Micafungin Concentrations in the Plasma and Burn Eschar of Severely Burned Patients

Abstract

Micafungin concentrations in plasma and burn eschar after daily intravenous infusion (1 h) of micafungin (200 to 300 mg) were investigated for six patients with severe burns. Micafungin treatment was initiated more than 72 h after the burn injuries. The peak and trough levels in the plasma after the initial administration and repeated administrations for more than 4 days were comparable with or slightly lower than the reported values for healthy volunteers. Micafungin concentrations in the plasma and burn eschar were between 3.6 and >1,000 times higher than the reported MIC₉₀s of micafungin against clinically important Candida and Aspergillus species.

TEXT

Advances in the intensive care of burn patients have improved patient survival but have also increased the incidence of fungal infection (10). Not only does burn injury damage the skin, it also affects many organ systems throughout the body, resulting in complex pathophysiological changes. The first 48 h following burn injuries correspond to the first phase, characterized by burn shock and severe hypovolemia (4, 8, 13, 17). Beyond 48 h after injury, the second hypermetabolic phase of the cardiovascular system appears; this phase is characterized by an increased cardiac output with a concomitant increase in blood flow to the kidneys and liver (4, 8, 13, 17). Thus, depending on the elapsed time since the event (generally 48 h), different pathophysiological changes may occur in patients with burn injuries (4, 8, 13). As a result, the pharmacokinetic parameters of drugs, including protein binding, distribution volume, and clearance (CL), are significantly altered in burn patients (4–6, 8, 10, 13, 14, 17). The half-life of fluconazole was 13% shorter and its CL was 30% greater for burn patients than the values in previous reports evaluating healthy volunteers and patients with normal renal function (5).

Micafungin (MCFG), an echinocandin antifungal agent, has a high clinical efficacy and safety when used for the treatment of deep-seated fungal infections in surgery and in emergency and intensive care medicine, indicating its usefulness as a first-line drug for both targeted and empirical therapies (1). However, the pharmacokinetics of MCFG in patients with burn injuries and the penetration of MCFG into the burn tissue (eschar) have not been previously reported, similar to the situations for other echinocandins in burn patients (6). In this report, we administered MCFG for the prevention and treatment of fungal infections in six critically ill burn patients and measured the plasma concentration of MCFG in six patients as well as the concentration in burn eschar from one of the patients.

Six adult patients with severe (more than 30% of total body surface area [TBSA]) burn injuries were admitted to Tohoku University Hospital Emergency Center, Sendai, Japan, and were sequentially enrolled between November 2008 and March 2010. All the patients were treated with 200 to 300 mg of MCFG once a day by intravenous infusion over a 1-h period. MCFG was initiated at more than 72 h after the burn injuries. Blood samples were collected at the end of the initial MCFG administration (peak level after initial administration), immediately before the second dosing (trough level after initial administration), at the end of MCFG infusion at least 4 days after the initial treatment (peak level after repeated administration), and immediately before the next dosing (trough level after repeated administration), since the concentrations in plasma during the repeated administration of MCFG reportedly reach a steady state by day 4 in healthy volunteers (2, 3). Samples of the burn eschar tissue were excised from representative lesions in residual third-degree burn areas. The MCFG concentrations in the plasma and burn eschar were measured using high-performance liquid chromatography (HPLC) according to previously reported methods (12, 19). Briefly, an internal standard (FR195743; Astellas Pharma Inc.) and acetonitrile were added to the plasma and tissue homogenates, and the resulting mixture was centrifuged. The supernatant was injected into the HPLC equipment, and the fluorescence intensity was determined at an excitation wavelength of 273 nm and an emission wavelength of 464 nm. The burn index, which is used as a burn severity index that takes into consideration both the area and the depth of the thermal injury, was calculated as the total third-degree area plus half of the total second-degree burn area (15). The study protocol was reviewed and approved by the Institutional Review Board at Tohoku University Hospital, and written informed consent was obtained from each patient before the initiation of any of the study-related procedures.

The demographic characteristics of the patients and the MCFG concentrations are summarized in Table 1. The mean body weight in the present study was 74.0 kg (range, 56.7 to 87.0 kg), which was 23% higher than that in a previously reported study examining healthy volunteers (60.2 kg) (3), and the patients were treated with 200 to 300 mg of MCFG, whereas the dose for the pharmacokinetic study for the healthy volunteers was 25 to 150 mg (3). On the other hand, micafungin exhibited a dose-proportional increase in the area under the concentration-time curve (AUC) and the maximum plasma concentration (C_max) in healthy volunteers (2, 3). Therefore, the plasma concentrations per body weight-normalized dose were calculated. The mean burned percentage of TBSA and the burn index of the patients were 66.7% (range, 36 to 85%) and 58.1 (range, 36.0 to 77.0), respectively. MCFG was initiated 5 to 11 days after the burn injuries occurred. The patients were treated with 300 mg of MCFG once daily, except for one patient (no. 6; 200 mg). The mean MCFG dose normalized according to the body weight was 3.84 mg/kg of body weight (range, 3.45 to 4.49 mg/kg). Five patients underwent surgery, and two received continuous hemodiafiltration. Treatment was not discontinued because of adverse events in any of the patients.

Table 1.

