Choice of Antibiotics, Pharmacokinetics, and Dose Adjustments in Acute and Chronic Renal Failure

Renal Disease

0025-7125/90 $0.00

+ .20

Choice of Antibiotics, Pharmacokinetics, and Dose Adjustments in Acute and Chronic Renal Failure Jack M. Bernstein, MD, * and Stanley D. Erk, PhDt

The past five decades have seen a proliferation in the number of agents available for the treatment of infectious diseases. At the present, antimicrobial agents are available for the treatment of bacterial, fungal, parasitic, and viral infections. In this article, we attempt to provide a brief overview of major agents presently in use, their metabolism and side effects, and modifications needed in the presence of renal dysfunction. Our review is by no means all inclusive, but it reflects the opinions of the authors about the agents included. Numerous review articles, texts, or pamphlets have appeared over the past 5 years that have provided comprehensive tables dealing with the interaction between virtually all antimicrobial agents and renal dysfunction. We will not attempt to replicate these here but would refer the interested reader to the appropriate sources. I, 5, 26, 35, 39 USE OF ANTIBIOTIC PHARMACOKINETICS

Pharmacokinetics is, of course, a mathematical description of the absorption, distribution, and elimination (including metabolism) of drugs as a function of concentration in vivo in relationship to time. The assumption has been that concentration of drug at the site of action is proportional to its therapeutic response. There is a wide variety of definitions and equations that may be used depending upon the specific situation. 48 However, only a From Wright State University School of Medicine; and Department of Veterans Affairs Medical Center, Day ton, Ohio *Professor of Medicine and Associate Professor of Microbiology and Immunology; and Chief, Infectious Diseases Section tAssistant Clinical Professor, Department ofPhannacology and Toxicology; and Pharmacologist

Medical Clinics of North America-Vol. 74, No. 4. July 1990

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JACK ~. BEHNSTEIN AND STA:-.ILEY

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few are important to know and use in the clinical scenario of antibiotic therapy in rcnal failure. Concepts that are of value are first-order elimination, half~life, volume of distribution, concentration at steady state, and Michaelis-Menten, or zero-order, processes. First-order elimination implies that there is a decrease in concentration of a drug by some constant fraction or rate over equal intervals. This assumption, which is a composite of multiple biological processes, allows the calculation of half-life, a constant. It is determined either graphically or by computer and is defined by the time required for the drug concentration to decrease by one half. The volume of distribution is a relationship of the initial dose divided by the concentration after "instantaneous" distribution throughout the body. Use of this relationship permits changes in therapeutic regimens with some degree of accuracy. Steady-state principles indicate that multiple doses given at constant intervals will reach greater than 95% of the final concentration within five half-lives. Michaelis-Menten, or zero-order, processes are representative of saturation kinetics, in which a constant amount of drug is eliminated over time. The clinician should take note that many of the pharmacokinetic parameters useful in the hospital are for general application and do not precisely reflect the exact circumstance in each individual. In this article, the two issues of primary concern are for drugs that are eliminated via the kidney and those that exhibit a narrow therapeutic index. The drug class that is most representative of both problems is the aminoglycosides. These drugs, of which gentamicin and tobramycin are similar in pharmacokinetic parameters, are widely used for the treatment of serious gram-negative infections despite yearly release of multiple new antibiotics. These antibiotics, and others, are reviewed briefly in the remainder of this article.

OVERVIEW OF ANTIMICROBIAL AGENTS ANTIBACTERIAL AGENTS

Penicillin and Ampicillin Penicillin is the prototypic beta-Iactam antibiotic and has been available since the 1940s. It has a half-life of approximately 30 minutes. It is predominantly excreted by the kidneys and is both filtered and secreted. Secretion may be inhibited by probenecid, thereby increasing serum levels and prolonging its half-life. Ampicillin was the first broad-spectrum penicillin. It is active against most community strains of Escherichia coli and Proteus mirabilis. It is approximately twice as active against Enterococcus faecalis than penicillin G but is only bacteriostatic against this organism. Ampicillin or penicillin therapy of E. faecalis infections proves bactericidal when an aminoglycoside is added to the therapeutic regimen. The utility of ampicillin against Haemophilus injluenzae has been somewhat decreased because of the increased prevalence of beta-Iactamase-producing strains. Amoxicillin/clavulanic acid and ampicillin/sulbactam have provided renewed activity

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against these beta-Iactamase-positive strains. This is discussed further under beta-Iactamase inhibitors. Penicillins are relatively nontoxic, but high levels can induce seizures. Ampicillin is excreted predominantly by renal mechanism. After a standard loading dose, dosage should be decreased by 75% in anephric patients. Because hemodialysis decreases serum levels by approximately 50%, half a loading dose should be given after each dialysis treatment. Peritoneal dialysis has little effect on serum levels. An excellent review of all the penicillin-class drugs, including the beta-Iactamase-stable penicillins and new clavulanic acid derivatives, may be found in reference 15. Penicillinase-Resistant Penicillins (Methicillin, N afcillin, Oxacillin) In the 1950s, beta-Iactamase production by staphylococci decreased the effectiveness of penicillin for the treatment of staphylococcal infections. The addition of an acyl side chain to penicillin inhibited the action of the beta-Iactamase and defined the class of semisynthetic penicillins. All of these agents have half-lives of approximately 1 hour and must be administered every 4 to 6 hours to assure maintenance of adequate antibiotic levels. Hemodialysis and peritoneal dialysis have little effect on serum levels of these drugs, and no dosage adjustment is needed. In patients with endstage renal disease (ESRD), the dosing interval should be doubled. Of the semisynthetic penicillins, methicillin is among the most active against Staphylococcus aureus, but it has the highest association with the occurrence of interstitial nephritis. Hepatotoxicity has been associated with oxacillin therapy. Nafcillin usage is less fraught with problems and is considered the antistaphylococcal penicillin of choice. Carboxypenicillins (Carbenicillin, TicarcilIin) Carbenicillin was the first broad-spectrum penicillin with significant antipseudomonal activity. Its half-life is approximately 1 hour in patients with normal renal function but mav increase to as much as 10 hours in ESRD. In order to attain adequat~ antipseudomonal activity in serum, large doses of carbenicillin (36 g/day) must be used. Because there is 4.7 mEq of sodium in each gram of active drug, almost 170 mEq of sodium may be administered each day, leading to problems with both sodium overload, kaliuresis, and hypokalemia. Ticarcillin is more active than carbenicillin against Pseudomonas, and a lower dose may be used (12 to 18 g/day); however, as with carbenicillin, sodium overload and hypokalemia occur. Use of this class of drugs may lead to abnormal bleeding times and inactivation of aminoglycosides. These adverse effects are discussed in the next section. U reidopenicillins (Mezlocillin, Piperacillin, Azlocillin) The ureidopenicillins, piperacillin, mezlocillin, and azlocillin, contain a substitution at the amino group of ampicillin. This provides activity against Pseudomonas and other more resistant gram-negative rods. These agents are active against the majority of anaerobic isolates found in clinical practice. The spectrum of these agents is similar, with the exception of mezlocillin,

