Antibiotic dosing in renal failure

0025-7125/95 $0.00

ANTIMICROBIAL THERAPY 11

+ .20

ANTIBIOTIC DOSING IN RENAL FAILURE Eufronio G. Maderazo, MD

In this article, the practical methods of adjusting doses of antibiotics in patients with abnormal renal function are discussed. The focus is mainly on simplifying the processes and calculations involved; for an extended review of the mechanisms and changes in antibiotic pharmacokinetics in renal failure, the interested reader is referred to a number of reviewsY-16, 25, 34 The effects of hemodialysis and peritoneal dialysis are not reviewed here; they are as yet not amenable to simplification (because of lack of standardization and excessive individual variability), they have been amply reviewed, and there are recently published guidelines for postdialysis replenishment. 1, 20, 28, 33 In making dose adjustments of antibiotics in renal dysfunction, there are several important practical and commonsense considerations. First, the initial dose (loading dose) is generally the same regardless of renal function, and adjustments are made for subsequent (maintenance) doses. Second, the calculated dose adjustments are only reasonable estimates, and individual variability can be determined only by measurements of drug concentrations in blood. The clinical importance of this consideration parallels the degree of toxicity of the drug being used and, in today's environment, perhaps also its cost. Third, the therapeutic indices of toxic antibiotics are not as narrow as implied by the apparent pharmacokinetic zeal for accurate calculations but rather is wide enough, as indicated by the usefulness of gross estimates of dosage changes suggested by various references.!' 2 Therefore, the desire, effort, and necessity to make accurate calculations of these changes should be tempered not only by the variability of individual patients and pub-

From the Department of Medicine, William W. Backus Hospital, Norwich, Connecticut MEDICAL CLINICS OF NORTH AMERICA VOLUME 79· NUMBER 4· JULY 1995

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lished pharmacokinetic data, but also with the practical or standard dose or dosing interval of drug. For example, it is not necessary to give antibiotics in fractions of a milligram; nor is it necessary to give them in intervals measured in minutes or seconds. For these reasons, rounding numbers to ease calculations can be used. Although the pharmacokinetic concepts involved in dosing adjustments in renal failure are not complex, the variously proposed formulas and equations are not amenable to calculations "in the head" and are, therefore, not attractive to clinicians, many of whom have shunned this undertaking and have relied on other resources. Unfortunately, these resources are not always available to the busy clinician, nor are the clinical pharmacists always around, and so there is a need for an easily remembered and simplified approach to the calculation of the adjusted dose or dosing interval of antibiotics in renal failure. DREM SYSTEM

The author and his coworkers have described how estimating of drug doses in the presence of renal failure can be made simpler.22 The method is called the DREM system (Dosing in Renopathy by Easy-touse Multipliers System) because it involves the use of multipliers to ease the calculations. When DREM was compared with other methods previously published," 2, 's, 29 the calculated daily maintenance doses for various antibiotics at various degrees of renal insufficiency were in general agreement and were within the wide dosage ranges recommended by others (Tables 1 and 2), with one exception (see Table 2). When compared with dosing recommendations of Hull and Sarubbi 19 for gentamicin there was close correlation between the two methods (correlation coefficient = 0.9). There were less trough values above 2 JvLg/mL with the DREM system, however, implying an advantage because an important goal of monitoring and dose adjustment for gentamicin is to avoid excessive trough levels above 2 JvLg/mL. The DREM system takes advantage of the proportionality of drug elimination and the maintenance dose of drug to bypass the usual pharmacokinetic equations and the tortuous calculations used to estimate the needed dose changes. The premise and the procedure can be stated simply as follows:

If a drug is totally eliminated by an organ and organ function is diminished, the adjusted dose of drug is proportional to the organ function remaining. Multiplying the fraction or percentage (the multiplier) of organ function remaining by the normal dose obtains the adjusted dose.

