THERAPEUTIC CONTROVERSIES Edited by Dennis F.Thompson and Marsha A. Raebel

CEPHALOSPORIN-INDUCED NEPHROTOXICITY: DOES IT EXIST? George G. Zhanel

ABSTRACf: The literaturehas been reviewed to determine whether cephalosporinshave been implicatedin causing nephrotoxicity and to assess the influenceof concomitantaminoglycoside therapy. Animal and human data have implicatedcephaloridineand cephalothinin causingnephrotoxicity, both alone and in combinationwith aminoglycosides. There are few data implicatingother cephalosporins in causing nephrotoxicity. Cefazolin, which is nephrotoxicin animals, has not been reported to produce nephrotoxicityin humans. Two studies have documentednephrotoxicitydue to ceftazidime, especially in patients with preexistingrenal impairment. Such patients should havetheir dosage adjusted to minimizeceftazidime-induced renal impairment. Finally,cephalosporinsother than cephaloridineand cephalothinhave not been documentedto increasethe risk of nephrotoxicity when used in combinationwith aminoglycosides compared with aminoglycosides alone. DICP Ann Pharmacother 1990;24:262-5.

SINCETHEIRINTRODUCTION in the early 196Os,the cephalo-

sporin antibiotics have demonstrated dependable clinical efficacy and a low order of toxicity.' However, in the mid1960s when reports of cephaloridine-induced nephrotoxicity started to surface, clinicians and researchers began to examine just how nephrotoxic cephalosporins are. 2 •3 To date, this question has not been adequately addressed. The literature has been reviewed to answer two specific questions: (1) have cephalosporins been implicated in causing nephrotoxicity, and (2) do patients receiving a cephalosporin and an aminoglycoside have an increased risk of neph-

GEORGE G. ZHANEL, Pharm.D .• is sponsored by the Pharmaceutical Manufacturers Association of Canada Health Research Foundation and the Medical Research Council of Canada. and is a Postdoctoral Research Fellow in Medical Microbiology and an Assistant Professor. Faculty of Pharmacy. University of Manitoba. Reprints: George G. Zhanel, Pharm.D .• Faculty of Pharmacy, University of Manitoba. Winnipeg. Manitoba, Canada R3T 2N2. DENNIS F. THOMPSON, Pharm.D., is the Director, Drug Information Service, and an Associate Professor of Pharmacy Practice, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190; and MARSHA A. RAEBEL, Pharm.D., is the Coordinator of Drug Information and Clinical Pharmacy, Scott and White Memorial Hospital, and an Assistant Professor of Medicine, Texas A&M University College of Medicine. Temple, TX 76508.

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rotoxicity over that incurred when an aminoglycoside is administered alone?

Cephaloridine Cephaloridine has been documented to be nephrotoxic in several species of animals. The order of sensitivity to the nephrotoxic effects is: rabbit>monkey>guinea pig>rat >mouse. 4 Cephaloridine causes dose-related damage to the cells of the midportion of the proximal convoluted renal tubule.Y Cephaloridine's high nephrotoxic potential appears to be related to its unusual renal transport. This cephalosporin is taken up by a common transport pump situated at the peritubular aspect of proximal tubular cells. Unlike other beta-Iactam antibiotics, however, cephaloridine seems to be unable to diffuse down its concentration gradient from the tubular cells into the lumen. Hence, it accumulates within these cells to a higher concentration than do other organic anions, and its rate of renal clearance indicates no net tubular secretion.v" Evidence for this mechanism is the finding that probenecid, which blocks entry of cephaloridine into the tubular cells via a contralumenal surface, completely prevents nephrotoxicity.v" The documentation is poor regarding how animal studies performed with cephaloridine and other cephalosporins can be extrapolated to humans.Y Prospective studies and case reports document over a hundred cases of cephaloridine-induced nephrotoxicity in humans. 7-!0 Renal dysfunction results from damage to the proximal cells of the renal tubule and pathologic studies document acute tubular necrosis. 7.8 With nephrotoxicity, there are granular and hyaline casts in the urinary sediment along with protein, and occasionally a fixed specific gravity of the urine (1.010) is documented." Serum creatinine and blood urea nitrogen (BUN) increase, not uncommonly accompanied by nausea and vomiting, but with a maintained diuresis." If cephaloridine is discontinued at this point or if proper dosage adjustment is made, recovery is complete. 8.9 However, if it is continued without dosage adjustment, oligoanuric renal failure occurs." The following risk factors for

