use of antibacterial agents in renal failure

Infect Dis Clin N Am 18 (2004) 551–579

Use of antibacterial agents in renal failure

Lawrence L. Livornese Jr, MDa,b,*,Dorothy Slavin, MDb,c, Brett Gilbert, DOb,Paul Robbins, DOd, Jerome Santoro, MDc,e

aDepartment of Medicine, Drexel University College of Medicine, 2900 W. Queen Lane,

Philadelphia, PA 19129, USAbDivision of Infectious Diseases, Lankenau Hospital, Lankenau Medical Building,

Suite 164, Wynnewood, PA 19096, USAcDepartment of Medicine, Thomas Jefferson University School of Medicine,

111 South 11th Street, Philadelphia, PA 19107, USAdDivision of Nephrology, Lankenau Hospital, Lankenau Medical Building,

Suite 130, Wynnewood, PA 19096, USAeDepartment of Medicine, Main Line Health System, Lankenau Hospital,

Wynnewood, PA 19096, USA

The kidney is the major organ for maintaining fluid and electrolytehomeostasis. Changes in renal function, whether associated with normalaging or disease, can have profound effects on the pharmacology ofantibacterial agents. It is imperative that clinicians have a basic un-derstanding of these consequences to prescribe antibacterial agents effec-tively in the face of impaired or changing renal function.

This article reviews the pharmacokinetics of antibacterial agents inpatients with normal and decreased renal function. The concepts of volumeof distribution, rate of elimination, loading and maintenance doses, andtherapeutic drug monitoring are delineated. Comment is made about theintermittent dosing of cefazolin with high-flux hemodialysis. The use of oncedaily aminoglycoside administration is reviewed. Newer and traditionalmethods of extracorporeal circulation and the resultant changes in anti-bacterial agent pharmacokinetics are discussed.

* Corresponding author. Department of Medicine, Drexel University College of

Medicine, 2900 W. Queen Lane, Philadelphia, PA 19129, USA.

E-mail address: [email protected] (L. Livornese).

0891-5520/04/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.idc.2004.04.013

mailto:[email protected]

552 L.L. Livornese Jr et al / Infect Dis Clin N Am 18 (2004) 551–579

Pharmacokinetics

Bioavailability and metabolism

Bioavailability refers to the degree that a drug is absorbed into the systemiccirculation after extravascular administration. Relatively few studies haveaddressed this issue in patients with renal failure. In chronic renal failurenumerous factors, such as nausea, vomiting, diabetic gastroparesis, andintestinal edema,may decrease gastrointestinal absorption. The conversion ofurea to ammonia by gastric urease, antacids, or the use of alkalating agents,such as bicarbonate and citrate, increases gastric pH thereby reducing levels ofdrugs that require an acidicmilieu for absorption [1]. Somedrugs are boundbyantacids and phosphate binders, which are commonly used in renal failure [2].In chronic renal failure, bioavailability is further reduced because of decreasedsmall bowel absorption [3]. First-pass hepatic metabolism may also bediminished in uremia leading to increased serum levels of oral antibacterialagents. Impaired plasma protein binding increases the level of free drug; thispermits more drug to bind to the site of action and conversely increases theamount of drug available for elimination bydialysis or hepaticmetabolism.Ofnote, the rates of glucuronidation, sulfated conjugation, and oxidation aregenerally unchanged in the presence of uremia [4].

Distribution and elimination

Plasma levels for a given drug are a function of the dose, bioavailability,volume of distribution (Vd), and rate of metabolism and excretion. The Vd iscalculated by dividing the amount of drug in the body by the plasmaconcentration. In general, drugs that are highly protein bound are foundmainly in the vascular space and have a small Vd. Those agents that are highlylipid soluble have a large Vd because they are able to penetrate body tissuesmore easily. Vd can exceed the total volume of body water because Vd isa mathematical calculation that does not necessarily correspond to a distinctphysiologic space (this is why the term ‘‘apparent Vd’’ is often used). Vd isimportant in calculating the plasma half-life (T1/2) of a drug.

The major routes of elimination of antibacterial agents and theirmetabolites are by the kidney and the liver. Small, generally inconsequential,amounts are lost in sweat, saliva, expired air, and breast milk. The rate ofelimination of most antibacterial agents follows first-order kinetics (ie, therate of elimination is proportional to the amount of drug in the body, and asthe amount of drug increases so does the rate of elimination).

There is an elimination constant K, such that rate of elimination = K �amount of drug in body. Because the amount of drug in the body can becalculated by multiplying the plasma concentration by the Vd one canrestate the equation as rate of elimination = K � Vd � plasma concentra-tion. Plasma drug clearance is calculated by dividing the rate of eliminationby the plasma concentration: plasma drug clearance = K � Vd.

553L.L. Livornese Jr et al / Infect Dis Clin N Am 18 (2004) 551–579

It is traditional that the rate of plasma clearance is expressed as the timerequired for the concentration of a drug to decline by 50% (T1/2). T1/2

remains constant at all times for all drugs that follow first-order kineticsbecause as the concentration decreases so does the rate of plasma clearance.Additionally, T1/2 is independent of the initial plasma concentration; it ispurely a function of K, the aforementioned elimination constant. Therefore,T1/2 = ln2/K = 0.693/K. By substituting for K from plasma drug clear-ance = K � Vd: T1/2 = (0.693)(Vd)/plasma drug clearance. The T1/2 isdetermined by only the Vd and the plasma clearance. Any process that altersthese changes the T1/2. In renal insufficiency, edema or ascites increase theVd of highly protein bound or water-soluble drugs resulting in lower thanexpected plasma levels. Muscle loss and dehydration can decrease Vd andlead to higher than expected concentrations of these same agents.

Creatinine clearance

The rate of elimination of drugs by the kidney depends on the glomerularfiltration rate (GFR), which is a function of the cardiac output. The proximaltubules have energy-dependent transport systems, which may secrete andreabsorb drugs. b-Lactams are actively secreted by this system. A 24-hoururine collection allows accurate determination of the endogenous creatinineclearance, which is a close approximation to the GFR (a small amount ofcreatinine is secreted in the proximal tubules). In practice, it is often too timeconsuming or impractical to obtain a 24-hour urine collection to determinethe GFR. The equation of Cockroft and Gault [5] can be used to estimatecreatinine clearance: Creatinine clearance in males = {(140-age) � totalbody weight in kg}/(72 � serum creatinine). In females the clearance is 85%of this value.

