Vancomycin monitoring : One or Two Serum levels?

1. Vancomycin monitoring : One or Two Serum levels? Syamhanin Adnan Pharmacy Dept, Hospital Sungai Buloh

2. Introduction • Vancomycin is a glycopeptide, first isolated from a strain of Streptomyces (now Amycolatopsis) orientalis from a sample of dirt send to scientist at Eli Lily ,found in a Borneo jungle in the mid-1950s • Approved for use by FDA (USA) in 1958 for treating penicillin-resistant Staphylococcus aureus infection. • Initially isolated from soil in Borneo and India and was nicknamed “ Mississippi mud” due to its color from impurities • Methicillin, first semi-synthetic penicillin was also approved in 1958, effective and less toxic option than vancomycin • Vancomycin as an alternative therapy in patients allergic or intolerant to other class of antibiotic • Emergence of MRSA led to resurgence interest in vancomycin as the gold standard of treatment

3. Mechanism of action • Large molecule – complex glycopeptide with a molecular weight of approximately 1,500 • Bactericidal – inhibit biosynthesis of bacterial cell wall, earlier crucial site than penicillin; no cross resistance • Active against most gram positive organism except enterococci (only bacteriostatic)

4. Pharmacokinetic properties :Key parameters • Bioavailability • Volume of distribution • Clearance • Half-life • Therapeutic plasma concentration

5. Bioavailabiliy and Distribution • Absorption • Less than 5%, poorly absorbed from gastrointestinal tract • Presence of inflammatory bowel may increase absorption • Distribution • Vd = 0.5 – 1.0 L/kg • 30-55% protein bound • Diffuse well into pleural, pericardial, synovial and ascitic fluid • Penetration into CSF is not reliable or predictable, therapeutic concentrations may be reached in patients with a acute meningitis • Case report of intraventricular infusion of 10mg daily resulted in vancomycin level in CSF of 606mcg/ml following 9 days of treatment in 50 y/o male with infected intracerebral hematoma. It is suggested that lower dose may be indicated and ventricular CSF levels to be determine with vancomycin intraventricular therapy. • Poor penetration into solid organ, 20-30% vancomycin serum concentration is achieved in lung tissue • A co-prescription of rifampicin as dual therapy has been suggested, but because it can cause resistance, high dose vancomycin aiming for trough of more than 20mg/L has been advocated (Jason A. Roberts; Jeffrey Lipman, Antibacterial Dosing in Intensive Care : Clinical Pharmacokinetics 2006: 45(8)

6. Clearance and Half-life • Clearance • Eliminated primarily by renal route (80-90% as unchanged) • CLvanco ~ CLcr • Some studies shown 17% of vancomycin is removed during hemodialysis, in CAPD-small but continuous; drug loss is significant • Half-life • 5-10 hours • 5 x half life to reach steady state ; 25 – 50 hours • ESRF : may approach 7 days • Normal renal function : interval of 8 – 12 hours

7. Therapeutic plasma concentration : • Therapeutic range of vancomycin was established in 1980s in healthy subjects who received 500mg of vancomycin yielding peak concentrations of 20 -40mg/L and trough concentratons of 5 – 10mg/L • Even though limited data exist to demonstrate a correlation between serum concentration and clinical success, routine drug monitoring based on rational of targeting the MBC (4-5x MIC) while reducing the potential renal adverse effects and ototoxicity • Serum levels of antibiotics must be high enough to kill the infecting organism and prevent further growth • Inadequate dosing and failure to sustained serum concentration may lead to increased resistance, progression of infection and higher mortality.

