Treatment Of A Cutaneous, Subcutaneous Apophysomyces Elegans, A Mucormycotic Fungi, Infection In A Bottlenose Dolphin (Tursiops Truncatus) With The New Antifungal Agent, Nyotran®
IAAAM 2000
Leslie M Dalton; Todd R Robeck

Abstract

At least six mucormycotic cases involving both captive and wild marine mammals have been reported. The two organisms identified in these cases were either Saksenaea vasiformis or Apophysomyces elegans.3 Both of these fungi are extremely rare and the number of cases reported in marine mammals may indicate a disproportionate susceptibility to these organisms. Human infections with these agents, despite aggressive therapy to include radical resection of infected limb or tissue, is associated with greater that 80% mortality.1 In dolphins, treatment for these organisms has never shown any promise and all cases have resulted in death. On 16 January 2000, we were presented with a 20-mo-old bottlenose dolphin, in apparent good health, that had a 5-cm by 2-mm laceration on the dorsal midline immediately caudal to the dorsal fin. By 20 January 2000, the laceration had grown to 10 cm in diameter and was slightly elevated. Two additional 4-cm diameter purplish colored lesions were observed. A blood sample revealed an elevated total white blood cell (tWBC) of 22,500 cells/mm3 characterized as a regenerative left shift (Table 1). The lesion on the lateral side was biopsied and the animal was started on the antifungal, itraconazole (Sporanox®, Janssen Pharmaceutica Inc., Titusville, NJ 08560 USA) and antibiotics.

Cultures and histopathology confirmed that the infectious agent was from the family mucorales. On 25 January 2000, the lesions had doubled in size. Serum chemistries reflected the progressive nature of the fungus with elevations in CK (creatinine kinase, 3248 U/L) and LD (lactate dehydrogenase, 1154 U/L) (Table 2). The animal was placed on the experimental anti-fungal, Nyotran® (Donated by Aronex Pharmaceuticals, Inc., The Woodlands, TX 78381 USA). Nyotran® is a liposomal form of nystatin and must be administered i.v. with a slow infusion rate. The liposomal formulation is believed to reduce nephrotoxicity. The drug was initially dosed at 4.2 mg/kg for a total dose of 700 mg, s.i.d. The drug was reconstituted using 5% dextrose in water (D5W ) and administered i.v. in the dorsal inter-vertebral venous sinus, approximately one-half the distance from the fluke to the caudal edge of the dorsal fin over a 2-hr period. A common drug related reaction observed in humans is pyrexia, which was also observed in this dolphin. Twenty-four hours after the first dose, the dolphin's BUN (blood urea nitrogen) and creatinine had elevated to 88 mg/dl and 5.1 mg/dl, respectively. The animal was immediately placed on 3 L of calf milk replacement formula2 p.o. q 8 hr and 2 L of LRS (Lactated Ringers solution) p.o. q 8 hr. In addition, the animal was administered 1 L of D5W i.v. prior to each additional dose of Nyotran®. Finally, the Nyotran® dose was cut to 400 mg i.v. s.i.d. Treatment continued at this level for 5 days until BUN and creatinine were normal (Table 2). Starting 31 January 2000, the Nyotran® dose was increased by 50 mg every other day (e.o.d.) until it reached 550 mg s.i.d. on 7 February 2000. Serum chemistries returned to near normal levels by 17 February 2000 (Table 2). Total WBC, which peaked at 65,900 cells/mm3 on 1 February return to 12,0000 cells/mm3 by 17 February. Due to an apparent response to treatment, and the animal's increasing discomfort during drug administration, the treatment schedule was changed to e.o.d. on 7 February and discontinued on 14 February. The lesion on the dorsal peduncle, caudal to the dorsal fin, sloughed on 18 February, leaving a 10 x 10 x 5 cm cavity. Ten days after discontinuing the Nyotran®, the margins of each lesion became active. Additional biopsies of wound margins cultured fungi. The cranial lesions on the side of the animal sloughed to the depths of the ribs, while the caudal lateral lesion had undermined the dorsal fin. Due to the extent of lesional progression and the animal's deteriorating condition, the dolphin was euthanatized.

Necropsy revealed three open lesions up to 20 cm in diameter with depths as deep as 12 cm. Also, enlarged and edematous adrenal glands and small pyogranulamatous masses throughout the lungs were observed. Apophysomyces elegans was cultured from all of these sites and histopathology confirmed the presence of fungal hyphae. All fungi in the class zygomycete are aggressive organisms that invade the vascular system causing extensive infarction and tissue necrosis. In dolphins, all of the previous cases have resulted in progressive advancement of the infection until death or euthanasia. Although this case had a similar outcome, apparent remission of the disease was observed during the treatment course. This is typical for human mucormycotic cases that exhibit "remission" of the infection during treatment. In these cases, the continual clinical dilemma is how long to treat an animal after resolution is believed to have been reached. This must be balanced with how well the animal is tolerating the treatments. In this case, and despite sedation, the animal was at a point where she would not tolerate the i.v. administration. Despite the outcome, we feel that if while pending the initial biopsy results we had acted immediately by placing the animal on Nyotran® and by performing radical resection of the skin and muscle lesion (excisional biopsy) while they were relatively small, the animal may have had a slim chance of survival.

