Pharmacology Consult

Aminoglycosides: not that bad for bad kidneys?

Aminoglycoside antibiotics are implicated as among the most nephrotoxic drugs available. During the past two decades, practitioners had all but abandoned the aminoglycosides as routine treatment options, reserving them for only the most serious infections or for cases of documented resistance. Their use was largely replaced by newer agents, including the fluoroquinolones and carbapenem drug classes. But the recent rise in multi-drug resistant gram-negative pathogens has thrust this drug class back into the spotlight and many institutions are now positioning aminoglycosides as prominent therapies for empiric treatment of suspected and document gram-negative infections.

These changes are being met with some level of resistance by practitioners, particularly by providers who were trained in the era of “avoid aminoglycosides at all costs.” Despite the compelling data to initiate effective therapy in a timely fashion and the favorable susceptibility profiles for aminoglycosides at many medical centers, the fear of nephrotoxicity is often cited as a reason to avoid use.

Aminoglycoside-induced nephrotoxicity

In a recent publication in Antimicrobial Agents and Chemotherapy, a group of investigators from Brazil examined aminoglycoside-associated nephrotoxicity among patients in the Intensive Care Unit. Several traditional risk factors were identified as risks for renal toxic effects, including diabetes, use of concomitant nephrotoxic drugs (such as ACE inhibitors, NSAIDS and amphotericin B), use of iodinated contrast and hypotension during aminoglycoside therapy. The results also showed a factor that was protective against aminoglycoside-induced nephrotoxicity: baseline renal dysfunction. In this particular study, an estimated glomerular filtration rate (GFR) of less than 60 mL/min/m2 at the initiation of the aminoglycoside was actually protective against subsequent nephrotoxicity.

Elizabeth Dodds Ashley, PharmD, MHS, BCPS
Elizabeth Dodds Ashley

In order to better explain this phenomenon, it is important to recall the mechanism of aminoglycoside-induced nephrotoxicity. Aminoglycosides are toxic to the kidney because a small, but appreciable, amount (estimated at 5% of the dose) is retained in the epithelial cells of the proximal tubule after renal elimination. This localized accumulation of aminoglycosides leads to structural alterations in the proximal tubule cells and can ultimately lead to the rupture of lysosomes and extensive mitochondrial damage. Tubular dysfunction is the result and patients develop a nonoliguric renal failure that typically is seen after approximately one week of therapy. Controversy remains over the precise mechanism behind the resulting decline in GFR, but it does appear to be related to the concentration of aminoglycoside that can be achieved in the proximal tubule.

Therefore, efforts to reduce aminoglycoside toxicity have been focused on decreasing cellular uptake. The most notable of these to have clinically demonstrated success was the use of consolidated dosing of aminoglycosides. The uptake of aminoglycosides by renal tubular cells is a saturable process. By giving the total daily amount of drug as a bolus as is done with once daily (or consolidated) dosing regimens, uptake is minimized and less toxicity occurs.

Effect of renal dysfunction

Baseline renal insufficiency may also minimize drug concentrations within the kidney. Patients with decreased GFRs may have impaired cellular uptake of the drug. Therefore, patients with underlying kidney disease may not be able to attain adequate drug concentrations in the renal cortex to exert aminoglycoside-induced toxicity. Additionally, with appropriate dose reductions for renal function, these patients are not receiving the same amount of aminoglycoside per dose because of their decreased kidney function. This may be further protective. In the recent report from Brazil, it was shown that patients with lower GFRs received less aminoglycoside on a mg per mg basis than those with baseline renal function considered within the normal range.

This theory of renal protection for patients with baseline renal dysfunction has been proposed for decades but remains unproven. Reduced toxicity in patients with lower baseline GFRs has not been a consistent finding in available studies. In fact, elevated serum creatinine and underlying renal disease have each been identified as risk factors for toxicity in other published studies. However, these findings do support that the drug can be safely given even in critically ill patients who have pre-existing renal disease.

