Opening a can of interesting worms

Writing medical education materials as a full time job has been incredible. It makes you cross check everything, and discover things you had never thought about.

For example, I was writing a case of a patient with urosepsis and acute kidney injury (SCr increased by 2.3x from baseline). I wanted the 5th year students to notice the antibiotic plan was currently Gentamicin, and expected them to speak to their senior/microbiology to discuss an alternative. I was aware of renal dose gentamicin being used in chronic kidney disease. However, I did not expect to find guidelines that said to give gentamicin for UTI even in acute kidney injury. Our own hospital guidelines also offered a single dose of gentamicin followed by Augmentin for UTI, even in acute renal failure. Whilst discussing the case with the other clinical teaching fellows, we got some input from a middle grade doctor who had worked in renal units who advised that once off gentamicin is safely given in AKI.

To me, this seemed to contradict some pretty fundamental ideas about acute kidney injury. The Renal Association guidelines state at section 4.1 that “Nephrotoxic medications should be stopped.” with 1A evidence to support this. Surely the very last thing you would do is start gentamicin, unless absolutely unavoidable? Why is it first line even in acute kidney injury, albeit a once only dose, followed by something else?

Microbiologists love gentamicin because it is amazingly effective for gram negatives. The MICs of gram negative bacteria are usually less than 2 mcg/ml for gentamicin. Gentamicin has two distinct antibacterial effects:

  1. It kills bacteria in a concentration dependent way (irreversibly binding the 30S subunit of the bacterial ribosome, interrupting protein synthesis). This is most pronounced when the concentration of gentamicin in the serum is about 8-10 times the MIC.
  2. It has a post antibiotic effect, which means bacterial growth is suppressed even when levels drop below the MIC. The higher the aminoglycoside dosage, the greater the post-antibiotic effect, up to a certain maximal response. This is caused by leukocytes having enhanced phagocytosis and killing activity after exposure to aminoglycosides

The half life in plasma is about two to four hours if the renal function is normal, and can increase up to 60 hours in a patient with essentially no renal function. In contrast, the half life in the renal cortex is about 100 hours. This explains how prolonged courses, which would allow gentamicin to accumulate in the renal cortex, can lead to nephrotoxicity.

Gentamicin can be thought of as following a two-compartment model; the plasma being one compartment and the tissues (importantly renal cortex) being the other. With repeated doses, tissue levels rise and lead to a continous release of gentamicin into the plasma. This can be reflected in an elevated trough level. (An elevated trough level might also represent an ‘overdose’ of the last dose, which has not yet been fully cleared.)

Nephrologists hate gentamicin because it causes nephrotoxicity, usually manifest as a nonoliguric renal failure from acute tubular necrosis. It’s worth noting that it is perfectly possible to develop a tubular problem without any changes in the GFR/creatinine. In the case of gentamicin-induced acute tubular necrosis, tubular obstruction from dead crap in the tubule increases the hydrostatic pressure inside the tubule and in the Bowmans’ capsule, which reduces filtration pressure gradient and, therefore, the glomerular filtration rate (GFR).

My main question at the moment is how does a once only dose of gentamicin differ from 72 hours of gentamicin in terms of nephrotoxicity risk and why. There are many factors at play, but one consistent factor is that nephrotoxicity is nearly always accompanied by tissue accumulation of gentamicin. Have a look at this diagram:

Screen Shot 2013-10-02 at 22.54.58

(This is on page 77 of  NephrotoxicityInteraction of Drugs with Membranes Systems Mitochondria-lysosomes by Jean-Paul Fillastre, 1978. I can’t find the actual paper, but its one by Schentag.)
This study showed that in 53 hospitalised patients (baseline SCr ranged from 10 to 148) who needed gentamicin, those who developed nephrotoxicity (defined as 50% increased in SCr from the baseline, 6 patients) consistently had elevated tissue concentrations of gentamicin than those who did not (47 patients). The nephrotoxic patients were similar age, sex and baseline SCr to the non nephrotoxic patients. It is very interesting that those without tissue accumulation did not develop nephrotoxicity. This could therefore explain why a once only dose of gentamicin appropriate for the patient’s current GFR may be not totally disastrous in AKI, and why it may be sensibly considered as part of the risk:benefit balancing act for a patient with AKI from urosepsis. That said, I’ve also found a paper by the same author which suggested that although renal accumulation was a risk factor for nephrotoxicity, this could occur even after the first dose. I’ll have to discuss this further with a microbiologist and nephrologist.

All this from trying to make a straightforward final year student AKI case. Total can of worms.

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