8. Peak and trough levels : • Peak level obtain during distribution phase probably will be lower, small variation in timing result large differences in measured peak level • Peak level must be obtained after the distribution phase is completed, allowing single compartment pharmacokinetics • It is recommended to obtained 1- 2 hours after a one hour infusion FIGURE 1. Vancomycin elimination: portrayed is a hypothetical concentration/time curve for a patient receiving vancomycin. During the distribution phase, serum concentration drops rapidly. This characteristic makes peak concentration monitoring at steady state extremely difficult. After distribution, the drug is cleared in a linear fashion. Multiple samples from this period may be helpful in predicting individual dosage regimens. Trough levels, taken immediately before a subsequent dose, assure that the MIC is exceeded and are most predictive of clinical efficacy. From:   Tam: J Intraven Nurs, Volume 22(6).November/December 1999.336

9. Peak level and concentration-dependent antibiotic: • Levels obtained and pharmacokinetic calculations as an adjunctive guide to the determination of dosing regimen, originally based on models used for aminoglycosides (concentration-dependent antibiotic), peaks to be therapeutically important for concentration-dependent antibiotic • Some data suggest bactericidal activity of vancomycin is not concentration-depedent • At concentration more than 5mg/ml (exceed minimal bactericidal concentration or 4-5 x MIC), further increase do not increase killing rate, time during which concentration exceeds MIC is important (T>MIC) • Studies suggest duration in vitro PAE is about 1.5-3 hours against S. aureus, may be longer in vivo • PAE allows longer interval for certain antibiotic (daily dosing aminoglycoside) but PAE for vancomycin is rather short (1.5 to 3 hours) • Peak level is not useful for vancomycin since it is not concentration-dependent? Wilhelm, Mark P.M.D; Estes, Lynn Pharm. D; Mayo Clinic Proceedings : Vancomycin, Volume 74(9) , September 1999, pp 928-935

10. One or Two Serum Levels ? • Based on principles that vancomycin therapy requires sustained therapeutic concentration while avoiding high peaks, it is recommended that optimal vancomycin levels could be ensured by measuring trough levels alone(Saunders NJ. Why monitoring peak vancomycin concentrations? Lancet 1994;344:1748-50) • “Traditional" trough concentrations of 5 to 10 mcg/mL are being reconsidered, evidence of increasing minimum inhibitory concentrations (MICs) of staphylococci to vancomycin • A prospective cohort study done by Hidayat et al (2006) of adult patients infected with MRSA at Huntington Hospital (from August 2004 through June 2005) was performed to determine the distribution of vancomycin MIC. Of 95 patients, 54% (n=51) were infected with high MIC strains (MIC of >=2mcg/ml) and 77% of this group of patients had pneumonia and/or bacteremia. • Higher trough concentrations (15 to 20 mcg/mL) are recommended in settings such as nosocomial and ventilator-associated pneumonia and in deep-seated staphylococcal infections (eg, endocarditis, prosthetic joint infections, CNS infections). American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005; 171:388.

11. Monitoring trough levels : Does it prevent drug toxicity and/or ensures therapeutic dosing of the drug ? • Vancomycin is now considered a relatively safe and tolerable drug. The original vancomycin preparation (‘Mississipi mud’) contained impurities that was associated with local and systemic reactions. • including venous irritation, chills, rash which were primarily infusion-related or attributed to contaminants in the manufacturing process • Improved purification procedures seem to have diminished the local toxicity associated with vancomycin • Two systemic adverse events continuted to complicate the use of vancomycin: nephrotoxicity and ototoxicity, monitoring it’s level (trough) has been a common practice • A recent large retrospective review of patients with MRSA health care – associated pneumonia suggested that aggressive dosing strategies to achieve trough level of more than 15mcg/ml may not offer any advantage over traditional dose target (5 to 15mcg/ml) (Jeffres et al, Predictors of mortality for MRSA health-care associated pneumonia : specific evaluation of vancomycin pharmacokinetic indices. Chest 2006 Oct ;130(4):947-55)

12. Serum levels : Correlation with efficacy and toxicity • Iwamoto et al (2003) conducted a retrospective study from 184 patients with MRSA infection receiving IV vancomycin, • Significant decrease in creatinine clearance in patients (n=111) did not receive TDM when compared with patients (n=73)received TDM during vancomycin therapy (p<0.05) • No significant difference in cumulative dose and duration of therapy in subgroup analysis in patients with MRSA bacteremia or pneumonia between those who received TDM (n=46) and not monitored (n=53) • Karam et al (1999) conducted a study comparing restrospective patients monitored with dosing adjustment (n=120) with a group of prospective patients (n=120) dosed using nomogram. • No statistical difference in both group with respect to organism eradication, cure, improvement, failure or toxicity • Patient population was young and nomogram was reliable for patients with creatinine clearance above 60ml/min

