Re: INDICES> Toxicity of combination: Aminoglycoside/ Cephlosporin (2)

["Janet McNeece" <Jmcneece@mail.rah.sa.gov.au>]

Indices: Combination of Aminoglycosides and Cephalosporins (2)

Summary
The nephrotoxic effects of aminoglycosides (particularly gentamicin
and tobramycin) can be increased by the concurrent use of
cephalosporins (particularly cefalotin [or cephalothin]).  However
some cephalosporins  (cefuroxime, cefotaxime, ceftazidime and
cefipime) appear not to interact adversely.1

Clinical evidence1
A number of studies and case reports describe an increase in
nephrotoxicity when gentamicin 2-9 or tobramicin 10,11 are used with
cefalotin [cephalothin].  However the opposite conclusion has been
reached by others 12-13.
Cefuroxime14 and cefotaxime15 are reported NOT to increase the
nephrotoxic effects of tobramycin.
Ceftazidime and tobramycin 16 or cefepime and amikacin17 have
been used together without the occurrence of a clinically important
adverse interaction.
A randomised double-blind trial in patients with sepsis showed the
following incidence of nephrotoxicity;  gentamicin & cefalotin 30.4%
(7 out of 23),  tobramycin & cefalotin 20.8% (5 out of 24),
gentamicin & methicillin 10% (2 of 20), tobramycin & methicillin
4.3% (1 of 23).18

Mechanism
Uncertain.1
The nephrotoxic effects of gentamicin and tobramycin are well
documented and it appears that these effects can be additive with
cefalotin [cephalothin] in some patients.  Doses which are well
tolerated separately can be nephrotoxic when given together.8

Importance and Management1
Concurrent use is not totally contraindicated but the patient?s
    renal function should be very closely monitored and dosages
    kept to a minimum1.  [ie the gentamicin level should be closely
    monitored from day 1 and the patients creatine and creatine
    clearance should be closely monitored.]
The risk of a clinically significant interaction is probably
    greatest if high doses are used in those with existing renal
    impairmant1. [If the patient has existing renal impairment the
    risk / benefit should be clear]
The combination of Gentamicin or tobramycin and cefalotin is
    probably best avoided, particularly in high risk patients1. The
    gentamicin/cefalotin interaction is very well documented and
    potentially serious, but there is less information about
    tobramycin with cefalotin.1


References
Stockley?sDrug Interactions 6th Edition.  Editor Ivan H Stockley Published
by
    the Pharmaceutical Press London.  2002.
PlagerJE.  Association of renal injury with combined cephalothin-gentamicin
    therapy among patients severely ill with malignant disease.  Cancer
1976;
    37: 1937-43
The EORTC International Antimicrobial Therapy Project Group.  Three
    antibiotic regimens in the treatment of infection in febrile
granulocytopenic
    patients and cancer.  J Infect Dis 1978; 137: 14-29
KleinknechtD.  Acute renal failure after high doses of gentamicin and
    cephalothin  Lancet 1973;I:1129
BobrowSN  et al.  Anuria and acute tubular necrosis associated with
    gentamicin and cephalothin JAMA 1972;222:1546-7
FillastreJP et al.  Acute Renal Failure associated with combined gentamicin
    and cephalothin therapy BMj 1973;2: 396-7
CabanillasF et al.  Nephrotoxicity of combined cephalothin-gentamicin
    regimen  Arch Intern Med 1975;135: 850-852
TvedegaardE.  Interaction between gentamicin and cephalothin as cause
    of acute renal failure.  Lancet 1976;ii: 581
HansenMM et al.  Nephrotoxicity in combined cephalothin and gentamicin
    therapy.  Acta Med Scand 1977;201,463-7
TobiasJS  et al.  Severe renal dysfunction after tobramycin/cephalothin
    therapy.  Lancet 1976; I: 425
KlasterskyJ  Empiric therapy for cancer patienmts: comparative study of
    ticarcillin-tobramycin, ticarcillin-cephalothin and
cephalothin-tobramycin
    Antimicrob Agents Chemother
FanningWL  et al.  Gentamicin and cephalothin associated rises in blood
    urea nitrogen.  Antimicrob Agents Chemother 1976;10:80-82
WellwoodJM  et al.  Evidence of gentamicin nephrotoxicity in patients with
    renal allografts  BMJ 1975;3: 278-81
TroliforsB et al.  Renal function in patients treated with tobtamycin-
    cefuroxime or tobramycin- penicillin G.  J Antimicrob Chemother 1983
;12:
    641-5
kuhlmannJ et al  Tobramycin nephrotoxicity; failure of cefotaxime to
    potentiate injury in the patient.  Naunyn Schmiedebergs Arch Pharmacol
    1981; 316 (suppl): R80
AronoffGR et al  interactions of ceftazidime and tobramycin in patients with
    normal and impaired renal function.  Antimicrob Agents Chemother 1990;
    34: 1139-42
BarbhaiyaRH et al  Lack of pharmacokinetic interaction between cefepime
    and amikacin in humans.  Antimicrob Agents in Chemother 1992; 36: 1382-6
WadeJC  et al.  Cephalothin plus aminoglycoside is more nephrotoxic than
    methicillin plus an aminoglycoside.  Lancet 1978; ii: 604-6

Janet McNeece
Senior Pharmacist
Medicines Information Centre
Royal Adelaide Hospital
South Australia

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