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cephaloridine nephrotoxicity have been identified: (1) excessive dosage (>6 g/d), (2) preexisting renal dysfunction, (3) concurrent nephrotoxic drugs (usually aminoglycosides), (4) concurrent loop diuretics (usually furosemide), (5) history of "hypersensitivity" to beta-lactams (type of reactions not described), (6) history of surgery at the beginning or during cephaloridine therapy (details unknown), and (7) severe illness (e.g., sepsis, hypotensionj.?"

Cephalothin Cephalothin, a chemical congener of cephaloridine, is also nephrotoxic.Y'P''? In high doses, cephalothin produces acute tubular necrosis in both rats and rabbits." In humans, cephalothin appears to produce two distinct types of nephrotoxicity: (1) acute tubular necrosis (mechanism thought to be damage to proximal cells of the renal tubule), and (2) allergic interstitial nephritis (mechanism thought to be hypersensitivity).6-17 Cephalothin-induced acute tubular necrosis occurs after several days of drug therapy. Initially, casts, cells, and/or protein appear in the urine. This is followed by increases in the serum creatinine and BUN. As with cephaloridine, most cases are reversible (renal indices return to baseline in days to weeks) if the drug is discontinued at this time. 8.9,13.14,16,17 If the drug is continued, oligo-anuric renal failure occurs. The major risk factor for cephalothininduced acute tubular necrosis is concurrent use of an aminoglycoside. 6,13,14,16,17 Cephalothin-induced allergic interstitial nephritis is considerably different from cephalothin-induced acute tubular necrosis. Patients may receive as little as a few doses to two weeks of drug therapy before signs of toxicity occur. 6,8,IO,14.15 Urinalysis demonstrates microscopic or gross hematuria, moderate proteinuria, and occasionally, renal tubular epithelial cells. Urinary eosinophils are not uncommon. In addition, patients often have a rash with fever and eosinophilia, and historically convey a previous allergic event to a beta-lactam." If cephalothin is discontinued at this point, recovery is almost always complete. 6,8,14,15

OtherCephalosporins Cefazolin has been reported to be the second most nephrotoxic cephalosporin in animals, after cephaloridine.v-" Cefazolin produces the same lesion in laboratory animals as does cephaloridine. 18 The differences in the relative degrees of renal toxicity of these drugs are due to different transport properties. Unlike cephaloridine, which demonstrates minimal secretion and thus attains extremely high concentrations in proximal tubular cells, cefazolin is secreted at a rate that is three to four times its estimated filtration rate. 4,18 Although cefazolin is the second most nephrotoxic cephalosporin in animals, no reported human cases of cefazolin-induced nephrotoxicity could be found in the literature. The reason for this discrepancy between animal and human data is unclear; however, it may be due to the lower doses used with cefazolin." Cephalexin, a cephalosporin with a chemical structure similar to cephaloglycin (a cephalosporin demonstrated to be as nephrotoxic as cephaloridine in rabbits and guinea pigs) has been implicated as nephrotoxic in humans. 19.20 Kunin and Finkelberg administered one week of ampicillin II g po, followed by one week of no drug, followed by a week of cephalexin II g po to five uremic patients. In four