13. Serum levels : Correlation with efficacy and toxicity • In-vitro vancomycin susceptibility study by Sakoulas et al. (2004) examines 30 different MRSA isolates from 30 patients with known clinical outcome in phase II and phase IV RCT to determine relationship between bactericidal activity and outcome • Authors speculate that wide varying vancomycin levels (without regards to peak or trough) required to successfully destroy the isolates during laboratory testing~might explain mixed therapeutic effectiveness results observed in clinical outcome of vancomycin • Whether MIC should be measured and reported after initiation of vancomycin therapy ?

14. Peak level : To be obtained or predicted ? • Based on principles that optimal vancomycin level could be ensured by measuring trough levels alone, a study was conducted by AndrAs et al (1997) to assess the performance of one-compartment Bayesian forecasting method to estimate vancomycin peak level on the basis of a single trough sample • Involves 79 adult patients with two measured vancomycin concentrations (C2h and Cmin). C2h were compare with prediction value using Bayesian forecasting method • The predicted peak level (C2h) were not significantly different from the observed and could be used to estimate vancomycin concentrations at 2 hours after dosing using only trough sample • However, all predictions were from normal renal function in steady state conditions AndrAs et al, Therapeutic Drug Monitoring : Vancomycin Monitoring : One or Two Serum Levels ?, Volume 19(6) Decemeber 1997, pp 614-619

15. Peak level : To be obtained or predicted ? • In another study conducted by Fofah et al (1999), involves 100 paired vancomycin concentrations in 87 infants to compare peak and trough values to yield a formula ( to predict vancomycin from trough) and later part was to evaluate the prediction formula • The peak vancomycin concentrations were weakly correlated with the values calculated using the prediction formula obtained • Authors conclude that peak vancomycin concentrations cannot reliably predicted from trough in neonatal clinical practice Fofah et al, The Pediatric Infectious Disease : Failure of Prediction of Peak Serum Vancomycin Concentrations from Trough Values in Neonates, Volume 18(3), March 1999, pp 299-301

16. Nomogram vs pharmacokinetic calculation • Various nomogram are available for empiric dosing based on population pharmacokinetics, useful before patient-specific pharmacokinetic parameters become available • May not work well in anuric patients or patients with rapidly changing renal function, in which serum drug level is used to adjust doses in these patients

17. Fig. 1 Moellering vancomycin nomogram for patients with reduced renal function. Reprinted with permission from Ann Intern Med.9From:   Levine: South Med J, Volume 101(3).March 2008.284-291

18. Table 4.-Mayo Medical Center Vancomycin Dosing Nomogram  From:   Wilhelm: Mayo Clin Proc, Volume 74(9).September 1999.928-935

19. Peak level • Lack of evidence that toxicity associated with peak levels • Difficulty in interpreting peak level because of non-compartmental model • If trough levels are in therapeutic range, it is unlikely peak levels would be above 40mcg/ml • It may be reasonable to perform intensive monitoring in high-risk patient and patients who have a poor therapeutic response • Peak level should be consider if therapy is prolonged and to confirm adequate serum concentrations into infection sites with limited vancomycin penetration Richard H Drew, PharmD, MS, BCPS

20. Trough level • Adequate trough levels may be associated with efficacy whereas high trough may increase the risk of nephrotoxicity • Which trough level to be targeted ? • Higher trough concentrations (15 to 20 microgram/mL) are recommended in settings such as nosocomial and ventilator-associated pneumonia and in deep-seated staphylococcal infections (eg, endocarditis, prosthetic joint infections, CNS infections) • Prevalence of MRSA strain of elevated MIC probably requires aggressive vancomycin dosing to achieve a trough greater than 15mcg/ml • Data on MIC of our MRSA strain ? If our MRSA strain is reported as strain of elevated MIC, probably it would warranted higher trough target