Pesola et al [6] suggest using ideal body weight instead of total bodyweight. Ideal body weight can be calculated using height and gender perDevine [7]: male ideal body weight = 50 kg þ 2.3 kg for each inch over 5 ft;female ideal body weight = 45.5 kg þ 2.3 kg for each inch over 5 ft. Thesecalculations are only valid when the renal function is stable and the serumcreatinine is constant. When the patient is oliguric or the serum creatinineis rapidly rising, the creatinine clearance should be assumed to be less than10 mL/min.

Serum creatinine alone is not a reliable measure of creatinine clearancebecause it is a function of the GFR and muscle mass. In the elderly ordebilitated patient the serum creatinine may seem normal even in thepresence of significant renal insufficiency. Trimethoprim and cimetidinecompete with creatinine for secretory pathways in the proximal tubule andmay cause an increase in serum creatinine without a change in the GFR[8,9]. A false elevation in serum creatinine has been reported with cefoxitin,cephalothin, and 5-flucytosine because of interference with certain creatinineassays [10,11].


Dosing of antibacterial agents in renal failure

Initial dose

The loading or initial dose is based on extracellular fluid volume and is notaltered in the presence of decreased renal function. The presence of ascites oredema may necessitate a larger dose, whereas dehydration may requirea reduction in dosage. When a loading dose is not used, four maintenancedoses are required to achieve a steady state. When antibacterial agents witha short T1/2 are used each maintenance dose acts as if it is a loading dose, andno separate initial dose is used. A loading dose is generally used when it isnecessary to achieve therapeutic plasma levels rapidly.

Maintenance dose

After the loading dose, subsequent maintenance doses frequently requiremodification in patients with decreased renal function. Table 1 outlinesspecific dosing guidelines for the use of antibiotics in patients with normaland diminished renal function. The classification is based on chemical classand then subdivided alphabetically.

The second through fifth columns indicate the percentage of drugexcreted unchanged, the T1/2 of each agent in normals and end-stage renaldisease, the percent protein binding, and volume of distribution, respec-tively. The later columns recommend dosing schedules based on renalfunction. Modifications of doses are dictated by the severity of renalimpairment as determined by the estimated GFR. Adjustments are labeledeither ‘‘D’’ for dose reduction or ‘‘I’’ for interval extension. In the dosereduction method (D), a percentage of the usual dose of antibacterial isgiven at the standard interval. In the interval extension method (I), the doseof the individual antibacterial agent remains constant, but the intervalbetween doses is extended. Additional dosing requirements for variousdialysis modalities, if available, are found in the last column. If informa-tion is available, supplementation for hemodialysis, continuous ambula-tory peritoneal dialysis, and continuous arteriovenous hemofiltration isindicated.

Once-daily aminoglycosides

In the era of antibiotic resistance, aminoglycoside antibiotics continue toplay a critical role in the treatment of certain gram-negative bacterialinfections. Because of their high side effect profile and their prolongedpostantibiotic effect, novel treatment approaches and dosing schedules havebeen implemented to limit toxicity [12,13]. In the last 10 years once-dailyaminoglycoside therapy has been introduced to take advantage of amino-glycoside pharmacodynamics, while attempting to reduce nephrotoxicityand ototoxicity [14]. Credence for this concept is supported by early animalstudies, which suggested that the incidence of acute renal failure could be


reduced by once-daily administration [15]. A meta-analysis performed byHatala et al [16] reviewed 13 studies and the authors concluded thatstandard and once-daily regimens had similar bacteriologic cure and thatonce-daily dosing showed a trend toward reduced toxicity and mortality.Other benefits of once-daily dosing include reduced costs and prolongedpostantibiotic effect.

Patient selection is important when considering a once-daily regimen.Only certain patient populations are appropriate for once-daily dosing;these include patients with pelvic inflammatory disease, gram-negativebacteremia, urinary tract infections, febrile neutropenia, gynecologic in-fections, and respiratory infections [17]. Once-daily aminoglycoside dosingshould not be used where little apparent benefit is expected, or where clinicalevidence is lacking. The following clinical scenarios preclude once-dailyaminoglycoside use: pregnancy, creatinine clearance less then 20 mL/min,bone and joint infections, central nervous system infections, infective endo-carditis, obesity, burns, and solid organ transplantation.

Initial dosing for once-daily aminoglycosides should be based oncreatinine clearance. Table 2 provides dosage adjustments in patients withrenal insufficiency. Serum drug levels with once-daily dosing of gentamicinor tobramycin should achieve a peak concentration of 15 to 20 lg/mL. Thetrough concentration should be less than 1 lg/mL [18,19].

Intermittent dosing cefazolin with hemodialysis

In hemodialysis patients with suspected bloodstream or vascular infec-tions, vancomycin and gentamicin are frequently given as empiric therapy.Often when an isolate is recovered, such as methicillin-susceptible Staphy-lococcus aureus, vancomycin is continued because doses may be given withhemodialysis and there is no need for additional intravenous access;however, the emergence of vancomycin-resistant enterococcus and concernsfor increasing resistance of S aureus to glycopeptides has led to recom-mendations to limit the use of vancomycin when possible [20].

Sowinski et al [21] studied the pharmacokinetics and clearance ofcefazolin in 25 uninfected subjects undergoing thrice-weekly hemodialysis.Fifteen subjects underwent hemodialysis with high-efficiency hemodialyzers,and 10 with high-flux hemodialyzers. Subjects were given an intravenousdose of 15 mg/kg cefazolin immediately after hemodialysis; both groupsmaintained cefazolin levels above the breakpoint for sensitive organisms(8 lg/mL), even with a 3-day interdialytic period.