patients, creatinine clearance measured during the study and two to three weeks later demonstrated only minor fluctuations from baseline. However, one patient whose renal function was stable during the study demonstrated a decline in creatinine clearance from 35.9 to 19.3 mLimin two weeks after finishing the cephalexin. At this time BUN was 71.4 mmollL and serum creatinine was 389 umol/L. In addition to having a history of renal disease the patient also had a history of hypertension. Follow-up one month after the cessation of cephalexin therapy demonstrated a decline in both BUN and serum creatinine to 47.1 mmollL and 274 umol/L, respectively. The creatinine clearance was not documented at this time." Fung-Herrera and Mulvaney reported on a 70-year-old diabetic man with a seven-day history of dysuria, fever, and chills. No hematuria was found and the urine specific gravity was 1.015. Urinalysis revealed pyuria and bacteriuria, but the urine culture demonstrated no growth. The BUN at this time was 6.7 mmollL; serum creatinine and creatinine clearance were not reported. An intravenous pyelogram demonstrated decreased excretion by the left kidney. The patient was given cephalothin 500 mg iv q6h for three days, and therapy then was changed to cephalexin 500 mg po q6h. The patient was discharged and advised to continue the cephalexin for ten days. Six days later (while still taking the cephalexin) the patient returned to the hospital complaining of severe chills and fever. He was weak, anorexic, and lethargic. Urinalysis showed pyuria and albuminuria with a urinary specific gravity ranging from 1.006 to 1.010. BUN was 46.1 mmollL and serum creatinine was 495 umol/L. After discontinuation of the cephalexin, the patient gradually improved and on discharge 17 days later his BUN and serum creatinine values were 13.2 mmollL and 168 urnol/L, respectively." The nephrotoxic potential of cefamandole has been studied in an animal model. Wold et al. evaluated the comparative nephrotoxicity of cefamandole, cephalothin, and cefazolin in rabbits. Each rabbit was given 2 mg/kg iv of test drug and renal toxicity was assessed 48 hours later. The order of nephrotoxicity, as assessed by serum creatinine, BUN, and histopathology, was cefazolin>cefamandole>cephalothin. No precise definition of nephrotoxicity was stated. The researchers concluded that since cefamandole is less nephrotoxic than cefazolin in this sensitive animal model, the possibility of significant nephrotoxicity arising from the clinical use of appropriate doses of cefamandole is minimal." Bint et al. reported possible cefuroxime-associated increases in BUN and serum creatinine in two patients. These patients received im cefuroxime courses of five to nine days (dosage not reported) for the treatment of Klebsiella aerogenes urinary tract infection. The actual values for BUN and serum creatinine were not given, and no mention was made of whether these increases in laboratory values were transient or permanent. 22 Although all third-generation cephalosporins have been reported to cause increases in serum creatinine and BUN, 23 specific cases of nephrotoxicity have been published only involving ceftazidime. 24,25 Norrby et al. administered ceftazidime 1g q8h for four to nine days to 15 patients for various bacterial infections. Patients with acute renal dysfunction due to renal infections or systemic diseases were excluded from the study as were patients with signs of

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dehydration and those requiring "high and/or changing doses" of potent diuretics. The average creatinine clearance before administration of the study drug was 82 mLimin. Ten of these patients demonstrated significant decreases (average decrease 11.3 mLimin) in glomerular filtration rate (GFR). Seven patients displayed increases in serum betajmicroglobulin. No follow-up was available to assess whether these values returned to normal after the end of treatment. 24 Alestig et al. treated various infections in 19 patients with normal and impaired renal function. These patients received ceftazidime 2 g bid for 7-31 days (mean 10 days). Eight patients were treated with oral furosemide and two with oral spironolactone. Seventeen patients demonstrated significant decreases (mean 10 mLimin, range 1-41 mLimin) in GFR during therapy. Significant increases in an enzyme originating from proximal tubular cells (alanine aminopeptidase) were also observed. The decreases in GFR were not related to concurrent administration of diuretics. The researchers concluded that the combined finding of reduction in GFR and increase in urinary excretion of alanine aminopeptidase during ceftazidime therapy indicated an effect on both renal glomeruli and tubules. These investigators suggested dosage adjustment in patients with preexisting renal impairment to minimize ceftazidimeinduced renal impairment. Follow-up of renal function several weeks after therapy was available for five patients and laboratory values had returned to pretreatment levels in all

five."