Patient characteristics and MCFG concentrations in plasma and burn eschar

Characteristic	Value or category for patient no.a:						Mean ± SD or mediana,b
	1	2	3	4	5	6
Sex	Female	Male	Female	Male	Male	Male
Age (yr)	37	82	31	47	19	64	46.7 ± 23.0
Body wt (kg)	66.8	76.9	77.8	79.0	87.0	56.7	74.0 ± 10.7
% of TBSA:
Burned	80	36	85	80	53	66	66.7 ± 19.1
With second-degree burns	13	0	16	45	3	26	17.2 ± 16.5
With third-degree burns	67	36	69	35	50	40	49.5 ± 15.3
Burn index	73.5	36.0	77.0	57.5	51.5	53.0	58.1 ± 15.2
Day of the initiation of MCFG administration after injury	5	5	11	8	6	11	7.7 ± 2.8
MCFG dose (mg)	300	300	300	300	300	200	283 ± 41
MCFG dose normalized according to body wt (mg/kg)	4.49	3.90	3.86	3.80	3.45	3.53	3.84 ± 0.37
Surgical operation	Yes	No	Yes	Yes	Yes	Yes
Continuous hemodiafiltration	Yes	No	No	Yes	No	No
Aspartate transaminase (IU/liter)	228	23	16	19	42	134	33*
Alanine transaminase (IU/liter)	18	12	10	2	16	92	14*
γ-Glutamyl transpeptidase (IU/liter)	15	27	95	35	7	53	31*
Total bilirubin (mg/dl)	0.8	1.2	1.1	2.5	1.6	0.5	1.2*
Serum albumin (g/dl)	2.2	1.9	3.0	3.9	3.7	1.6	2.6*
Blood urea nitrogen (mg/dl)	26	17	26	35	18	29	26*
Serum creatinine (mg/dl)	2.7	0.8	0.5	2.5	0.8	0.8	0.8*
Creatinine clearance (ml/min)	30	77	200	41	183	75	76*
MCFG concn in plasma (μg/ml)
Peak level after initial administration	24.2 [5.39]	17.3 [4.43]	24.2 [6.28]	14.8 [3.90]	13.6 [3.94]	10.1 [2.86]	17.4 ± 5.8 [4.47 ± 1.21]
Trough level after initial administration	6.1 [1.36]	5.4 [1.38]	3.6 [0.93]	3.5 [0.92]		1.8 [0.51]	4.1 ± 1.7 [1.02 ± 0.36]
Peak level after repeated administration	27.9 [6.21]	19.5 [5.00]	24.9 [6.46]	23.6 [6.21]	18.1 [5.25]	11.3 [3.20]	20.9 ± 5.9 [5.39 ± 1.22]
Trough level after repeated administration	6.1 [1.36]	6.2 [1.59]	5.7 [1.48]	7.9 [2.08]	3.0 [0.87]	2.3 [0.85]	5.2 ± 2.1 [1.34 ± 0.51]
MCFG concn in burn eschar (μg/ml)
Trough level after initial administration						4.0 (2.2)
Trough level after repeated administration						14.8 (6.4)

^aValues in brackets show MCFG concentrations per dose, normalized according to the body weight (unit: [μg/ml]/[mg/kg]). Values in parentheses show the burn eschar/plasma concentration ratios.

^bAn asterisk indicates that the value is a median.

The mean (range) peak and trough concentrations in plasma of MCFG per MCFG dose normalized with body weight after the initial administration of MCFG and those after repeated administration for at least 4 days in the burn patients were 4.47 (2.86 to 6.28), 1.02 (0.51 to 1.38), 5.39 (3.20 to 6.46), and 1.34 (0.65 to 2.08) (μg/ml)/(mg/kg), respectively, and were comparable with or slightly lower than the reported mean values after dosing with 75 mg of MCFG in healthy volunteers (6.59, 1.31, 8.81, and 2.10 [μg/ml]/[mg/kg], respectively) (3).

MCFG binds strongly to human plasma (99.8%), and albumin is the main binding protein (3, 7, 18). Burn injury affects many organ systems throughout the body, resulting in complex pathophysiological changes, including changes in plasma protein levels (8). In this study, no obvious relationships between the plasma MCFG concentrations and the laboratory parameters for hepatic and renal function, serum albumin, surgical operation, and continuous hemodiafiltration were observed (Table 1), similar to data in previous reports (7, 9, 11, 16). On the other hand, the distribution volume in patients with burns is known to be altered by changes in the extracellular fluid volume (8). Early after burn injury, large quantities of fluid are exogenously administered, expanding the blood and extracellular fluid volume and resulting in interstitial edema (8). Therefore, the increase in the extracellular fluid volume may reduce the plasma MCFG concentration.

The concentrations of MCFG in burn eschar were measured in one patient (no. 6) (Table 1) after the administration of 200 mg of MCFG once daily. The trough concentrations in the burn eschar after the initial administration and repeated administrations were 4.0 and 14.8 μg/ml, respectively; these values were 2.2 to 6.4 times higher than those for plasma. The concentrations of MCFG in plasma and in burn eschar were between 3.6 and >1,000 times higher and between 8 and >1,000 times higher, respectively, than the reported MIC₉₀ of MCFG against clinically important Candida species, including C. albicans (MIC₉₀, 0.0156 to 0.5 μg/ml), C. glabrata (0.016 to 0.25 μg/ml), and C. tropicalis (0.0313 to 0.5 μg/ml), and Aspergillus species, including A. fumigatus (<0.0156 μg/ml) (9). Because the MCFG concentrations in the burn eschar were determined only for one patient, these observations should be verified in further studies with a larger patient sample size. On the other hand, a proportion of the administered dose may have been eliminated from the wound surface via exudative fluid (8). Therefore, further studies examining the penetration of MCFG into other tissues, such as exudative fluid, are needed.

In conclusion, the concentrations of MCFG in plasma from patients with severe burn injuries were comparable with or slightly lower than the reported values for healthy volunteers. In addition, MCFG seems to be capable of penetrating burn eschar.