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which is slightly less active against Pseudomonas, and azlocillin, which is slightly less active against enteric gram-negative bacilli. The ureidopenicillins are eliminated by zero-order processes, which consist of glomerular filtration and tubular secretion (60 to 80%), although 10 to 20% of the drug is eliminated in the bile. In persons with normal renal function, the serum half~life is approximately 1 hour. Patients with a creatinine clearance (C cr) less than 5 mllmin have a half-life of approximately 2 to 6 hours. Four hours of hemodialysis may remove 30 to 50% of the drugs, necessitating an additional 1-g dose after dialysis. 17 U reidopenicillins may acetylate platelets, leading to prolongation of bleeding time. 18 This may be accentuated in patients with ESRD, in which the serum half~life is prolonged. Cross-inactivation may occur between ureidopenicillins and aminoglycosides when the serum half-life is prolonged. Similarly, coadministration of ureidopenicillins and aminoglycosides through the same intravenous line may lead to coinactivation. An amide compound is formed after the lactam ring of the ureidopenicillin is cleaved by an amino group on the aminoglycoside. The ureidopenicillin-aminoglycoside complex is both microbiologically and immunologically inactive, and supplemental doses of both aminoglycosides and penicillins may have to be given. This reaction also occurs with carbenicillin but at a rate approximately 10 times greater. 41 Beta-Lactamase Inhibitors In order to adequately treat H. injluenzae meningitis due to betalactamase-producing organisms, clinicians utilized combination therapy of a penicillinase-resistant penicillin (eg, methicillin) with ampicillin. The methicillin effectively inactivates the beta-lactamases, allowing ampicillin to exhibit a bactericidal effect against the H. injluenzae. Several compounds have been synthesized that have little intrinsic antimicrobial therapy by themselves but are potent inhibitors of staphylococcal beta-lactamases. These include clavulanic acid, sulbactam, and tazobactam. These drugs havc been combined with beta-lactam antibiotics to yield an agent that has an extended spectrum and activity against many beta-Iactamase-producing organisms. It is important to note that these "new" drugs are not active against organisms containing inducible, chromosomally mediated betalactamases such as Pseudomonas and Enterobacter species. Drugs that are commercially available include Augmentin (amoxicillin and clavulanic acid), I Timentin (ticarcillin and clavulanic acid), and Unasyn (ampicillin and sulbactam). Various other combination drugs are under development. The toxicity of these agents is predominantly that which is seen with the parent compound. Usage of Augmentin has been associated with diarrhea in up to 10% of patients. Slight or no dose adjustment is necessary for ESRD or dialysis. First-Generation Cephalosporins (Cephalothin, Cephapirin, Cefazolin) The first-generation cephalosporins are active against all gram-positive cocci except Enterococcus faecalis, which is resistant to all presently available cephalosporins. Cephalothin and cephapirin have serum half-lives of approximately 30 minutes, which increase to 2 to 3 hours in the presence

CHOICE OF ANTIBIOTICS, PlIAI\l\1ACOKI;\lETICS, AND DOSE ADJUSTMENTS

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of anuria. The use of cephalothin in conjunction with an aminoglycoside has been thought by some to potentiate nephrotoxicity. Cefazolin has essentially replaced cephalothin on many hospital formularies owing to its longer serum half-life (1. 5 hours), which leads to less-frequent dosing and cost savings. Because of differences in both metabolism and half-life, cephalothin/ cephapirin and cefazolin behave differently in the presence of ESRD. The half-life of cephalothin is prolonged to 2 to 3 hours, necessitating a quartering of the dose. Hemodialysis does not remove cephalothin whereas peritoneal dialysis does and supplemental dosing should be given after peritoneal dialysis. The half-life of cefazolin is dramatically prolonged in ESRD, increasing to 36 to 60 hours. After a normal loading dose, one half dose should be given each 48 hours. Peritoneal dialysis does not affect serum cefazolin levels, whereas hemodialysis effectively removes it, necessitating 500 mg of cefazolin after each hemodialysis to maintain levels. Second-Generation Cephalosporins (Cefamandole, Cefoxitin, Cefuroxime, Cefotetan, Cefonicid, Ceforanide, Cephaloridine) The second-generation cephalosporins share increased activity against most enteric gram-negative rods except Pseudomonas aeruginosa and decreased activity against Staphylococcus aureus. 34 They differ predominantly in their half-lives and in some subtleties of their antimicrobial spectrum. Cefuroxime is the only agent in the group with any appreciable cerebrospinal fluid penetration. 34 Most of these agents share toxicities in common with first-generation cephalosporins. Both cefotetan and cefamandole have an n-methyl thiotetrazole side chain. 40 The presence of this chain has been implicated in both inhibition of synthesis of clotting factors and a disulfiramlike reaction in patients who have ingested ethanol. Clotting-factor abnormalities have been reported more frequently with cefamandole than with cefotetan. Cephaloridine usage was associated with appreciable nephrotoxicity, as a result of which it is no longer used. Owing to the complexity of this group, differences between agents are illustrated in Table 1. Third-Generation Cephalosporins (Moxalactam, Ceftazidime, Ceftizoxime, Cefoperazone, Cefotaxime) The third-generation cephalosporins are extremely broad spectrum agents and are widely used. They are extremely active against most enteric gram-negative rods, are less active than the first- and second-generation agents against S. aureus, and, in general, penetrate into the cerebrospinal fluid.:J There is significant overlap between agents in both spectrum and pharmacokinetics. Cefoperazone has good Pseudomonas activity and, owing to significant hepatic metabolism, is not affected by ESRD. Cefoperazone has a methyl thiotetrazole ring, as a result of which both an antabuse-like effect and a coagulopathy may occasionally be seen. Cefotaxime and ceftizoxime are similar and have good aerobic and anaerobic activity. Cefotaxime has an active metabolite that may be synergistic with the parent compound. Ceftriaxone has poor anaerobic and antipseudomonal activity but has an extremely long half-life, making once-daily dosing feasible. Ceftazidime has a relatively short serum half-life but has the best activity