If creatinine clearance (CLcr), the widely accepted measure of kidney function, is then set at 100 mL/minute, which is the approximate

Table 1. COMPARISON OF THE SUGGESTED MAINTENANCE DOSE FOR SEVEN ANTIBIOTICS AS A PERCENTAGE OF USUAL DOSE AT VARIOUS LEVELS OF RENAL FUNCTION Suggested Maintenance Dose of 7 antibiotics (% of usual dose)* PDR29

Bennett et aP CLcr (mUmin)

DREM for all 7 drugs

Genta, Kana, Tobra

Strep

100 90 80 70 60

100 90 80 70 60

60-90 60-90 60-90 60-90 60-90

50 40 30 20 10

50 40 30 20 10

30-70 30-70 30-70 30-70 20-30

N ....

Amantadine

Vanco

Genta, Kana, Tobra, Amik

Netil

Vanco

% Doset

100 100 100 100 100

30-100 30-100 30-100 30-100 30-100

100 84 80 76 56

100 90 80 70 60

100 90 80 70 60

100

200 mg/day

100

200 mg/day

75

200/100 mg alternate

30-90 30-90 30-90 30-90 20-30

30-100 10-30 10-30 10-30 10

53 48 42 25 19

55 45 32 22 12

50 40 30 20 10

50 50 30 22 11

100 mg/day 100 mg/day 200 mg twice weekly 100 mg thrice weekly 200/100 alternating every 7 days

Amik ~ Amikacin; Genta ~ gentamicin; Kana ~ kanamycin; Netil netilmicin; Strep ance. 'Values are % of usual daily maintenance dose ~ CLcr. tAverage daily dose as a percentage of normal (usual) adult dose of 200 mg.

I.C

Horadam et al'·

~

streptomycin; Tobra

~

tobramycin; Vanco

~

Dosing Regimen

days

vancomycin; CLcr

~

creatinine clear-

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Table 2. COMPARISON OF THE SUGGESTED MAINTENANCE DOSE FOR TWO ANTI-HIV DRUGS AS A PERCENTAGE OF USUAL DOSE AT VARIOUS LEVELS OF RENAL FUNCTION Suggested Doses of Foscarnet and Gancyclovir (% of usual dose) DREM

CLcr (mUmin)

Applicable for both drugs'

90-100 80-90 70-80 60-70 50-60 40-50 30-40 20-30 10-20

90-100 80-90 70-80 60-70 50-60 40-50 30-40 20-30 10-20

Information from Package Inserts of Drugs Foscarnet (induction)t

Foscarnet (maintenance)t

90-100 80-90 70-80 60-70 50-60 40-50 35-42 30

87-100 87 83-87 79-83 70-79 70 63-70 63

:j:

:j:

Gancyclovirt

100 100 50 50 50 25 25 13 13

*Values are % of usual daily maintenance dose ~ CLcr. tModified from package inserts of the drug. There is sufficient difference between dosing adjustments for maintenance doses of foscarnet with DREM and the manufacturer's recommendation. For now, follow the manufacturer's recommendations. :j:The manufacturer does not recommend use in patients with CLcr <20 mUmin. CLcr ~ Creatinine clearance.

adult male value, the patient's CLcr equals the maintenance dose of drug expressed as a percentage of the normal dose. This percentage is the dose multiplier (CLcr/lOO), and the adjusted dose can then be obtained by multiplying this with the usual dose. Thus, for aminoglycosides or vancomycin, drugs that are (almost) totally eliminated by the renal route, a drop in renal function to 50% of normal requires a maintenance dose that is 50% of the usual (50% or 50/100 = the dose multiplier). If changing the interval of dosing is preferred to reduction in dose, the adjusted interval is inversely proportional to the organ function remaining, and the change of the dosing interval equals the reciprocal of the percentage of organ function remaining. For example, a 50% drop in renal function requires lengthening the dosing interval to two times the usual duration (interval multiplier = reciprocal of 50/100 = 100/50 = 2); thus, a drug usually dosed every 12 hours is dosed every 24 hours (2 X 12). Readers interested in the mathematical derivation and basis of the multipliers are referred to the Appendix. FURTHER SIMPLIFICATION WITH THE DREM SYSTEM

Further simplification of DREM can be achieved by (1) estimating CLcr from available or easily obtainable clinical data and (2) rounding of numbers. The simplest and most widely accepted method of estimating the patient's CLcr is with the method of Cockcroft and Gault8 because it is dependent on easily obtainable data:

