Gentamicin Dosing Strategies for Dogs with SubclinicalRenal Dysfunction
DONITA L. FRAZIERt AND J. EDMOND RIVIERE*
Laboratory of Toxicokinetics, North Carolina State University School of Veterinary Medicine,Raleigh, North Carolina 27606
Received 8 June 1987/Accepted 16 September 1987
Twenty-six subtotally nephrectomized dogs were used as a model for subclinical renal dysfunction to evaluatethe nephrotoxic potential of gentamicin administered according to four different dosage regimens. Dosageswere individualized based on the pharmacokinetic disposition of drug in each dog. Gentamicin at 3.75 + 0.15mg/kg (mean ± standard error of the mean, total daily dose) was given for 12 days in two or three divided dailydoses (BID and TID, respectively) or in a 2-h or 4-h once-daily variable-rate infusion (2HI and 4HI,respectively) with loading dose. Analyses of serum chemistries and pharmacokinetic data were performed onthe ratio of pretreatment versus posttreatment parameters in individual animals. While serum chemistries andhistopathology revealed no significant differences in toxicity between treatment groups, pharmacokineticanalysis revealed a significant difference in the ratio of pretreatment versus posttreatment gentamicin clearance(1.35 ± 0.22, BID; 2.44 ± 0.52, TID; 0.91 ± 0.08, 2HI; 0.91 ± 0.07, 4HI). By using mean populationpharmacokinetic parameters (all dogs), predicted times for each treatment group administered 3.75 mg/kg perday to achieve concentrations in serum above the MICs of 2, 4, 6, and 8 ,ug/ml, respectively, were 7.8, 4.2, 2.0,and 0.6 (BID); 6.1, 3.0, 0.5, and 0.2 (TID); 7.1, 5.3, 4.2, and 3.5 (2HI); and 7.4, 5.8, 4.8, and 4.0 (4HI) h daily.This study suggests that decreasing the total daily dosage of drug may decrease the incidence of gentamicin-induced nephrotoxicity. Regardless of the dosage regimen, however, regimens may differ significantly inpredicted therapeutic efficacy. Predicted 30-min postdosing concentrations in serum were lowest in dogsadministered drug TID, and gentamicin clearance decreased in this group with treatment, suggesting that thisregimen may be the least efficacious as well as the most prone to causing future nephrotoxicity.
The incidence of nephrotoxicity secondary to therapy withgentamicin and other aminoglycosides has been well docu-mented. However, this class of drugs remains an essentialtherapeutic agent for the treatment of severe gram-negativeinfections. Traditionally, clinicians have altered doses basedon serum creatinine or creatinine clearance in an effort tominimize toxicity. Individuals with compensated subclinicalrenal dysfunction marked by a decreased number of func-tional nephrons and normal serum creatinine levels present adiagnostic dilemma, requiring that dosage alteration bebased on individual clearance of drug. Decreasing the dosagebased on clearance does not preclude toxicity, however,since exposure to drug on a per-nephron basis is increased inpatients with reduced functional renal mass (4, 8).
Previous studies have suggested that some dosage regi-mens may be less nephrotoxic than others. High peak andhigh trough concentrations in serum have been implicated asrisk factors for development of nephrotoxicity in humans(27). Studies in experimental animals have shown that in-creasing the dosage interval may be less nephrotoxic thandecreasing the dose and keeping the interval constant (1, 23).Continuous infusions of low concentrations of aminoglyco-sides may lead to greater cortical accumulation of drug thanintermittent injections and therefore predispose to nephro-toxicity (12, 25).
Equally important as the consideration regarding toxicityis that dosage regimens should be designed to maximizetherapeutic efficacy. Studies have shown increased efficacywith increasing the peak concentration of gentamicin and
* Corresponding author.t Present address: University of Tennessee College of Veterinary
Medicine, Knoxville, TN 37901.
