EDUCATIONAL COMMENTARY VANCOMYCIN MONITORING

EDUCATIONAL COMMENTARY VANCOMYCIN MONITORING Commentary provided by: Julie Hall, MHS, MT (ASCP) Assistant Dean, College of Health Professions Assistant Professor, Medical Laboratory Science Grand Valley State University Grand Rapids, MI Educational commentary is provided through our affiliation with the American Society for Clinical Pathology (ASCP). To obtain FREE CME/CMLE credits, click on Earn CE Credits under Continuing Education on the left side of the screen. Learning Outcomes On completion of this exercise, the participant should be able to: describe the use of vancomycin; identify the trough serum vancomycin reference range for patients with nonsevere infection; identify the trough serum vancomycin reference range for patients with severe, invasive infections; explain the appropriate time to measure trough serum vancomycin levels; and discuss the adverse effects associated with vancomycin toxicity. Introduction Most antimicrobial drugs have established dosing regimens that provide for their safe and effective use without requiring laboratory monitoring. For some, however, there is a narrow range between the therapeutic and toxic concentrations, and these require therapeutic drug monitoring to ensure efficacy, prevent toxic effects, and reduce the emergence of resistant strains of microbial pathogens. Vancomycin (vancomycin hydrochloride) is one such antimicrobial drug that has garnered a great deal of attention over the past decade. Debate has ensued over the use of serum vancomycin concentrations to measure clinical effectiveness and prevent drug-induced toxic effects, and about the appropriate therapeutic ranges for serum vancomycin concentrations. Use In the early 1950s, a chemist at Eli Lilly and Company set out to develop antibiotics to treat penicillinresistant staphylococci. Bacteria isolated from the soil in Indonesia, Streptomyces orientalis, produced a substance that proved promising to their efforts and led to the creation of vancomycin, a glycopeptide antibiotic. Vancomycin was approved by the Food and Drug Administration and became commercially available in 1958. 1 This antibiotic exhibits time-dependent killing, as opposed to concentration-dependent killing, of gram-positive bacteria by inhibiting the formation of the bacterial cell wall and damaging the cell membrane. Use of early formulations was limited due to associated toxic effects and the arrival of the first semisynthetic penicillins - methicillin sodium, oxacillin sodium, and nafcillin sodium - at approximately the same time. However, the 1980s saw a resurgence in vancomycin use owing to the emergence of American Proficiency Institute 2018 2 nd Test Event 1

penicillinase-producing methicillin-resistant Staphylococcus aureus (MRSA) infections and pseudomembranous enterocolitis. 2 Vancomycin s proven effectiveness against penicillin-resistant staphylococci and clostridia make it a valuable alternative to penicillin for the treatment of patients with penicillin allergies, an effective tool in the treatment of patients with MRSA infections, and a successful treatment option for pseudomembranous enterocolitis. Although it is primarily given intravenously for the treatment of invasive gram-positive organisms due to its poor absorption by the gastrointestinal tract, it is ideal for treatment of pseudomembranous enterocolitis when taken orally. The main route of excretion of vancomycin is primarily the kidneys, making renal function an important factor in establishing a dosing regimen. Dosing for maintenance of therapeutic levels can be difficult and is usually based on established nomograms or algorithms that take into account the severity and site of the infection, body weight, renal function as determined by creatinine clearance, and trough serum vancomycin concentration. 3 Therapeutic Ranges Owing to vancomycin s time-dependent rather than concentration-dependent killing, approximately 6-hour half-life, and subsequent long distribution phase, trough serum vancomycin concentrations are more reliable than peak vancomycin concentrations for measuring drug efficacy. There is significant variability in peak concentrations among patients and there is no evidence to support a correlation between peak vancomycin concentrations and efficacy or toxicity. 4 There is often confusion when evaluating vancomycin for therapeutic effectiveness and toxic effects because two different therapeutic ranges are recommended for trough serum vancomycin concentrations, depending on the severity of the infection. For patients with nonsevere infections, such as infections of the skin, soft tissue, or urinary tract, trough serum concentrations should be maintained between 10 and 15 µg/ml. For improved penetration and improved clinical outcome in severe infections such as sepsis, central nervous system infections, bacteremia, hospital-acquired pneumonia, osteomyelitis, and endocarditis, trough serum concentrations should be maintained between 15 and 20 µg/ml. 5 Subtherapeutic levels (less than 10 µg/ml) should be avoided because they have been shown to result in treatment failure and the potential for the development of resistant strains of organisms. 4 Timing of Blood Draws The best predictor of good clinical outcomes for patients undergoing treatment with vancomycin is the ratio of the area under the serum drug concentration time curve to the minimum inhibitory concentration (AUC/MIC) due to large variability in vancomycin pharmacokinetics among patients. Although AUC/MIC ratios of 400 or greater are optimal to achieve clinical effectiveness for the treatment of S aureus infections with an MIC less than 1 mg/l, it is often difficult to obtain multiple serum vancomycin American Proficiency Institute 2018 2 nd Test Event 2