ANTIBIOTIC DOSING IN RENAL FAILURE

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CLcr = [140 - Age (years)] X Weight (kg) Serum creatinine (mg/ dL) X 72 The CLcr for women is calculated at 85% of the value for men to correct for their smaller muscle mass. It is faster and easier to subtract 15% rather than to multiply by 0.85, and a fast and simple rule for determining 15% is 10% + 1f2 of 10% (thus, 15% of 80 = 8 + 4 = 12). Because the average man is approximately 70 kg, the weight and 72 may cancel each other out in the average man, further simplifying the equation as follows: 140 - Age (years) CLcr = -----""------"'-------'---Serum creatinine (mg/ dL) The significance of the weight factor, however, increases as it deviates further away from 70, in which case the ideal weight should be used, or the actual weight if it is less than the ideal weight: Ideal weight for men = 50 kg + 2.3 kg/inch above 5 feet Ideal weight for women = 45 kg + 2.3 kg/inch above 5 feet Determination of CLcr by the standard 24-hour urine collection is not only impractical, but also has its own inherent problems (incomplete urine collection among others) and is not, therefore, recommended. Further ease in calculation can be attained by rounding numbers (CLcr can be rounded to the nearest 10; the 2.3 kg/inch factor for calculating the ideal weight can be rounded to 2 without incurring considerable error). This rounding is acceptable because therapeutic indices of the most toxic group of antibiotics are not so narrow as to disallow a 5% to 15% error, and clinical variability usually exceeds these percentages. Nonetheless, clinicians must avoid excessive errors. As a general rule, it is best to avoid errors exceeding 20% unless there is supportive evidence that it is acceptable; e.g., gross guidelines for dosing changes in renal failure recommend similar doses for a wide range of CLcr exceeding well beyond 20% (see Table 1). To illustrate how rounding can simplify calculations, consider a male patient with an estimated CLcr of 54 mL/minute, who might normally require 150 mg every 8 hours of tobramycin; the CLcr is rounded to 50 and the adjusted dose is 75 mg every 8 hours (50/100 X 150 = 0.5 X 150 = 75). The clinician can order the 75 mg (every 8 hours) dose or opt to round it to 80 mg because the CLcr was rounded down to 50 from 54, and 80 mg is a practical unit dose for gentamicin. Suppose that the clinician wanted to be accurate and used 54 mL/ minute in the calculation; the calculated dose would be 81 mg every 8 hours. Suppose also that the trough concentration obtained with this dosing is 1.5 f1g/mL; the trough concentration had the patient been given 75 mg would be 1.4 f1g/ mL. Most clinicians would not consider this difference significant for clinical purposes. The same patient requiring vancomycin normally dosed at 1 g every 12 hours has an adjusted dosing interval of 1 g every 24 hours

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(dosing interval = 100/50 X 12 = 2 X 12 = 24). Supposing that the clinician used the CLcr of 54 in the calculation, the dosing interval calculated would be 22.2 hours. The difference again would also not be clinically relevant, and the dosing interval, if ordered, would be considered impractical by most pharmacy services. DREM IN ONCE-DAILY DOSING OF AMINOGL YCOSIDES

The antibiotics listed in Table 3 are those that require close monitoring and adjustments in renal failure because they are relatively toxic and are almost exclusively eliminated by the kidneys. Of these, the most frequently used are probably the aminoglycosides and vancomycin, and the two most commonly used aminoglycosides are gentamicin and tobramycin. For a variety of reasons, a minority of hospitals prefer to use amikacin or netilmicin. Gentamicin and tobramycin have significant differences in microbiologic activities (gentamicin is more active against Serratia and possesses greater synergistic activity with (3-lactams against Enterococcus, whereas tobramycin is more active against most other gram-negative bacilli, particularly Pseudomonas aeruginosa), but only minor pharmacokinetic differences, which are not clinically relevant. There has been interest in administering the total daily dose of Table 3. ANTIMICROBIALS REQUIRING MAJOR DOSING ADJUSTMENTS IN RENAL FAILURE BY VIRTUE OF TOXICITY AND HIGH RENAL ELIMINATION Antimicrobial Aminoglycosides Amikacin Gentamicin Kanamycin Netilmicin Streptomycin Tobramycin Antifungal Flucytosine Antivirals Acyclovir Amantadine Foscarnet Gancyclovir Glycopeptides Teicoplanin Vancomycin Polymyxins Colistin Polymyxin B

% Nonrenal Elimination'

5 5 5 5 5 5 5

10 10 10 10

o 5

10 10

'Estimates for non renal elimination were rounded to the nearest 5% and have varied from study to study. Data from references 28 and 33.