with increasing the ratio of the peak concentration to theMIC (16-18, 26). Dosage reductions based on serum creati-nine levels may not achieve concentrations in excess of theMIC for the infecting organism in 30% or more of patients(22).While clinical evidence of toxicity or efficacy is generally
apparent, it is difficult to make definitive comparisons ofdosage regimens in human patients because dosages, meth-ods of administration, and definitions of resistance are notstandardized. This study used subtotally nephrectomizeddogs as a model for patients with reduced functional renalmass without overt signs of renal disease. Serum creatininelevels were within normal limits, but clearance of drug wasdecreased compared with that in dogs with normal kidneys.The standard gentamicin dosage for dogs, extrapolated fromthe human dosage of 5 mg/kg per day by using the half-life ofthe drug and the body weight of the dogs, has been deter-mined to be 9 mg/kg given in three daily doses of 3 mg/kgeach (23). This dose is not nephrotoxic in dogs with intactkidneys. The dosage was decreased based on the pharmaco-kinetic disposition of drug in each dog and administered atthe standard interval (8 h), a lengthened interval (12 h), orrelatively high 2-h or 4-h variable-rate infusions with loadingdoses (concentration in serum at steady state [C,s], 10 or 15p.g/ml). These dosage regimens were evaluated for theirtendency to produce toxicity, and predictions about thera-peutic efficacy were made.
MATERIALS AND METHODSTwenty-eight dogs were used in a randomized complete
block design with each block consisting of four treatmentgroups (BID, drug administered twice daily intramuscularly;TID, drug administered three times daily intramuscularly;
2HI, 2-h intravenous infusion at a C,, of 15 ,ig/ml once daily;4HI, 4-h intravenous infusion at a C,, of 10 ,ug/ml oncedaily). One block of infused dogs was later removed from thestudy because they were inadvertently administered infu-sions at a lower C, A complete physical examination,complete blood count, and determination of serum creati-nine and serum urea nitrogen levels were performed on eachdog prior to entry into the study to rule out confoundingdisease states. Female dogs were used because tubularsecretion of creatinine occurs in male dogs, complicatingevaluation of renal function. Dogs were housed singly inmetabolism cages in a controlled environment and fedWayne laboratory dog chow (Allied Mills, Chicago, Ill.) andwater ad libitum throughout the study.From 3/4 to 7/8 of functional renal mass was removed by
an aseptic surgical procedure described previously (23).Renal function was allowed to stabilize for 53 days postop-eratively, and serum creatinine, serum urea nitrogen, andurine production were monitored throughout this time pe-riod. Dosing with gentamicin began when the serum creati-nine level had stabilized and was within normal limits (0.90to 1.94 mg/dl).Dogs were administered gentamicin for 12 days. Genta-
micin dosages were individualized to the pharmacokineticdisposition of drug in each dog 6 days prior to dosing. Thissingle-dose pharmacokinetic study consisted of an intrave-nous bolus of drug followed by blood collections at 0, 15, 30,and 45 min and at 1, 1.5, 2, 4, 6, and 8 h postdosing.Gentamicin concentrations were determined by radioimmu-noassay (Diagnostic Products, Los Angeles, Calif.) from astandard curve prepared by a logit-log technique. The sen-sitivity was approximately 0.1 ,ug/ml, and the coefficient ofvariation was no greater than 10% for replicate samples.Concentration-time data were fit to a biexponential disposi-tion function where C, = Ae-" + Be-' by using anautomated curve-stripping procedure (CStrip) followed byweighted nonlinear least-squares regression (SAS NLIN); Aand B are the intercepts, a. and a are the slopes of thedistribution and elimination phases, respectively, and t is thetime elapsed since dosing (23). The biexponential model waschosen based on the Cp statistic and F test (StatisticalAnalysis Systems [SAS]).Dosages were calculated based on desired maximum and
minimum C,,s for dogs administered drug BID and TID.Minimum concentrations were less than 1 ,ug/ml, and targetmaximum concentrations were 20 and 12 ,ug/ml for BID andTID regimens, respectively. These concentrations representthose extrapolated to time zero and correspond to 30-minpostdosing concentrations in serum between 5 and 10 ,ug/ml,the range considered therapeutic in humans. By assuming atwo-compartment model, the dose was determined by D =CmaxVc [(k2l- a)/( - a)(1 - e OT) + (k21- P3)( - )(1 -e 1 9Df11 where Cmax is the maximum concentration of drug