Cephalosporin-Aminoglycoside Combinations The issue whether cephalosporins when used concomitantly with aminoglycosides increase the risk of nephrotoxicity over that incurred by aminoglycosides alone surfaced when reports were published suggesting an unexpectedly high rate of nephrotoxicity in patients receiving this combination. 8 •13•26 Analysis of the combined use of cephalothin and an aminoglycoside has demonstrated conflicting results. 27-29 In a study of granulocytopenic patients with cancer who had normal initial renal function and lacked other predisposing causes, Gaya et al. reported a rate of nephrotoxicity (rise in serum creatinine of > 130 urnol/l) of 5.3 percent in individuals who received carbenicillin and cephalothin, 3.9 percent in patients who received carbenicillin and gentamicin, and 14.3 percent in those who received cephalothin and gentamicin. 27 Klastersky et al. investigated patients with disseminated cancer (not necessarily granulocytopenic) who demonstrated a recent onset of clinical symptoms suggestive of severe infection (rectal temperature >38.3°C, shaking chills, hypotension). One hundred eighty-six patients were randomized to one of three treatment groups: cephalothinticarcillin, ticarcill in-tobramycin, and cephalothintobramycin. Subjects were excluded if their baseline serum creatinine level was ~ 150 umol/L. Randomization ensured that the groups were similarly matched with respect to size, age, sex, site of infection, and type of infecting organism. No reference was made to excluding patients who were concomitantly receiving other potential nephrotoxins. Doses for ticarcillin and cephalothin were 10 g tid and 3 g tid, respectively. Tobramycin was administered tid at a total daily dose of 4.5 mg/kg (unknown whether total body weight or lean body weight). The mean duration of treatment was approximately seven days in each group. These 264



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investigators documented a rate of nephrotoxicity (rise in serum creatinine from baseline of ~177 umol/L) of 2 percent with cephalothin-ticarcillin, 6 percent with ticarcillintobramycin, and 21 percent with cephalothin-tobramycin. 28 In a retrospective study by the Boston Collaborative Drug Surveillance Program, the hospital records of a ninehospital region were analyzed to assess drug-induced nephrotoxicity due to the combination of gentamicin and cephalothin. All patients who received gentamicin and cephalothin alone or in combination were identified, and from this list patients who had received other potential nephrotoxins (e.g., amphotericin B, colistin) or who had undergone surgery were excluded. Patients were not excluded if they received diuretics; however, the distribution of patients who had received diuretics was similar in each group. The three groups, each containing approximately 300 patients, were distributed similarly with respect to age, sex, baseline BUN, diagnosis, and duration of antibiotic therapy. Nephrotoxicity was defined as a rising BUN ascribed to the relevant antibiotic under study in those instances where it occurred at least 24 hours after treatment was begun and not more than 24 hours after treatment was stopped. The rise in BUN from baseline averaged 21 mmollL and ranged from 3.6 to 118 mmollL. The incidence of nephrotoxicity was 2.9 percent in patients who had received cephalothin alone, 8.6 percent in patients who had received gentamicin alone, and 9.3 percent in patients who had received the combination, thus providing evidence against the combination of cephalothin and gentamicin substantially increasing the incidence of nephrotoxicity over that of an aminoglycoside alone;" The contradictory human data are further confused by the fact that in experimental animals, cephalosporins appear to prevent aminoglycoside nephrotoxicity." No prospective, randomized, comparative trials have demonstrated that cephalosporins other than cephalothin potentiate the nephrotoxic effects of aminoglycosides. These data indicate that cephaloridine or cephalothin in combination with an aminoglycoside may increase the risk of nephrotoxicity over that incurred with an aminoglycoside alone; however, this has not been proven with other cephalosporins.

Summary Animal and human data have convincingly implicated cephaloridine in causing nephrotoxicity and thus this agent should not be used. Cephalothin both with and without aminoglycosides is also nephrotoxic. Therefore, since safer, equally effective cephalosporins are available, this agent should not be used. There are few animal and human data to suggest that cephalosporins, with the exception of cephaloridine and cephalothin, are nephrotoxic. However, limited data suggest that cefazolin is nephrotoxic in animals, and ceftazidime is nephrotoxic in humans, especially in patients with preexisting renal impairment. In addition, there are no data suggesting that cephalosporins, other than cephaloridine and cephalothin, increase the incidence of nephrotoxicity of aminoglycosides when used in combination. Finally, the dosages of cephalosporins should be adjusted for patients with renal impairment to prevent accumulation of the drug and thus minimize the effect on the kidneys.w The author wishes to thank L. Dingman and s. Singh for their expert secretarial assistance.