In a previous study, Fogel et al [22] concluded that for anurichemodialysis patients, cefazolin can be used effectively at a dose of 1 gintravenously after each hemodialysis session. A number of nonanuricsubjects were included in the study by Sowinski et al [21]. A total of10 subjects produced enough urine to calculate cefazolin renal clear-ance, although only three could be considered nonoliguric (urine output

Table 1

Rec

or renal function

in

Dru 10–50 \10 Supplement for dialysis

Am

A 30%–70%

q 12–18 h

20%–30%

q 24–48 h

Hemo 2/3 normal dose

after dialysis

CAPD 15–20 mg/L

CAVH Dose for GFR

10–50 and

measure levels

G 30%–70%

q 12 h

20%–30%

q 24–48 h


after dialysis

CAPD 3–4 mg/L

CAVH Dose for GFR

10–50 and

measure levels

N 20%–60%

q 12 h

10%–20%

q 24–48 h


after dialysis

CAPD 3–4 mg/L

CAVH Dose for GFR

10–50 and

measure levels

S q 24–72 h q 72–96 h Hemo 1/2 normal dose

after dialysis

CAPD 20–40 mg/L

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18(2004)551–579

ommended drug dosages and adjustments for patients in renal failure

Adjustment f

GFR, mL/m

g

Excreted

unchanged

%

Half-life

(normal/

ESRD)

hours

Plasma

protein

binding %

Volume

of

distribution

L/kg

Dose for

normal

renal

function Method >50

inoglycoside antibiotics

mikacin 95 1.4–2.3/

17–150

\5 0.22–0.29 5 mg/kg

q 8 h

D and I 60%–90%

q 12 h

entamicin 95 1.8/20–60 \5 0.23–0.26 1–1.7 mg/kg

q 8 h

D and I 60%–90%

q 8–12 h

etilmicin 95 1–3/35–72 \5 0.19–0.23 5 mg/kg

q 8 h

D and I 50%–90%

q 8–12 h

treptomycin 70 2.5/100 35 0.26 1 g/d I q 24 h

CAVH Dose for GFR

10–50 and

measure levels

T

h

30%–70%

q 12 h

20%–30%

q 24–48 h


after dialysis

CAPD 3–4 mg/L

CAVH Dose for GFR

10–50 and

measure levels

Cep

C 50%–100% 50% Hemo 250 mg after

dialysis

CAPD 250 mg q 8–12 h

CAVH Not applicable

C q 12–24 h q 24–48 h Hemo 0.5–1 g after

dialysis

CAPD 0.5 g/d

CAVH Not applicable

C q 12 h q 24–48 h Hemo 0.5–1 g after

dialysisa

CAPD 0.5 g q 12 h

CAVH Dose for GFR

10–50

C q 12 h q 24 h Hemo 300 mg after

dialysis

CAPD Not applicable

CAVH Not applicable

C 50% 50% q 24 h Hemo No data

CAPD No data

CAVH No data

(continued on next page) 557

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obramycin 95 2.5/27–60 \5 0.22–0.33 1–1.7 mg/kg

q 8 h

D and I 60%–90%

q 8–12

halosporin antibiotics

efaclor 70 1/3 25 0.24–0.35 250–500 mg

q 8 h

D 100%

efadroxil 70–90 1.4/22 20 0.31 0.5–1 g q 12 h I q 12 h

efazolin 75–95 2/40–70 80 0.13–0.22 0.5–2 g q 8 h I q 8 h

efdinir 18 1.7/16 60–70 0.35 300 mg q 12 h I q 12 h

efditoren 99 1.6/4.7 88 9.3 200–400 mg

q 12 h

D and I 100%

Table

stment for renal function

, mL/min

Drug 10–50 \10 Supplement for dialysis

Ce h q 16–24 h q 24–48 h Hemo 1 g after dialysis

CAPD Dose for GFR

\10

CAVH Not

recommended

Ce 75% 50% Hemo 300 mg after

dialysis

CAPD 200 mg/d

CAVH Not applicable

Ce 100% 100% Hemo 1 g after dialysis

CAPD None

CAVH None

Ce q 8–12 h q 24 h Hemo 1 g after dialysis

CAPD 1 g q 24 h

CAVH 1 g q 12 h

Ce 50% 25% Hemo 1 g after dialysis

CAPD 1 g/d

CAVH 750 mg q 12 h

Ce q 8–12 h q 24–48 h Hemo 1 g after dialysis

CAPD 1 g/d

CAVH Dose for GFR

10–50

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18(2004)551–579

1 (continued )

Adju

GFR

Excreted

unchanged

%

Half-life

(normal/

ESRD)

hours

Plasma

protein

binding %

Volume

of

distribution

L/kg

Dose for

normal

renal

function Method >50

fepime 85 2.2/18 16 0.3 0.25–2 g q 8 h I q 12

fixime 18–50 3.1/12 50 0.6–1.1 200 mg q 12 h D 100%

foperazone 20 1.6–2.5/

2.9

90 0.14–0.20 2 g q 12 h 100%

fotaxime 60 1/15 37 0.15–0.5 1 g q 8 h I q 6 h

fotetan 75 3.5/13–25 85 0.15 1–2 g q 12 h D 100%

foxitin 80 1/13–23 41–75 0.2 1–2 g q 6–8 h I q 8 h

Cefpodoxime 30 2.5/26 26 0.6–1.2 200 mg q 12 h I q 12 h q 16 h q 24–48 h Hemo 200 mg after

dialysis only

CAPD Dose for GFR

\10

CAVH Not applicable

250 m

q 12–16 h

250 mg q 24 Hemo 250 mg after

dialysis

CAPD Dose for GFR

\10

CAVH Dose for GFR

\10

q 24–48 h q 48 h Hemo 1 g after

dialysis

CAPD 0.5 g q 24 h

CAVH Dose for GFR

10–50

50% 25% Hemo 400 mg after

dialysis

CAPD Not applicable

CAVH Not applicable

q 12–24 h q 24 h Hemo 1 g after dialysis

CAPD 0.5–1 g q 24 h

CAVH Dose for GFR

10–50

100% 100% Hemo None

CAPD 750 mg q 12 h

CAVH Dose for GFR

10–50

100% 100% Hemo Dose after

dialysis


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Cefprozil 65 1.7/6 40 0.65 500 mg q 12 h D and I 250 mg

q 12 h

Ceftazidime 60–85 1.2/13–25 17 0.28–0.4 1–2 g q 8 h I q 8–12 h

Ceftibuten 56 2/22 65 0.21 400 mg q 24 h D 100%

Ceftizoxime 57–100 1.4/35 28–50 0.26–0.42 1–2 g

q 8–12 h

I q 8–12 h

Ceftriaxone 30–65 7–9/12–24 90 0.12–0.18 1–2 g

q 12–24 h

100%

Cefuroxime-axetil 90 1.2/17 35–50 0.13–1.8 250–500 mg

q 12 h

100%

Table 1 (continued )

