## The TDM of Vancomycin

Question #1. B.C., a 65-year old, 45-kg man with a serum creatinine concentration of 2.2 mg/dL, is being treated for a presumed hospital-acquired, MRSA infection. Design a dosing regimen that will produce peak concentration less than 40 to 50 mg/L and through concentrations of 5 to 15 mg/L.

Target Plasma Concentration

Clearance and Volume of Distribution

The first step in calculating an appropriate dosing regimen for B.C. is to estimate his pharmacokinetic parameters (i.e., volume of distribution, clearance, elimination rate constant, and half-life).

The volume of distribution for B.C. can be calculated by using Equation 13.1.

V (L) = 0.17 (age in years) + 0.22 (TBW in kg) + 15

So, B.C.'s expected volume of distribution would be: V (L) = 0.17 (65 yrs) + 0.22 (45 kg) + 15 = 36.0 L [Equation 13.1]

Using Equation 13.2 and Equation 13.4 to calculated B.C.'s expected creatinine clearance and vancomycin clearance.

Clcr for males (mL/min) = (140 – Age)(Weight in kg) / [(72)(SCrss)] [Equation 13.2]

Vancomycin Cl ≈ Clcr [Equation 13.4]

For B.C. the vancomycin Cl ≈ (140 – 65 yrs)(45 kg) / [(72)(2.2 mg/dL)] = 21.3 mL/min = 1.28 L/hr

The calculated vancomycin clearance of 1.28 L/hr and the volume of distribution of 36.0 L then can be used to estimate the elimination rate constant of 0.036 hr-1. And the corresponding vancomycin half-life can be calculated, which equals (0.693)(V) / Cl = 19.5 hr.

In clinical practice, loading doses of vancomycin are seldom administered. This is probably because most clinicians prescribe about 15 mg/kg as their maintenance dose.

C0 = (S)(F)(Loading Dose) / V = (1)(1)(15 mg/kg x 45 kg) / 36 L = 18.8 mg/L ≈ 20 mg/L (Equation 13.8)

If you want to administer a loading dose, the loading dose = (V)(C) / [(S)(F)] = (36.0 L)(30 mg/L) / [(1)(1)] = 1080 mg or ≈ 1000 mg.

During the steady-state, Css max = Css min + [(S)(F)(Dose) / V] (Equation 13.5). This equation is based on several conditions including: 1) Steady state has been achieved; 2) the measured plasma concentration is a trough concentration; and 3) the bolus dose is an acceptable model (infusion time <1/6 half-life).

In the clinical setting, trough concentrations are often obtained slightly before the true trough. Because vancomycin has a realtive long half-life, most plasma concentrations obtained within 1 hour of the true trough can be assumed to have met condition 2 above.

Since vancomycin follows a multicompartmental model, it is difficult to avoid the distribution phase when obtaining peak plamsa concentrations. If peak levels are to be measured, samples should be obtained at least 1 or possibly 2 hours after the end of the infusion period. It is difficult to evaluate the appropriateness of a dosing regimen that is based on plasma samples obtained before steady state. Additional plasma concentrations are required to more accurately estimate a paient's apparent clearance and half-life, and to ensure that any dosing adjustments based on a non-steady-state trough concentration actually achieve the targeted steady-state concentrations.

Maintenance Dose

The maintenance dose can be calculated by a number of methods. One approach might be to first approximate the hourly infusion rate required to maintain the desired average concentration. Then, the hourly infusion rate can be multiplied by an appropriate dosing interval to calculate a reasonable dose to be given on an intermittent basis. For example, if an average concentraion of 20 mg/L is selected (approximately halfway between the desired peak concentration of ≈ 30 mg/L and trough concentration of ≈ 10 mg/L), the hourly administration rate would be 25.6 mg/hr.

Maintenance Dose = (Cl)(Css ave)(tau) / [(S)(F)]

For this patient the 24 hour dose should be (1.28 L/hr)(20 mg/L)(24 hr) / [(1)(1)] = 614 mg ≈ 600 mg

– or –

Maintenance delivery rate = Dose/tau = (Cl)(Css ave) / [(S)(F)]

For this patient the maintenance deliver rate = (1.28 L/hr)(20 mg/L) / [(1)(1)] = 25.6 mg/hr

The second approach that can be used to calculate the maintenance dose is to select a desired peak and trough concentration that is consistent with the therapeutic range and B.C.'s vancomcin half-life. For example, it steady-state peak concentrations of 30 mg/L are desired, it would take approximately two half-lives for that peak level to fall to 7.5 mg/L. Since the vancomycin half-life in B.C. is approximately 1 day, the dosing interval would be 48 hours. The dose to be administered every 48 hours can be calculated as follows using Equation 13.5:

Dose = (V)(Css max – Css min) / [(S)(F)] = (36.0 L)(30 mg/L – 7.5 mg/L) / [(1)(1)] = 810 mg ≈ 800 mg

The peak and trough concentrations that are expected using this dosing regimen can be calcualted by using Equations 13.12 and 13.14, respectively.

Css max = (S)(F)(Dose) / {V x [1- e(-k*tau)]} = 27.0 mg/L (Equation 13.12)

Note that although 27 mg/L is an acceptable peak, the actual clinical peak would normally be obtained approximately 1 hour after the end of a 1-hour infusion, or 2 hours after this calculated peak concentration, and would be about 25 mg/L, as calculated by Equation 13.13.

C2 = C1[e(-k*t)] = 25.1 mg/L (Equation 13.13)

The calculated trough concentration would be about 5 mg/L.