O'l

...

..o

Increased activity vs resistant aerobic gram-negative bacteria

Cefotetan

Abbreviations: ESRD

end-stage renal disease, TV2

= half~life.

3-4

20-40

2.5-3.5

Long

Ceforanide

TU2

15 70

1.2-1.4 4-4.5

Cefuroxime Cefonicid

Cefoxitin

24-48

2:20

16-18

Good H. injluenzae activity Best anaerobic activity of second generation Good CSF levels Long Tv,

Cefamandole

ANURIC TV2 (HR)

Tl!2 (HR)

SPECIAL ATrRlBUTES

AGENT

NORMAL

As above Vz dose every 72 hr '/2 dose every 48 hr Full dose every 48 hr

'/2 dose every 48 hr As above

ESRD

DOSAGE IN

Table 1. Characteristics of Second-Generation Cephalosporins

Yes; give % dose post dialysis Yes; give Vz dose every 24 hr

Yes No

Yes

Yes

HE~IODIALYSIS>

No

No No

DIALYSIS

PERITONEAL

CHOICE OF ANTIBIOTICS, PIIARI\IACOKINETICS, AI\:O DOSE AOJUSTI\IENTS

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against Pseudomonas of all the third-generation agents. 2R Moxalactam usage was associated with life-threatening coagulopathies and has been all but abandoned by clinicians. Differences between agents are illustrated in Table 2. Monobactams Aztreonam is the first member of a new class of antibiotics designated as the monobactams. These drugs are characterized by activity against gram-negative pathogens without any significant activity against either gram-positive or anaerobic pathogens. Some clinicians have touted these drugs as substitutes for aminoglycosides because of the lack of any significant nephrotoxicity or other significant untoward reactions associated with the monobactams. Moreover, the lack of significant activity against anaerobes allows the selective elimination of gut enteric flora without altering the number of anaerobic organisms. Aztreonam is cleared predominantly (75%) by the kidneys. Its serum half-life ranges from 2 hours in persons with normal renal function to 6 hours in anephric patients. It is effectively cleared by hemodialysis but is only minimally cleared by peritoneal dialysis. 19 Dosage is normally 1 to 2 g every 6 to 8 hours. It should be reduced to 75% of this dose in patients with a C cr of 60 mllmin, 50% in patients with a C" of 30 mllmin, and 25% in anephric patients. Alternatively, the dosage interval may be increased by the reciprocal of the noted percentage. 27 Carbapenems (Imipenem-Cilastatin) Imipenem is thc first carbapenem antibiotic to be released for clinical use. It is an extremely potent and broad-spectrum antibiotic with activity against the majority of gram-negative, gram-positive, and anaerobic pathogens. A notable exception is methicillin-resistant Staphylococcus aureus, which is resistant to its action. It is rapidly degraded by dehydropeptidases in renal tubular cells and is nephrotoxic in both rabbits and rhesus monkeys. For this reason, imipenem is administered as a dual drug with cilastatin, a potent inhihitor of renal dehydropeptidase. The inhibition of this enzyme prevents both degradation and uptake by the tubular cells, thereby effectively preventing nephrotoxicity.6 Imipenem has a half-life of less than 1 hour in patients with normal renal function, rising to 3.7 hours in functionally anephric patients. Hemodialysis decreases the anephric half-life by approximately .50%, whereas peritoneal dialysis has only a slight effect on serum levels. 29 High imipenem serum levels may induce seizures, thus necessitating careful use of this drug in the presence of impaired renal function. 14 Quinolones (Ciprofloxacin, Norfloxacin, Ofloxacin, Enoxacin, Fleroxacin) The fluoroquinolones represent a major advance in antimicrobial chemotherapy.50 They are biochemically related to nalidixic acid but have a much expanded spectrum that encompasses the majority of gram-negative rods, including Pseudomonas aeruginosa, gram-positive pathogens, including Staphylococcus aureus and Streptococcus pyogenes, and Haemophilus and Neisseria species. They have minimal activity against anaerobes.

O'l O'l

o

,...

13-40

2.5-3

Abbreviations: ESRD

Moxalactam

end-stage renal disease, Tl!2

half-life.

9-11 2:20

6-8 1

Longest Tl!Z Best Pseudomonas activity of third generation Bleeding problems; no longer used by most clinicians

Ceftriaxone Ceftazidime

Reduce dose by 90% after loading dose

36

1.3

Increased activity vs

Ceftizoxime

Providencia a~d Acinetobacter

Decrease dose by 50% Rednce dose by 90% after loading dose Normal dosing '12 dose every 48 hr

2.5

Cefotaxime

Cefoperazone

1

DOSAGE IN ESRD

Normal dosing

T1I2

T]/2 (HR)

2

ANUHlC

NORMAL

2

SPECIAL ATTRIBUTES

Good Pseudomonas activity Metabolite active

AGENT

No

lIEMODIALYSIS:'

Yes

No Yes; give 1/2 dose after dialysis

Yes; Vz dose after dialysis Yes; give dose after dialysis

Table 2. Characteristics of Third-Generation Cephalosporins

No

?