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aminoglycosides once daily rather than in two or three divided doses. This mode of administration results in high peak and low or undetectable trough concentrations. The method derives its rationale from, and takes advantage of, several pharmacokinetic and pharmacodynamic characteristics of aminoglycosides. First, aminoglycosides exhibit concentration-dependent bactericidal action, meaning that the greater the drug concentration, the more efficient the bacterial killing. 23 Second, amino glycoside toxicity is time dependent; thus, toxicity occurs following exposure to sustained drug levels for a long time but not from short exposures to high concentrations.]' 31, 35 Third, aminoglycosides have a relatively long postantibiotic effect, so that viable bacteria continue to die or be inhibited for many hours during the antibiotic-free interval. 36 For aminoglycosides, the postantibiotic effect may last up to 7.5 hours depending on the peak concentration achieved. An increasing number of clinical studies have confirmed the utility of this method of administration in humans (reviewed by references 17 and 21 ).17,21,26,27,32 In 1992, the author and coworkers reported their regimen and monitoring nomogram for once-daily dosing of tobramycin and gentamicin. 2h The goal of the regimen was to achieve peak serum concentrations approaching 20 fLg/mL (10 times the minimum inhibitory concentration [MIC] of the majority of clinically significant gram-negative isolates and 5 times the National Committee on Clinical Laboratory Standards (NCCLS)-defined susceptible range of:=;4 fLg/mL). To achieve this peak, the author and coworkers used a dose of 7 mg/kg. Initial dosing interval was based on estimated CLcr by the method of Cockcroft and Gault: CLcr (mLlmin) 2:60

59-40 39-20

Dosing interval (hr) 24

36 48

and subsequent interval adjustments were made using a single 12-hour "random" serum concentration: 12-hour concentration (JLg/mL) :0;3 3-5

5-7 >7

Dosing interval (hr) 24

36

48

Monitor concentrations and dose as appropriate

This can be easily remembered as the 3-5-7 nomogram. In the initial 19 patients studied, the mean (± SD) peak was 18.5 ± 6.3 fLg/ mL. Experience with the first 500 patients using this dosing regimen and monitoring nomogram revealed a 1.2% nephrotoxicity (compared with historical controls of 5%), no clinically apparent ototoxicity, no apparent alterations in clinical response, and no episode of neuromuscular blockade. 27 This experience has now expanded to more than 2000 patients with no change in findings. The DREM system can be used to adjust the dosing interval in oncedaily dosing of tobramycin or gentamicin. The dosing interval multiplier is the same (100/CLcr), but the normal dosing interval to use for calcula-

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tion should be 18 hours instead of 24 hours, to minimize the inappropriate extension of the drug-free interval as the dosing interval is prolonged with increasing renal failure. Table 4 shows the relative decay of gentamicin or tobramycin levels in serum as a function of time after dose and CLcr in a hypothetical 70-kg man receiving 7 mg/kg of gentamicin, assuming a volume of distribution of 0.35 L/kg and normal half-life of 2.5 hours. An additional benefit of once-daily dosing not previously mentioned but important in the author's experience is that the long dosing interval allows ample time to reassess in case of changing renal function, a common event in clinical practice. There is time to recheck the serum creatinine or serum drug concentrations before giving the next dose. For example, if there is a significant change in the serum creatinine (>0.5 mg/dL/24 hours), one can recheck the serum creatinine and the drug concentration. A new CLcr can then be recalculated using the new serum creatinine value or the method described by Chow and Schweizer? Some have suggested using a short timed urine collection to recalculate the "true" CLcr, but individualized drug clearance can be obtained more directly with serum drug concentrations than with CLcr. A simple approach to follow (for gentamicin and tobramycin) is always to get a 12-hour drug level with the first dose. (Waiting for steady-state is not required because all doses in once-daily dosing are loading doses.) If the level exceeds the predicted value using the 3-5-7 nomogram, an 18or 24-hour drug level is obtained. The percent drop in drug level in the 6 hours between 12 and 18 hours is the same percent drop for the next 6 hours between 18 and 24 hours. For example, if the 12-hour level is 5 fLg/mL and the 18-hour level is 2.5 fLg/mL (a drop of 50%), the level at 24 hours (6 hours later) can be estimated to be 1.25 fLg/mL (50% of Table 4. ESTIMATED SERUM CONCENTRATION AS A FUNCTION OF TIME AFTER DOSE AND CREATININE CLEARANCE IN A 70-KG MAN GIVEN A DOSE OF 7 MG/KG* CLcr (mUmin) 100 90 80 70 60 50 40 30t 20t 10t