While the data remain somewhat inconsistent on aminoglycoside-induced nephrotoxicity, it is important that practitioners gain a new level of familiarity with the use of aminoglycosides. Since their widespread use began more than 20 years ago, many advances have been made in dosing strategies and monitoring techniques to detect aminoglycoside-induced toxicity at an earlier stage in treatment. Additionally, nephrotoxicity attributed to aminoglycosides is considered reversible of caught early and appropriate withdrawal of the drug occurs in a timely fashion. Administering aminoglycosides in 2009 is much different than in the late 1980s and can be safely conducted for the majority of patients. Furthermore, the risk of nephrotoxicity is usually outweighed by the benefits of providing effective antimicrobial therapy.

Other important effects

While discussing toxicities of aminoglycosides, there are two other important effects that should be mentioned: vestibular toxicity and neuromuscular blockade. The latter received attention recently since there appeared to be an increase in frequency of neuromuscular blockade in some patients receiving rapid infusions of gentamicin. This relatively rare effect of aminoglycoside therapy has been linked to rapid infusions of the drug or potentially contaminated lots of medication.

Vestibular toxicity is similar to the nephrotoxic effects of this drug class in that it appears related to peak serum drug concentrations. The toxicity is believed to be related to high drug concentrations within the cochlea. The transport mechanism responsible for this accumulation is also saturable and this likely explains the lower incidence of hearing loss and other neurologic effects for patients receiving consolidated dosing regimens. This also may account for the reason that patients requiring hemodialysis can receive high aminoglycoside doses without developing vestibular toxicity despite long concentrations above desired trough concentrations.

The aminoglycoside antibiotics are clearly associated with some significant toxicity. Recent teachings, however, to avoid this drug class except for rare cases do not seemed justified based on the evidence and recent advances in drug administration and monitoring. The current state of gram-negative resistance makes these agents an essential part of any infectious disease practice’s armamentarium and appropriate use even in the sickest of patients with underlying renal disease can be safely carried out with appropriate monitoring.

Aminoglycoside antibiotics are implicated as among the most nephrotoxic drugs available. During the past two decades, practitioners had all but abandoned the aminoglycosides as routine treatment options, reserving them for only the most serious infections or for cases of documented resistance. Their use was largely replaced by newer agents, including the fluoroquinolones and carbapenem drug classes. But the recent rise in multi-drug resistant gram-negative pathogens has thrust this drug class back into the spotlight and many institutions are now positioning aminoglycosides as prominent therapies for empiric treatment of suspected and document gram-negative infections.

These changes are being met with some level of resistance by practitioners, particularly by providers who were trained in the era of “avoid aminoglycosides at all costs.” Despite the compelling data to initiate effective therapy in a timely fashion and the favorable susceptibility profiles for aminoglycosides at many medical centers, the fear of nephrotoxicity is often cited as a reason to avoid use.

Aminoglycoside-induced nephrotoxicity

In a recent publication in Antimicrobial Agents and Chemotherapy, a group of investigators from Brazil examined aminoglycoside-associated nephrotoxicity among patients in the Intensive Care Unit. Several traditional risk factors were identified as risks for renal toxic effects, including diabetes, use of concomitant nephrotoxic drugs (such as ACE inhibitors, NSAIDS and amphotericin B), use of iodinated contrast and hypotension during aminoglycoside therapy. The results also showed a factor that was protective against aminoglycoside-induced nephrotoxicity: baseline renal dysfunction. In this particular study, an estimated glomerular filtration rate (GFR) of less than 60 mL/min/m2 at the initiation of the aminoglycoside was actually protective against subsequent nephrotoxicity.

