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.