No

No

DIALYSIS

PERITONEAL

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Bioavailability is excellent, allowing the oral treatment of conditions heretofore relegated to intravenous therapy, Ciprofloxacin is most active, and norfloxacin and fleroxacin are least active against Pseudomonas. At the present time (late 1989), only ciprofloxacin and norfloxacin are licensed for use in the United States. Norfloxacin is only licensed for the treatment of urinary tract infections. Toxicity is minimal, as less than 5% of patients may complain of nausea and mild upper gastrointestinal distress. Crystalluria may occur with high doses of these agents. The quinolones are excreted by both glomerular filtration and tubular secretion. Half-lives are increased by two- to fourfold in ESRD. Fleroxacin has a half-life of 8 to 12 hours, which effectively allows once daily dosing. Hemodialysis readily removes the quinolones, whereas peritoneal dialysis is less effective in this regard. Aminoglycosides (Gentamicin, Tobramycin, Netilmicin, Amikacin) Gentamicin was released in the United States in 1969. Tobramvcin was released 6 years later. Amikacin has the broadest spectrum of these agents owing to its resistance to aminoglycoside-inactivating enzymes. Minimal inhibitory concentrations of amikacin against gram-negative bacteria are higher, in general, than those of gentamicin or tobramycin; however, given the usual threefold higher doses used, both antibacterial activity and toxicity are similar to that of other aminoglycosides. Netilmicin is intermediate between gentamicin and amikacin in its resistance to inactivation. All have proved useful in treatment of systemic infections and remain widely used. Minimal hepatic metabolism occurs for these drugs; however, there have been reports of increased nephrotoxicity during depression of liver function. Almost all elimination is via the renal pathways, resulting in inordinately high urine concentrations of the unmetabolized drug. 8 This is both an advantage in that urinary tract infections can be easily managed and a disadvantage in that kidney damage begins immediately. This is manifested by impairment in the concentrating ability of the kidney, producing a reversible nonoliguric acute renal failure. If the dosage is not adjusted to reflect appropriate peak and trough levels, irreversible nephrotoxicity and ototoxicity may occur. Aminoglycoside toxicities are well described and include reversible nephrotoxicity, irreversible ototoxicity, and neuromuscular blockade (especially in patients with myasthenia gravis). Numerous studies have been conducted in attempts to show that one aminoglycoside is either more or less toxic or more efficacious than another. Generally speaking, these drugs are interchangeable, with susceptibilities and cost being the primary considerations. Loading doses of 2 mg/kg (5 to 7.5 mg/kg for amikacin) should be given almost irrespective of renal function, body demographics, or age. The major difficulties in utilizing the aminoglycosides are that body type, hydration status, renal function, and disease type all affect half-life, clearance, volume of distribution, and subsequent serum peaks and troughs. It has been found that peaks greater than 12 f.Lg/ml (35 f.Lg/ml for amikacin), troughs greater than 2 f.Lg/ml (10 f.Lg/ml for amikacin), duration of treatment, and concurrent nephrotoxic drugs are risk factors for nephrotoxicity. 25, 32 Maintenance doses are empirically started. Patients with normal renal function should begin at 3 to 5 mg/kg/day (15 mg/kg/day for amikacin),

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depending on severity of illness. In our medical center, with many geriatric patients, this dose is divided by 2 and given at 12-hour intervals for patients over 6.5 years old. For patients under 6.5, the dose is divided by 3 and given at 8-hour intervals. Patients with renal insufficiency have dosages adjusted by age, C ce (as calculated by Cockcroft-Gault equation), and hydration status. The initial peak and trough are taken at the third dose, which is at essentially steady state, except for patients with unusually long half-lives. All patients should then have their regimen adjusted based on the reported serum levels. With the availability of pharmacokinetic services, personal computers, hand-held programmable calculators, and software from many sources (some free), empiric therapy past the third day and use of nomograms are no longer acceptable. The computerized techniques routinely and accurately predict the regimens necessary to attain peaks between 4 and 10 I-lg/ml and troughs below 2 I-lg/ml (20 to 30 I-lg/ml and 1 to 8 I-lg/ml, respectively, for amikacin). Owing to excessive concerns over nephrotoxicity, physicians generally underdose these medications. 4 Adjustments made on pharmacokinetic principles will achieve therapeutic levels, decrease toxic events, and decrease time to effect a cure. Aminoglycosides are cleared by hemodialysis. If dosing is desired under these circumstances, half a loading dose should be given after each 4-hour dialysis treatment. Peritoneal dialysis removes varying amounts of these drugs and 36 hours of dialysis may remove 20 to 2.5% of the drug from the serum. Under these circumstances, supplemental doses should be used accordingly. Vancomycin Vancomycin is a glycopeptide antibiotic that was introduced into the United States in 19.56. It still has wide use in treatment of Staphylococcus at/reus and, in our institution, is the drug of choice for methicillin-resistant S. at/reus (MRSA).38 The purity of vanco~ycin has been improved dramatically from the days in which it was known as "Mississippi mud." Side effects such as phlebitis and the so-called red-neck syndrome have become less common as the purity has improved. For systemic infections, vancomycin is infused intravenously. Nominal dosages of 1 g every 12 hours for adults with normal renal function should be infused over at least I-hour duration to prevent red-neck syndrome. 3:3 Occasionally, rates as slow as 3 hour infusion must be used. This complicates the pharmacokinetic picture because of a prolonged distribution phase, making a two-compartment model more appropriate than the usual one-compartment description. The half-life of the distribution phase ranges from 0 . .5 to 1..5 hours, whereas the terminal elimination phase is around 6 hours. 20 As with the aminoglycosides, ototoxicity and nephrotoxicity are the chief concerns. Few studies have well documented the drug serum concentrations above which toxicity occurs; however, some authors have recommended keeping peak levels below 40 I-lg/ml and troughs below 10 I-lg/ml. 29 Other authors have demonstrated that vancomycin and the aminoglycosides are synergistic in regards to nephrotoxicity. Trough and peak levels should be drawn 1 hour before and 1 hour after the infusion, respectively, for this drug also, particularly in the event of renal insufficiency. Half-lives may be so extensive