Css min = (S)(F)(Dose / V)[e(-k*tau)] / [1 – e(-k*tau)] = (Css max)[e(-k*tau)] = 4.8 mg/L (Equation 13.14 and 13.15)

This process of checking the expected peak and trough concentrations is most appropriate when the dose or the dosing interval has been changed from a calculated value (e.g., twice the half-life) to a practical value (e.g., 8, 12, 18, 24, 36, or 48 hours). Many institutions generally prefer not to use dosing intervals of 18 or 36 hours because the time of day whent the next dose is to be given changes, potentially resulting in dosing errors. If different plasma vancomycin concentrations are desired, Equations 13.12 and 13.14 can be used target specific vancomycin concentrations by adjusting the dose and/or the dosing interval.

A third alternative is to rearrange Equation 13.14, such that the dose can be calculated:

Dose = (Css min)(V)[1 – e(-k*tau)] / {(S)(F)[e(-k*tau)]} (Equation 13.16)

## Fidaxomicin Beats Vancomycin for C difficile in Cancer

I have read a similar article before. It was about Fidaxomicin and CDAD too. But today this newer one describes more exactly. This article compares fidaxomicin to vancomycin in aspects of cure rate in terms of initial clinical cure, recurrence, and sustained response. According to this article fidaxomicin appears to be better than vancomycin in treating Clostridium difficile-associated diarrhea (CDAD). However, vancomycin also can treat CDAD effiaciously, according to the data shown in these studies.

According to the North American study, clinical cure rate of fidaxomicin was 87.7% and that of vancomycin was 86.8%. From this point both fidaxomicin and vancomycin are able to treat CDAD satisfactorily. However, differ between the two drugs does exist. The incidence of recurrence with vancomycin over fidaxomicin were 26.9% vs 12.7%. And the sustained response rates of fidaxomicin over vancomycin were 76.6% vs 63.4%. Thus from these two aspects fidaxomicin appears to be better than vancomycin.

I want to emphasize that we should compare these two drugs in the specific group population – the cancer survivors. According to the studies, those with cancers treated with fidaxomicin had significantly higher clinical cure and sustained clinical cure rates and significantly lower rates of recurrence than patients treated with vancomycin.

One more thing is that the price of these two drug is not considered in this article. I check the price of fidaxomicin and vancomycin. The dosage of fidaxomicin is 200 mg po Bid, that of vancomycin is 125 mg po Qid. The cheapest vancomycin capsule’s unit price is \$27.78 (per 125 mg/capsule, Vancocin-VIROPHARMA INCO), and that of fidaxomicin tablet is \$135 (per 200 mg/tablet). So a 10-day course we need \$2700 for fidaxomicin vs \$1111.2 for vancomycin. From this perspective I think we should use vancomycin to treat CDAD first, fidaxomicin should be the alternative. However considering the lower recurrence rate and higher sustained response rate, the fidaxomicin regimen’s cost may be less than vancomycin’s.

References

April 4, 2012 (London, United Kingdom) — Fidaxomicin (Dificid, Optimer Pharmaceuticals) treatment was superior to vancomycin for initial cure, recurrence, and sustained response, according to a subanalysis of patients with cancer and Clostridium difficile–associated diarrhea (CDAD).

In addition, concomitant antibiotics had less effect on clinical cure rate with fidaxomicin than with vancomycin, according to data from a phase 3 clinical trial conducted in Europe and North America. Both studies were presented here at the 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).

Oliver A. Cornely, MD, oncologist/hematologist and infectious diseases physician from the University Hospital Cologne in Germany, led the European/North American phase 3 study (OPT-80-004). He presented the results of a subanalysis of data from both studies.

The European/North American multicenter, randomized, controlled, double-blind, noninferiority study was published in February (Lancet Infect Dis. 2012;12:281-289). An earlier phase 3 study of fidaxomicin conducted in the United States and Canada was published last year (N Engl J Med. 2011;364:422-431).

The subanalysis of cancer patients with CDAD was presented here at ECCMID for the first time.

Fidaxomicin is a novel macrocyclic antibiotic with a narrow spectrum of activity against Gram-positive bacteria and minimal activity against normal gut flora. “Fidaxomicin is not absorbed, which makes it like a magic bullet because it stays where it is needed in extremely high concentrations,” Dr. Cornely told Medscape Medical News.

Further to the North American study, results of the second phase 3 trial in 509 patients from Europe and North America also demonstrated that clinical cure for fidaxomicin was noninferior to vancomycin in the modified intent-to-treat population (87.7% vs 86.8%).

Dr. Cornely emphasized the recurrence rates with fidaxomicin. “This is the first point at which we see a difference in the 2 antibiotics, and it is a large difference,” he said. “We see double the incidence of recurrence with vancomycin over fidaxomicin [26.9% vs 12.7%; difference, 14.2%; 95% confidence interval [CI], –21.4% to –6.8%; P < .001]. It cuts the recurrence rate in half. A high recurrence rate is expected with vancomycin in a very sick population, but this is still an extreme.”

These findings were also reflected in the sustained response rates, which showed fidaxomicin was superior to vancomycin (76.6% vs 63.4%; difference, 13.2%; 95% CI, 5.2% to 20.9%; P = .001).

Cancer Patients a Special Population

The subanalysis in cancer patients was drawn from data derived from the 2 phase 3 trials. “Patients with cancer are a population of special interest because of their lower response rates, and they are very prone to recurrent disease,” Dr. Cornely told Medscape Medical News. (more…)