Dose Interval (h)

Estimated Serum concentration (,...g/ml)

Calculated

Practical

6h

12 h

18 h

24 h

36 h

48 h

18 20 23 26 30 36 45 51

24 24 24 24 24-36 36 48 48

3.8 4.5 5.3 6.2 7.4 8.7 10.3 12.1 14.3 16.9

0.7 1.0 1.4 1.9 2.7 3.8 5.3 7.4 10.3 114.3

0.1 0.2 0.4 0.6 1.0 1.7 2.7 4.5 7.4 12.1

<0.1 <0.1 0.1 0.2 0.4 0.7 1.4 2.7 5.3 10.3

<0.1 0.1 0.4 1.0 2.7 7.4

<0.1 0.1 0.4 1.4 5.3

:I: :I:

:I: :I:

'Assumptions: Volume of distribution = 0.35 Ukg; normal half-life = 2.5 hours. tNonrenal losses (1-10%) may need to be replaced in very low CLcr «30 mUmin) to avoid underdosing because of their added importance as renal function declines; thus, a 10% nonrenal elimination is 50% of total drug elimination at a CLcr of 10 mUmin (10% of normal function). :tMonitor levels and dose as appropriate. CLcr = Creatinine clearance.

ANTIBIOTIC DOSING IN RENAL FAILURE

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2.5). This procedure allows a more direct and accurate measure of individualized decay of serum drug concentration than is possible with CLcr calculated by the best of methods. The 6- or 12-hour timing between samples makes the calculation of levels at standard dosing intervals easier. Several situations demand extra caution. First, clinicians have little experience using the once-daily dosing regimen in pediatric patients. These patients have much higher creatinine and drug clearances of many drugs, including aminoglycosides. In the author's limited experience with pediatric patients, it appears that at least 10 mg/kg of gentamicin or tobramycin is needed to achieve a peak of ~20 f.Lg/mL and maintain adequate levels (see the case report and Fig. 1). Another area of concern is severe renal failure (CLcr <30 mL/ minute). Once-daily dosing in these cases exposes them to prolonged high concentrations exceeding 2 f.Lg/mL, and the needed washout period prolongs exposure to subtherapeutic levels. Although the latter is not of much concern because aminoglycosides are usually used in conjunction with a f3-lactam or vancomycin for synergistic activity, the toxicity issue is. Added to this concern is the relative difficulty of monitoring auditory function in ill patients. Consequently, in patients with severe renal dysfunction, it is preferable to limit single large dosings to a maximum of 5 mg/kg and limit the number of doses to one to two doses for CLcr of 10 or less, two doses for CLcr of 20, and three doses for CLcr of 30. This regimen should cover the patient for at least 6 days. If after that period the patient continues to require antimicrobials, the author's preference is to use another antibiotic or accept a higher risk of toxicity. If prolonged aminoglycoside use is needed for synergy in these patients, KJ., 7 y.o. male, 25 kg Gentamicin, 250 mg iv daily 100

~::I. d 0

'E

10

~

......

E .., u

(3

F;::::

~

e ~

en

.........

0.1

~ o

2hrs: 11.6 6hrs: 4.1 12hrs: 1.2

4

8

12

16

20

24

Time, hrs.