nt for renal function

/min


CAPD Dose for GFR

\10

CAVH Not applicable

C 8–12 h q 24 h Hemo Dose after

dialysis

CAPD Dose for GFR

\10

CAVH 1 g q 12 h

C 12 h q 12 h Hemo Dose after

dialysis

CAPD Dose for GFR

\10

CAVH Not applicable

Ma

A 00% 100% Hemo None

CAPD None

CAVH None

C 5% 50%–75% Hemo Dose after

dialysis

CAPD None

CAVH None

D 00% 100% Hemo None

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Adjustme

GFR, mL

g

Excreted

unchanged

%

Half-life

(normal/

ESRD)

hours

Plasma

protein

binding %

Volume

of

distribution

L/kg

Dose for

normal

renal

function Method >50 1

efuroxime-sodium 90 1.2/17 33 0.13–1.8 0.75–1.5 g

q 8 h

I q 8 h q

ephalexin 98 0.7/16 20 0.35 250–500 mg

q 6 h

I q 8 h q

crolide antibiotics

zithromycin 6–12 10–60/? 10–50 18 250–500 mg

q 24 h

100% 1

larithromycin 15 2.3–6/22 70 2.4 500 mg q 12 h D 100% 7

irithromycin 2 8/8 13–50 0.8 500 mg q 24 100% 1

CAPD None

CAVH None

E 100% 100% 50%–75% Hemo None

CAPD None

CAVH None

Mis

A 100% 50%–75% 25% Hemo 0.5 g after

dialysis

CAPD Dose for GFR

\10

CAVH Dose for GFR

10–50

C 100% 100% 100% Hemo None

CAPD None

CAVH None

C 100% 50% Avoid Hemo Avoid

CAPD Avoid

CAVH Avoid

C 100% 100% 50%–75% Hemo Dose after

dialysis

CAPD Dose for GFR

\10

CAVH Dose for GFR

10–50

C 100% 100% 100% Hemo None

CAPD None

CAVH None

(continued on next page)

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rythromycin 15 1.4/5.6 60–95 0.78 250–500 mg

q 6–12 h

D

cellaneous antibacterials

ztreonam 75 1.7–2.9/

6–8

55 0.1–2 1–2 g

q 8–12 h

D

hloramphenicol 10 1.6–3.3/

3–7

45–60 0.5–1 12.5 mg/kg

q 6 h

ilastin 60 1/12 44 0.22 with

imipenem

D

lavulanic acid 40 1/3–4 30 0.3 100 mg

q 4–6 h

D

lindamycin 10 2–4/3–5 60–95 0.6–1.2 150–900 mg

q 6–8 h

Tab

t for renal function

/min


D q 24 h q 48 h Hemo Give after HD

on HD days

CAPD 4 mg/kg q 48 h

CAVH 4 mg/kg q 48 h

I 50% 25% Hemo Dose after

dialysis

CAPD Dose for GFR

\10

CAVH Dose for GFR

10–50

L 100% 100% Hemo No data

CAPD No data

CAVH No data

E 100% 50% Hemo 150 mg after

dialysis

CAPD No data

CAVH No data

M

h

250–500 mg

q 12 h

250–500

mg q 24 h

Hemo Dose after

dialysis

CAPD Dose for GFR

\10

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le 1 (continued )

Adjustmen

GFR, mL

g

Excreted

unchanged

%

Half-life

(normal/

ESRD)

hours

Plasma

protein

binding %

Volume

of

distribution

L/kg

Dose for

normal

renal

function Method >50

aptomycin 78 9/28 92 0.1 4 mg/kg

q 24 h

I q 24 h

mipenem 20–70 1/4 13–21 0.17–0.3 0.25–1 g q 6 h D 100%

inezolid 30 4.5/? 31 40–50 400–600 mg

q 12 h

100%

rtapenem 38 4/6 85–95 8.2 1 g q 24 h D 100%

eropenem 65 1.1/6–8 Low 0.35 0.5–1 g q 6 h D and I 500

mg q 6

CAVH Dose for GFR

10–50


dialysis

CAPD Dose for GFR

\10

CAVH Dose for GFR

10–50

avoid avoid Hemo Not applicable

CAPD Not applicable

CAVH Not applicable

q 12–24 h q 12–48 h Hemo Dose after

dialysis

CAPD 0.75–1.5 g/d

CAVH 750 mg q 12 h

q 18 h q 24 h Hemo 1 g after dialysis

CAPD 1 g q 24

CAVH Dose for GFR

10–50

q 8–12 h q 12–24 h Hemo 2 g after dialysis

CAPD 3 g/d

CAVH Not applicable

100% 100% Hemo None

CAPD None

CAVH None

75% 50% Hemo 1/3 dose after

dialysis

CAPD Dose for GFR

\10


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Metronidazole 20 6–14/7–21 20 0.25–0.85 7.5 mg/kg

q 6–12 h

D 100%

Nitrofurantoin 30–40 0.5/1 20–60 0.3–0.7 50–100 mg

q 6 h

D 100%

Sulbactam 50–80 1/10–21 30 0.25–0.50 0.75–1.5 g

q 6–8 h

I q 6–8 h

Sulfamethoxazole 70 10/20–50 50 0.28–0.38 1 g q 8 h I q 12 h

Sulfisoxazole 70 3–7/6–12 85 0.14–0.28 1–2 g q 6 h I q 6 h

Synercid

(quinupristin/

dalfopristin)

15 0.9/? 55–78 1 7.5 mg/kg 100%

19 0.75/? 11–26 1 q 8–12 h

Tazobactam 65 1/17 22 0.21 1.5–2.25 g/d D 100%

Tab

renal function

Dru –50 \10 Supplement for dialysis

CAVH Dose for GFR

10–50

T 48 h q 72 h Hemo Dose for GFR

\10

CAPD Dose for GFR

\10

CAVH Dose for GFR

10–50

T 18 h q 24 h Hemo Dose after

dialysis

CAPD q 24 h

V 0 mg

q 24–48 h

500 mg

q 48–96 h

Hemo Dose for GFR

\10

CAPD Dose for GFR

\10

CAVH Dose for GFR

10–50

Pen

A 8–12 h q 24 h Hemo Dose after

dialysis

CAPD 250 mg q 12 h

CAVH Not applicable

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le 1 (continued )