concentrations to determine the AUC. Trough serum vancomycin concentrations are considered an alternative to AUC and are recommended as the most accurate and practical method for monitoring vancomycin effectiveness and guiding dosage adjustments. 6 For patients with stable renal function, trough serum vancomycin concentrations should be measured immediately before administration of the fourth dose, at steady state. After the initial steady-state trough vancomycin concentration, routinely monitoring trough vancomycin concentrations in patients undergoing a lower-intensity dosing regimen for fewer than 3 days is not necessary as long as there is no evidence of renal dysfunction. For patients with unstable renal function, dosing intervals are established based on spot serum concentrations until renal function is stable. Spot concentration timing is based on the rate and direction of change in the serum creatinine concentration (renal function). Serum creatinine and trough serum vancomycin concentrations should be monitored at least weekly for patients taking vancomycin for more than 5 days, with a target trough of 15 to 20 µg/ml. This group includes patients with invasive infections, those with renal dysfunction, those who are morbidly obese, those who are critically ill, and those concurrently treated with nephrotoxic medications. 5 Dosage Adjustments Dosage adjustments should be guided by trough levels. Patients with trough serum vancomycin concentrations less than 10 µg/ml should have their dosage adjusted by increasing the total daily dose and not changing the dosing interval. For patients with trough concentrations more than 5 µg/ml above the therapeutic range, subsequent doses should be withheld and vancomycin levels should be monitored daily until trough concentrations are in the therapeutic range. Once in the recommended therapeutic range, a new dosing regimen should be initiated. For patients with trough levels above their recommended therapeutic range by 5 µg/ml or less, a new dosing regimen should be established and implemented at the next scheduled dose. After the fourth dose, at steady state, trough serum vancomycin concentration should be measured to confirm that the dosage adjustment has brought the level to the therapeutic range. 5 Toxic Effects Early preparations of vancomycin were nicknamed Mississippi Mud for their brown color from impurities. A number of adverse effects were associated with those early preparations, including ototoxicity and nephrotoxicity. To this day, many of the adverse effects attributed to the drug originated from the impurities associated with preparations used before the 1980s. 7 Although there is still much debate on the toxic effects associated with vancomycin, recent studies have shown that toxic effects are infrequent with vancomycin monotherapy at typical dosing protocols. Toxic effects are more likely with vancomycin administration in patients with renal insufficiency, those receiving vancomycin concurrently with other American Proficiency Institute 2018 2 nd Test Event 3

nephrotoxic or ototoxic drugs, or administration at high doses for prolonged periods. 2 To date, there is little data to support toxicity-associated adverse effects with specific serum concentrations. 4 More frequently, patients experience an infusion-related response, manifesting in what is known as red man syndrome. This histamine-like response produces tingling and flushing of the upper body during or immediately after infusion and has been attributed to rapid infusion of large doses of the antibiotic. Red man syndrome is unrelated to serum vancomycin concentration and is short-lived, usually diminishing after the infusion is completed. 2 Summary After more than 50 years, vancomycin continues to be one of the most widely used antibiotics in the treatment of serious gram-positive infections. The use of serum trough concentrations at recommended levels is essential to monitor clinical effectiveness and make necessary dosage adjustments, keeping in mind that recommended target trough ranges vary depending on the site and severity of the infection. Maintaining the appropriate serum trough ranges will improve clinical outcomes and help to reduce the emergence of resistant strains of pathogens. Despite early reports of associated toxic effects, evidence shows that toxic effects are rare when vancomycin is used in the absence of other nephrotoxic or ototoxic agents. Although there are a number of medications for the treatment of invasive, resistant gram-positive infections, vancomycin continues to be a clinically effective and cost-efficient option. References 1. Levine DP. Vancomycin: a history. Clin Infect Dis. 2006;42(1):S5-S12. 2. Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1):82-98. 3. Hisham M, Zogheib M, Homoud A, Al-Tawfiq JA. Safety and outcome of pharmacy-led vancomycin dosing and monitoring. Chemotherapy. 2015;6(1):3-7. 4. Rybak MJ, Lomaestro BM, Rotschafer JC, Moellering RC Jr, Craig WA. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49(3):325-327. 5. Drew RH, Sakoulas G. Vancomycin: parenteral dosing, monitoring, and adverse effects in adults. In: Hooper DC, Baron EL, eds. UptoDate. Waltham, MA: Wolters Kluwer; 2017. https://www.uptodate.com/contents/vancomycin-parenteral-dosing-monitoring-and-adverse-effectsin-adults. Accessed December 20, 2017. American Proficiency Institute 2018 2 nd Test Event 4

6. Ayazkhoo L, Mousavi S, Ramazani F, Ayatollahi-Tafti M, Sa'dabadi Z. Vancomycin utilization evaluation: are we dosing appropriately? J Pharm Care. 2013;1(4):149-152. 7. Avent ML, Vaska VL, Rogers BA, Cheng AC, van Hal SJ. Vancomycin therapeutics and monitoring: a contemporary approach. Intern Med J. 2013;43(2):110-119. ASCP 2018 American Proficiency Institute 2018 2 nd Test Event 5