Figure 1. Serum concentration versus time curve of gentamicin given at a dose of 10 mg/kg IV to a 7-year-old boy.

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such as for enterococcal endocarditis, the traditional dosing regimen is used with the usual dosing interval adjustments. Note that there are as yet no convincing data for or against the use of the once-daily dosing of gentamicin (plus ampicillin treatment) for enterococcal endocarditis. Other situations that require caution include patients with chronic liver or hepatobiliary disease with ascites, obesity, and severe burns because they appear to be especially prone to aminoglycoside toxicity.5, 9,10,24 In these patients, part of the problem appears to be that the volume of distribution is less predictable. Moreover, there may be a dissociation between creatinine and drug clearances. These cases are often treacherous because they may seem to be stable in a dosing regimen when trough levels would begin to rise without a concomitant rise in serum creatinine initially. In these patients, monitoring should be done not only with serum creatinine, but also with drug levels, and, as in patients with severe renal dysfunction, aminoglycosides should be used sparingly, cautiously, or not at all. DREM IN ANTIBIOTICS THAT ARE ONLY PARTLY ELIMINATED BY THE KIDNEYS

The DREM system can also be used to calculate the dose adjustments of most, if not all, drugs that are only partly eliminated by the kidneys. The process simply involves calculating separately and adding together the renally and nonrenally eliminated drug. For example, a patient whose CLcr is 10 mL/minute and who needs ceftriaxone (standard dose 2 g daily given as 1 g every 12 hours), which has a renal fraction of 0.46, has an adjusted daily dose of 1.172 g daily [(2 X 10/ 100)0.46 + (2)0.54 = (0.2)0.46 + 1.08 = 0.092 + 1.08 = 1.172]. This is rounded to 1.0 g given daily or 500 mg given every 12 hours. These calculations can be made simpler if the renal and nonrenal fractions are rounded to 0.5 (50%) each. The adjusted dose (1.1 g) can be calculated without a calculator, which is still rounded to 1.0 g. CHANGING THE DOSE OR CHANGING THE DOSING INTERVAL

With DREM, one can adjust the dose or the dosing interval. As a general rule, the author prefers to change the interval of dosing for aminoglycosides and adjust the dose for [3-lactams. For aminoglycosides, one wishes to achieve high peaks and low troughs for reasons already mentioned (i.e., the drug's concentration-dependent bactericidal activity and trough [concentration]-dependent toxicity). [3-Lactams have time-dependent bactericidal activity, no significant nephrotoxicity, and short or absent postantibiotic effects except perhaps against staphylococci. 6 These drugs are, therefore, preferably given in smaller doses at shorter intervals or by continuous infusion. 6

ANTIBIOTIC DOSING IN RENAL FAILURE

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For vancomycin, the author often combines changes of both the dose and the dosing interval because many patients suffer from disturbing gastrointestinal side effects with 2 g intravenously. Changing the dosing interval is essentially for convenience and cost considerations. VANCOMYCIN PECULIARITIES

One should remember that the newer, more efficient high-flow / high-flux hemodialysis systems (polysulfone, cellulose triacetate, and polyacrylonitrile dialyzers)ll can remove vancomycin and that a dose of 1 g maintains adequate concentrations (trough 2"5 j.Lg/mL) for only 5 to 7 days. Those who check postdialysis serum concentration of vancomycin must recognize the rebound phenomenon, in which levels several hours after dialysis are higher than that obtained immediately postdialysis. 4 , 11, 30 This phenomenon is due to the delayed transport of extravascular drug to the intravascular compartment relative to the rate of drug removal from blood. The immediate postdialysis level, therefore, overestimates the amount of total body drug removed and may not be used to calculate pharmacokinetic parameters. As a general rule, the actual drop of body stores is only approximately one half of that reflected by the drop in serum levels measured immediately after dialysis. Thus, if the serum concentration drops from 20 j.Lg/mL predialysis to 13 j.Lg/mL immediately postdialysis (35% decrease), the actual drop should be roughly 17.5%, and the corrected serum concentration should be 16 to 17 j.Lg/mL.4,30 Case Report

