LAS VEGAS – Polymyxins are back on the scene due to the worrisome increase in multidrug-resistant gram-negative bacterial infections.
"These drugs were taken off the shelf many years ago because of their severe nephrotoxicity, but they’ve entered the arena again because they’re very effective – and their toxicity has reemerged as well," Dr. Mark A. Perazella warned at a meeting sponsored by the National Kidney Foundation.
Dr. Mark A. Perazella
Drug-induced renal injury accounts for 18%-27% of all acute kidney injury in hospital cases. Antimicrobial agents are among the top causes of drug-related nephropathy, particularly in the hospitalized population, he added.
The incidence of acute kidney injury associated with polymyxin B and polymyxin E (colistin) in contemporary practice is a whopping 30%-60%, depending upon the cumulative dose and duration of therapy, comorbid conditions, and whether other nephrotoxic medications are being used concomitantly. Often an individual’s risk of acute kidney injury is at the high end of this range because the polymyxins are viewed as agents of last resort, and vancomycin – a nephrotoxin in its own right, albeit a less potent one – is commonly on board.
Plus, patients with a serious multidrug-resistant gram-negative infection often have multiple comorbidities and are in a weakened state, further predisposing them to acute kidney injury upon exposure to a nephrotoxin, added Dr. Perazella, professor of medicine and director of the acute dialysis unit at Yale University in New Haven, Conn.
There are no randomized trial data to define polymyxin dosing parameters that maximize efficacy and minimize renal risk, which is clearly dose and duration dependent. For example, in a retrospective study of 173 adults on polymyxin B, the incidence of acute kidney injury was 60%; 10% required dialysis, and 14% had to discontinue treatment because of nephrotoxicity. The median cumulative dose of polymyxin B in patients with acute kidney injury was 1,578 mg, as compared with 800 mg in those without acute kidney injury. Concomitant vancomycin was used by 82% of patients with and by 55% without acute kidney injury (J. Infect. 2012;65:80-7).
The reported incidence of acute kidney injury in patients on vancomycin is most often in the 10%-20% range. Risk is higher in patients with multiple comorbidities and increases with higher cumulative doses and longer-duration therapy. In an effort to improve cure rates, the target vancomycin trough level has increase from 10-20 mg/dL to 15-20 mg/dL. That higher trough level means more cases of acute kidney injury, according to Dr. Perazella.
The randomized prospective ZEPHYR study highlighted fixed-dose linezolid as an attractive alternative to dose-optimized vancomycin for treatment of hospital-acquired methicillin-resistant Staphylococcus aureus pneumonia. In a randomized study of 165 participants, the clinical cure rate was significantly better with linezolid by a margin of 58%-47%. The incidence of nephrotoxicity was 8% in the linezolid group, compared with 18% with vancomycin.
Dr. Perazella reported having no financial conflicts.