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Cepludosporin Nephrotoxicity

References I. CALDWELL JR,CLUFF LE. Adversereactionsto antimicrobialagents. .l4MA 1974;230:77-80. 2. ATKJNSON RM, CURRJE JP, DAVIS B, et aI. Acute toxicity of cephaloridine,an antibiotic derivedfromcephalosporin C. Toxicol Appl Pharmacoll966;8:398-406.

3. WELLES JS,GIBSON WR. HARRIS PN. Toxicity distribution andexcretion of cephaloridine in laboratory animals. Antimicrob Agents Chemother 1966;1965:863-9. 4. TUNE BM. Relationship between the transportand toxicity of cephalosporinsin the kidney. J Infect Dis 1975;132: 189-94. 5. TUNE BM. FRAVERT D. Mechanisms of cephalosporin nephrotoxicity: a comparison of cephaloridine and cephaloglycin. Kidney Int 1980; 18:591-600.

6. BARZA M. The nephrotoxicity of cephalosporins: an overview. J Inject Dis 1978;137(suppl):S60-73. 7. BENNER EJ. Renal damageassociated with prolonged administration of ampicillin, cephaloridine, andcephalothin. Antimicrob Agents Chemo-

26. KLEINKNECHT D.GANEVAL D, DROZ D. Acuterenalfailure after high dosesof gentamicin andcephalothin. Lancet 1973;1:1129. 27. GAYA H,KLASTERSKY J, SCHIMPFF sc. Nephrotoxicity during combinedtherapy withgentamicin andcephalothin (abstract). In: Program and abstracts of the 15thInterscienceConferenceon Antimicrobial Agents andChemotherapy, 1975:40I. 28. KLASTERSKY J. HANSGENS C. DEBUSSCHER L. Empiric therapyfor cancer patients: comparative study of ticarcillin-tobramycin, ticarcillin-cephalothin, ana cephalothin-tobramycin. Antimicrob Agents Chemother 1975;7:640-5.

29. FANNING WL, GUMP D,JICK H.Gentamicin- andcephalothin-associated rises in blood urea nitrogen. Antimicrob Agents Chemother 1976; 10:80-2.

30. WFT FC, PATEL V, YUM MN, et aI. Nephrotoxicity ofcephalosporin-gentamicin combinations in rats. Antimicrob Agents Chemother 1976; 9:831-9.

ther 1%9;9:417-20.

8. FOORD RD. Cephaloridine, cephalothinand the kidney. J Antimicrob Chemother 1975;/(suppl):119-33. 9. APPEL GB, NEU HC. The nephrotoxicity of antimicrobial agents. N Engl J Med 1977;296:663-70.

10. COOPER K. BENNET WM. Nephrotoxicity of common drugs used in clinical practice. Arch Intern Med 1987; 147:1213-8. II. RAHAL JJ, MEYERS BR, WEINSTEIN L. Treatment of bacterial endocarditis withcephalothin. N Engl J Med 1%8;279:1305-9. 12. PICKERING MJ, SPOONER GR. QUESADA A,et aI. Declining renalfunction associated withadministration of cephalothin. South Med J 1970; 63:426-8. 13. BOBROW SN,JAFFE E, YOUNG RC. Anuria and acute tubular necrosis associated withgentamicin and cephalothin. .l4MA 1972;222: 1546-7. 14. BURTON JR. LICHTENSTEIN NS. COLVIN RB, et aI. Acute renal failure duringcephalothin therapy. JAMA 1974;229:679-82. 15. ENGLEJE. DRAGOJ, CARLIN B,et aI. Reversible acuterenalfailure after cephalothin. Ann Intern Med 1975;83:232-3. 16. CARLING rc, IDELSON BA, CASANO AA, et aI. Nephrotoxicity associated with cephalothin administration. Arch Intern Med 1975;