Table 1. Hematologic parameters from bottlenose dolphin with an A. elegans infection.

Date

Hg

Hct

Plt

TWBC

Bands

Neutrophils

Lymphocytes

Monocytes

Fibrinogen

 

(g/dl)

(%)

(103/mm3)

(mm3)

(mm3)

(mm3)

(mm3)

(mm3)

(mg/dl)

Refa

15.2

43

173

8300

0

4565

2905

83

340

36544

13.2

39

127

22500

1350

18225

1800

675

941

36548

14.2

40

115

27500

1650

21175

2200

1375

1036

36550

13.7

40

89

47200

4248

36816

2832

2832

950

36551

12.8

36

71

49500

3960

40590

3465

1485

964

36552

12

34

72

38500

1540

31185

4235

1155

1298

36553

13.1

35

69

42400

1272

32648

4240

3392

824

36554

12.8

36

89

47400

1896

40290

2844

1896

703

36555

13

36

84

50600

506

46046

1012

2024

846

36556

12.5

35

73

65900

3295

58651

1318

2636

827

36557

12.6

35

49

55700

557

51244

557

2228

870

36558

12.3

35

58

45000

1350

40050

450

3150

900

36559

11.9

33

64

39800

398

34228

1592

3184

833

36562

11.3

32

57

24700

247

20995

1482

1729

770

36564

11.2

31

90

27200

544

24208

1904

544

777

36566

10.8

31

69

31900

957

26158

3509

957

768

36568

10.1

29

36

25300

506

20240

2277

2277

724

36569

10.1

29

57

22000

440

16940

2860

1760

36572

10.5

31

73

12600

252

10206

1890

378

616

36577

9.4

28

206

18000

180

15300

900

1260

625

36583

9.1

27

271

42700

427

35014

4270

2989

936

a. Reference value from animal prior to infection.

Table 2. Serum chemistry values from a bottlenose dolphin with an A. elegans infection.

Date

BUN

Creatinine

ALP

ALT

AST

CK

LD

Fe

 

(mg/dl)

(mg/dl)

(U/L)

(U/L)

(U/L)

(U/L)

(U/L)

(μg/dl)

Refa

50

1.2

1731

16

129

224

497

271

36544

21

1.2

325

33

129

69

543

95

36548

36

1.1

174

42

209

207

849

33

36549

41

1.1

179

56

284

3248

1154

73

36550

88

5.1

165

936

1390

349

2252

85

36551

85

6.9

148

657

960

198

1459

74

36552

51

5.7

182

474

757

170

1303

63

36553

47

3.8

184

323

579

117

936

42

36554

44

2.6

171

226

419

110

822

32

36555

47

2

164

173

367

238

772

42

36556

42

1.7

169

131

301

295

802

34

36557

43

1.4

202

98

247

256

767

35

36558

50

1.5

159

79

224

310

602

40

36559

48

1.4

190

67

216

266

674

62

36562

52

1.5

208

53

209

219

561

63

36564

41

1.3

205

60

301

625

720

22

36566

45

1.3

245

49

249

272

665

49

36568

44

1.3

307

39

199

200

548

41

36572

71

1.4

400

28

115

140

509

99

36577

60

1.2

460

18

91

144

399

45

36583

41

1.3

293

15

73

143

391

27

a. Reference value from animal prior to infection.

Acknowledgments

We thank Dr. Tony Williams from Aronex Pharmaceuticals, Inc. (The Woodlands, TX, 78381) for ensuring we had a continuous supply of Nyotran®. We also thank Dr. Mike Rinaldi for his advice during therapy. This is a SeaWorld San Antonio technical contribution number 2000-02-T

References

1.  Holland J. 1997b. Emerging zygomycoses of humans: Saksenaea vasiformis and Apophysomyces elegans. Curr. Top. Med. Mycol. 8: 27-34.

2.  Reidarson TH, J McBain. 1998c. Total nutritional support of two adult Commerson's dolphins (Cephalorhynchus commersoni). San Diego, California. 29th: 46.

3.  Reidarson TH, JM McBain, LM Dalton, MG Rinaldi. 1999a. Diagnosis and treatment of fungal infections in marine mammals. In: Fowler,M.E. and E.R.Miller (ed.). Zoo and Wild Animal Medicine. Current Therapy 4. W.B. Saunders, Philadelphia, PA. Pp. 478-85.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Leslie M. Dalton, BA, DVM
Sea World of Texas
San Antonio, TX, USA

Todd R. Robeck, BS, DVM, PhD
Sea World of Texas
San Antonio, TX, USA


MAIN : All : Apophysomyces
Powered By VIN
H
E
L
P

CONTACT US

777 W. Covell Blvd., Davis, CA 95616

mailto:vingram@vin.com

PHONE

  • Toll Free: 800-700-4636
  • From UK: 01-45-222-6154
  • From anywhere: (1)-530-756-4881
  • From Australia: 02-6145-2357
SAID=27