in serum, Vc is the volume of the central compartment, k21 isthe rate constant for drug transfer from the peripheral to thecentral compartment, and T is the dosing interval (11).Dogs receiving gentamicin by 2HI or 4HI were adminis-
tered drug by computer-driven infusion pumps. The steady-state infusion was divided into two phases: loading dose(C,,Vc) and steady-state infusion rate CssVc(klo + K12e7k2lT),where T is the elapsed time of the infusion, k1o is the overallelimination rate constant, and k12 is the rate constant fordistribution of drug from the central compartment to theperipheral compartment in an open two-compartment phar-macokinetic model (7, 8). Serum samples were collecteddaily to determine whether the target CSS was achieved. Ondays 1 and 12, blood was collected from dogs in all treatmentgroups, beginning at 30 min postdosing or after the end ofinfusion and ending 8 h later for determination of drugclearance.Serum and 24-h urine collection samples obtained on days
2 and 3 and days 16 and 17 were measured for creatinine,urea nitrogen, Na, K, and osmolality by techniques de-scribed previously (23). Posttreatment collections were cho-sen (days 16 and 17) because it may take several days afterrenal insult before elevations in serum creatinine and ureanitrogen levels occur. Statistical analysis was done on theaverage of the two consecutive 24-h clearances. Addition-ally, changes in each of these clinical parameters wereevaluated by the relative change in each individual dog(prevalue versus postvalue). Dogs were sacrificed with so-dium pentobarbital on day 17. Renal tissue samples werecollected and processed routinely for light microscopy. Thepresence of casts, tubular necrosis, regeneration, tubulardilatation, and interstitial inflammation was scored blindlyby the following scale: 0, none of that lesion observed; 1,less than 5% of tubules or interstitium affected; 2, 5 to 20%affected; 3, 20 to 40% affected; and 4, more than 40%affected.One-way analysis of variance was conducted on all clini-
cal, pharmacokinetic, and histopathological parameters withthe SAS program. All values are shown as mean ± standarderror of the mean (SEM) for six dogs (2HI, 4HI) or sevendogs (BID, TID).
RESULTS
Histopathology revealed tubular necrosis, regeneration,and interstitial inflammation in all treatment groups. Therewere no significant differences between the histopathologicalscores of the four treatment groups (Table 1). Similarly,serum creatinine levels increased and creatinine clearancedecreased in all groups receiving gentamicin treatment, butthese changes were not significantly different betweengroups (Table 2).
Pretreatment pharmacokinetic parameters were not signif-
icantly different between groups (Table 3). Treatment withgentamicin resulted in decreased clearance of drug only in
C 0 the TID group. When this change in clearance was evaluatedon a per-dog basis (pre- versus postvalue), the treatment
^-' ~-. groups were significantly different (P < 0.001) (Table 4).E3 v2 > Although day 12 steady-state volumes of distribution (V,,)
I+ I+ I+ I+ were significantly different, the ratios of day 1 to day 12 VssIt o o o values analyzed on a per-dog basis were not significantlym> 00 o x v: different. Elimination half-lives (t4/2s) of drug increased in allg2 groups. The greatest increase was in the TID group, but this
0 swas not significantly different from the other groups, prob-ably because of the small sample size and variability in
1±I+ 1+It volume of distribution (since t112 is determined by bothCL..A.. 3 clearance [CLI and volume of distribution [V1: t412 =
0.693 V/CL).0.OOOOG Mean dosages administered to treatment groups were not
91 Xo be x °o° _significantly different (Table 4); however, the dogs on 2HIo It+It+It+l+ x and 4HI regimens received slightly higher doses. To evaluate. o 0 0 0 0 - treatment groups for therapeutic efficacy, mean population
kinetic parameters were calculated from data for all 26 dogs,and the mean total daily dose for all dogs was- determined to
-Rocb>oobe 3.75 mg/kg. Predicted concentration-time profiles for each:4.1 .71 .A .j treatment group administered 3.75 mg/kg per day are shown1+It It It It (> in Fig. 1. The peak concentrations for the BID and TIDoj !A :P1 vregimens shown in the figure were extrapolated zero-time
concentrations (y intercept A) and therefore are presumablyhigher than measurements in clinical patients obtained 30 to
i .. a. ,. O ;,, 60 min postdosing. Predicted times at which gentamicin3It ItItI 2. r concentrations in serum would be above the specified MICsx >c: ?o 02 m of 2, 4, 6, and 8 1g/ml were determined to be 7.8, 4.2, 2.0,
'IC . £ oand 0.6 (BID); 6.1, 3.0, 0.5, and 0.2 (TID); 7.1, 5.3, 4.2, and3.5 (2HI); and 7.4, 5.8, 4.8, and 4.0 (4HI) h daily from these
ooooQt c ~~~~~predicted profiles (Fig. 2).