21. Vancomycin dosing and serum concentration monitoring in adults – updateRichard H Drew, PharmD, MS, BCPS • Monitoring not required • IV treatment less than 4 days • Trough level • IV treatment >4 days • End-stage renal disease and are likely to receive more than one dose • Receiving other nephrotoxic drugs (eg, cyclosporine A, amphotericin B, aminoglycosides) • Morbid obesity • Rapidly changing or unpredictable renal function • Peak and trough level • IV treatment >4 days • Selected infections (eg, endocarditis, osteomyelitis, CNS infections), which require confirmation of serum concentrations of vancomycin within the upper therapeutic range

22. Dosing strategies to sustain T>MIC • Sustained therapeutic concentration (T>MIC) may be achieve with continuous infusion/more frequent dosing • A study done by M.D Kitzis and F.W.Goldstein (2006) comparing continuous infusion of vancomycin (loading dose of 1g and total of 2-6g daily) with conventional dosing (2x1g or 4 x 500mg) in 1737 patients, trough serum were determined after 36-48h • For fully susceptible MRSA infection (MIC less than 4mg/L), 19% of conventional dosing and 7.9% of continuous infusion failed to receive adequate dose (trough level below 15mg/L). • Therapeutic failure increase in GISA (glycopeptide-intermediate S. aureus). 87.8% and 79.1% in conventional dosing and continuous infusion respectively. M.D Kitzis and F.W.Goldstein, European Society of Clinical Microbiology and Infectious Disease : Monitoring of vancomycin serum levels for the treatment of staphylococcal infections, volume 12 Number 1, January 2006, pp 81-95

23. Risk factor associate with treatment failure • A retrospective case-control study was performed at Fletcher Allen Health Care (FAHC) in Burlington, Vt, to examine factors associated with persistent MRSA bacteremia, all episodes of MRSA bacteremia from 1998 to 2004 were reviewed. • Cases of persistent MRSA bacteremia were defined as having an initial positive MRSA blood culture and at least 1 positive MRSA blood culture drawn 5 or more days after beginning treatment with intravenous vancomycin • A control was defined as a patient who had an initial positive MRSA blood culture, no further positive MRSA blood cultures 48 hours or more after beginning treatment with intravenous vancomycin, and at least 1 follow-up negative blood culture. • Of 251 MRSA bloodstream infections, 20 patients met the case definition and were compared with 40 patients who met definitions as controls were randomly selected Bessette, Erika L. PharmD*; Ahern, John W. PharmD, BCPS*†; Alston, W. Kemper MD, MPHâ€, Infectious Disease in Clinical Practice :Risk Factors for Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia Despite Treatment With Vancomycin  Volume 15(3), May 2007, pp 174-177

24. Risk factor associate with treatment failure • The median number of foreign devices, an intravascular device or septic phlebitis as a site of infection, and a maximum vancomycin minimum inhibitory concentration of 2 µg/mL were significantly associated with persistent bacteremia. • Authors conclude that the relationship between the vancomycin MIC and treatment outcome and the changes in the MIC during therapy warrant further investigation. Bessette, Erika L. PharmD*; Ahern, John W. PharmD, BCPS*†; Alston, W. Kemper MD, MPHâ€, Infectious Disease in Clinical Practice :Risk Factors for Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia Despite Treatment With Vancomycin  Volume 15(3), May 2007, pp 174-177

25. Pharmacokinetic calculation in HSB • Manual process in HSB, both peak and trough level is needed in the manual pharmacokinetic calculation to recommend a dosing adjustment • Patient most likely to require vancomycin plasma concentration monitoring are those at highest risk of therapeutic failure or potential drug toxicity • If trough level is inadequate/patient response suggest treatment failure and a dosing adjustment is highly recommended, both peak and trough level is probably necessary • Otherwise, monitoring only trough level is sufficient

26. Conclusion • Trough level closely related to MIC, 4-5 times above MIC, current practice do not measure MIC and is not reported after initiation of vancomycin therapy • Existing evidence does not seem to support routine serum therapeutic monitoring (peak level) for vancomycin dosing to improve clinical outcome • However, regular monitoring to allow dose adjustment in patients with renal dysfunction and those receiving nephrotoxic agents or at risk of treatment failure is still recommended • This topic clearly the focus of debate and merits regular surveillance to gauge on how the literature on this issue develops over time