A 7-year-old boy developed an infection with osteomyelitis of a crushinjured right big toe. Pseudomonas aeruginosa, which was sensitive to ceftazidime and gentamicin, was repeatedly grown from deep wound cultures. The patient was started on ceftazidime and gentamicin. Gentamicin was initially given intravenously at 7 mg/kg once daily based on the author's experience with adults. Because 12-hour serum concentration was undetectable, the patient's dose was increased to 10 mg/kg and serum concentrations were as follows: 2 hours = 11.6 f.Lg/mL; 6 hours = 4.1 f.Lg/mL; 12 hours = 1.2 (see Fig. 1). On the 21st day of treatment, he developed leukopenia, which necessitated discontinuation of ceftazidime. Gentamicin was therefore continued to the 28th day. No nephrotoxicity or apparent ototoxicity was noted. Patient is well more than 2 months after completion of treatment.

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3. Bennett WM, Plamp CE, Gilbert DN, et al: The influence of dosage regimen on experimental gentamicin toxicity: Dissociation of peak serum levels from renal failure. J Infect Dis 140:576-580, 1979 4. Bohler J, Reetze-Bonorden P, Keller E, et al: Rebound plasma level after haemodialysis with highly permeable membranes. Eur J Clin Pharmacol 42:635-639, 1992 5. Boucher BA, Kuhl DA, Hickerson WL: Pharmacokinetics of systemically administered antibiotics in patients with thermal injury. Rev Infect Dis 14:458-463, 1992 6. Brook 1, Craig W A, Drusano GL, et al: Continuous vs. intermittent infusion of betalactam antibiotics: A potential advance (proceedings from a Roundtable. Moellering RC, moderator). Infect Med 9B:6-32, 1992 7. Chow MSS, Schweizer R: Estimation of renal creatinine clearance in patients with unstable serum creatinine concentration: Comparison of multiple methods. Drug Intell Clin Pharm 9:385-390, 1986 8. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 9. Corcoran GB, Salazar DE, Schentag JJ: Excessive aminoglycoside toxicity in obese patients. Am J Med 85:279, 1988 10. Desai TK, Tsang TK: Aminoglycoside toxicity in obstructive jaundice. Am J Med 85:47-50, 1988 11. DeSoi CA, Sahm DF, Umans JG: Vancomycin elimination during high-flux hemodialysis kinetic model and comparison of four membranes. Am J Kid Dis 20:354-360, 1992 12. Dettli L: Drug dosage in renal disease. Clin Pharmacokinet 1:126-134, 1976 13. Fabre J, Balant L: Renal failure, drug pharmacokinetics, and drug action. Clin Pharmacokinet 1:99-120, 1976 14. Gambertoglio GJ: Renal disease and pharmacokinetics. In Benet LZ, Massoud N, Gambertoglio JG (eds): Pharmacokinetic Basis for Drug Treatment. New York, Raven Press, 1984, pp 111-145 15. Gambertoglio GJ: Effects of renal disease: Altered pharmacokinetics. In Benet LZ, Massoud N, Gambertoglio JG (eds): Pharmacokinetic Basis for Drug Treatment. New York, Raven Press, 1984, pp 149-171 16. Gibson TP: Influence of renal disease on pharmacokinetics. In Evans WE, Schentag JJ, Jusko WJ (eds): Applied Pharmacokinetics. Spokane, WA, Applied Therapeutics, 1986, pp 83-115 17. Gilbert DW: Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 35:399-405, 1991 18. Horadam VW, Sharp JG, Smilack JD, et al: Pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function. Ann Intern Med 94:454458, 1981 19. Hull JH, Sarubbi FA Jr: Gentamicin serum concentration: Pharmacokinetic predictions. Ann Intern Med 85:183-189, 1976 20. Lee Cc, Marbury TC: Drug therapy in patients undergoing haemodialysis. Clinical pharmacokinetic considerations. Clin Pharmacokinet 9:42-66, 1984 21. Levison ME: New dosing regimens for aminoglycoside antibiotics. Ann Intern Med 117:693-694, 1992 22. Maderazo EG, Sun H, Jay GT: Simplifying antibiotic dose adjustments in renal insufficiency: The DREM System. Lancet 340:767-770, 1992 23. Moore RD, Leitman P, Smith CR: Clinical response to aminoglycoside therapy: Importance of the ratio of peak concentration to minimum inhibitory concentration. J Infect Dis 155:93-97, 1987 24. Moore RD, Smith CR, Lietman PS: Increased risk of renal dysfunction due to interaction of liver and aminoglycoside. Am J Med 80:1093-1097,1986 25. Neis AS: Principles of drug therapy. In Wyngaarden JB, Smith LH Jr, Bennett JC (eds): Cecil Textbook of Medicine, ed 19. Philadelphia, WB Saunders, 1992, pp 81-92 26. Nicolau DP, Freeman CD, Belliveau PP, et al: Once-daily aminoglycosides (ODA): Alternate dosing methods and monitoring nomogram [abstract no. 208]. In Programs and Abstracts of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy (Anaheim). Washington, DC, American Society for Microbiology, 1992 27. Nicolau DP, Freeman CD, Nightingale CH, et al: Once-daily aminoglycosides (ODA): Experience with 500 patients in a hospital-wide program [abstr no. 85]. In Programs

