SAN FRANCISCO—New data document a strong association between the use of flucloxacillin with single-dose gentamicin in patients undergoing joint replacement surgery and the development of acute kidney injury (AKI).

The investigators, who are with the Dumfries & Galloway Royal Infirmary in Dumfries, Scotland, reported their findings at the American Academy of Orthopaedic Surgeons 2012 Annual Meeting.

Principal investigator Chris Isles, MD, consultant nephrologist, said his institution had recently decided to replace cefuroxime for the prevention of superficial and deep wound infection after joint replacement surgery with flucloxacillin plus single-dose gentamicin.  The decision was made in order to decrease the incidence of Clostridium difficile diarrhea, which can be asymptomatic in some patients or life-threatening in others when pseudomembranous colitis is present.  Although their use is now considered routine for primary joint arthroplasty, some antibiotics, including second- and third-generation cephalosporins, may increase the risk of C. difficile diarrhea.      

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However, the unintended consequence of the switch to flucloxacillin/gentamicin was an increase in the incidence of AKI, which Dr. Isles’ team had initially noticed when AKI requiring hemodialysis developed in three patients after arthroplasty.  

To explore the issue more closely, they examined the incidence of AKI sequentially in 198 patients undergoing elective hip or knee replacement surgery at their institution over a recent 12-month period.

The study included 52 patients who received high-dose flucloxacillin and single-dose gentamicin in whom the investigators had first noticed an increased incidence of AKI; a group of 48 consecutive patients who received cefuroxime prophylaxis; 46 patients who were given low-dose flucloxacillin with single-dose gentamicin. In addition, because the problem of AKI did not appear to have been completely resolved, an additional 52 patients received cefuroxime.

The four groups were similar with respect to age, gender, type of operation, American Society of Anesthesia grade, mode of anesthesia, baseline serum creatinine, pre-operative co-morbidity, pre-operative medication, and post-operative hypotension.

Overall, 27 (52%) patients receiving high-dose flucloxacillin with single-dose gentamicin experienced AKI by RIFLE criteria (a 1.5 times increase in serum creatinine level or a fall in glomerular filtration rate by more than 25% relative to baseline values). Recipients of high-dose flucloxacillin plus single-dose gentamicin had a 14.5 times increased risk of AKI compared with patients in the first cefuroxime group after adjusting for confounders.

Additionally, AKI was found in four (8%) patients in the first cefuroxime group, 10 (22%) patients in the low-dose flucloxacillin with single-dose gentamicin group, and seven (14%) in the second cefuroxime group.

RIFLE class F AKI (defined as a rise in serum creatinine level to three times baseline value) developed in seven patients. Of these, six had received high-dose and one had received low-dose flucloxacillin. Three patients in the high-dose flucloxacillin group needed temporary dialysis, and two of the three underwent a renal biopsy that indicated acute tubulo-interstitial nephritis.

No patient in the study experienced C. difficile diarrhea.

Dr. Isles emphasized that the findings must be interpreted cautiously given that the study was neither randomized nor controlled. Furthermore, it was not possible to rule out a seasonal effect because the study was conducted over a single 12-month period.

Meanwhile, he said “the finding of an odds ratio of 14.5 linking high-dose flucloxacillin plus single-agent gentamicin with AKI after adjusting for possible confounders supports the view that one or the other or both antibiotics may be nephroxotic in this setting.”

Finally, he noted that, since the study, his institution has reverted back to the use of cefuroxime as prophylaxis for primary joint arthroplasty.