Adjustment for

GFR, mL/min

g

Excreted

unchanged

%

Half-life

(normal/

ESRD)

hours

Plasma

protein

binding %

Volume

of

distribution

L/kg

Dose for

normal

renal

function Method >50 10

eicoplanin 40–60 33–190/

62–230

60–90 0.5–1.2 6 mg/kg

q 24 h

I q 24 h q

rimethoprim 40–70 9–13/

20–49

30–70 1–2.2 100–200 mg

q 12 h

I q 12 h q

ancomycin 90–100 6–8/

200–250

10–50 0.47–1.1 1 g q 12 h D and I 500 mg

q 6–12 h

50

icillins

moxicillin 50–70 0.9–23/

5–20

15–25 0.26 250–500

mg q 8 h

I q 8 h q

Ampicillin 30–90 0.8–1.5/ 20 0.17–0.31 250 mg–2 g I q 6 h q 6–12 h q 12–24 h Hemo Dose after

dialysis

CAPD 250 mg q 12 h

CAVH Dose for GFR

10–50

100% 100% Hemo None

CAPD None

CAVH Not applicable

100% 100% Hemo None

CAPD None

CAVH None


dialysis

CAPD Dose for

GFR\10

CAVH Dose for

GFR 10–50


dialysis

CAPD Dose for

GFR\10

CAVH Not applicable

q 6–8 h q 8 h Hemo Dose after

dialysis

CAPD Dose for

GFR\10

CAVH Dose for

GFR 10–50

1–2 g q 8 h 1–2 g q 12 h Hemo 3 g after dialysis

CAPD Dose for

GFR\10

(continued on next page)

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7–20 q 6 h

Dicloxacillin 35–70 0.7/1–2 95 0.16 250–500

mg q 6 h

100%

Nafcillin 35 0.5/1.2 85 0.35 1–2 g q 4–6 h 100%

Penicillin G 60–85 0.5/6–20 50 0.3–0.42 0.5–4 million

U q 4 h

D 100%

Penicillin VK 60–90 0.6/4.1 50–80 0.5 250 mg q 6 h 100%

Piperacillin 75–90 0.8–1.5/

3.3–5

30 0.18–0.30 3–4 g q 4 h I q 4–6 h

Ticarcillin 85 1.2/11–16 45–60 0.14–0.21 3 g q 4 h D and I 1–2 g q 4 h

Table 1 (continued )

nt for renal function

/min

D 10–50 \10 Supplement for dialysis

CAVH Dose for

GFR 10–50

Q

50%–75% 50% Hemo 50% q 12 h

CAPD 50% q 8 h

CAVH 50% q 12 h

50% NA Hemo No data

CAPD No data

CAVH No data

100% 50% Hemo No data

CAPD No data

CAVH No data

500 mg

then

250 mg iv

q 24

500 mg

then

250 mg q

48 h

Hemo 500 mg then

250 mg q

48 h

CAPD 500 mg then

250 mg q

48 h

CAVH 500 mg then

250 mg q

24 h

566

L.L.Livo

rnese

Jret

al/Infect

DisClin

NAm

18(2004)551–579

Adjustme

GFR, mL

rug

Excreted

unchanged

%

Half-life

(normal/

ESRD)

hours

Plasma

protein

binding %

Volume

of

distribution

L/kg

Dose for

normal

renal

function Method >50

uinolone antibacterials

Ciprofloxacin 50–70 3–6/6–9 20–40 2.5 400 mg IV or

500–750 mg

po q 12 h

D 100%

Clinafloxacin 50–70 5/15 50 2.4 200 mg q 12 h D 100%

Gatifloxacin 82–88 7–8/? 20 2 400 mg q 24 h D 100%

Levofloxacin 87 6–8/35 30 74–112 500 mg iv 24 h D & I 500 mg

q 24 h

Moxifloxacin 96 12/ 40 2–3.5 400 mg q 24 h 100% 100% 100% Hemo No data

CAPD No data

CAVH No data

2 h q 12–24 h Avoid Hemo Not applicable

CAPD Not applicable

CAVH Not applicable

% 200

mg q 12 h

25%–50%

q 24 h

Hemo 100 mg q 12 h

CAPD Dose for

GFR\10

CAVH 300 mg q 24 h

% 100% 100% Hemo None

CAPD None

CAVH None

% 100% 100% Hemo None

CAPD None

CAVH None

% 100% 100% Hemo None

CAPD None

CAVH None

–12 h q 12–24 h q 24 h Hemo None

CAPD None

CAVH None

enous hemofiltration; D, dose reduction; ESRD, end-stage

567

L.L.Livo

rnese

Jret

al/Infect

DisClin

NAm

18(2004)551–579

14.5–16.2

Norfloxacin 30 3.5–6.5/8 14 \0.5 400 mg q 12 h I q 1

Ofloxacin 68–80 5–8/28–37 25 1.5–2.5 400 mg q 12 h D 100

Trovafloxacin 50 10.5–12.2/? 76 1.3 100–300

mg q 24 h

100

Tetracycline antibacterials

Doxycycline 33–45 15–24/

18–25

80–93 0.75 100 mg q 12 h 100

Minocycline 6–10 12–16/

12–18

70 1–1.5 100 mg q 12 h 100

Tetracycline 48–60 6–10/

57–108

55–90 >0.7 250–500

mg qid

I q 8

Abbreviations: CAPD, continuous ambulatory peritoneal dialysis; CAVH, continuous arteriov

renal disease; GFR, glomerular filtration rate; HD, hemodialysis; I, interval extension.a See text for additional dosing comments.


[ 400 mL/d). All 25 subjects in this study maintained adequate cefazolinlevels despite the production of variable amounts of urine.

