Lesson of the month 2: An easily missed cause of confusion

Discussion

Several of this patient's symptoms, particularly the swinging fevers, led those caring for her to believe that her deterioration was due to ongoing sepsis. While beta-lactam neurotoxicity is relatively well recognised it was overlooked in this clinical setting until quite late in the course of her illness. This case highlights several learning points of interest to all those involved in caring for patients receiving antibiotics.

The effects of beta-lactams on the central nervous system (CNS) have been known since the 1940s when classic experiments by Walker et al on macaque monkeys showed that injecting penicillin into their cerebral cortex left them listless and uninterested in their surroundings.¹ In humans, the clinical manifestations of toxicity include confusion, disorientation, twitching, somnolence, myoclonus and convulsions.^2,3 The mechanism of action of beta-lactam neurotoxicity is thought to be the antagonistic action of the beta-lactam ring on the GABA receptor in the brain. As GABA is the main inhibitory neurotransmitter in the brain, its inhibition results in CNS excitation and seizures. Cephalosporins, like penicillins, contain a beta-lactam ring and are thus also associated with neurotoxicity.⁴ Among the cephalosporins, ceftazidime is considered to be particularly prone to causing CNS disturbances.⁵ In one series, the incidence of seizures with ceftazidime was reported to be as high as 3 in 1,000 patients.⁶ The mean daily dose for those developing neurotoxicity was 4 g and EEG evidence of NCSE was found in 75% of patients where it was performed.⁶ Myoclonus was reported in 50%. Background renal dysfunction and prior CNS lesions are known to add to the risk of antibiotic induced seizures.^7,8 The time to developing encephalopathy from starting a cephalosporin has been reported as between 1 and 10 days.⁹ Our patient had been on ceftazidime for nearly 1 month before any confusion was noted. However, once she developed renal dysfunction the confusion ensued very quickly. Ceftazidime is exclusively renally excreted and the half-life of the drug increases significantly as glomerular filtration rate (GFR) decreases.¹⁰ This patient's ceftazidime dose was not decreased as she developed acute kidney injury and thus it is likely increased drug levels resulted in or exacerbated the CNS toxicity.

Some beta-lactams are known to be directly nephrotoxic causing acute tubular necrosis affecting the proximal tubule, particularly if intracellular drug concentrations are high.¹¹ Cephaloridine is actively transported into the proximal tubular cells via the baso-lateral membrane and there is little secretion into the lumen on the apical side, which results in high intracellular concentrations; this puts it among the most nephrotoxic beta-lactams.¹¹ Ceftazidime on the other hand does not accumulate in tubular luminal cells in high concentrations and thus is not traditionally associated with nephrotoxicity. Even so, clinical studies have shown that ceftazidime can in fact result in renal impairment. In one study, the authors showed that GFR, as measured by EDTA clearance, fell by a mean of 9.6 mL/min during treatment with ceftazidime despite serum creatinine remaining unchanged. In the group of patients with estimated GFR of less than 30 mL/ min at the start of therapy, the effects on kidney function were even more pronounced.¹² Another study has shown that the incidence of acute kidney injury increases with the number of potentially nephrotoxic drugs a patient is exposed to, and our patient had several courses of antibiotics that may have cumulatively worsened the toxic effects.¹³ It is also possible that intravenous contrast administered in the first days of her admission during attempts to salvage the limb contributed to her renal dysfunction but the timing of the acute kidney injury would not support this.¹⁴ Finally, this patient had nominally normal kidney function on admission but had had a previous above knee amputation so had reduced muscle mass. Thus, her estimated GFR may have overestimated her true kidney function and belied her risk of developing renal toxicity with ceftazidime. Acute interstitial nephritis has also been reported with ceftazidime but there was little evidence for this with no rash or eosinophilia and a quick recovery following dialysis (albeit with concomitant drug cessation).¹⁵

Swinging temperatures are also a well-recognised feature of beta-lactam drugs.¹⁶ The timing of onset of the fevers related to beta-lactams has been reported at a median of 8 days after starting the offending drug but can occur after weeks to several months later.¹⁶ As in this case, drug fever can result in clinical confusion. The inflammatory markers were only modestly elevated and were declining (Fig 1) despite the very high spiking temperatures and there was no convincing source of sepsis. Thus, in retrospect, the picture was much more typical of drug toxicity.

Grill and Maganti have suggested that EEG may be useful in detecting drug-induced NCSE in patients developing encephalopathy on potentially neurotoxic medications.⁵ The finding of NCSE should prompt the immediate cessation of any possible offending drug and anti-epileptic medications may be required, at least temporarily. In normal renal function, stopping the cephalosporin should bring about resolution of encephalopathy in 2–7 days; however, Grill and Maganti still recommend that haemodialysis or hemofiltration be considered in those who have renal impairment.⁵ A number of factors determine how dialysable any particular drug is, including the degree of protein binding and molecular weight.¹⁷ Only the unbound fraction is available for diffusion across dialysis membranes. As the molecular weight of a drug increases, diffusion of the drug across a membrane progressively decreases; this means that large drugs like vancomycin are relatively poorly removed by dialysis.¹⁸ Ceftazidime, which has a relatively low molecular weight of 636.6 Daltons and is 90% unbounded, is very effectively removed by dialysis.¹⁹

This case serves to remind clinicians of the potentially toxic effects of beta-lactam antibiotics, especially in the context of renal failure. It also highlights that not all fevers are caused by infection but can be a consequence of the antibiotics used to treat them. Further, it demonstrates why a deteriorating patient, even in the presence of improving markers of infection, should prompt consideration of drug toxicity. Beta-lactam toxicity can be treated very effectively by withholding the drug and, if appropriate, initiating intensive haemodialysis. Extreme vigilance is important when prescribing antibiotics and dose adjustments are imperative when chronic kidney disease is present or acute kidney injury has occurred.