ANTI-INFECTIVE
The
Effect of Tobramycin on Handling of Vancomycin
Myrna
Y. Munar,
PharmD,
Lawrence
A. Golper,
Thomas
Elzinga,
MD,
and
William
MD,
Robert
M. Bennett,
the
AGENTS
Renal
Brummett,
PhD,
MD
Studies in experimental animals and humans have suggested that enhanced renal and auditory toxicity occur with concurrent vancomycin and aminoglycoside treatment. In volunteers, systemic vancomycin clearance at steady-state was measured simultaneously with renal clearances of vancomycin, creatinine, inulin, and para-aminohippurate. Group I (n = 9) received vancomycin 5 mg/kg IV for 1 hour, then 1.1 mg/kg/hr for 3 hours. Group II (n = 7) received vancomycin plus tobramycin (2 mg/kg IV over 30 mm). Groups did not differ demographically. Audiograms were obtained before and after vancomycin. Plasma samples were collected serially for vancomycin and tobramycin pharmacokinetic studies. Serum concentration versus time data were fit to a two-compartment model for vancomycin and a one-compartment model for tobramycin. For all volunteers, creatinine, inulin and para-ammnohippurate clearance, and audiograms were not altered from baseline and were not statistically different between groups. No significant effect of tobramycin on vancomycin pharmacokinetics was observed. Conversely, vancomycin had no significant effect on tobramycin pharmocokinetics. The nephrotoxic synergism of vancomycin and tobramycin is not explained by short-term differences in renal handling.
T
he use of a combination aminoglycoside has
broad-spectrum
of vancomycin become widespread
antibiotic
regimens
plus
because
an in
of
proven activity against most gram-positive and gram-negative pathogens. Indications for combined use of these agents include severe infections caused by methicillin-resistant staphylococci,1 enterococcal endocarditis in penicillin-allergic patients,2 treatment of peritonitis in CAPD patients,3 prophylaxis for cardiopulmonary bypass surgery,4 and empiric therapy of febrile episodes in neutropenic cancer patients.5 Despite proven efficacy, the overall clinical benefit of each agent is hampered by known dosedependent renal and auditory toxicities.
Nephrotoxicity associated with aminoglycoside use has been well documented with an overall frequency of 5 to 10% 68 The incidence of nephrotoxicity
From
resulting
from
the College
Medicine,
vancomycin
of Pharmacy.
Division
of
Oregon
Nephrology
Sciences Munar,
University. Portland, PharmD, OP 18, OSU
Oregon
Health
Portland,
618
Sciences
therapy
State
and Oregon. College
University,
#{149} J CIIn Pharmacol
University,
Hypertension, Address for of Pharmacy
3181
OR 97201-3098.
1991;31:618-623
is not
SW Sam
well
Department Oregon reprints: Portland
Jackson
of Health
Myrna V. Campus. Park
Road,
established but it appears to range from 0 to 7%9 When these drugs are used in combination a greater incidence of nephrotoxicity has been observed. Experiments done in rats have demonstrated enhanced nephrotoxicity with concurrent vancomycin and aminoglycoside administration compared with either agent used alone.1012 Available data on adult and pediatric patients show conflicting findings.1319
However, a majority of these reports tive if not synergistic nephrotoxicity tion vancomycin and aminoglycoside
do suggest addiwith combinatherapy. One
clinical trial showed “synergistic” toxicity because the frequency of nephrotoxicity associated with combination therapy (35%) exceeded the cumulative frequency of nephrotoxicity for each separate drug.15 The mechanism for this apparent synergism was not
evaluated. Another combination comycin with an
limitation to the is the development is less incidence
ototoxic rate
use
of these agents in of ototoxicity. Van-
than the aminoglycosides of
The
Effect of Tobramycin on Handling of Vancomycin
Myrna
Y. Munar,
PharmD,
Lawrence
A. Golper,
Thomas
Elzinga,
MD,
and
William
MD,
Robert
M. Bennett,
the
AGENTS
Renal
Brummett,
PhD,
MD
Studies in experimental animals and humans have suggested that enhanced renal and auditory toxicity occur with concurrent vancomycin and aminoglycoside treatment. In volunteers, systemic vancomycin clearance at steady-state was measured simultaneously with renal clearances of vancomycin, creatinine, inulin, and para-aminohippurate. Group I (n = 9) received vancomycin 5 mg/kg IV for 1 hour, then 1.1 mg/kg/hr for 3 hours. Group II (n = 7) received vancomycin plus tobramycin (2 mg/kg IV over 30 mm). Groups did not differ demographically. Audiograms were obtained before and after vancomycin. Plasma samples were collected serially for vancomycin and tobramycin pharmacokinetic studies. Serum concentration versus time data were fit to a two-compartment model for vancomycin and a one-compartment model for tobramycin. For all volunteers, creatinine, inulin and para-ammnohippurate clearance, and audiograms were not altered from baseline and were not statistically different between groups. No significant effect of tobramycin on vancomycin pharmacokinetics was observed. Conversely, vancomycin had no significant effect on tobramycin pharmocokinetics. The nephrotoxic synergism of vancomycin and tobramycin is not explained by short-term differences in renal handling.
T
he use of a combination aminoglycoside has
broad-spectrum
of vancomycin become widespread
antibiotic
regimens
plus
because
an in
of
proven activity against most gram-positive and gram-negative pathogens. Indications for combined use of these agents include severe infections caused by methicillin-resistant staphylococci,1 enterococcal endocarditis in penicillin-allergic patients,2 treatment of peritonitis in CAPD patients,3 prophylaxis for cardiopulmonary bypass surgery,4 and empiric therapy of febrile episodes in neutropenic cancer patients.5 Despite proven efficacy, the overall clinical benefit of each agent is hampered by known dosedependent renal and auditory toxicities.
Nephrotoxicity associated with aminoglycoside use has been well documented with an overall frequency of 5 to 10% 68 The incidence of nephrotoxicity
From
resulting
from
the College
Medicine,
vancomycin
of Pharmacy.
Division
of
Oregon
Nephrology
Sciences Munar,
University. Portland, PharmD, OP 18, OSU
Oregon
Health
Portland,
618
Sciences
therapy
State
and Oregon. College
University,
#{149} J CIIn Pharmacol
University,
Hypertension, Address for of Pharmacy
3181
OR 97201-3098.
1991;31:618-623
is not
SW Sam
well
Department Oregon reprints: Portland
Jackson
of Health
Myrna V. Campus. Park
Road,
established but it appears to range from 0 to 7%9 When these drugs are used in combination a greater incidence of nephrotoxicity has been observed. Experiments done in rats have demonstrated enhanced nephrotoxicity with concurrent vancomycin and aminoglycoside administration compared with either agent used alone.1012 Available data on adult and pediatric patients show conflicting findings.1319
However, a majority of these reports tive if not synergistic nephrotoxicity tion vancomycin and aminoglycoside
do suggest addiwith combinatherapy. One
clinical trial showed “synergistic” toxicity because the frequency of nephrotoxicity associated with combination therapy (35%) exceeded the cumulative frequency of nephrotoxicity for each separate drug.15 The mechanism for this apparent synergism was not
evaluated. Another combination comycin with an
limitation to the is the development is less incidence
ototoxic rate
use
of these agents in of ototoxicity. Van-
than the aminoglycosides of