Kuypers et al [23] used a fixed postdialysis dose of 2 g intravenouscefazolin in 15 uninfected hemodialysis patients, 14 of whom used high-fluxmembranes. The weight-based range of doses for this group was from 19.2to 37.7 mg/kg. Trough levels of cefazolin were obtained before subsequentdialysis sessions, and remained well above the minimal inhibitory concen-tration for susceptible organisms. A higher incidence of adverse effects wasseen in this study, however, raising the concern that the higher serum levelsof cefazolin achieved in this study led to undesirable side effects. Thesestudies demonstrate clearly that cefazolin can be administered on either

Table 2

Suggested single daily dosage requirements of aminoglycosides: adjustment for renal

insufficiency

Estimated level (ug/mL) at

EST CR CL

(mL/min)

Dosage

Interval (h)

Dose

(mg/kg) 1 h 18 h 24 h

Gentamicin/tobramycin

>80 24 5 20 \1 \1

70 24 4 16 \1 \1

60 24 4 16 1.5 \1

50 24 3.5 14 1 \1

40 24 2.5 10 1.5 \1

30 24 2.5 10 2.5 1.5

20 48 4 16 2 1

10 48 3 12 3 2

Hemodialysisa 48 2 8 6 5

Amikacin, kanamycin, streptomycin

>80 24 15 60 \1 \1

70 24 12 48 2.5 \1

50 24 7.5 30 3.5 1

30 24 4 20 5 3

20 48 7.5 30 3.3 1

10 48 4 16 5 3

Hemodialysisa 48 3 20 15 12

Netilmicin

>80 24 6.5 15 \1 \1

70 24 5 — — —

50 24 4 — — —

30 24 2 — — —

20 48 3 — — —

10 48 2.5 — — —

Hemodialysisa 48 2 — — —

Abbreviations: ESTCRCL, estimated creatine clearance.a Dose posthemodialysis.

Data fromGilbert DW, Bennett WM. Use of antimicrobial agents in renal failure. Infect Dis

Clin North Am 1989;3:517–31; and Gilbert DN, Mollering RC, Sande MA. The Sanford guide

to antimicrobial therapy 2003. Hyde Park, VT: Antimicrobial Therapy; 2003.


a weight-based or fixed-dose schedule after each dialysis session and canprovide a safe and effective alternative to vancomycin for susceptibleorganisms.

Serum levels

Because of potential toxicity, especially when combined, antimicrobialserum levels are most useful, and are generally obtained, when usingvancomycin or aminoglycosides. There is an increased incidence ofnephrotoxicity when these agents are combined. Appropriate dosingrequires consideration of multiple factors including patient weight, extra-cellular fluid shifts, renal function, hypoalbuminemia, location and severityof infection, and potential for toxicity. When administering aminoglycosidesit is even more important to establish safe serum levels in patients withunderlying renal failure because the potential for toxicity is greater.

Vancomycin drug levels have been reviewed extensively and are based onearly reports of clinical observation and toxicity [24]. Vancomycin exhibitsconcentration-independent killing in vitro and its pharmacokinetics areaffected by inoculum size. Serum levels, however, do not always correlatewith a favorable microbiologic response [25]. In contrast to aminoglyco-sides, vancomycin levels have not consistently correlated with toxicity andtheir use continues to be debated in the literature [26–29].

Unlike vancomycin, aminoglycosides exhibit concentration-dependentkilling. This is important clinically because bactericidal activity is directlyproportional to concentration levels [30]. Nevertheless, levels must befollowed closely with aminoglycosides because increased trough levels havecorrelated with nephrotoxicity [31]. Tables 1 and 2 can be used as guidelinesto help attain appropriate levels but in no way ensure their achievement.

Peak and trough concentrations are measured after achieving steady-state concentration. The latter correlates with the fourth dose in patientswith normal renal function assuming a loading dose has not been given. Thepeak concentration is measured approximately 30 to 60 minutes aftercompletion of infusion rather than immediately following the dose to allowfor rapid phase distribution to occur; otherwise, the measurement reflectsonly the plasma volume and not the extracellular compartment. Troughlevels are obtained before the next scheduled dose. Random levels areobtained in patients with underlying renal disease where the T1/2 issufficiently prolonged and intermittent dosing is being used.

Dialysis

When renal failure progresses to the point of uremia or inadequate urineoutput (oliguria), dialytic intervention is indicated. Typically, dialysis is


begun when the GFR or creatinine clearance is less than 15 mL/min fordiabetic patients or less than 10 mL/min for nondiabetic patients. There area number of dialytic modalities used in both acute and chronic renal failure.

Hemodialysis

Standard, thrice-weekly, intermittent hemodialysis is the mainstaytherapy of end-stage renal failure [32]. Box 1 summarizes the factorsaffecting drug clearance by hemodialysis. The clearance of low-molecular-weight antibiotics (\500 d) is dependent on blood flow rates, dialysate flowrates, and dialyzer surface area. As a rule, higher-molecular-weight drugs(>500 to 5000 d) are poorly dialyzed by conventional dialyzers. There is anever-increasing trend, however, toward using larger, more permeable (high

Box 1. Factors affecting hemodialysis drug clearance

Drug propertiesMolecular weightChargeLipid or water solubilityVd (tissue binding)Protein bindingOther forms of steric hindranceMembrane bindingRapid excretion by another pathwayRed blood cell partitioning

Hemodialyzer propertiesBlood flowSurface areaMembrane permeabilityPore sizeFluid films (membrane geometry)

Dialysate propertiesFlow rateSolute concentrationpHTemperature

Miscellaneous propertiesConvective transports during ultrafiltration

Data from Golper TA, Bennett WM. Drug usage in dialysis patients. In:Nissenson R, Fine RN, Gentile DE, editors. Clinical dialysis, 2nd edition. Norwalk(CT): Appleton and Lange; 1990. p. 608–30.


flux) membranes. These membranes have been shown to enhance theclearance of middle molecules, more recently defined as compounds ofmolecular weight 500 to 12,000 d, and increase the removal of both small-and larger-molecular-weight antibiotics [33–36]. To reduce the clearance ofantibiotics during high-flux hemodialysis and avoid subtherapeutic druglevels, the administration of antibiotics at the end of a dialysis session or theuse of higher intradialytic doses has been recommended [34,37–39]. Whenthe transport properties of a drug or antibiotic are not known, Maher[40,41] has proposed that the hemodialysis clearance of unbound drug canbe estimated by multiplying the urea clearance by the ratio of the molecularweight of urea (60 d) to the antibiotic’s molecular weight: KX = Kurea �60/MWx, where K is clearance, X is the antibiotic involved, and MW ismolecular weight.

The nephrologist administering the dialysis therapy should be able toprovide an estimate of the urea clearance for a given treatment. Fortunately,the dialyzability of many antibiotics and postdialysis supplement require-ments has been established [40–42]. These are summarized in Table 1.

