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Novmeber 2008

Question Q. Our laboratory reports the reference range for vancomycin serum trough levels at 5 to 10 µg/mL. Pharmacologists and P&T committees at some of our hospitals are requesting this range be increased in light of the growing incidence of resistant organisms. Many laboratories, including several large reference labs, also report 5 to 10 µg/mL as their reference range. Is there a consensus that this range should be increased? Should it be increased?

A. There is much that is controversial, uncertain, or evolving about vancomycin monitoring. In the past, many have felt monitoring was not necessary. Those who advocate monitoring may be interested in ensuring adequate treatment or avoiding toxicity, or both. This review will include current concepts, examples of trough ranges now in use, and citations from the large number of publications that are helping shape current opinion on vancomycin usage.

Despite the increasing availability of alternative antibiotics, parenteral vancomycin remains an important, widely used, and generally effective treatment for a variety of gram-positive infections. A good outcome without toxic effect usually results when patients have normal renal function, no other risk factors for nephrotoxicity, no indication for an aggressive dosing regimen or prolonged course, and a prompt clinical response. Such patients may be treated without any levels obtained. Factors that have been associated with increased risk of renal damage while on vancomycin include concurrent aminoglycoside administration, preexisting renal disease (with CrCl <60 used as one guide), and hypotensive episodes.

Levels are commonly obtained in the many patients where the situation is less than ideal, especially for staphylococcal infections. Usually only a trough level is obtained, since peaks add little value except possibly in serious infections or with extremes of patient weight. In the following discussion, only trough values will be described. A nomogram using calculated creatinine clearance and body weight may be used to select an initial dose and interval. After three to four doses, a trough level may be drawn and the dosage adjusted if necessary.

Trough ranges of 5 to 10 or 5 to 15 µg/mL are still commonly used as a guide for most circumstances. A 2006 survey found few pharmacists routinely using a guideline higher than 15.1 However, selective use of even higher troughs has been advocated for more serious infections such as Staphylococcus aureus pneumonia, and higher trough ranges of 15 to 20 or 15 to 25 µg/mL may be used by some physicians and institutions when more aggressive dosing is considered to be of value. At our hospital, the pharmacy department manages most patients on vancomycin using standard dosing with a goal in the range of 5 to 15 µg/mL, but it has an altered approach to dosing and monitoring if individual physicians write orders for a specific higher level on selected patients. Random levels obtained on dialysis patients may be as high as 40 µg/mL for this group of patients only.

Methicillin-resistant Staphylococcus aureus, or MRSA, infections are seen with increasing frequency and have reported mortality higher than that of methicillin-sensitive Staphylococcus aureus infections. For more severe MRSA infections such as pneumonia, where antibiotic penetration may be a challenge, pharmacokinetic evidence suggests that higher levels might yield fewer treatment failures.2 Contributing to concern is the concept of treatment failure due to a gradual increase in the minimum inhibitory concentrations (MICs) of staphylococcal strains that still test as susceptible by routine methods (MIC 1 to 2 µg/mL), so-called MIC creep.3 Achieving higher levels theoretically might help compensate for such increases in resistance.

However, even with many years of use and the preceding considerations, it is still difficult to consistently correlate either toxicity or outcome directly to levels greater than 15 µg/mL, and definitive prospective studies have yet to be performed. There have been retrospective studies to examine these issues. Among them was a recent report correlating trough levels greater than 15 with renal toxicity, though cause and effect were not clearly established.4 Some have found improved outcomes with higher levels.5 However, conflicting evidence has also been presented.6 A recent review notes the vast literature on vancomycin monitoring, the uncertainties still present, and the difficulty and importance of seeking to distinguish evidence, anecdote, and opinion in this literature.7 Another useful review of the current situation is by Kollef.8 A need for more outcome data has been expressed.

One finding that may have confounded outcome studies is the variability with which strains are killed by vancomycin, a parameter not routinely assessed currently as a part of routine susceptibility testing or monitoring.9

In summary, there are theoretical reasons for attempting to improve patient outcomes by more aggressive vancomycin dosing, and physicians are increasingly administering more aggressive doses. Although traditional vancomycin trough guidelines are still applicable in many circumstances, there is accumulating evidence that higher trough ranges may be warranted, at least in some circumstances. These higher trough ranges may be valid to implement with an awareness of the uncertain tradeoffs between toxicity and outcome, and with close monitoring of the vancomycin level and renal function. Collaboration among the laboratory, the pharmacy, and infectious disease may be of help in reaching a consensus on guidelines for an institution’s needs.