DISCUSSION
Gram-negative bacilli have become the most prevalent.0 Oagents of bacteremia in the United States. Three-fourths of
these infections may be hospital acquired. Fatality rates are1+1+1+1+ high because the age of patients and severity of underlying
disease have increased. In gram-negative sepsis, patientsurvival is associated with early peak drug levels, with a\0 0x 2: large percentage of deaths occurring early during the course
C~~~~~CD of therapy; therefore, achievement of high concentrations of
drug as early as possible..is an essential goal (17; JastremskiI+ I+ I+ I+ and Chelluri, Ann. Emerg. Med. 15:634-635, 1986).
>Sos3 203- C
S_ v .0 0
_...C._...........-
A48 12 16 20 24
1+1+1+1+ T i10 NOIttI It .e Tim (Hr,,, ,° ,,°, | = ~~~~~FIG. 1. Predicted concentration-time profiles for subtotallyo°°°so ~~~~~~nephrectomized dogs administered 3.75 mg of gentamicin per kg on
the BID (-... ), TID (---), and 2HI and 4HI ( ) regimens.
Gentamicin concentrations 1 h postinfusion of greater than 7pLg/ml have been associated with more successful outcomesin gram-negative pneumonia (18). In contrast to the presentstudy, infusion studies generally have not achieved serumconcentrations this high (2, 3, 15).
Other patients requiring special consideration in designingdosage regimens are those in whom barriers may inhibitpenetration of an antimicrobial agent. Penetration of amino-glycosides into bronchial secretions and cerebrospinal fluidis limited to approximately 20% of the concentrations inserum, and therefore it may be difficult to achieve therapeu-tic concentrations of drug in these areas without inducingnephrotoxicity (15, 24). Since most antibiotics enter respira-tory fluids by passive diffusion (19), these drugs may becleared from the bronchial lumen by passive reabsorptionwhen concentrations in blood fall below bronchial concen-trations as well as by the mucociliary apparatus. Prolonginghigh concentrations in serum by using variable-rate infusionsmay increase aminoglycoside transport into the bronchialtree and decrease removal by absorption. With an increasingincidence of gram-negative endocarditis, associated withincreased age, cardiac surgery, and prosthetic valves (9),alternative aminoglycoside dosing regimens may improvetherapeutic efficacy and decrease the incidence ofnephrotoxicity that often accompanies required prolongedhigh-dose therapy (21, 29).Recent studies have indicated that the therapeutic efficacy
of aminoglycosides depends on peak concentrations and thearea under the curve (AUC). Theoretically, total AUCshould not differ for the four regimens evaluated (AUC =DICL); however, the AUC should be expected to be less for"each" dose in the BID or TID regimen compared with the2HI and 4HI regimens because each dose is less. Infusionstudies involving evaluation of therapeutic efficacy generallydo not include administration of a loading dose, and since theinfusions are given at a constant rate, concentrations inserum during a significant portion of the infusion are belowthe steady-state serum concentrations. Use of a variable-rateinfusion pump allows one to achieve target concentrationsthroughout the infusion period. Actual concentrations inserum achieved with the infusions in this study exceeded theconcentrations achieved with intramuscular dosing.