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that intervals of 48 hours between doses are not uncommon in this class of patients. Computer-driven pharmacokinetic analysis is almost a requirement for them, although nomograms have been utilized in urinary tract infections. 30 Chloramphenicol Chloramphenicol was one of the first truly broad-spectrum parenteral agents. It has activity against many gram-positive and gram-negative organisms (not Pseudomonas) and is an excellent antianaerobic agent. Its use is rarely (:s 1 :40, 000) associated with aplastic anemia. 46 A dose-related marrow suppression is associated with doses of greater than 50 mg/kg/day. Neonates may contract the "gray baby" syndrome, which is characterized by circulatory collapse, if they receive more than 25 to 50 mg/kg/day; this syndrome is probably related to inadequate hepatic metabolism due to an immature liver. Metabolism of chloramphenicol is predominantly hepatic, and the serum half-life of 3 hours is not significantly prolonged in ESRD. Hemodialysis removes significant amounts of the drug, and dialysis treatments should be followed by a supplemental dose. Peritoneal dialysis has a slight effect on serum levels. A more significant problem occurs if the patient has concurrent hepatic insufficiency or failure. In these cases, chloramphenicol levels should be monitored. Clindamycin Clindamycin is a 7-chloro derivative of lincomycin. Owing to the superior activity of clindamycin, lincomycin is no longer used. Clindamycin has excellent activity against Bacteroides fragilis and is also active against S. aureus, although it is not bactericidal against staphylococci. Clindamycin was the prototypic drug associated with pseudomembranous colitis due to Clostridium difficile;42 however, it has been demonstrated that virtually any antibiotic can lead to this condition. Clindamycin is metabolized predominantly by the liver, and dosage adjustment in ESRD is unnecessary unless hepatic failure complicates ESRD. Its serum half-life of 2 to 4 hours is not prolonged in ESRD and not affected by dialysis. Metronidazole This drug was originally utilized for the treatment of amoebic and trichomonal infections. Over the past decade, its bactericidal activity against anaerobic bacteria has made it popular for the treatment of anaerobic infections.' Use is occasionally associated with both vestibular toxicity and a peripheral neuropathy. Some patients develop a tinny taste in their mouths and nausea and vomiting. Metronidazole is slightly cleared by the kidneys. Its half-life of 6 to 10 hours is not significantly prolonged in ESRD. Hemodialysis may decrease blood levels somewhat. Some clinicians recommend decreasing the dose in ESRD because of the possible accumulation of toxic metabolites. 22 Sulfamethoxazole-Trimethoprim (Co-trimoxazole) and Tetracyclines (Minocycline, Doxycycline, Tetracycline) Co-trimoxazole is comprised of a fixed ratio of 80 mg of trimethoprim for each 400 mg of sulfamethoxazole. These two agents block two sequential

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steps in the folate biosvnthetie pathway of microorganisms. The drug is active against many bacteria and has been successfully used to treat Pneumocystis carinii pneumonia. The majority of adverse reactions seen with co-trimoxazole relate to the sulfa moiety. Blood dyscrasias, including agranulocytosis, nausea and vomiting, rashes, and Stevens-Johnson syndrome have all been reported. AIDS patients appear especially intolerant to co-trimoxazole. 9 The serum half-life of sulfamethoxazole is 8 to 10 hours, and for trimethoprim, 10 to 12 hours. These half-lives are approximately doubled in ESRD. After a full loading dose, patients should receive 25% of their dose every 12 hours. Hemodialysis effectively removes co-trimoxazole, and a full maintenance dose should be given after each dialysis. Tetracycline is a broad-spectrum agent that binds to the 30s subunit of bacterial ribosomes and inhibits bacterial protein synthesis. Tetracycline accumulates in renal f~lilure because of an increase in its half-life from 6 to 12 hours to 18 to 30 hours. At high concentrations, tetracyclines have an antianabolic efIect. Minocycline has a longer half-life (15 to 20 hours) but also accumulates in ESRD. Of the tetracyclines, only doxycycline is unaffected bv renal failure and, if needed, can be used. 49 "Outdated" tetracycline has been shown to cause a "Fanconi-like" syndrome that is manifested by hyperchloremic normal anion-gap acidosis, nephrosis, and aminoaciduria. Tetracycline is cleared somewhat by hemodialysis but, as noted, should be avoided in patients with renal failure. ANTI~IYCOBACTERIAL AGENTS

In this scction, we deal briefly with the four most common antituberculous agents in use today. A concise review may be found in reference 13. Streptomycin, which is still used in the combination therapy of Mycobacterium tuberculosis, has pharmacologic and toxicologic properties similar to other aminoglycosides. Isoniazid Isoniazid (IN H) remains a first-line drug in thc treatment of infections duc to Mycobacterium tuberculosis. Unfortunately, toxic side effects are occasionally seen with its use. Peripheral neuropathy may occur after several months of use but can be prcvented by the administration of 10 mg of pyridoxine for each 100 mg of INH. Hepatoxicity is common, and most patients will show an elevation in their transaminases. Frank hepatitis is unusual, but its incidcnce increases in patients older than 35 years of age. Slight adjustments need to be made for renal failure because the normal INH serum half-life of 0.5 to 1.5 hours is barely prolonged in ESRD. Bccausc a major metabolic route of inactivation is acetylation, anephric "slow acetylators" should probably receive no more than 200 mg/ day. No dosing is necessary following hemodialysis or peritoneal dialysis. Rifampin Rifampin is an oral agent that inhibits DNA-dependent RNA polymerase. It is active against aerobic bacteria, such as S. aureus, as well as

