Servais H, Mingeot-Leclercq MP, and Tulkens PM

Antibiotic-induced nephrotoxicity

In: Toxicology of the Kidney (Target Organ Toxicology Series) chap. 16, pp 635-685, J.B. Tarloff & L.H. Lash, eds., CRC Press, Boca Raton, Fla., ISBN 0-415-24864-7

Book Chapter

Antibiotics have long been and remain a major cause of drug-related renal toxicity, causing both acute renal failure and tubulo-interstitial disease, depending of the drug under study.  Most cases of acute renal failure are related to acute tubular necrosis, for which aminoglycosides have long been one of the leading causes.  Tubulointerstitial disease is more commonly seen with b-lactams (hypersensitivity nephropathy), but can also be caused indirectly by aminoglycosides.  Two complicating factors make the nephrotoxicity of antibiotics more common than expected.  First, many of these drugs are given in combination, either between them-selves or with other drugs.  Consequently, the second agent, as exemplified with vancomycin for aminoglycosides, or aminoglycosides for non-steroidal antiinflamatory agents, may aggravate the toxicity of the first one.  Second, many antimicrobials are removed from the body essentially or at least predominantly through the renal route.  The serum levels of these drugs will therefore increase as the renal function becomes impaired, either because of the drug toxicity it-self or because of a concomitant renal damage caused by another drug or by another cause of nephrotoxic reaction.  This does not only apply to drugs eliminated by glomerular filtration but also to those that are removed from the body by tubular secretion if the renal function is severely compromised (creatinine clearance of 20 mL/ min or less).  These situations are far from exceptional in severely ill patients for which effective antimicrobial chemotherapy must put into action.  Thus, toxic levels of aminoglycosides and vancomycin are often observed in these patients unless close monitoring of both the renal function and of the drugs them-selves is performed.  The same may occurs with certain penicillins, fluoroquinolones, and tetracyclines, for which drug monitoring in not routinely performed.  These considerations explain many cases of antibiotic-related toxicities, and call upon attention for a careful adjustment of doses, based on age, sex, body weight, and renal function.  The clinician must however be warned against inappropriate moves towards low doses of antimicrobials for fear of toxicity (a trend that was frequent in the late 80's, early 90's).  It is indeed now well established that inefficient antimicrobial therapy is conductive to clinical failures as well as to risks of resistance (Craig, 2001), thereby exposing the patient to additional toxicities related to the persistence of the infection and the need to prolong the therapy.  Efforts must be directed at selecting the most appropriate antibiotic, to administer it at the maximal acceptable dose (which will define the peak serum concentration, the area under the 24 h serum concentration, and the the time during which the serum concentration will remain above the critical treshold (Amsden et al., 2000), while at the same time keeping away from drugs and conditions that may cause unacceptable renal insult. 
    In this chapter, we will review the data available on three classes of antimicrobial agents that have been most commonly associated with renal toxicities, namely the aminoglycosides, the b-lactams, and vancomycin.  The other antibiotics will only be briefly touched upon namely because data are more scanty and the mechanisms often less clear.