjusted drugs, but realistically one can adjust either the dose OR the interval, because the risk of toxicity is rather low, and the patients tend to tolerate high peaks of concentration.
• Practically speaking, β-lactams are usually interval-adjusted. This is actually a case of historical inertia. Back in the day, a bottle of Timentin cost a few hundred dollars, and rather than draw up a carefully dose-adjusted amount (and throw the rest in the garbage) the penny-pinching intensivists would try to maximise the bacterial-death-toll-per-dollar-spent by interval adjusting it instead.

A list of toxic antibiotics which rely significantly on renal excretion:

• β-lactams, cephalosporins, carbapenems: apart from notable exceptions (eg. ceftriaxone dicloxacillin and flucloxacillin), they are all reliant on renal clearance.
• Aminoglycosides: gentamicin and amikacin are both filtered freely by the glomerulus, and not reabsorbed.
• Fluconazole; unlike all the other "azoles".
• Aciclovir, gancyclovir
• Vancomycin which is itself reasonably nephrotoxic (Ray et al, 2016)

A list of antibiotics which do NOT require any dose adjustment in renal failure:

• Linezolid: it is cleared by both renal and nonrenal mechanisms.
• Clindamycin: its clearance is predominantly hepatic
• Amphotericin (liposomal or otherwise): it damages the kidney, but does not rely on it for excretion. No dose adjustment is necessary.
• Clavulanate: notably, the amoxycillin in Augmentin is cleared renally, but the clavulanate is not.
• Azithromycin: it distributes so widely, that renal clearance plays virtually no role in its halflife; the drug disappears from the bloodstream because it is soaked up by the tissues.
• Ceftriaxone: some of it is cleared renally, but biliary excretion can accomodate a decrease in glomerular filtration.
• Voriconazole (but it does sometimes come with a cyclodextrin vehicle which can accumulate in renal failure, causing "hallucinations secondaires au voriconazole")

Other notables:

• Moxifloxacin
• Rifampicin
• Anidulofungin
• Doxycycline and tigecycline

For a historical footnote, Linton and Lawson from the Western Infirmary of Glasgow published an editorial about this back in 1970.