CIIOICE OF ANTIBIOTICS, PIlAR~IACOKINETICS. Al'\[) DOSE ADjlIST!\[ENTS

1071

mycobacteria, Rifampin increases the metabolism of oral anticoagulants, contraceptives, corticosteroids, and sulfonylurea, thus necessitating dosage adjustments, A flu-like syndrome may be seen soon after taking rifampin and may rarely be associated with acute renal failure, especially with repeated therapy. Rifampin usage is also associated with hepatotoxicity, which may be enhanced when it is administered concurrently with INH. Rifampin diffuses readily into all bodily secretions, resulting in reddishorange tears, urine, saliva, and so forth. Rifampin's serum half-life of 2 to 5 hours is not prolonged in ESRD. Dialysis has no effect on serum levels. Ethambutal Ethambutal remains a first-line drug for the treatment of tuberculosis. Occasional cases of reversible retrobulbar neuropathy, leading to defects in red-green vision, are seen. These cases are rare at the standard dose of 15 mg/kg/day. Ethambutal has a normal serum half-life of 3 to 4 hours, which is prolonged to 18 to 20 hours in ESRD. One third of the normal daily dose should be given when the Cc, is less than 10 ml/min. Hemodialysis should be followed by a 5-mg/kg supplemental dose, as should peritoneal dialysis. Pyrazinamide Pyrazinamide has recently found favor in multiple-drug "short courses" for the treatment of M. tuberculosis. It is hepatotoxic in a small percentage of patients. The major route of removal is renal, but it is also hydrolyzed and hydroxylated. Pyrazinamide interferes with the excretion of urate, leading to high uric acid levels and exacerbations of gout. 45 Care should be exercised if using this drug in ESRD, because toxic levels might accumulate.

ANTIFUNGAL AGENTS

Amphotericin B Amphotericin B remains the drug of first choice for the treatment of invasive fungal infections. Unfortunately, use of amphotericin B is associated with a myriad of side effects, including fever, chills, nausea, vomiting, and headache. Anemia may occur after weeks or months of use. The drug is intrinsically nephrotoxic, and a major question that arises with its use is not if but when the patient will develop adverse effects. After a variable period of time, patients may develop hypokalemia, hypomagnesemia, and renal tubular acidosis, presumably as a result of damage to the renal tubular cell membrane, Elevations in serum creatinine indicate the onset of decreased renal function. In most cases, these abnormalities will reverse after the drug has been discontinued. Nonrenal side effects, such as fever, chills, and phlebitis, may be dealt with by pretreatment of patients with analgesics, antipyretics, and meperidine and by the addition of corticosteroids to the infusion. Hypokalemia and hypomagnesemia are best dealt with by replacement therapy with the respective salts. Once the creatinine has increased twofold over the baseline level, it would be advisable to

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change the dosage interval to two to three times weekly. It is important to realize that amphotericin B is not cleared by the kidney and intrinsic renal function has no bearing on either the appropriateness of use or the dose used. Hemodialysis or peritoneal dialysis has no effect on clearance of the drug. 2 Flucytosine (5-Fluorocytosine) Flucytosine is a cytosine analogue that interferes with fungal nucleic acid syntheSis. It is predominantly active against yeasts such as Candida, Torulopsis, and Cryptococcus. It is frequently used in synergy with amphotericin B. Solitary use of flucytosine rapidly leads to the emergence of resistant isolates. Nausea and vomiting are frequent side effects. Hematosuppression may occur owing to the conversion of flucytosine to 5fluorouracil. Flucytosine has a normal half-life of 3 to 4 hours that increases to 60 to 80 hours ill ESRD. Normal four-times-daily dosing must be decreased to approximately once every 48 hours when the C cr is less than 10 mllmin. Hemodialysis reduces serum levels by 50 to 75%; a supplemental dose of 20 mg/kg should be given after each dialysis. Peritoneal dialysis clearance is 14 mllmin. Azoles The azole derivatives ketoconazole and miccnazole held promise of being major steps forward in the treatment of fungal infections. Miconazole was released in the mid-1970s for intravenous use. Shortly thereafter, significant problems with it became apparent. Rapid intravenous infusion of miconazole led to cardiorespiratory arrest or anaphylaxis. 15 Patients with Candida infections or coccidioidomycosis who were treated with miconazole had unacceptably high relapse rates. Ketoconazole proved superior to miconazole both in its spectrum and its availability as an oral drug that was readily absorbed from an acid environment (patients with achlorhydria cannot absorb it). Ketoconazole proved effective in the treatment of histoplasmosis and blastomycosis and became the drug of choice for chronic mucocutaneous candidiasis. Problems with ketoconazole have been seen related to its suppression of testosterone synthesis, occasional nausea and vomiting, and, more infrequently, hepatitis. 44 Neither miconazole nor ketoconazole is appreciably cleared in the urine, and their half-lives (4 to 24 hours and 2 to 8 hours, respectively) are unaffected by ESRD. Hemodialysis or peritoneal dialysis would not be expected to have any significant effect on blood levels.

ANTIVIRAL AGENTS

Adenine Arabinoside and Acyclovir In this discussion, we deal with agents active against herpes simplex virus, varicella zoster virus, and cytomegalovirus virus. Historically, vidarabine was utilized for the treatment cl both severe herpes simplex and varicella zoster virus infections. 10, 47 Vidarabine is a relatively insoluble