Intermittent hemodialysis also remains the mainstay treatment of acuterenal failure. In this setting, however, it may be performed more or less oftenthan thrice weekly. It becomes very important to be aware of the dialysisschedule and to monitor antibiotic levels. Unfortunately, unless thelaboratory’s determination of the antibiotic level is performed and reportedquickly, the next dose of antibiotic is likely to have been administered beforethe trough level is known. In fact, the trough level obtained predialysis isobviously higher than the level at the end of dialysis when the next doseis typically administered. It is important to know when the trough level isobtained. If taken at the end of dialysis, there is no realistic opportunity forthe level to be known by the time of dosing, unless administration is delayed.

Continuous renal replacement therapy

Increasingly in acute renal failure, continuous methods of renal re-placement therapy are being used. These include continuous arteriovenoushemofiltration, continuous venovenous hemofiltration, continuous arterio-venous hemodialysis, and continuous venovenous hemodialysis.

Hemofiltration (continuous arteriovenous hemofiltration, continuousvenovenous hemofiltration) refers to the removal of an ultrafiltrate ofplasma in which there is solute loss only by convection or solvent drag, notdiffusion. The plasma is filtered but no dialysate is used, so solute onlymoves along with plasma water. The efficiency of drug (or any solute)removal is related to the sieving coefficient (SC), which is the mathematicalexpression of the ability of a solute to cross a membrane convectively. TheSC is determined by the ratio of the concentration of the substance in theultrafiltrate to the plasma. When the patient is on continuous arteriovenoushemofiltration, the concentration of the substance may be different in


arterial versus venous samples. For practical purposes of antibiotic or drugadministration, the arterial and venous can be assumed to be equal:SC = [UF]/[A], where UF is the concentration of the antibiotic in theultrafiltrate and A is arterial concentration. An SC of 1 means thata substance freely crosses the membrane and is removed in the sameconcentration as it exists in the plasma. An SC of zero means there is noremoval (typically because of extensive size or protein binding factors). Therate of antibiotic clearance equals SC � UFR, where UFR is theultrafiltration rate.

Table 3 lists the SC for intravenous antibacterials commonly used to treatserious infections. Because continuous method of renal replacement therapyis by definition continuous, antibiotic levels in this setting more accuratelyreflect true real-time estimates of patient antibiotic levels than withintermittent hemodialysis. The two formulae used to determine the amountof antibiotic removed are amount antibiotic removed (in milligrams) = ul-trafiltrate concentration (milligrams per liter) � ultrafiltration rate (liters perminute) � time of procedure (minutes). This method depends on being ableto obtain antibiotic levels in the ultrafiltrate. The second method is toextrapolate the ultrafiltrate concentration from the plasma sample wherebyultrafiltrate concentration = [plasma] � unbound fraction (because only the

Table 3

Sieving coefficient

Antibacterials SC

Amikacin 0.9

Amphotericin B 0.3

Amphotericin B, liposomal 0.10

Ampicillin 0.7

Cefoxitin 0.6

Ceftazidime 0.9

Ceftriaxone 0.2

Ciprofloxacin 0.8

Gentamicin 0.8

Imipenem 1

Metronidazole 0.8

Mezlocillin 0.7

Oxacillin 0.02

Penicillin 0.7

Sulfamethoxazole 0.9

Vancomycin 0.8

There is usually a close correlation between sieving coefficient and unbound fraction because

only the free or unbound drug is available for removal by hemofiltration.

Abbreviations: SC, sieving coefficient.

Data fromGolper TA. Drug removal during continuous renal replacement therapy. In: Rose

BD, editor. Uptodate. Wellesley (MA): UpToDate; 2004; and Golper TA. Update on drug

sieving coefficients and dosing adjustments during continuous renal replacement therapies.

Contrib Nephrol 2001;132:349–53.


unbound fraction is filtered). The protein-bound fraction for commonlyused antibiotics in the critical care setting is provided in Table 1. It should benoted that these protein binding data are for healthy people and may be lessreliable in critically ill patients. Nonetheless, the amount of antibioticremoved (in milligrams)= [plasma] (milligrams per liter) � unboundfraction � ultrafiltration rate (liters per minute) � time of procedure(minutes). Note that the plasma sample should reflect a steady-state levelhalfway between maintenance doses and after at least three half-lives. Box 2provides a summary of predicting antibiotic removal during continuousarteriovenous hemofiltration [32,43–45].

Continuous hemodialysis

Removal of antibiotics during continuous arteriovenous hemodialysis orcontinuous venovenous hemodialysis occurs largely by diffusion across thedialyzer membrane into the drug-free dialysate on the other side of themembrane. Convection or solvent drag is a less significant factor in drugremoval in this modality. The two major limiting factors to antibioticremoval by diffusion are protein binding and molecular size. The type ofmembrane and its permeability characteristics are important determinantsof antibiotic and drug removal. As a rule, the membranes used incontinuous methods of renal replacement therapy are at least as permeable(and often more so) than those used in intermittent hemodialysis. Dosing formaintenance and additional or loading doses can be calculated when thedesired plasma concentration of the antibiotic is known. The presentlyobserved level is subtracted from the desired level. The difference inconcentrations (in milligrams per liter) � volume of distribution (in litersper kilogram) � body weight (in kilograms) represents the amount of

Box 2. Predicting continuous arteriovenous hemofiltrationdrug removal using blood concentrations

1. Determine steady-state blood concentration (from arteriallines).

2. Determine fraction not bound to circulating plasmaproteins (see Table 1).

3. Determine ultrafiltration rate from bedside dialysis flow sheet.4. Amount of drug removed (per time) is the steady-state

arterial blood concentration times the unbound fractiontimes the ultrafiltration rate.

Adapted from Golper TA, Wedel SK, Kaplan AA, et al. Drug removal duringcontinuous arteriovenous hemofiltration: theory and clinical observations. InternArtif Organs 1985;8:307–12.


antibiotic necessary to achieve the desired antibiotic plasma level. Thisformula can be applied when the amount of antibiotic removal has not beendirectly measured or calculated [32,44,46,47].

