P&T News: September 2002

Drawing Vancomycin Serum Levels: Is It Really Necessary?

Sarah Johnson, Pharm.D.
Peer Review Status: Internally Peer Reviewed R. Todd Wiblin MD, MS, Division of Infectious Diseases and Associate Hospital Epidemiologist.

Vancomycin is a glycopeptide antibiotic with bactericidal activity against gram positive microorganisms. It is used to treat methicillin-resistant staphylococcal infections and coagulase negative staphylococci, as well as metronidazole-resistant Clostridium difficile and penicillin-resistant enterococci. The FDA approved parenteral vancomycin in 1958. The initial formulation was impure and was thought to have contributed to cases of adverse effects, such as vancomycin-associated hearing loss and nephrotoxicity, that were reported during the 1950s and 1960s.^1-4 Concerns about the impurities in the initial formulations of the product potentially leading to nephro- and ototoxicity, case reports of nephro- and ototoxicity, as well as the advent of less toxic penicillinase-resistant penicillins and cephalosporins, resulted in vancomycin being infrequently prescribed. However, in the late 1970s through the present time, the emergence of methicillin-resistant infections and enterococci as a significant pathogen has resulted in an increased use of parenteral vancomycin.⁴ Although the vancomycin formulation used today is a pure product, serum level sampling has frequently been recommended for all patients on vancomycin therapy as a method to prevent the perceived risk of nephro- and ototoxicity associated with vancomycin, and maintaining specific serum levels has been thought to contribute to improved efficacy.³

"Appropriate" vancomycin serum levels have been widely published, with the proposed "therapeutic range" being trough levels of 5 to 15 mcg/ml and peak levels of 20 to 40 mcg/ml. For many years, it was assumed that maintaining a patient within these proposed ranges would ensure efficacy and prevent toxicity; however, in recent years, the common practice of drawing vancomycin serum levels has been questioned. Currently, no data are available supporting the direct effect of vancomycin serum level concentrations on clinical outcome as long as levels exceed the MIC for the treated organism; and in most patients, drawing vancomycin levels is not warranted.

Frequently Asked Questions Associated with Vancomycin Serum Levels

Where did the usual "therapeutic range" originate?

Vancomycin was administered to healthy people, serum levels were drawn, and those levels became the "therapeutic range" that we use today.^2,3 The therapeutic range was not derived by clinical studies on the relationship of serum levels to efficacy and/or toxicity.

Aminoglycoside serum levels are frequently drawn, why not monitor vancomycin serum levels?

Aminoglycoside and vancomycin pharmacokinetics are similar; however, data are available supporting the relationship of aminoglycoside peak serum levels to increased efficacy. There is no evidence that specific vancomycin peak serum levels are associated with improved efficacy. Aminoglycosides exhibit concentration-dependent activity; therefore, antimicrobial activity of an aminoglycoside is dependent on higher initial drug concentrations. Vancomycin exhibits concentration-independent (time-dependent) activity at usual therapeutic doses, meaning that antimicrobial activity of vancomycin is dependent on the time the vancomycin serum level is above the MIC of the organism being treated. For most organisms that are susceptible to vancomycin, the MIC is <2 mcg/ml. Trough serum levels may be useful in select patients for ensuring that the vancomycin serum level is above the MIC for most of the dosing interval. However, studies in adult and pediatric patient populations using various dosing regimens consisting of fixed vancomycin doses, dosing nomograms, and doses individualized by pharmacokinetic calculations to produce peak and trough serum levels within a defined therapeutic range all demonstrate clinical effectiveness in the treatment of gram-positive infections.^5-11 Appropriate dosing (15 mg/kg every 12 hours) of vancomycin (dependent on weight, age, and renal function) usually results in therapeutically safe and effective levels.

Is monitoring of serum levels needed to prevent or predict ototoxicity and/or nephrotoxicity?

No clear relationship between vancomycin therapy and ototoxicity has ever been established. Case reports of ototoxicity were confounded with the concurrent use of ototoxic drugs or disease states known to be associated with hearing loss (e.g., meningitis).² The first case of hearing loss was reported in 1958 in a patient being treated for endocarditis.¹ Serum levels in this patient were found to be >80 mcg/ml. Nephrotoxicity due to vancomycin has been better supported in the literature; however, many of these case reports were also confounded by the use of concurrent nephrotoxic drug therapy (e.g., aminoglycosides). Some retrospective and prospective studies have indicated that nephrotoxicity may occur with vancomycin use; however, toxicity has occurred when the vancomycin serum concentrations were within the proposed "therapeutic range" (trough concentrations of 5 to 15 mcg/ml and peak concentrations of 20 to 40 mcg/ml).²

In which patients should vancomycin serum levels be monitored?

• Measurement of peak serum concentrations is not recommended since vancomycin exhibits concentration-independent (time-dependent) activity; peak serum levels are not useful.
• Patients receiving vancomycin short-term or for prophylaxis (<48 hours) should not have serum concentrations drawn.

  Routine monitoring of vancomycin serum levels is not recommended unless therapy is longer than 5 days AND the patient meets one of the criteria for measurement of a trough concentration listed below.

  Although data do not support the relationship between trough levels and toxicity, measurement of a single trough concentration may be useful to be sure that the serum concentration remains above the MIC for most of the dosing interval. Trough levels may be useful in the following patients:

• Patients receiving higher than normal doses needed for better penetration to the site of infection (e.g., meningitis).
• Patients with altered volumes of distribution (e.g., burn patients, trauma patients).
• Patients in whom treatment is failing.
• Patients with rapidly changing renal function who are not receiving peritoneal or hemodialysis.
• Patients with normal renal function requiring long-term therapy (e.g., 4 to 6 weeks or longer).