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compound that is cleared by renal mechanisms, Because of its significant toxicity, vidarabine is almost never used. Acyclovir is a nucleoside analogue that was previously known as acycloguanosine. Acyclovir was bioengineered to be specific for the phosphorylated specifically by the thymidine kinase enzyme of herpes simplex virus and, as such, has relatively low toxicity. It has a serum half-life of 2 to 4 hours in normal renal function and 20 hours in ESRD. Higher doses of acyclovir need to be used for varicella zoster virus infections 36 and have also been used experimentally in the treatment of the chronic fatigue syndrome. Renal impairment has occasionally been associated with high doses and may be due to an obstructive nephropathy. In patients with impaired renal function, the dosage interval should be increased from 4 to 8 hours in mild renal failure and to every 48 hours in ESRD. Acyclovir is cleared by hemodialysis, and a supplemental dose should be given after each dialysis. Ganciclovir Ganciclovir (Cytovene) is a nucleic acid analogue previously known as DHPG that specifically inhibits cytomegalovirus DNA replication. It is solely approved for the treatment of cytomegalovirus retinitis in immunocompromised patients. Ganciclovir is relatively toxic and is frequently associated with bone marrow suppression. Ganciclovir is almost exclusively excreted unchanged by the kidneys and has a normal half-life of approximately 3 to 4 hours. Patients with ESRD have a half-life of approximately 11 hours. Patients with a normal C n should receive 5 mg/kg every 12 hours, whereas those with ESRD should receive a normal loading dose followed by 2.5 mg/kg every 24 hours thereafter. Because the drug is cleared by hemodialysis, one half of a loading dose should be supplemented after each hemodialysis treatment. 37 Zidovudinc Zidovudine is the only approved drug for the treatment of human immunodeficiency virus (lIlY) infection. The agent is a relatively selective inhibitor of retroviral reverse transcriptases. At the present time, zidovudine is only available as a 100-mg oral formulation. The plasma half-life of zidovudine is approximately 1 hourY Renal clearance accounts for a significant proportion of the metabolism of the drug. There are few data available concerning the use of zidovudine in patients with impaired renal function. It is likely that dosing will have to be modified in a manner similar to acyclovir. Ribavirin Ribavirin is a synthetic nucleoside analogue with a broad spectrum of activity against a variety of DNA and RNA viruses. In the United States, it is indicated solely for the aerosol treatment of respiratory syncytial virus infections. In general, no major toxicity has been associated with aerosol ribavirin use in North America. Ribavirin has also been used intravenously for the treatment of Lassa fever. Dose-dependent hematosuppression has been seen with intravenous administration. The metabolism of ribavirin is poorly understood. It is both metabolized

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by the liver and excreted by the kidneys, with a half-life of approximately 9 hours. 11 The drug accumulates in red blood cells, thereby prolonging the terminal half-life. 16 It is unclear how much of an adjustment in dosage should be made for renal insufficiency. The fate of ribavirin during peritoneal or hemodialysis is unknown. Amantadine and Rimantadine Amantadine and rimantadine are both adamantane compounds that have been evaluated for both the prophylaxis and treatment of influenza A infections. Metabolism is predominantly by renal excretion, with a half-life of approximately 12 to 18 hours. 23 Amantadine usage is associated with central nervous system (CNS) side effects such as nightmares, dysphoria, confusion, and seizures. Rimantadine has a serum half-life that is approximately twice that of amantadine (25 to 36 hours).50 Rimantadine has little, if any, CNS toxicity but is associated with gastroenterologic side effects such as dyspepsia in a small percentage of patients. Serum levels of both drugs will markedly increase in the face of renal insufficiency. In ESRD, dosing should be weekly, alternating 200 mg and 100 mg doses of amantadine on an every-other-week schedule. 24 It is unclear what effect hemodialysis and peritoneal dialysis have on amantadine levels.

SUMMARY A multitude of antimicrobial agents have become available over the past two decades. Appropriate use of these drugs demands not only an understanding of the antimicrobial spectrum of the agent but of the necessary dose adjustments because of renal or hepatic impairment. The use of computer-assisted pharmacokinetic modeling for dosing potentially toxic drugs such as aminoglycosides and vancomycin should be utilized whenever possible.

REFERENCES 1. Amoxicillin-clavulanic acid (Augmentin). Med Lett Drugs Ther 26:99, 1984 2. Atkinson AI, Bennett JE: Amphotericin B pharmacokinetics in humans. Antimicrob Agents Chemother 13:271, 1978 .3. Barriere SL, Flaherty JF: Third-generation cephalosporins: A critical evaluation. Clin Pharm 3:351, 1984 4. Bauer LA, Bloun: Influence of age on amikacin pharmacokinetics in patients without renal disease: Comparison with gentamicin and tobramycin. Eur J Clin Phannacol 24:639, 1983 5. Bennett W.\!, Aronoff CR, Colper TA, et al: Drug prescribing in renal failure: Dosing guidelines for adults. Philadelphia, American College of Physicians, 1987 6. Berman SI. Sugihara JC, Nakamura JM, et al: Multiple-dose study of imipenem/cilastatin in patients with end-stage renal disease undergoing long-term hemodialysis. Am J Med. 78(suppl 6A):1l3, 1985 7. Brogden RN, Heel RC, Speight TM, et al: Metronidazole in anaerobic infections: A review of its activity, pharmacokinetics and therapeutic use. Drugs 16:387, 1978 8. Carson CC, Paulson DF, Rudd C: Overview of first line amikacin therapy for urologic infections. Am J Med 79 (sup pI 1A):51, 1985