References

  1. Paladino JA, Sunderlin JL, Adelman MH, et al. Observations on vancomycin use in U.S. hospitals. Am J Health Syst Pharm. 2007;64:1633–1641.
  2. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and health-care-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388–416.
  3. Sakoulas G, Moise-Broder PA, Schentag J, et al. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol. 2004;42:2398–2402.
  4. Jeffres MN, Isakow W, Doherty JA, et al. A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health-care-associated methicillin-resistant Staphylococcus aureus pneumonia. Clin Ther. 2007;29(6):1107–1115.
  5. Hidayat LK, Hsu DI, Quist R, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006;166(19):2138–2144.
  6. Jeffres MN, Isakow W, Doherty JA, et al. Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices. Chest. 2006;130:947–955.
  7. Lee P, DiPersio D, Jerome RN, et al. Approaching and analyzing a large literature on vancomycin monitoring and pharmacokinetics. J Med Libr Assoc. 2007;95:374–380.
  8. Kollef MH. Limitations of vancomycin in the management of resistant staphylococcal infections. Clin Infect Dis. 2007;45(Suppl 3):S191–S195.
  9. Jones RN. Microbiological features of vancomycin in the 21st century: minimum inhibitory concentration creep, bactericidal/static activity, and applied breakpoints to predict clinical outcomes or detect resistant strains. Clin Infect Dis. 2006;42(Suppl 1):S13–S24.

Steven M. Johnson, MD
Director of Microbiology and Serology
Christian Hospital
St. Louis, Mo.

Question Q. What are the clinical applications for the Roche AmpliChip CYP450 test?

A. The AmpliChip is an FDA-cleared device marketed by Roche. The device is used to interrogate specific polymorphisms and gene duplications in a subset of the CYP450 superfamily of genes so important to drug metabolism, namely, CYP450 2D6 and 2C19. The device has specific allelic coverage: 27 allelic variations for CYP2D6 and three allelic variations for CYP2C19.

Knowledge of specific genotypes is associated with predictable phenotypes that laboratorians may report to treating physicians to better manage patient symptoms through rational therapy choices. Thus, so-called extensive and (to a large extent) intermediate metabolizers are the types of individuals for whom “one size fits all” drugs were developed. Of course, “one size does not fit all,” and some drugs are not efficacious in some individuals while some drugs cause adverse reactions in other individuals. So-called poor metabolizers given drugs metabolized via pathways controlled by these genes will poorly metabolize such drugs, gain no therapeutic benefit, and continue to take the normal dosage (designed for extensive metabolizers) until a potentially toxic drug concentration is reached, generating an adverse drug event. So-called ultrarapid metabolizers (again, a phenotype predictable from the genotype generated by the chip-based test) will ultrarapidly metabolize a drug and receive little or no therapeutic benefit. Knowledge of genotype, therefore, in the form of a pathology consult based on AmpliChip results, can be used to rationally tailor drug choice and dosage. In our CLIA/CAP laboratory, since we are not pharmacists, we include a pharmacist’s consult with each AmpliChip test report to more completely inform the physician. Software associated with this FDA-approved DNA chip reads the array results, provides a genotype, and associates it with a specific phenotype.

The CYP450 2D6 gene may be interrogated before using tamoxifen in breast cancer patients. With the resultant information, physicians can learn which patients may be poor metabolizers of tamoxifen and who would more likely benefit from a tamoxifen alternative. Furthermore, some drugs inhibit the very enzymes the body uses to metabolize tamoxifen to the active metabolite that fights breast cancer. It is valuable to learn a patient’s CYP450 genotype to more rationally manage breast cancer and its ­sequelae using various drugs.1

It is best to keep in mind that the AmpliChip is just one method by which laboratories can interrogate CYP450 genes, their genotypes, the predictable phenotype, and the clinical implication, but it is the only FDA-cleared device for such interrogation. (There are FDA-cleared devices for warfarin metabolism, which depends on the products of two different genes.)

The table here contains a partial list of drugs metabolized by the enzymes whose genes are represented on the AmpliChip. A more complete list of substrates, inhibitors, and inducers of these enzymes is available online.2

References

  1. www.molecularstation.com/research/the-impact-of-cytochrome-p450-2d6-metabolism-in-women-receiving-adjuvant-tamoxifen-17115111.html
  2. http://www.medicine.iupui.edu/flockhart/table.htm

Daniel H. Farkas, PhD
Executive Director
Center for Molecular Medicine
Grand Rapids, Mich.

 

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