  Under some conditions, neither peaks nor troughs may be useful; however, random serum concentration levels may be drawn for the following patients:

• Patients on hemodialysis. Monitor random serum level concentrations to be sure that they remain adequate. Vancomycin is not cleared by hemodialysis.
  • One dose of 15 mg/kg (rounded to the nearest 500 mg) should be given based on the patient's "dry weight" (weight after dialysis).
  • Serum concentrations may be drawn periodically to ensure that therapeutic levels are maintained (approximately every 4 to 7 days).
  • Re-dose the patient when the random serum concentration is <15 mcg/ml.
  • Regularly scheduled doses may be given once clearance is assessed.
  • For patients on scheduled dialysis, most will require dosing once weekly.
• Patients on peritoneal dialysis. A dose every 7 to 10 days should be adequate.
• Patients on continuous venovenous hemofiltration (CVVH). Dosing every 48 hours should be adequate.

Should vancomycin serum levels be obtained in pediatric patients?

Routine monitoring is not recommended for pediatric patients unless therapy will last for more than 72 hours. Measurement of a single trough concentration at steady state (with the third dose) is recommended for:

• Neonates (only if therapy will be continued for more than 72 hours).
• Children receiving higher than normal doses (usual dose 40 mg/kg/day divided every 6 hours) needed for better penetration to the site of infection (e.g., meningitis).
• Children with altered volumes of distribution (e.g., burn patients, trauma patients).
• Children in whom treatment is failing.
• Children with rapidly changing renal function and who are not receiving peritoneal or hemodialysis.
• Children receiving concurrent nephrotoxic medications (e.g., aminoglycosides, amphotericin B).

What is the correct way to administer vancomycin and obtain vancomycin serum levels?

• Administer vancomycin over at least 60 minutes for doses <1 gram. All doses > 1 gram should be administered over at least 90 minutes.
• Flush the IV line after administration.
• If vancomycin is administered via a peripheral site, the serum level should be drawn from the opposite extremity.
• Trough levels should be drawn immediately prior to a dose and should not be drawn before steady state conditions are achieved (vancomycin generally reaches steady state by the third dose).
• Although not recommended, if a peak level is desired, it should be drawn at least 60 minutes after the end of the infusion.

In addition to the high cost of vancomycin serum levels (approximately $60 per level), fine tuning vancomycin regimens to produce serum concentrations within the "therapeutic range" often results in needless changes in dose and the potential for inappropriate alterations in therapy due to inappropriate serum sampling techniques.

The "Guide to Appropriate Use and Monitoring of Vancomycin" (Pharmacy and Therapeutics Subcommittee-approved pocket guide) contains information on vancomycin serum sampling. You can receive a copy of the pocket guide by calling the Drug Information Center.

References

1. Mayo Clin Proc 1958; 33:172- 81.

2. Clin Infec Dis 1994;18:533-43.

3. Pharmacotherapy 1999;19:257-66.

4. Mayo Clin Proc 1991; 66:1165-70

5. J Pediatr 1980; 96:119-26.

6. Ann Intern Med 1982; 97:344-50.

7. Antimicrob Agents Chemother 1991; 35:451-7.

8. J Antimicrob Chemother 1982; 9:69-74.

9. Ann Intern Med 1981; 94: 343-6.

10. Clin Pharm 1987; 6:795-9.

11. Clin Pharm 1991; 10:129-32.

Levofloxacin (Levaquin®), the primary fluroquinolone anti-infective at UIHC, is known to have decreased oral bioavailability when administered with products containing multivalent cations such as aluminum, calcium, magnesium, iron, and zinc. This drug interaction between levofloxacin and multivalent cations may lead to decreased effectiveness of oral levofloxacin.

Levofloxacin is capable of forming chelate complexes with metal ions that cause a reduction in oral bioavailability. However, it is possible to avoid this interaction by administering levofloxacin at least two hours before or two hours after the administration of products containing multivalent cations. This separation of medications is necessary to ensure that the patient is absorbing the proper amount of levofloxacin to attain adequate blood levels and eradicate the infection.

To ensure the effectiveness, appropriate administration times of oral levofloxacin with respect to concurrent cations must be employed. Levofloxacin should be administered at least two hours before or two hours after administration of products containing multivalent cations such as aluminum, calcium, magnesium, iron, and zinc. Examples of products containing multivalent cations are listed below.

UIHC Formulary Examples:

Antacids:

Magnesium and Aluminum Hydroxide (Maalox®, Mylanta®, Mylanta II®)

Magnesium Hydroxide (Milk of Magnesia®)

Aluminum Hydroxide, Magnesium Trisilicate (Gaviscon®)

Aluminum Hydroxide (Amphojel®, Alu-Cap®)

Calcium Carbonate (Tums®)

Iron Products:

Ferrous Sulfate (Fer-In-Sol®)

Ferrous Gluconate

Ferrous Fumarate

Iron-polysaccaride complex (Niferex-150®)

Multiple Vitamin Plus Mineral Preparations:

ADEKs®

Tri-Vi-Flor drops®

Flintstones Complete®

Vi-Daylin Plus Iron ADC®

Tri-Vi-Sol with Iron Drops®

Vi-Daylin/F ADC Plus Iron Drops®

Other Medications:

Sucralfate (Carafate®)

Magnesium Oxide (Mag-Ox®, Uro-Mag®)

Zinc Sulfate

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