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9. Cockerill FR, Edson RS: Trimethoprim-sulfamethoxazole. 'vlayo Clin Proc 62:921, 1987 10. Connor JD: Comparative pharmacology of nudeoside analogues with antiviral activity. In Mills I. Corey L (eds): Antiviral Chemotherapy: l\'ew Directions fc)r Clinical Application and Rcsearch. New York, Elsevier, 1986, p 138 11. Connor JD, Hintz 'vI, Van Dyke R, et al: Clinical Applications of Ribavirin. New York, Academic Press, 1984, p 107 12. Conte JE, Barriere SL: l\lanual of Antibiotics and Infectious Diseases, ed VI. Philadelphia, Lea & Febiger, 1988 13. Drugs for tuberculosis. Med Lett Drugs Ther 28:6, 1986 14. Enf RHK, Munsif AN, et al: Seizure propensity with imipenem. Arch Intern Med 149:1881, 1989 1.5. Fainstein V, Bodey GP: Cardiorespiratory toxicity due to miconazole. Ann Intern Med 93:432, 1980 16. Fernandez H, Banks G, Smith R: Ribavirin: A dinical overview. Eur J Epidemiol 2:1, 1986 17. Francke EL, Appel GB, Neu lIC: Pharmacokinetics of intravenous piperacillin in patients undergoing chronic hemodialysis. Antimicrob Agents Chemother 16:788, 1979 18. Chanbusarakum P, Murray 1': Analysis of the interactions between piperacillin, ticarcillin, or carbenicillin and aminoglycoside antibiotics. Antimicrob Agents Chemother 14:.50.5, 1981 19. Gerig .IS, Bolton ND, Swabb EA, et al: Effect of hemodialysis and peritoneal dialysis on aztreonam pharmacokinetics. Kidney Int 26:308, 1984 20. Gerson B: Antimicrobial agents. In Essentials of Therapeutic Drug Monitoring. New York, Igaku-Shoin, 1983, p 2.59 21. Gibson TP, Demetriades JL, Bland .lA: Imipenem/cilastatin: Pharmacokinetic profile in renal insuffiCiency. Am J Med 78(suppl 6A):.54, 198.5 22. Goldman P: Metronidazole. l\' Engl J 'vIed 303:1212, 1980 23. Hayden FG, Minocha A, Spyker DA, et al: Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults. Antimicrob Agents Chemother 29:339, 1986 24. Horadam VW, Sharp JG, Smilack .ID, et al: Pharmacokinetics of amantadine hydrochloride in suhjects with normal and impaired renal function. Ann Intern 'vIed 94:4.54, 1981 25. Humes HD, et al: Aminoglycoside nephrotoxicity. Kidney Int 33(4):900, 1988 26. Kaye D: Antibacterial agents: Pharmacodynamics, pharmacology, new agents. Infect Dis Clin ~orth Am 3(3): 1989 27. Mihindu JCL, Scheld WM, Bolton ND, et al: Pharmacokinetics of aztreonam in patients with various degrees of renal dysfunction. Antimicrob Agents Chemother 24:2.52, 1983 28. Moellering RC: Ceftazidime: A new broad-spectrum cephalosporin. Pediatr Infect Dis 4:390, 198.5 29. ivloellering RC: Pharmacokinetics of vancomycin. J Antimicrob Chemother 14(suppl D):43, 1984 30. Moellering RC, Krogstad D.I, Greenblatt DJ: Vancomycin therapy in patients with impaired renal function: A nomogram for dosage. Ann Intern Med 94:434, 1981 31. l\'elson .ID: Cefuroxime: A cephalosporin with unique applications to pediatric practice. Pediatr Infect Dis 2:394, 1983 32. Pan coast S.I: Aminoglycoside antibiotics in clinical use . .'vIed Clin North Am 72:581, 1988 :33. Pau AK, Khakoo R: Red neck syndrome with slow infusion of vancomycin. N Engl J Med 313:756, 198.5 34. Sanders CV, Greeberg RN. Marier RL: Cafamandole and cefoxitin. Ann Intern Med 103:70, 198.5 35. Sanford JP: Guide to Antimicrobial Therapy 1989. West Bethesda, MD, Antimicrobial Therapy Inc, 1989 36. Shepp OH, Dandliker PS, Meyers JD: Treatment of varicella-zoster virus infection in severely immunocompromised patients: a randomized comparison of acyclovir and vidarabine. N Engl J Med 314:208, 1986 37. Sommadossi J-p, Bevan R, Ling T, et al: Clinical pharmacokinetics of gancidovir in patients with normal and impaired renal function. Rev Infect Dis lO(suppl 3):S.507, 1988 38. Sorrell TC, Packham DR, Shanker SI. et al: Vancomycin therapy for methicillin resistant Staphylococcus aureus. Ann Intern Med 97:344, 1982

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39. Symposium on antimicrobial agents. Mayo Clin Proc 62:789, 901, 1007, 1l08, 1987 40. Symposium on cefotetan. Am J Obstet Gynecol 154:945, 1986 41. Surbone A, Yarchoan R, McAtee N, et al: Treatment of the acquired immune deficiency syndrome (AIDS) and AIDS-related complex with a regimen of 3' -azido-2' ,3' -dideoxythymidine (azidothymidine or zidovudine) and acyclovir. Ann Intern Med 198:534, 1988 42. Tedesco FJ: Clindamycin and colitis: A review. J Infect Dis 5(suppl):S95, 1977 43. Thompson MB, Russo ME, et al: Gentamicin inactivation by piperacillin or carbenicillin in patients with ESRD. Antimicrob Agents Chemother 21:268-273, 1982 44. Tucker WS, Snell BB, Island DP, et al: Reversible renal insufficiency induced by ketoconazole. JAMA 253:2413, 1985 45. Van Scoy RE, Wilkowske CJ: Antituberculous agents. Mayo Clin Proc 62:1129, 1987 46. Wallerstein RO, Condit PK, Kasper CK, et al: Statewide study of chloramphenicol therapy and fatal aplastic anemia. JAM A 208:2045, 1969 47. Whitley RJ, Soong SJ, Dolin R, et al: Adenine arabinoside therapy of biopsy proven herpes simplex encephalitis. N Engl J Med 297:289, 1977 48. Winter ME: Basic Clinical Pharmacokinetics, ed 2. Spokane, W A, Applied Therapeutics Inc, 1988, p 376 49. Wislon WR, Cockerill FR: Tetracyclines, chloramphenicol, erythromycin and c1indamycin. Mayo Clin Proc 62:906, 1987 .50. Wolfson JS, Hooper DC: The fluoroquinolones: Structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrob Agents Chemother 28:581, 1985 51. Wright AJ, Wilkowske CJ: The penicillins. Mayo Clinic Proc 62:806, 1987

Address reprint requests to Jack '>1. Bernstein, MD Wright State University School of Medicine Department of MedicinelVA Campus PO Box 927 Day ton, OH 45401-0927