Since infusions were administered only once daily, a validconcern is that breakthrough bacteremia may occur. Thepredicted number of hours per day during which resistantorganisms would be exposed to concentrations of drugbelow a specified MIC was calculated to be lower for theinfusion regimens than for the intermittent doses (Fig. 2).This was most notable for resistant organisms (MICs greaterthan 4 ,ug/ml). The length of time of subtherapeutic concen-trations between doses should also be considered. Thepredicted time in a dosing interval during which levels inserum would be below 4 ptg/ml was approximately 7 h for theTID regimen, 10 h for the BID regimen, and 18 h for the 2HIand 4HI regimens. Recent studies have demonstrated a post-antibiotic effect that may explain therapeutic efficacy with
regimens having drug concentrations in serum below theMICs for the infecting organisms for prolonged periods oftime (5, 10). This effect appears to vary with the organismand the AUC of the antibiotic; therefore, postantibioticeffect may depend on the dose and peak concentration ofdrug, and dosage regimens may differ in this phenomenon.
In contrast to the low doses used to assess the efficacy ofinfusions, studies designed to assess toxicity typically usesupratherapeutic concentrations of drug (20). Most studieshave used infusions that were administered for -6 h daily.This study evaluated the toxicity of four regimens withreduced dosages based on individual drug clearance. Aprevious study in our laboratory showed that steady-stateinfusions that achieved concentrations in serum of 6 ,ug/mlfor 6 h were nephrotoxic to subtotally nephrectomized dogs(8). Therefore, the present study was designed to achievehigher steady-state concentrations of drug for a shorterperiod of time while keeping the total daily dose approxi-mately the same. Gentamicin clearances were somewhatlower in the present study, resulting in greater reductions indose than in the previous study (3.75 ± 0.15 versus 5.6 ± 1.2mg/kg per day, mean ± SEM).Only in dogs administered drug TID did gentamicin clear-
ance decrease significantly. This has been associated with aprenephrotoxic state in humans (25). It cannot be concludedwith certainty that this regimen is more nephrotoxic than theothers because histopathological lesions were not signifi-cantly different from those in the other groups. Peak con-centrations were lower in this group than in the other groups,and efficacy should be of concern in cases involving resistantorganisms.The suggestion that steady-state infusions that achieve
high concentrations in serum for relatively short periods oftime might be less nephrotoxic than intermittent doses is notunexpected. Others have found greater renal cortical uptakewith low levels of continuous drug infusion and low doses offrequently administered aminoglycoside than with highdoses given once daily (6, 12). Gentamicin uptake in rats is
C-
6-
.ocu
4 6 8MIC (ug/mL)
FIG. 2. Predicted time to achieve concentrations in serum abovethe MICs for dogs administered 3.75 mg of gentamicin per kg on theBID (O), TID (0), 2HI (A), and 4HI (a) regimens.
nonlinear, with the apparent Km being approximately 15,ug/ml (13). Another study by the same group showed thatsubtotal nephrectomy in rats resulted in an increase in Ki,,with no clear saturation occurring during a 6-h gentamicininfusion (28). They concluded that gentamicin uptake wasdiminished in rats with renal failure, particularly at lowconcentrations. With constant low-level infusion, however,one could expect a greater total accumulation of drug inpatients with renal failure because transport is not saturable.To our knowledge, uptake kinetics have not been clearlydefined for dogs.No definite recommendations can be made for the use of
these regimens in clinical cases. In light of the low serumconcentrations achieved by the TID regimen and the de-crease in drug clearance with gentamicin treatment, thisregimen should probably be avoided in patients withsubclinical renal dysfunction. There is some experimentalevidence that high doses of aminoglycosides administeredonce daily can be efficacious in certain infections (14), butthis needs to be verified in other disease models. The resultsof this study suggest that further studies should be done toassess the effects of variable-rate infusions that achieve highdrug concentrations in serum for short durations on thepenetration of aminoglycosides into "protected" compart-ments and the efficacy of these regimens in achieving curesin various infections. The clinician should consider alterna-tive antimicrobial agents when renal dysfunction, eitherovert or subclinical, necessitates significant reduction of theaminoglycoside dose. With the increasing proportion ofelderly in our population and the increase in the number ofgram-negative infections in this group, it will become in-creasingly important to design efficacious dosage regimensthat are minimally nephrotoxic.
ACKNOWLEDGMENTS
This study was supported in part by Public Health Service grantAM-31862 from the National Institute of Arthritis, Diabetes, andDigestive and Kidney Diseases.
J. W. Sagartz is acknowledged for excellent assistance in patho-logical analysis. We also thank M. Tioran, L. Jackson, I. Fitch, andD. McLamb for technical assistance.
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