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28. 29. 30. 31. 32. 33. 34. 35. 36.

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and Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (New Orleans). Washington, DC, American Society for Microbiology, 1993 O'Brien MA, Mason NA: Systemic absorption of intraperitoneal antimicrobials in continuous ambulatory peritoneal dialysis. Clin Pharm 11:246-254, 1992 Physician's Desk Reference, ed 4. Montvale, NJ, Medical Economics Data, 1994 Pollard TA, Lampasona V, Akkerman S, et al: Vancomycin redistribution: Dosing recommendations following high-flux hemodialysis. Kidney Int 45:232-237, 1994 Powell SH, Thompson WL, Luthe MA, et al: Once-daily versus continuous aminoglycoside dosing: Efficacy and toxicity in animals and clinical studies of gentamicin, netilmicin, and tobramycin. J Infect Dis 147:918-932, 1983 Prins JM, Buller HR, Kuijper EJ, et al: Once versus thrice daily gentamicin in patients with serious infections. Lancet 34:335-339,1993 Reetze-Bonorden P, Bohler J, Keller E: Drug dosage in patients during continuous renal replacement therapy. Pharmacokinetic and therapeutic considerations. Clin Pharmacokinet 24:362-379, 1993 St. Peter WL, Redic-Kill KA, Halstenson CE: Clinical pharmacokinetics of antibiotics in patients with impaired renal function. Clin Pharmacokinet 22:169-210, 1992 Wood CA, Norton DR, Kohlhepp SJ, et al: The influence of tobramycin dosage regimens on nephrotoxicity, ototoxicity, and antibacterial efficacy in a rat model of subcutaneous abscess. J Infect Dis 158:13-22, 1988 Zhanel CC, Hoban DJ, Harding JK: The postantibiotic effect: A review of in-vitro and in-vivo data. mcp Ann Pharmacother 25:153-163, 1991

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APPENDIX

Mathematical Derivation of Multipliers

The recommendations of DREM are based on sound pharmacokine tic principles. It simply presents the same principles in a more practical, digestible, and easily remembered form because tables, nomograms, and the more convoluted calculations are not easily assimilated, committed to memory, or always available. When drug is totally eliminated by glomerular filtration, creatinine clearance (CLcr) is proportional to drug clearance and the adjusted dose of the drug and inversely proportional to the dosing interval. Thus: CLcr ex drug clearance ex drug dose ex 1/ dose interval Dividing all elements of the above statement by their respective normal or usual values equalizes all as a fraction of normal. Thus: CLcr _ drug clearance _ Drug dose nCLcr - nDrug clearance - uDrug dose therefore:

CLcr Drug dose = -CL n cr

Dosing interval

l/Dosing interval

1/ uDosing interval

X

nDrug dose

CLcr = ----uJi)

X

nDrug dose

nCLcr = CLcr

X

uDosing interval

100 = CLcr

X

uDosing interval

where Drug dose is the adjusted dose, and n or u is normal or usual as the case may be.

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