Peritoneal dialysis in end-stage renal failure

Peritoneal dialysis as a chronic modality is used by less than 15% of theend-stage renal failure population. The most common variety is continuousambulatory peritoneal dialysis in which the patient performs four exchangesper day (draining 2 L of dialysate then instilling two fresh liters of dialysateinto the peritoneal cavity where it dwells for 4–6 hours). Some patients usecontinuous cycler peritoneal dialysis machines, which perform a number ofexchanges with shorter dwell times during the night so the patient is freeduring the day. Often the patient performs an extra exchange during the dayto enhance adequacy of dialysis. In peritoneal dialysis, intraperitonealantibiotic administration can be used to load, maintain, or remove plasmalevels. Heparin and insulin, which are common intraperitoneal additives, donot affect the activity or stability of intraperitoneal antibiotics [48]. Thefactors affecting peritoneal drug clearance are listed in Box 3. Intraperito-neal dosing guidelines for commonly used antibiotics are found in Table 4,whereas intravenous dosing and supplementation are described in Table 1[32,48,49]. There is an inverse semilogarithmic relationship betweenperitoneal clearance and molecular weight. For most drugs, the peritonealclearance of unbound drug can be calculated by multiplying the ureaclearance (20 mL/min) by the ratio of the square root of the weight of urea(60 d) over the square root of the antibiotic’s molecular weight. Chargedantibiotics diffuse slower than neutral ones. As a rule, drugs not removed byhemodialysis are also not cleared by peritoneal dialysis [50].

Peritoneal dialysis in acute renal failure

Acute peritoneal dialysis may have variable dwell times from no dwelltime to 6 hours (similar to continuous ambulatory peritoneal dialysis). Inthe setting of long dwell times (4–6 hours), the guidelines in the tables citedshould be appropriate for antibiotic dosing. In short dwell times, in-traperitoneal dosing may not be cost effective or as predictable in deliveringor removing antibiotic from the blood. In the critical care setting, multiplefactors may adversely affect clearance, such as hypotension or hypoperfu-sion of the mesenteric circulation, ileus, peristalsis, and dialysate tempera-ture [51,52]. In a patient receiving acute peritoneal dialysis with short dwells,it may be wisest to administer antibiotics intravenously and exploit theperitoneal dialysis as a means of clearing the drug to allow trough levels todevelop. As with any continuous method of renal replacement therapy,continuous administration, intravenous or intraperitoneal, could otherwiseresult in the absence of safe trough levels with potential antibiotic-relatedtoxicity. Because the number of exchanges per day (and hence degree of


antibiotic clearance achieved) may change frequently in the critical caresetting, it is important to communicate closely with the nephrologistoverseeing the peritoneal dialysis to help adjust antibiotic loading, mainte-nance, and removal based on the amount of dialysis being prescribed.

Adverse effects of antibacterial agents in renal failure

Numerous adverse effects have been reported from the use of antibac-terial agents in patients with renal failure. Many of these are related toinappropriate dosing, whereas others stem from pathologic changes

Box 3. Factors affecting peritoneal dialysis drug clearance

Drug propertiesMolecular weightChargeLipid or water solubilityVd (tissue binding)Protein bindingOther forms of steric hindranceRapid excretion by another pathwayRed cell partitioning

Intrinsic peritoneal membrane propertiesSurface blood flowSurface areaLocationSclerosisPore sizeVascular diseaseFluid films

Dialysate propertiesFlow rateVolumeChemical compositionDistributionTemperature

Miscellaneous propertiesUltrafiltrationClearance-raising additives

Data from Golper TA. Drugs and peritoneal dialysis. Dial Transplant 1979;8:41–3.


associated with uremia. An excellent review of this topic has been publishedby Manian et al [53].

Neurologic toxicity, including psychosis, visual and auditory hallucina-tions, myoclonus, and seizures has been reported with the use of penicillin,imipenem, b-lactams, acyclovir, amantadine, and quinolones [54–57].Ototoxicity, in the form of reversible auditory dysfunction, can result fromhigh dosages of erythromycin [58]. It remains unclear whether renal failureis an independent risk factor for aminoglycoside or vancomycin-inducedototoxicity. Sulfonamide-induced hypoglycemia is believed to be the resultof the structural similarity of sulfamethoxazole and hypoglycemic agents.Sulfamethoxazole may stimulate insulin secretion and can displace oralhypoglycemic agents from serum proteins making more free drug available[59,60]. This interaction can be further exacerbated by decreased clearance

Table 4

Intraperitoneal antibiotic dosing guidelines

Loading dose

Drug (mg/kg) (mg/L) Maintenance dose (mg/L)

Aminoglycosides

Amikacin 6 15

Gentamicin 1.7 5

Netimicin 1.7 5

Tobramycin 1.7 5

Cephalosporins 500–1000 125–250

Penicillins

Ampicillin 500 50

Azlocillin 1000 125–250

Carbenicillin 1000 125–250

Cloxacillin 1000 125

Mezlocillin 1000 125–250

Nafcillin 1000 125

Penicillin 106 U 50,000 U

Piperacillin 1000 125–250

Ticarcillin 1000 125–250

Miscellaneous agents

Aztreonam 500 250

Ciprofloxacin 10 10–20

Clindamycin 300 150

Erythromycin 150 75

Imipenem 500 200

Metronidazole 15 (IV) 10

Rifampina

Sulfamethoxazole 200 � 2 wk 100 � 2 wk

Trimethoprim 40 � 2 wk 20 � 2 wk

Vancomycin 500–1000 15

a Administered orally at an adult dose of 600 mg/d.

Data from Golper TA, Bennett WM. Drug usage in dialysis patients. In: Nissenson R, Fine

RN, Gentile DE, editors. Clinical dialysis. 2nd edition. Norwalk (CT): Appleton and Lange;

1990. p. 608–30.


and protein binding of sulfamethoxazole in uremia. Platelet aggregationabnormalities induced by high doses of penicillins exacerbate the plateletdysfunction of uremia and vitamin K deficiency, and augment the effect ofheparin with hemodialysis [61–63]. Renal failure does not seem to be anindependent risk factor for the coagulopathy associated with cephalosporinscontaining the N-methyl-thiotetrazole side chain; vitamin K deficiency,often present in renal failure, seems to be the culprit [64]. Fluoroquinoloneshave been associated with spontaneous Achilles tendon rupture in patientswith underlying renal failure [65]. The tetracycline antibiotics (with theexception of doxycycline) should be avoided in patients with renal in-sufficiency because there has been an increased incidence of hepatotoxicity.Rarely, acute fatty necrosis of the liver can occur in patients with underlyingrenal dysfunction [66].

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use of antibacterial agents in renal failure

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