EXTRACfO Se hizo una revision de la literatura medica con el fin de determinar si las cefalosporinas han estado involucradas en el desarrollo de nefrotoxicidad, y si su riesgo se incrementa con el uso concomitante de aminoglucosidos. Segun datos obtenidos en estudios realizados en animales y en humanos, la cefaloridina y la cefalotina, administradas solas 0 en combinaci6n con arninoglucosidos, conllevan al desarrollo de nefrotoxicidad. Existen pocos estudios que demuestran que las cefalosporinas, con excepcion de la dos mencionadas, son nefrotoxicas. Sin embargo, informacion limitada sugiere que la cefazolina es nefrotoxica en animales, y que la ceftazidima es nefrot6xica en humanos, especial mente en pacientes con insuficiencia renal preexistente. Finalmente, se recomienda que las dosis de cefalosporinas sean ajustadas en pacientes con deterioro renal a fin de prevenir su acumulacion y minimizar su efecto sobre el riii6n.

135:797-801.

17. PASTERN AK DP, STEPHENS BG. Reversible nephrotoxicityassociated withcephalothin therapy. Arch Intern Med 1975;135:599-602. 18. SILVERBLATT F. HARRJSON WO, TURCK M. Nephrotoxicity of cephalosporin antibiotics in experimental animals. J Infect Dis 1973; 182(suppl):S367-72. 19. KUNIN CM. FINKELBERG Z. Oral cephalexin and ampicillin: antimicrobial activity, recovery inurine,andpersistence inbloodof uremic patients. Ann Intern Med 1970;72:349-56. 20. FUNG-HERRERA CG,MULVANEY WP Cephalexinnephrotoxicity: reversible nonoliguric acute renal failure and hepatotoxicity associated withcephalexin therapy. .l4MA 1974;229:318-9. 21. WOLD JS,WELLES JS,OWEN NY, et aI. Toxicological evaluation of cefamandole nafate in laboratory animals. J Infect Dis 1978; /37(suppl):S51-9. 22. BINT AJ, BULLOCK DW, SPELLER DCE, et aI. Cefuroxime therapy forurinary tract infections caused by multi-resistant,epidemic Klebsiella aerogenes. J Antimicrob Chemother 1979;5: 189-93. 23. ZHANEL GG.BRUNHAM RC. Third-generationcephalosporins. Can J HospPharm 1988;4/:183-94.

24. NORRBY SR, BURMAN LA, LINDERHOLM H, et aI. Ceftazidime: pharmacokinetics inpatients andeffectson therenalfunction. J Antimicrob Chemother 1982;10:199-206.

25. ALESTIG K.TROLLFORS B,ANDERSON R,et aI. Ceftazidime and renal function. J Antimicrob Chemother 1984;/3:177-81.

ENCARNACION C. SUAREZ RESUME Une revue de litterature a ete effectuee pour documenter la nephrotoxicite associee aux cephalosporines et pour determiner I'inftuence d'une therapie concomitante avec des aminoglycosides. Des donnees, tant chez les animaux que chez les humains, ont confirme la nephrotoxicite de la cephaloridine et de la cephalothine, utilisees seules ou en association avec les aminoglycosides. A I'exception de ces deux dernieres, peu de donnees sont disponibles pour incriminer les cephalosporines comme agent casual de nephrotoxicite. La cefazoline, qui est nephrotoxique chez les animaux, ne semble pas produire de nephrotoxicite chez les humains. Deux etudes documentent une nephrotoxicite induite par la ceftazidime, specialement chez des patients presentant une dysfonction renale pre-existante. II est suggere que la dose de ceftazidime soit ajustee en tenant compte de la fonction renale pour minimiser son effet sur Ie rein. Finalement, les cephalosporines, autres que la cephaloridine et la cephalothine, ne semblent pas augmenter Ie risque de nephrotoxicite lorsqu'elles sont utilisees en association avec les aminoglycosides, par rapport aux aminoglycosides utilises seuls.

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Cephalosporin-induced nephrotoxicity: does it exist?

The literature has been reviewed to determine whether cephalosporins have been implicated in causing nephrotoxicity and to assess the influence of con...
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