Elizabeth Dodds Ashley, PharmD, MHS, BCPS
Elizabeth Dodds Ashley

In order to better explain this phenomenon, it is important to recall the mechanism of aminoglycoside-induced nephrotoxicity. Aminoglycosides are toxic to the kidney because a small, but appreciable, amount (estimated at 5% of the dose) is retained in the epithelial cells of the proximal tubule after renal elimination. This localized accumulation of aminoglycosides leads to structural alterations in the proximal tubule cells and can ultimately lead to the rupture of lysosomes and extensive mitochondrial damage. Tubular dysfunction is the result and patients develop a nonoliguric renal failure that typically is seen after approximately one week of therapy. Controversy remains over the precise mechanism behind the resulting decline in GFR, but it does appear to be related to the concentration of aminoglycoside that can be achieved in the proximal tubule.

Therefore, efforts to reduce aminoglycoside toxicity have been focused on decreasing cellular uptake. The most notable of these to have clinically demonstrated success was the use of consolidated dosing of aminoglycosides. The uptake of aminoglycosides by renal tubular cells is a saturable process. By giving the total daily amount of drug as a bolus as is done with once daily (or consolidated) dosing regimens, uptake is minimized and less toxicity occurs.

Effect of renal dysfunction

Baseline renal insufficiency may also minimize drug concentrations within the kidney. Patients with decreased GFRs may have impaired cellular uptake of the drug. Therefore, patients with underlying kidney disease may not be able to attain adequate drug concentrations in the renal cortex to exert aminoglycoside-induced toxicity. Additionally, with appropriate dose reductions for renal function, these patients are not receiving the same amount of aminoglycoside per dose because of their decreased kidney function. This may be further protective. In the recent report from Brazil, it was shown that patients with lower GFRs received less aminoglycoside on a mg per mg basis than those with baseline renal function considered within the normal range.

This theory of renal protection for patients with baseline renal dysfunction has been proposed for decades but remains unproven. Reduced toxicity in patients with lower baseline GFRs has not been a consistent finding in available studies. In fact, elevated serum creatinine and underlying renal disease have each been identified as risk factors for toxicity in other published studies. However, these findings do support that the drug can be safely given even in critically ill patients who have pre-existing renal disease.

While the data remain somewhat inconsistent on aminoglycoside-induced nephrotoxicity, it is important that practitioners gain a new level of familiarity with the use of aminoglycosides. Since their widespread use began more than 20 years ago, many advances have been made in dosing strategies and monitoring techniques to detect aminoglycoside-induced toxicity at an earlier stage in treatment. Additionally, nephrotoxicity attributed to aminoglycosides is considered reversible of caught early and appropriate withdrawal of the drug occurs in a timely fashion. Administering aminoglycosides in 2009 is much different than in the late 1980s and can be safely conducted for the majority of patients. Furthermore, the risk of nephrotoxicity is usually outweighed by the benefits of providing effective antimicrobial therapy.

Other important effects

While discussing toxicities of aminoglycosides, there are two other important effects that should be mentioned: vestibular toxicity and neuromuscular blockade. The latter received attention recently since there appeared to be an increase in frequency of neuromuscular blockade in some patients receiving rapid infusions of gentamicin. This relatively rare effect of aminoglycoside therapy has been linked to rapid infusions of the drug or potentially contaminated lots of medication.

Vestibular toxicity is similar to the nephrotoxic effects of this drug class in that it appears related to peak serum drug concentrations. The toxicity is believed to be related to high drug concentrations within the cochlea. The transport mechanism responsible for this accumulation is also saturable and this likely explains the lower incidence of hearing loss and other neurologic effects for patients receiving consolidated dosing regimens. This also may account for the reason that patients requiring hemodialysis can receive high aminoglycoside doses without developing vestibular toxicity despite long concentrations above desired trough concentrations.

The aminoglycoside antibiotics are clearly associated with some significant toxicity. Recent teachings, however, to avoid this drug class except for rare cases do not seemed justified based on the evidence and recent advances in drug administration and monitoring. The current state of gram-negative resistance makes these agents an essential part of any infectious disease practice’s armamentarium and appropriate use even in the sickest of patients with underlying renal disease can be safely carried out with appropriate monitoring.